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United States Patent Application 20070196508

Kind Code A1

Heuer; Marvin A. ; et al. August 23, 2007

Nutritional composition and method for increasing creatine uptake and retention in skeletal muscle, increasing muscle mass and strength, increasing exercise capacity and for aiding recovery following exercise

Abstract

The present invention relates to a dietary supplement that comprises at least Creatine or derivatives thereof, Taurine or derivatives thereof and a source of Phosphate. The dietary supplement may further comprise one or more of the following: Double Fermented Triticum aestivum, Dextrose, Isomalt, Trehalose, D-Mannose, Mulberry extract, Enicostemma littorale Blume, Scoparia dulcis, Tarragon extract, Andrographis paniculata, Chromium or derivatives thereof, Glutamine and Alpha Lipoic Acid. The present invention may also provide a method for increasing Creatine uptake and retention in skeletal muscle, increasing muscle mass and strength, increasing exercise capacity and aiding in recovery following exercise as well as supporting the immune system during periods of intense training.

Inventors: Heuer; Marvin A.; (Mississauga, CA) ; Clement; Kenneth;

(Mississauga, CA) ; Chaudhuri; Shan; (Mississauga, CA) ; Ramsbottom; James D.; (Mississauga, CA) ; Thomas; Megan K.; (Mississauga, CA)

Correspondence Name and Address:

Iovate Health Sciences Research Inc. 5100 Spectrum Way Mississauga ON L4W 5S2 US

Serial No.: 522266

Series Code: 11

Filed: September 14, 2006

U.S. Current Class: 424/601; 424/725; 424/745; 424/750; 424/777; 514/184; 514/440; 514/53; 514/553; 514/554;

514/563

U.S. Class at Publication: 424/601; 424/725; 424/777; 424/745; 514/184; 514/553; 514/554; 514/440; 514/563; 424/750;

514/53

Intern'l Class: A61K 36/899 20060101 A61K036/899; A61K 31/205 20060101 A61K031/205; A61K 31/715

20060101 A61K031/715; A61K 33/42 20060101 A61K033/42; A61K 31/385 20060101

A61K031/385; A61K 31/185 20060101 A61K031/185; A61K 31/555 20060101 A61K031/555; A61K 36/605 20060101

A61K036/605

Claims

1. A dietary supplement comprising at least a combination of Creatine or derivative thereof, Taurine or derivative thereof and a source of Phosphate. 2. The dietary supplement of claim 1, wherein said source of Phosphate is selected from the list of Dipotassium Phosphate, Disodium Phosphate, Magnesium Phosphate. 3. The dietary supplement of claim 1, further comprising at least one of Double Fermented Triticum aestivum, Trehalose, and Isomaltose. 4. The dietary supplement of claim 1, further comprising at least one of an extract of Mulberry, Enciostemma Littorale Blume, Scoparia Dulcis, and extract of Tarragon, Andrographis Paniculata, and a derivative of Chromium. 5. The dietary supplement of claim 1, further comprising at least one of Andrographis Paniculata, and Glutamine. 6. The dietary supplement of claim 1, further comprising at least one of Alpha Lipoic Acid and an extract of Mulberry. 7. A method of increasing the energy stores in a muscle and prolonging the ability of a muscle to perform work comprising the step of administering to an individual a dietary supplement comprising Creatine or derivative thereof, Taurine or derivative thereof and a source of Phosphate. 8. The method of claim 7, wherein said source of Phosphate is selected from the list of

Dipotassium Phosphate, Disodium Phosphate, Magnesium Phosphate. 9. The method of claim 8, wherein the dietary supplement further comprises at least one of Double Fermented Triticum aestivum, Dextrose, Trehalose, and Isomaltose. 10. The method of claim 9, wherein the ingredients of the dietary supplement are provided in amounts suitable to increase muscular Creatine retention in an individual. 11. The method claim 8, wherein the dietary supplement further comprises at least one of an extract of Mulberry, Enciostemma Littorale Blume, Scoparia Dulcis, and extract of Tarragon, Andrographis Paniculata, and a derivative of Chromium. 12. The method of claim 11, wherein the ingredients of the dietary supplement are provided in amounts suitable to maintain a blood sugar level plateau in an individual in order maintain insulin secretion. 13. The method of claim 8, wherein the dietary supplement further comprises Andrographis Paniculata, and Glutamine. 14. The method of claim 13, wherein the ingredients of the dietary supplement are provided in amounts suitable to support the immune system in an individual during intense bouts of physical training. 15. The method of claim 8, wherein the dietary supplement further comprises at least one of Alpha Lipoic Acid and an extract of Mulberry. 16. The method of claim 15, wherein the ingredients of the dietary supplement are provided in amounts suitable to reduce food intake leading to fat loss and weight loss. 17. The method of claim 15, wherein the ingredients of the dietary supplement are provided in amounts suitable to supply antioxidant to an individual. 18. A dietary supplement comprising:about 10 g of Creatine or derivative thereof;about 2.1 g of Taurine or derivative thereof;about 0.5 g of an acceptable a Phosphate donor;about 0.1 g of Double Fermented Triticum aestivum; about 82 g of Dextrose;about 0.001 g of Trehalose;about 0.001 g of Isomaltose;about 0.025 g of an extract of Mulberry;about 0.001 g of Enciostemma Littorale Blume;about 0.001 g of Scoparia Dulcis; about 0.001 g of and extract of Tarragon;about 0.001 g of Andrographis Paniculata; about 0.0003 g of a derivative of Chromium Polynicotinate;about 0.002 g of Glutamine;about 0.25 g of Alpha Lipoic Acid.

Description

RELATED APPLICATIONS

[0001]The application is related to and claims benefit of priority to U.S. Provisional Patent Application Ser. No. 60/776,325, entitled "Compositions and method for increasing bioavailability of compositions for performance improvement", filed Feb. 23, 2006, the disclosure of which is hereby fully incorporated by reference. FIELD OF THE INVENTION [0002]The present invention relates to the composition of a dietary supplement provided for increasing Creatine uptake and retention in skeletal muscle, increasing muscle mass and strength, increasing exercise capacity and aiding in recovery following exercise as well as providing support for the immune system during intense periods of exercise. Furthermore, a method for achieving the same by way of administration of the composition is presented. SUMMARY OF THE INVENTION [0003]The foregoing needs, and other needs and objectives which will become apparent in the following description, are achieved in the present invention which comprises a dietary composition and method for enhancing Creatine uptake and retention in skeletal muscle, increasing muscle mass and strength, increasing lean muscle mass, and supporting the immune system of an individual, e.g., a human or an animal, during intense training periods. According to an embodiment of the present invention, there are provided compositions and methods which minimize catabolism and promote muscle anabolism, particularly in response to exercise. For example the compositions and methods may allow an individual to increase muscle size, strength or endurance training as well as reduce recovery time and facilitate an increased training volume leading to the same. [0004]According to an embodiment of the present invention, there are provided compositions and methods which comprise at least a combination of Creatine or derivatives thereof, Taurine or derivatives thereof and a source of Phosphate. [0005]According to additional or alternative embodiments of the present invention, there are provided compositions and methods that further comprise at least one of Double Fermented Triticum aestivum, Dextrose, Isomalt, Trehalose, D-Mannose, an extract of Mulberry, Enicostemma littorale Blume, Scoparia dulcis, an extract of Tarragon, Andrographis paniculata, Chromium or derivatives thereof, Glutamine and Alpha Lipoic Acid. DETAILED DESCRIPTION OF THE INVENTION [0006]In the following description, for the purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one skilled in the art that the present invention may be practiced without one or more of these specific details.

[0007]The present invention, according to various embodiments thereof, is directed to a dietary supplement for increasing Creatine uptake and retention in skeletal muscle, increasing muscle mass and strength, increasing exercise capacity and aiding in post-exercise recovery as well as providing support for the immune system during intense exercise training periods. The present invention comprises at least a source of Creatine or derivative thereof, Taurine or derivative thereof and a source of Phosphate. According to various embodiments, the present invention may further comprise combinations of Double Fermented Triticum aestivum, Dextrose, Isomalt, Trehalose, D-Mannose, an extract of Mulberry, Enicostemma littorale Blume, Scoparia dulcis, an extract of Tarragon, Andrographis paniculata, Chromium or derivatives thereof, Glutamine and Alpha Lipoic Acid. Definitions [0008]As used herein, "Carbohydrate" refers to at least a source of carbohydrates such as, but not limited to, monosaccharides, disaccharides, oligosaccharides, polysaccharides or derivatives thereof. [0009]As used herein, "Creatine" refers to the chemical N-methyl-N-guanyl Glycine, (CAS Registry No. 57-00-1), also known as, (alpha-methyl guanido) acetic acid, N-(aminoiminomethyl)-N-glycine, Methylglycocyamine, Methylguanidoacetic Acid, or N-Methyl-N-guanylglycine. Additionally, as used herein, "Creatine" also includes derivatives of Creatine such as esters, and amides, and salts, as well as other derivatives, including derivatives that become active upon metabolism. Furthermore, Creatinol (CAS Registry No. 6903-79-3), also known as Creatine-O-Phosphate, N-methyl-N-(beta-hydroxyethyl)guanidine O-Phosphate, Aplodan, or 2-(carbamimidoyl-methyl-amino)ethoxyphosphonic acid, is henceforth in this disclosure considered to be a Creatine derivative. [0010]As used herein, "Phosphate" refers to at least a source of Phosphate ions such as, but not limited to, Dipotassium Phosphate, Disodium Phosphate, Magnesium Phosphate or derivatives thereof. [0011]Carbohydrate ingestion is known to stimulate the secretion of insulin which in turn facilitates the uptake of glucose into skeletal muscle via glucose transporter 4 (GLUT4) translocation (Wang W, Hansen P A, Marshall B A, Holloszy J O, Mueckler M. Insulin unmasks a COOH-terminal Glut4 epitope and increases glucose transport across T-tubules in skeletal muscle. J Cell Biol. 1996 October; 135(2):415-30). Glucose is then converted to and stored as glycogen and triglycerides. Concomitant with this, insulin inhibits the release and synthesis of glucose (Khan A H, Pessin J E. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia. 2002 November; 45(11):1475-83). Moreover, insulin also plays an important role in protein metabolism where it inhibits the breakdown of protein or proteolysis (Volpi E and Wolfe B. Insulin and Protein Metabolism. In: Handbook of Physiology, L. Jefferson and A. Cherrington editors. New York: Oxford, 2001, p. 735-757; Boirie Y, Gachon P,

Cordat N, Ritz P, Beaufrere B. Differential insulin sensitivities of glucose, amino acid, and albumin metabolism in elderly men and women. J Clin Endocrinol Metab. 2001 February; 86(2):638-44). Furthermore, insulin promotes the uptake of amino acids into muscle and stimulates protein synthesis (Biolo G, Declan Fleming R Y, Wolfe R R. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest. 1995 February; 95(2):811-9), particularly following exercise (Biolo G, Williams B D, Fleming R Y, Wolfe R R. Insulin action on muscle protein kinetics and amino acid transport during recovery after resistance exercise. Diabetes. 1999 May; 48(5):949-57). Insulin has also been shown to stimulate Creatine uptake by muscle cells (Odoom J E, Kemp G J, Radda G K. regulation of total creatine content in a myoblast cell line. Mol Cell Biochem. 1996 May 24; 158(2):179-88). Alpha Lipoic Acid has been shown to have insulin-like properties, which further aid in the retention of Creatine. (Streeper R S, Henriksen E J, Jacob S, Hokama J Y, Fogt D L, Tritschler H J. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol. 1997 July; 273(1 Pt 1):E185-91; Ziegler D, Hanefeld M, Ruhnau K J, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999 August; 22(8):1296-301). Via the combination of Creatine with Alpha Lipoic Acid and a small amount of carbohydrate, Creatine retention as compared to Creatine and carbohydrate alone is significantly improved (Burke D G, Chilibeck P D, Parise G, Tarnopolsky M A, Candow D G. Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine and phosphagen concentration. Int J Sport Nutr Exerc Metab. 2003 September; 13(3):294-302). Therefore, it is deemed to be advantageous that, for the purposes of Creatine retention, the actions of insulin be enhanced. Furthermore, it may be advantageous to increase the activity and availability of Creatine in skeletal muscle. [0012]Combinations comprising some of the aforementioned ingredients have been shown to offer further benefit to muscle building and increasing strength. In one clinical trial, 32 males were divided into four groups of eight subjects. Group 1 received a combination of Creatine/Dextrose/Taurine/Alpha Lipoic Acid, Group 2 received Creatine plus grape juice, Group 3 received Creatine plus water, and group 4 a placebo. At Day 28 of the experiment, Group 1 had demonstrated greater improvements in body composition and muscular endurance as compared to the other three groups (Kalman D S, Colker C M, Swain M A, Shi Q, Maharam L G. A double-blind, randomized clinical trial evaluating different creatine monohydrate formulations in resistance trained males. Med Sci Sports Exerc. 2000, 32(5), Supplement abstract 562). In a further study, Creatine/Dextrose/Alpha Lipoic Acid was found to provide improved results versus supplementation with whey protein alone in terms of muscle mass gain (Kalman D S, Colker C M, Swain M A, Antonio J. A Double-Blind Clinical Evaluation Comparing Two Popular Dietary Supplements Purported to Enhance Lean Body Mass. FASEB. 2000, 14(4):A619). In an eight week study which included diet and weight training, subjects consuming a combination comprising Creatine/Dextrose/Taurine/Ascorbic Acid/Chromium/Alpha Lipoic Acid/Phosphorus gained significantly more mass than

subjects consuming Protein/Dextrose alone (Tarnopolsky M A, Parise G, Yardley N J, Ballantyne C S, Olatinji S, Phillips S M. Creatine-dextrose and protein-dextrose induce similar strength gains during training. Med Sci Sports Exerc. 2001 December; 33(12):2044-52). [0013]Not wishing to be bound by theory, it is herein believed that the activity of insulin initiated by the ingestion of carbohydrates, such as Dextrose as comprised in the present invention, can be enhanced and sustained by insulin potentiators such as, including but not limited to, Taurine, Alpha Lipoic Acid, an extract of Mulberry, Chromium, Glutamine, Enicostemma littorale Blume, Scoparia dulcis, an extract of Tarragon and Andrographis paniculata. In another embodiment, the present invention may comprise one or more of Isomalt, Trehalose or D-Mannose to further potentiate the secretion or activity of insulin. The enhanced activity of insulin may facilitate increased uptake and retention of Creatine, as incorporated into the present invention, by skeletal muscle. Subsequently, the increase in Creatine retention may facilitate increased muscle growth, increased muscle endurance and reduced post-exercise recovery time by virtue of the biological role of Creatine. Furthermore, advantageously, the biological role of Creatine may be aided by ensuring adequate Phosphate availability by the addition of supplemental Phosphates. Creatine [0014]Creatine is a naturally occurring amino acid derived from the amino acids glycine, arginine, and methionine. Although it is found in meat and fish, it is also synthesized by humans. Creatine is predominantly used as a fuel source in muscle. About 65% of Creatine is stored in muscle as Phosphocreatine (Creatine bound to a Phosphate molecule) (Casey A, Constantin-Teodosiu D, Howell S, Hultman E, Greenhaff P L. Metabolic response of type I and II muscle fibers during repeated bouts of maximal exercise in humans. Am J Physiol. 1996 July; 271(1 Pt 1):E38-43). Muscular contractions are fueled by the dephosphorylation of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP) and without a mechanism to replenish ATP stores, the supply of ATP would be totally consumed in 1-2 seconds (Casey A, Greenhaff P L. Does dietary creatine supplementation play a role in skeletal muscle metabolism and performance? Am J Clin Nutr. 2000 August; 72(2 Suppl):607S-17S). Phosphocreatine serves as a major source of Phosphate from which ADP is regenerated to ATP. Six seconds following the commencement of exercise, muscular concentrations of Phosphocreatine drop by almost 50% (Gaitanos G C, Williams C, Boobis L H, Brooks S. Human muscle metabolism during intermittent maximal exercise. J Appl Physiol. 1993 August; 75(2):712-9). [0015]Creatine supplementation has been shown to increase the concentration of Creatine in the muscle (Harris R C, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992 September; 83(3):367-74) and further said supplementation enables an increase in the resynthesis of Phosphocreatine (Greenhaff P L, Bodin K, Soderlund K, Hultman E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J

Physiol. 1994 May; 266(5 Pt 1):E725-30) leading to a rapid replenishment of ATP within the first two minutes following the commencement of exercise. [0016]In the early 1990's it was first clinically demonstrated that supplemental Creatine can improve strength and reduce fatigue (Greenhaff P L, Casey A, Short A H, Harris R, Soderlund K, Hultman E. Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci (Lond). 1993 May; 84(5):565-71). Resistance training with supplemented creatine experiments display a result of increased strength and fat-free mass over a placebo in sedentary females (Vandenberghe K, Goris M, Van Hecke P, Van Leemputte M, Vangerven L, Hespel P. Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol. 1997 December; 83(6):2055-63) and in male football players (Vandenberghe K, Goris M, Van Hecke P, Van Leemputte M, Vangerven L, Hespel P. Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol. 1997 December; 83(6):2055-63). In addition to increasing fat-free mass and strength, Creatine supplementation increases muscle fiber cross sectional area (Volek J S, Duncan N D, Mazzetti S A, Staron R S, Putukian M, Gomez A L, Pearson D R, Fink W J, Kraemer W J. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Med Sci Sports Exerc. 1999 August; 31(8):1147-56) thereby increasing muscle volume. High-intensity exercise performance of both males and females is also improved by supplemental Creatine (Tarnopolsky M A, MacLennan D P. Creatine monohydrate supplementation enhances high-intensity exercise performance in males and females. Int J Sport Nutr Exerc Metab. 2000 December; 10(4):452-63; Burke D G, Silver S, Holt L E, Smith Palmer T, Culligan C J, Chilibeck P D. The effect of continuous low dose creatine supplementation on force, power, and total work. Int J Sport Nutr Exerc Metab. 2000 September; 10(3):235-44). Creatine supplementation may also benefit individuals with muscle dystrophy disorders by reducing muscle loss (Walter M C, Lochmuller H, Reilich P, Klopstock T, Huber R, Hartard M, Hennig M, Pongratz D, Muller-Felber W. Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study. Neurology. 2000 May 9; 54(9):1848-50). [0017]Furthermore, there is evidence that Creatine may have antioxidant properties (Lawler J M, Barnes W S, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun. 2002 Jan. 11; 290(1):47-52; Sestili P. Martinelli C, Bravi G, Piccoli G, Curci R, Battistelli M, Falcieri E, Agostini D, Gioacchini A M, Stocchi V. Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med. 2006 Mar. 1; 40(5):837-49). The antioxidant activity of Creatine may additionally aid post-exercise muscle recovery. [0018]Creatine retention has been shown to be markedly improved by the concomitant ingestion with carbohydrates, up to 60% better, which may further be related to increased insulin concentration (Green A L, Hultman E, Macdonald I A, Sewell D A, Greenhaff P L. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol. 1996 November; 271(5 Pt 1):E821-

6). Furthermore, glucose and Creatine uptake by muscle cells has been shown to be stimulated by insulin (Odoom J E, Kemp G J, Radda G K. regulation of total creatine content in a myoblast cell line. Mol Cell Biochem. 1996 May 24; 158(2):179-88). Thus, the ingestion of Creatine combined with a source of carbohydrates is recommended to improve retention. It may also be beneficial to include a source of protein at the time of Creatine ingestion (Steenge G R, Simpson E J, Greenhaff P L. Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans. J Appl Physiol. 2000 September; 89(3):1165-71). [0019]U.S. Pat. No. 5,767,159 purports to describe a method for increasing muscle capacity and replenishing ATP by administering daily Creatine in healthy mammals. The amount of said Creatine is at least 0.2-0.4 g per kg body weight and not less than 15 g in a 70 kg mammal to be taken for at least 2 days but not more than 7 days. The Creatine is administered in solution which may further include other conventional nutrients such as lipids, carbohydrates, amino acids, electrolytes, trace elements and vitamins. [0020]U.S. Pat. No. 5,968,544 purports to describe compositions containing Creatine for human consumption suitable for use in a drink or as dry powder stable for storage. The Creatine is provided in an acidic yogurt-based semi-liquid composition or forms an acidic solution when mixed with water. [0021]U.S. Pat. No. 5,973,199 purports to describe compositions for water soluble Creatine salts usable in foods. [0022]U.S. Pat. No. 5,968,900 purports to describe compositions and methods for increasing Creatine and glycogen concentration in muscle by increasing blood plasma insulin concentration. In one described embodiment, the compositions described are composed of Creatine or Creatine derivatives with a carbohydrate, wherein the carbohydrate is said to cause an increase in blood plasma insulin levels, which results in increases Creatine retention. [0023]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement includes Creatine or derivatives thereof. A serving of the dietary supplement may include from about 3 g to about 15 g of Creatine or derivatives thereof. The preferred dosage of a serving of the dietary supplement comprises about 10 g of Creatine or derivatives thereof. Taurine [0024]Taurine, an amino acid found primarily in nerve and muscle tissue, is generally considered to be a conditionally-essential amino acid, being only required under certain circumstances. As it is not utilized for protein synthesis, Taurine is found in the free form or in some small peptides. The accumulation of Taurine within cells is mediated via a high affinity sodium-dependent transporter (Ramamoorthy S, Leibach F H, Mahesh V B, Han H, Yang-Feng T, Blakely R D, Ganapathy V. Functional characterization and chromosomal localization of a cloned taurine transporter from human placenta. Biochem

J. 1994 Jun. 15; 300 (Pt 3):893-900). The expression of this Taurine transporter is induced by differentiation program of myocytes (muscle cells) (Uozumi Y, Ito T, Hoshino Y, Mohri T, Maeda M, Takahashi K, Fujio Y, Azuma J. Myogenic differentiation induces taurine transporter in association with taurine-mediated cytoprotection in skeletal muscles. Biochem J. 2006 Mar. 15; 394(Pt 3):699-706). Exercise-induced hormones are also known to activate the Taurine transporter (Park S H, Lee H, Park T. Cortisol and IGF-1 synergistically up-regulate taurine transport by the rat skeletal muscle cell line, L6. Biofactors. 2004; 21(1-4):403-6). Moreover, genetically modified mice lacking the Taurine transporter have depleted Taurine levels in all muscle and have impaired skeletal muscle function (Warskulat U, Flogel U, Jacoby C, Hartwig H G, Thewissen M, Merx M W, Molojavyi A, Heller-Stilb B, Schrader J, Haussinger D. Taurine transporter knockout depletes muscle taurine levels and results in severe skeletal muscle impairment but leaves cardiac function uncompromised. FASEB J. 2004 March; 18(3):577-9) [0025]One of the main roles of Taurine is the regulation of fluid balance and is released by contracting muscles (Cuisinier C, Michotte De Welle J, Verbeeck R K, Poortmans J R, Ward R, Sturbois X, Francaux M. Role of taurine in osmoregulation during endurance exercise. Eur J Appl Physiol. 2002 October; 87(6):489-95). Taurine has also been shown to modulate the contractile function of mammalian skeletal muscle (Bakker A J, Berg H M. Effect of taurine on sarcoplasmic reticulum function and force in skinned fast-twitch skeletal muscle fibres of the rat. J Physiol. 2002 Jan. 1; 538(Pt 1):185-94). In rats, the Taurine concentration in muscle decreases as a result of exercise (Matsuzaki Y, Miyazaki T, Miyakawa S, Bouscarel B, Ikegami T, Tanaka N. Decreased taurine concentration in skeletal muscles after exercise for various durations. Med Sci Sports Exerc. 2002 May; 34(5):793-7) and oral supplementation with Taurine has been shown to maintain the concentration of Taurine in muscle and prolong exercise performance (Miyazaki T, Matsuzaki Y, Ikegami T, Miyakawa S, Doy M, Tanaka N, Bouscarel B. Optimal and effective oral dose of taurine to prolong exercise performance in rat. Amino Acids. 2004 December; 27(3-4):291-8; Yatabe Y, Miyakawa S, Miyazaki T, Matsuzaki Y, Ochiai N. Effects of taurine administration in rat skeletal muscles on exercise. J Orthop Sci. 2003; 8(3):415-9). [0026]In a model of spontaneous diabetes, Taurine supplementation has been shown to improve insulin sensitivity in rats (Nakaya Y, Minami A, Harada N, Sakamoto S, Niwa Y, Ohnaka M. Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes. Am J Clin Nutr. 2000 January; 71(1):54-8). Furthermore, Taurine improves glucose metabolism in insulin resistant rats (Nandhini A T, Anuradha C V. Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats. Amino Acids. 2002; 22(1):27-38), suggesting that Taurine has insulin-like properties which may improve Creatine uptake and retention within muscle cells. Supplementation with Taurine has additionally been shown to reduce exercise-induced oxidative damage and enhance recovery (Zhang M, Izumi I, Kagamimori S, Sokejima S, Yamagami T, Liu Z, Qi B. Role of taurine supplementation to prevent exercise-induced oxidative stress in healthy young men. Amino Acids. 2004 March; 26(2):203-7).

[0027]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement includes Taurine or derivatives thereof. A serving of the dietary supplement may include from about 0.5 g to about 3 g of Taurine or derivatives thereof. The preferred dosage of a serving of the dietary supplement comprises about 2.1 g of Taurine or derivatives thereof. Phosphate [0028]Phosphate, or phosphorus, is the second most abundant mineral in the body with calcium being the most abundant. As a Phosphate salt with calcium, Phosphate is involved in the formation of bone and teeth. In other salt complexes, Phosphate is involved in acid-base balance. Phosphate is also important for the structures of DNA and cell membranes. One of the most important roles of Phosphate is energy production in muscle as ATP and Phosphocreatine. Phosphate is also part of a compound in red blood cells known as 2,3 DPG (2,3-diphosphoglycerate), which facilitates the release of oxygen to the muscle tissues. [0029]Supplemental Phosphate salts have been shown to increase the concentration of 2,3 DPG in red blood cells, increasing VO2 max (a measure of aerobic fitness) and a reduction in the production of lactate (Cade R, Conte M, Zauner C, Mars D, Peterson J, Lunne D, Hommen N, Packer D. Effects of phosphate loading on 2,3-diphosphoglycerate and maximal oxygen uptake. Med Sci Sports Exerc. 1984 June; 16(3):263-8). Moreover, Phosphate has also been shown to enhance oxygen uptake and run performance without affecting the level of 2,3 DPG (Kreider R B, Miller G W, Williams M H, Somma C T, Nasser T A. Effects of phosphate loading on oxygen uptake, ventilatory anaerobic threshold, and run performance. Med Sci Sports Exerc. 1990 April; 22(2):250-6). [0030]The metabolic rate can also be increased by Phosphate supplementation (Nazar K, Kaciuba-Uscilko H, Szczepanik J, Zemba A W, Kruk B, Chwalbinska-Moneta J, Titow-Stupnicka E, Bicz B, Krotkiewski M. Phosphate supplementation prevents a decrease of triiodothyronine and increases resting metabolic rate during low energy diet. J Physiol Pharmacol. 1996 June; 47(2):373-83). [0031]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement includes a source of Phosphate or derivatives thereof. A serving of the dietary supplement may include from about 0.1 g to about 1.5 g of Phosphate or derivatives thereof. The preferred dosage of a serving of the dietary supplement comprises about 0.18 g of elemental Phosphate or derivatives thereof. Alpha Lipoic Acid [0032]Alpha Lipoic Acid (ALA) is an enzyme found in the cellular energy-producing structures, the mitochondria. ALA works in synergy with vitamins C and E as an antioxidant in both the water- and fat-soluble environments.

[0033]In rats supplemented with ALA, the negative age-related changes in mitochondrial function, accumulated oxidative damage and metabolic rate were all improved (Hagen T M, Ingersoll R T, Lykkesfeldt J, Liu J, Wehr C M, Vinarsky V, Bartholomew J C, Ames A B. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999 February; 13(2):411-8). As such, the antioxidant activity of ALA is likely involved in the prevention of cell death due to an improvement in oxidative stress (Arivazhagan P, Juliet P, Panneerselvam C. Effect of di-alpha-lipoic acid on the status of lipid peroxidation and antioxidants in aged rats. Pharmacol Res. 2000 March; 41(3):299-303). Furthermore, ALA has been linked to a beneficial increase in high-density lipoproteins (Wollin S D, Wang Y, Kubow S, Jones P J. Effects of a medium chain triglyceride oil mixture and alpha-lipoic acid diet on body composition, antioxidant status, and plasma lipid levels in the Golden Syrian hamster. J Nutr Biochem. 2004 July; 15(7):402-10) possibly due to its known effects as an antioxidant. [0034]Additionally, ALA appears to possess a dual action related to hunger and .beta.-oxidation of fat. First, the activity of AMP-activated protein kinase, which acts as an energy sensor in the hypothalamus, is reduced by ALA in rodents, this results in a profound weight loss by reducing food intake and enhancing energy expenditure (Kim M S, Park J Y, Namkoong C, Jang P G, Ryu J W, Song H S, Yun J Y, Namgoong I S, Ha J, Park I S, Lee I K, Viollet B, Youn J H, Lee H K, Lee K U. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004 July; 10(7):727-33). Second, ALA increases Uncoupling Protein-1 in rodent adipocytes while increasing AMP-activated protein kinase in skeletal muscle cells and increasing glucose uptake and energy expenditure (Lee W J, Koh E H, Won J C, Kim M S, Park J Y, Lee K U. Obesity: the role of hypothalamic AMP-activated protein kinase in body weight regulation. Int J Biochem Cell Biol. 2005 November; 37(11):2254-9). Therefore, ALA seemingly has different effects in different tissues. However, in adipocytes or muscle cells ALA increases fatty acid oxidation, leading to an increase in energy expenditure and a decrease in weight and food intake. [0035]U.S. Pat. Nos. 6,136,339 and 6,620,425 disclose compositions and methods for enhancing an athlete's muscle size or strength using a combination of Creatine, Alpha Lipoic Acid and optionally Dextrose, to be taken mixed with water daily following exercise. [0036]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Alpha Lipoic Acid or derivatives thereof. A serving of the dietary supplement may include from about 0.005 g to about 0.4 g of Alpha Lipoic Acid or derivatives thereof. The preferred dosage of a serving of the dietary supplement comprises about 0.25 g of Alpha Lipoic Acid or derivatives thereof. Dextrose [0037]Dextrose is a simple sugar or monosaccharide commonly known as D-glucose.

Also known as `grape sugar` or `blood sugar`, it is found mainly in honey and fruits and is a building-block of glycogen, cellulose and starch. Recently, Dextrose was shown to boost the performance a female rowers as compared to ribose, which had been theorized to replenish muscle energy (Dunne L, Worley S, Macknin M. Ribose versus dextrose supplementation, association with rowing performance: a double-blind study. Clin J Sport Med. 2006 January; 16(1):68-71). [0038]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Dextrose. A serving of the dietary supplement may include from about 50 g to about 100 g of Dextrose. The preferred dosage of a serving of the dietary supplement comprises about 75 g of Dextrose. Mulberry Extract [0039]Mulberry (Morus alba) is an edible plant used in Chinese medicine which is rich in flavonoids possessing antioxidant activity (Doi K, Kojima T, Makino M, Kimura Y, Fujimoto Y. Studies on the constituents of the leaves of Morus alba L. Chem Pharm Bull (Tokyo). 2001 February; 49(2):151-3). Orally administered mulberry extracts of Mulberry reduced blood glucose levels of both non-diabetic and streptozotocin-treated diabetic rats, commensurate with decreased food intake (Musabayane C T, Bwititi P T, Ojewole J A. Effects of oral administration of some herbal extracts on food consumption and blood glucose levels in normal and streptozotocin-treated diabetic rats. Methods Find Exp Clin Pharmacol. 2006 May; 28(4):223-8). Orally consumed extracts of Mulberry have also been shown to inhibit increases in blood glucose resulting from the ingestion of carbohydrates such as sucrose in humans and rats (Oku T, Yamada M, Nakamura M, Sadamori N, Nakamura S. Inhibitory effects of extractives from leaves of Morus alba on human and rat small intestinal disaccharidase activity. Br J Nutr. 2006 May; 95(5):933-8). Furthermore, extracts of Mulberry confer neuroprotective benefits (Kang T H, Oh H R, Jung S M, Ryu J H, Park M W, Park Y K, Kim S Y. Enhancement of neuroprotection of mulberry leaves (Morus alba L.) prepared by the anaerobic treatment against ischemic damage. Biol Pharm Bull. 2006 February; 29(2):270-4) and may further attenuate the development of atherosclerotic lesions (Enkhmaa B, Shiwaku K, Katsube T, Kitajima K, Anuurad E, Yamasaki M, Yamane Y. Mulberry (Morus alba L.) leaves and their major flavonol quercetin 3-(6-malonylglucoside) attenuate atherosclerotic lesion development in LDL receptor-deficient mice. J Nutr. 2005 April; 135(4):729-34). [0040]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Mulberry extract. A serving of the dietary supplement may include from about 0.01 g to about 0.05 g of Mulberry extract. The preferred dosage of a serving of the dietary supplement comprises about 0.025 g of Mulberry extract. Chromium [0041]Chromium is an essential trace mineral that is used to control blood sugar levels by

aiding insulin, which can help control or reduce weight. Chromium is poorly absorbed by the body and must therefore be combined with a more efficiently absorbed compound such as niacin as in the case of polynicotinate. Chromium likely exerts its main function as a component or a co-factor of the glucose tolerance factor, which is involved in insulin sensitivity. [0042]Chromium has been shown clinically to increase lean mass (Bahadori B, Wallner S, Schneider H, Wascher T C, Toplak H. Effect of chromium yeast and chromium picolinate on body composition of obese, non-diabetic patients during and after a formula diet. Acta Med Austriaca. 1997; 24(5):185-7) and reduce body fat when combined with exercise (Grant K E, Chandler R M, Castle A L, Ivy J L. Chromium and exercise training: effect on obese women. Med Sci Sports Exerc. 1997 August; 29(8):992-8). Moreover, chromium has also been shown to increase high density lipoproteins (HDL i.e. `good` cholesterol) (Riales R, Albrink M J. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men. Am J Clin Nutr 1981; 34:2670-8). Numerous clinical studies have demonstrated the relationship between supplemental Chromium and improved insulin activity and glucose metabolism (Anderson R A. Chromium in the prevention and control of diabetes. Diabetes Metab. 2000 February; 26(1):22-7). [0043]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include a derivative of Chromium. A serving of the dietary supplement may include from about 0.001 g to about 0.005 g of a derivative of Chromium. The preferred dosage of a serving of the dietary supplement comprises about 0.003 g of a derivative of Chromium. Glutamine [0044]Glutamine is the most abundant amino acid found in muscle and has important functions as a precursor for the synthesis of other amino acids. Many cells required for immune function rely on Glutamine as source for energy production. [0045]Physical activity can deplete Glutamine levels, and as such, Glutamine is often considered to be a `conditionally essential` amino acid. A study examining the Glutamine levels of groups involved in several different types of activities or sports found that powerlifters and swimmers had lower Glutamine levels than cyclists and non-athletes (Hiscock N, Mackinnon L T. A comparison of plasma glutamine concentration in athletes from different sports. Med Sci Sports Exerc. 1998 December; 30(12):1693-6), suggesting that high resistance load activities require increased amounts of Glutamine. Moreover, this depletion of Glutamine has been linked to immunosuppression often resulting from intense training (Newsholme E A. Biochemical mechanisms to explain immunosuppression in well-trained and overtrained athletes. Int J Sports Med. 1994 October; 15 Suppl 3:S142-7). Supplementation with Glutamine in conjunction with additional antioxidants can increase body weight, body cell mass, and intracellular water when compared with placebo (Shabert J K, Winslow C, Lacey J M, Wilmore D W. Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with

weight loss: a randomized, double-blind controlled trial. Nutrition. 1999 November-December; 15(11-12):8604). Glutamine is also capable of stimulating insulin secretion (Tanizawa Y, Nakai K, Sasaki T, Anno T, Ohta Y, Inoue H, Matsuo K, Koga M, Furukawa S, Oka Y. Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion: identification and characterization of a GLUD1 gene mutation and insulin secretion studies with MIN6 cells overexpressing the mutant glutamate dehydrogenase. Diabetes. 2002 March; 51 (3):712-7). [0046]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Glutamine or a derivative thereof. A serving of the dietary supplement may include from about 0.001 g to about 0.005 g of Glutamine or a derivative thereof. The preferred dosage of a serving of the dietary supplement comprises about 0.002 g of Glutamine or a derivative thereof. Enicostemma littorale Blume [0047]Enicostemma littorale Blume is a flower-producing herb found in South America, Africa, and Asia. In rat models of diabetes, Enicostemma littorale extract can enhance glucose-induced insulin release thereby effectively lowering blood glucose levels (Maroo J, Vasu V T, Aalinkeel R, Gupta S. Glucose lowering effect of aqueous extract of Enicostemma littorale Blume in diabetes: a possible mechanism of action. J Ethnopharmacol. 2002 August; 81(3):317-20; Maroo J, Vasu V T, Gupta S. Dose dependent hypoglycemic effect of aqueous extract of Enicostemma littorale blume in alloxan induced diabetic rats. Phytomedicine. 2003 March; 10(2-3):196-9). Furthermore, Enicostemma littorale extract counters the changes in several metabolic enzymes and antioxidants observed in diabetic rats, including lowering thiobarbituric acid reactive substances and lipid hydroperoxides while increasing the concentration of reduced glutathione and the activities of superoxide dismutase and catalase (Srinivasan M, Padmanabhan M, Prince P S. Effect of aqueous Enicostemma littorale Blume extract on key carbohydrate metabolic enzymes, lipid peroxides and antioxidants in alloxan-induced diabetic rats. J Pharm Pharmacol. 2005 April; 57(4):497-503). The lipid profile of rats fed cholesterol was also improved by administration of Enicostemma littorale extract (Vasu V T, Modi H, Thaikoottathil J V, Gupta S. Hypolipidaemic and antioxidant effect of Enicostemma littorale Blume aqueous extract in cholesterol fed rats. J Ethnopharmacol. 2005 Oct. 3; 101(1-3):277-82). [0048]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Enicostemma littorale Blume. A serving of the dietary supplement may include from about 0.0005 g to about 0.003 g of Enicostemma littorale Blume. The preferred dosage of a serving of the dietary supplement comprises about 0.001 g of Enicostemma littorale Blume. Scoparia dulcis (Scotch Brum) [0049]Scoparia dulcis is a tropical herb found in abundance in South America and the Amazon rainforest and has been used traditionally for multiple treatments including

diabetes. Extracts of Scoparia dulcis provide both antidiabetic and antihyperlipidemic actions in normal and experimentally diabetic rats (Pari L, Latha M. Antihyperlipidemic effect of Scoparia dulcis (sweet broomweed) in streptozotocin diabetic rats. J Med Food. 2006 Spring; 9(1):102-7). Scoparia dulcis extract has also demonstrated antioxidant and neuroprotective activity (Pari L, Latha M. Protective role of Scoparia dulcis plant extract on brain antioxidant status and lipidperoxidation in STZ diabetic male Wistar rats. BMC Complement Altern Med. 2004 Nov. 2; 4:16). [0050]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Scoparia dulcis. A serving of the dietary supplement may include from about 0.0005 g to about 0.003 g of Scoparia dulcis. The preferred dosage of a serving of the dietary supplement comprises about 0.001 g of Scoparia dulcis. Tarragon Extract (Artemisia dracunculus) [0051]Russian Tarragon (Artemisia dracunculus) is a perennial herb widely used in cooking. Historically, it has been used as a natural blood cleanser and as a treatment for headaches and dizziness. Current studies are examining the use of an ethanolic extract of Russian Tarragon for the treatment of hyperglycemia associated with diabetes. The toxicology of this extract has been evaluated, and has been shown to be safe and non-toxic (Ribnicky D M, Poulev A, O'Neal J, Wnorowski G, Malek D E, Jager R, Raskin I. Toxicological evaluation of the ethanolic extract of Artemisia dracunculus L. for use as a dietary supplement and in functional foods. Food Chem Toxicol. 2004 April; 42(4):585-98). Essential oil extracted from Artemisia dracunculus may also have potential as an anticonvulsant and as a mild sedative (Sayyah M, Nadjafnia L, Kamalinejad M. Anticonvulsant activity and chemical composition of Artemisia dracunculus L. essential oil. J Ethnopharmacol. 2004 October; 94(2-3):283-7). [0052]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Tarragon extract. A serving of the dietary supplement may include from about 0.0005 g to about 0.003 g of Tarragon extract. The preferred dosage of a serving of the dietary supplement comprises about 0.001 g of Tarragon extract. Andrographis paniculata [0053]Andrographis paniculata is a medicinal herb used traditionally throughout Asia used to treat a number of conditions. Clinical studies have demonstrated an immunity-enhancing benefit of Andrographis paniculata supplementation by reducing the occurrence and severity of common cold symptoms (Caceres D D, Hancke J L, Burgos R A, Sandberg F, Wikman G K. Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study. Phytomedicine. 1999 October; 6(4):217-23) and upper-respiratory tract infections (Melchior J, Spasov A A, Ostrovskij O V, Bulanov A E, Wikman G. Double-blind, placebo-controlled pilot and

phase III study of activity of standardized Andrographis paniculata Herba Nees extract fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infection. Phytomedicine. 2000 October; 7(5):341-50). Additionally, Andrographis paniculata has been shown to possess antipyretic, fever-reducing, activity similar to that of aspirin (Vedavathy S, Rao K N. Antipyretic activity of six indigenous medicinal plants of Tirumala Hills, Andhra Pradesh, India. J Ethnopharmacol. 1991 May-June; 33(1-2):193-6). Furthermore, Andrographis paniculata has been shown to reduce chemically-induced liver toxicity in experimental mice (Kapil A, Koul I B, Banerjee S K, Gupta B D. Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata. Biochem Pharmacol. 1993 Jul. 6; 46(1):182-5). [0054]Andrographis paniculata extract possesses antihyperglycemic and antioxidative activities in both normal and chemically-induced diabetic rats (Zhang X F, Tan B K. Antihyperglycaemic and anti-oxidant properties of Andrographis paniculata in normal and diabetic rats. Clin Exp Pharmacol Physiol. 2000 May-June; 27(5-6):358-63). The antidiabetic properties of Andrographis paniculata are believed to be due at least in part to enhanced glucose metabolism (Zhang X F, Tan B K. Anti-diabetic property of ethanolic extract of Andrographis paniculata in streptozotocin-diabetic rats. Acta Pharmacol Sin. 2000 December; 21(12):1157-64). [0055]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Andrographis paniculata. A serving of the dietary supplement may include from about 0.0005 g to about 0.003 g of Andrographis paniculata. The preferred dosage of a serving of the dietary supplement comprises about 0.001 g of Andrographis paniculata. Double Fermented Triticum aestivum [0056]Double Fermented Triticum aestivum is a whole-grain wheat product low in simple sugars and high in complex carbohydrates. This produces a more level glucose/insulin response rather than the typical `spike` resulting from simple sugar ingestion. As such, Double Fermented Triticum aestivum is marketed towards overweight or obese individual or individuals with impaired glucose tolerance. Double Fermented Triticum aestivum was found effective at reducing the risks associated with development of type 2 diabetes such as elevated fasting blood glucose levels and obesity (Rave K, Dellweg S, Hovelmann U, Heise T, Dieck H T. Impact of a Diet with Balantose.TM. on Insulin Resistance, Lipids and Body Weight: Results of a Randomized, Controlled Cross-Over Study in Obese Subjects with High Risk for Type 2 Diabetes. 65.sup.th Annual Scientific Sessions, American Diabetes Association 2005, Abstract 1765-P). [0057]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Double Fermented Triticum aestivum. A serving of the dietary supplement may include from about 0.05 g to about 0.3 g of Double Fermented Triticum aestivum. The preferred dosage of a serving of the dietary supplement comprises about 0.1 g of Double Fermented Triticum aestivum.

Isomalt [0058]Isomalt is a disaccharide sugar substitute derived from sucrose which is less sweet than, and is often mixed with, more conventional sweeteners. Being only partially digested in the intestines, isomalt results in a low blood glucose effect, has benefits similar to that of dietary fiber, and has a caloric value of about half that of sugar. Moreover, Isomalt has been shown to promote healthy bowel function without impairing metabolic function (Gostner A, Schaffer V, Theis S, Menzel T, Luhrs H, Melcher R, Schauber J, Kudlich T, Dusel G, Dorbath D, Kozianowski G, Scheppach W. Effects of isomalt consumption on gastrointestinal and metabolic parameters in healthy volunteers. Br J Nutr. 2005 October; 94(4):575-81; Gostner A, Blaut M, Schaffer V, Kozianowski G, Theis S, Klingeberg M, Dombrowski Y, Martin D, Ehrhardt S, Taras D, Schwiertz A, Kleessen B, Luhrs H, Schauber J, Dorbath D, Menzel T, Scheppach W. Effect of isomalt consumption on faecal microflora and colonic metabolism in healthy volunteers. Br J Nutr. 2006 January; 95(1):40-50). [0059]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Isomalt. A serving of the dietary supplement may include from about 0.0005 g to about 0.003 g of Isomalt. The preferred dosage of a serving of the dietary supplement comprises about 0.001 g of Isomalt. Trehalose [0060]Trehalose is a naturally occurring disaccharide found in plants, invertebrates and fungi and is about half as sweet as sucrose or table sugar. Trehalose has been discovered to be able to inhibit the aggregation of some proteins and thus has potential in the prevention of diseases linked to such events such as Huntington's disease (Tanaka M, Machida Y, Niu S, Ikeda T, Jana N R, Doi H, Kurosawa M, Nekooki M, Nukina N. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med. 2004 February; 10(2):148-54). [0061]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include Trehalose. A serving of the dietary supplement may include from about 0.0005 g to about 0.003 g of Trehalose. The preferred dosage of a serving of the dietary supplement comprises about 0.001 g of Trehalose. D-Mannose [0062]Mannose is a monosaccharide found in some fruits including cranberry. It is absorbed slowly in the gastrointestinal tract, with most being excreted in the urine. D-mannose has been theorized to aid in the treatment of urinary tract infections by virtue of being able to bind to the surface proteins of infection-causing bacteria, thereby facilitating their clearance (Schaeffer A J, Chmiel J S, Duncan J L, Falkowski W S. Mannose-sensitive adherence of Escherichia coli to epithelial cells from women with recurrent urinary tract infections. J Urol. 1984 May; 131(5):906-10).

[0063]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement may include D-mannose. A serving of the dietary supplement may include from about 0.0005 g to about 0.003 g of D-mannose. The preferred dosage of a serving of the dietary supplement comprises about 0.001 g of D-mannose. [0064]According to various embodiments of the present invention, the dietary supplement may be consumed in any form. For instance, the dosage form of the dietary supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid capsule, a tablet, a caplet, or as a dietary gel. The preferred dosage forms of the present invention is as a powder beverage mix or a drink product. Fine-Milling of Active Constituents [0065]As set forth above, the dosage form of the dietary supplement, in accordance with the example embodiments set forth below, may be provided in accordance with customary processing techniques for herbal and/or dietary supplements, wherein the active ingredients are suitably processed into a desired form. In accordance with various embodiments of the present invention, one or more ingredients of the diet supplement are processed so as to form fine-milled particles. For instance, in various embodiments, one or more ingredients of the dietary supplemental are processed by a large-scale dry milling technique that produces fine particles, preferably known as fine-milled particles. The use of dry milling techniques, in combination with excipients and polymers, to form fine-milled particles has been shown to improve flow and dispersability, stability, resistance to moisture, bioavailability, and dissolution/release properties. Formulations benefit by containing fine-milled particles for the purpose of providing the one or more ingredients in particle sizes that optimize one or more of the flow and dispersability, stability, resistance to moisture, bioavailability, and dissolution/release properties of the one or more ingredients in a dietary supplement. In vitro tests designed to simulate the environment of a stomach were performed to test the dissolution rate of fine-milled particle tablets versus non-fine-milled. These test showed that in tablets produced from fine-milled particles the time to 100% dissolution was approximately 15 minutes. In the case of non-fine-milled particle compositions, only 90% dissolution was observed after 120 minutes. In preferred embodiments, the dietary supplemental contains fine-milled particles having an average size between about 50 nm and about 2 nm. [0066]U.S. Provisional Patent Application 60/776,325 discloses a method for improving the absorption, palatability, taste, texture, and bioavailability of compounds by increasing the solubility of said compounds in proprietary formulations for the purposes of enhancing or improving muscle size, growth and/or recovery time and/or weight loss. The increased bioavailability of the compound or ingredients is achieved by reducing the particle size via "fine-milling" thereby increasing the surface area-to-volume ratio each particle, thus increasing the rate of dissolution. The compositions and methods disclosed promote increased bioavailability by increasing the total surface area of poorly soluble

particles, thereby increasing the rate of absorption. [0067]As used herein the, term "fine-milled" and/or "fine-milling" refers to the process of micronization. Micronization is a mechanical process that involves the application of force to a particle, thereby resulting in a reduction in the size of the particle. The force, in the case of micronization, may be applied in any manner such as, e.g., the collision of particles at high rates of speed, grinding, or by an air-jet micronizer. In preferred embodiments, fine-milled particles are obtained by jet-milling with nitrogen and compressed air. [0068]As used herein, the term "particle size" refers to the diameter of the particle. The term "average particle size" means that at least 50% of the particles in a sample will have the specified particle size. Preferably, at least 80% of the particles in a sample will have the specified particle size, and more preferably, at least 90% of the particles in a given sample will have the specified particle size. [0069]The size of a particle can be determined by any of the methods known within the art. Methods for particle size determination which may be employed are for example, e.g., sieves, sedimentation, electrozone sensing (Coulter counter), microscopy, and/or Low Angle Laser Light Scattering. The preferred methods for the particle size determination of the present invention are those methods which are most commonly used in the pharmaceutical industry, such as laser diffraction, e.g., via light scattering Coulter Delsa 440SX. [0070]The fine-milling process may be employed in the processing of one or more of the ingredients of the present invention in the dosage forms of tablets, e.g., immediate-release film coated, modified-release and fast-dissolving; capsules or tablets, e.g., immediate-release and modified-release; liquid dispersions; powders; drink mixes, etc. [0071]Preferably, the dietary supplement of the present invention is consumed by an individual in accordance with the following method: As a dietary supplement, a serving of said dietary supplement may be taken by means of mixing in about 360-450 ml of an acceptable aqueous fluid at least one (1) time daily wherein each serving is comprised of two (2) scoops comprising about 100 g total mass of the dietary supplement. Said dietary supplement may be consumed approximately 0 to 60 minutes following a workout, or in the morning upon waking on non-workout days. In this manner, the dietary supplement may increase Creatine uptake and retention in skeletal muscle, increase muscle mass and strength, increase exercise capacity and aid in post-exercise recovery as well as provide support for the immune system during intense exercise training periods. [0072]Furthermore, the dosage form of the supplemental composition may be provided in accordance with customary processing techniques for herbal and dietary supplements in any of the forms mentioned above. Additionally, the dietary supplement set forth in the example embodiments herein may contain any appropriate number and type of excipients, as is well-known in the art.

[0073]The present dietary supplement or those similarly envisioned by one of skill in the art, may be utilized in compositions and methods for increasing Creatine uptake and retention in skeletal muscle, increasing muscle mass and strength, increasing exercise capacity and aiding in post-exercise recovery as well as providing support for the immune system during intense exercise training periods of an individual, e.g. a human or an animal in a formulation designed to be consumed at least one time per day. [0074]Although the following examples illustrate the practice of the present invention in three of its various embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and example. EXAMPLE 1 [0075]A serving of the dietary supplement comprises the following ingredients in powdered beverage mix form. The dietary supplement comprises for example: about 74 g of pharma grade Dextrose 99 DE, about 9 g of Creatine monohydrate, finely ground or milled, about 2.1 g of Taurine, about 0.33 g of Dipotassium Phosphate, about 0.33 g of Magnesium Phosphate, about 0.26 g of Sodium Alpha Lipoic Acid, about 0.025 g of and extract of Mulberry, about 0.003 g of Chromium polynicotinate, about 0.001 g of Anhydrous Creatine, about 0.001 g of Taurine ethyl ester HCl, about 0.001 g of Glutamine AKG 2:1, about 0.001 g of Glutamine ethyl ester HCl, about 0.001 g of Enicostemma littorale Blume, about 0.001 g of Scoparia dulcis, about 0.001 g of an extract of Tarragon, about 0.001 g of Andrographis paniculata. [0076]Directions: As a dietary supplement, 2 scoops, comprising about 100 g total mass of the dietary supplement are administered by a means of mixing said dietary supplement in 360-450 ml of an acceptable aqueous fluid at least one (1) time daily. Said serving is to be consumed approximately 0 to 60 minutes following a workout or in the morning upon waking on non-workout days. EXAMPLE 2 [0077]A serving of the dietary supplement comprises the following ingredients in powdered beverage mix form. The dietary supplement comprises for example: about 75 g of pharma grade Dextrose 99 DE, about 9 g of finely ground Creatine monohydrate, about 2.1 g of Taurine, about 1 g of fine-milled Creatine monohydrate, about 0.33 g of Dipotassium Phosphate, about 0.33 g of Disodium Phosphate, about 0.26 g of the Sodium salt of Alpha Lipoic Acid, about 0.025 g of an extract of Mulberry, about 0.003 g of Chromium polynicotinate, about 0.001 of Anhydrous Creatine, about 0.001 g of Dicreatine malate, about 0.001 g of Creatine HCA salt, about 0.001 g of Taurine ethyl ester HCl, about 0.001 g of Glutamine AKG 2:1, about 0.001 g of Glutamine ethyl ester HCl, about 0.001 g of Enicostemma littorale Blume, about 0.001 g of Scoparia dulcis, about 0.001 g of an extract of Tarragon extract, and about 0.001 g of Andrographis paniculata.

[0078]Directions: As a dietary supplement, 2 scoops, comprising about 100 g total mass of the dietary supplement are administered by a means of mixing said dietary supplement in 360-450 ml of an acceptable aqueous fluid at least one (1) time daily. Said serving is to be consumed approximately 0 to 60 minutes following a workout or in the morning upon waking on non-workout days. EXAMPLE 3 [0079]A serving of the dietary supplement comprises the following ingredients in powdered beverage mix form. The dietary supplement comprises for example: about 75 g of pharma grade Dextrose 99 DE, about 9 g of finely ground Creatine monohydrate, about 2.1 g of Taurine, about 1 g of fine-milled Creatine monohydrate, about 0.33 g of Dipotassium Phosphate, about 0.33 g of Disodium Phosphate, about 0.33 g of Magnesium Phosphate, about 0.26 g of Sodium Alpha Lipoic Acid, about 0.1 g of Double Fermented Triticum aestivum, about 0.025 g of an extract of Mulberry, about 0.003 g of Chromium polynicotinate, about 0.001 g of Anhydrous Creatine, about 0.001 g of Creatine Dicreatine malate, about 0.001 g of Creatine pyroglutamate, about 0.001 g of Creatine HCA salt, about 0.001 g of Taurine ethyl ester HCl, about 0.001 g of Glutamine AKG 2:1, about 0.001 g of Glutamine ethyl ester HCl, about 0.001 g of Enicostemma littorale Blume, about 0.001 g of Scoparia dulcis, about 0.001 g of and extract of Tarragon, about 0.001 g of Andrographis paniculata, about 0.001 g of Isomalt, about 0.001 g of Trehalose, about 0.001 g of D-mannose. [0080]Directions: As a dietary supplement, 2 scoops, comprising about 100 g total mass of the dietary supplement are administered by a means of mixing said dietary supplement in 360-450 ml of an acceptable aqueous fluid at least one (1) time daily. Said serving is to be consumed approximately 0 to 60 minutes following a workout or in the morning upon waking on non-workout days. [0081]In the foregoing specification, the invention has been described with specific embodiments thereof, however, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.

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United States Patent Application 20070237786

Kind Code A1

Heuer; Marvin A. October 11, 2007

Diet supplement for causing rapid weight loss, controlling appetite, managing stress, supporting relaxation, combating fatigue and supporting mental well-being.

Abstract

Compositions and methods for administering to the diet of humans a composition for inducing rapid weight loss, controlling appetite, managing stress and supporting mental well-being, supporting relaxation, and combating fatigue. A diet supplement comprising Calcium and Potassium double salt of Garcinia Cambogia Extract supplying 60% Hydroxycitric Acid, Gymnema Sylvestre Leaf Extract, Rhodiola Rosea Root Extract, Theanine Astaxanthin Algae Extract, Chromium Polynicotinate, Hoodia Gordonii, N-olyl-phosphatidyl ethanolamine (NOPE)/EGCG blend, Vinpocetine, Russian Tarragon Extract, N-acetyl tyrosine, and Withania Somnifera Root Extract is provided. Said diet supplement is comprised of at least Hoodia Gordonii wherein the extract does not contain any extract from the root of the plant.

Inventors: Heuer; Marvin A.; (Mississauga, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 5100 SPECTRUM WAY MISSUSSAUGA ON L4W 5S2 CA

Assignee Name and Adress:

Smartburn Formulations Ltd Mississauga CA

Serial No.: 765476

Series Code: 11

Filed: June 20, 2007

U.S. Current Class: 424/195.17; 424/725

U.S. Class at Publication: 424/195.17; 424/725

Intern'l Class: A61K 36/00 20060101 A61K036/00; A61K 36/02 20060101 A61K036/02; A61K 36/18 20060101

A61K036/18; A61P 3/04 20060101 A61P003/04

Claims

1-20. (canceled) 21. A method for promoting weight loss comprising the oral administration to a mammal a dietary supplement comprising: Hoodia Gordonii or an extract of Hoodia Gordonii; a Calcium and Potassium double salt of Garcinia Cambogia Extract supplying 60% Hydroxycitric Acid; a leaf extract of Gymnema Sylvestre; Chromium Polynicotinate; and a blend of N-olyl-phosphatidyl Ethanolamine/EGCG, wherein the Hoodia Gordonii or Hoodia Gordonii is devoid of material from the roots of said Hoodia Gordonii. 22. The method of claim 21 wherein the dietary supplement further comprises at least one ingredient selected from the group comprising an extract of Russian Tarragon and Vinpocetine. 23. The method of claim 21, wherein the dietary supplement is administered to the mammal at least once daily. 24. A method for promoting weight loss while concomitantly reducing feelings of anxiety and stress in a mammal comprising the oral administration to a mammal a dietary supplement comprising: Hoodia Gordonii or an extract of Hoodia Gordonii; and an effective amount of Theanine, wherein the Hoodia Gordonii or Hoodia Gordonii extract to devoid any material from the roots of said Hoodia Gordonii. 25. The method of claim 24 wherein the dietary supplement further comprises at least one ingredient selected from the group comprising an extract of Rhodiola Rosea, N-acetyl Tyrosine and an extract of Withania Somnifera Root wherein said at least one ingredient is provided in an amount effective to aid in reducing feelings of anxiety and stress in the mammal. 26. The method of claim 24 wherein the dietary supplement further comprises an extract of Russian Tarragon wherein said Russian Tarragon is provided in an amount effective to induce a feeling of relaxation in the mammal. 27. The method of claim 24 wherein the dietary supplement further comprises at least one

ingredient selected from the group comprising an extract of Algae providing Astaxanthin, and Vinpocetine wherein said at least one ingredient is provided in an amount effective to support mental well-being in the mammal. 28. The method of claim 24, wherein the dietary supplement is administered to the mammal at least once daily.

Description

RELATED APPLICATIONS [0001] The application is related to and claims benefit of priority to the Applicant's co-pending U.S. Provisional Patent Application Ser. No. 60/691,945 entitled "Diet Supplement for Causing Rapid Weight Loss, Controlling Appetite, Managing Stress, Supporting Relaxation, Combating Fatigue and Supporting Mental Well-Being," filed Jun. 17, 2006, the disclosure of which is hereby fully incorporated by reference. FIELD OF THE INVENTION [0002] The present invention relates to a diet supplement for causing rapid weight loss, controlling appetite, managing stress, supporting relaxation, combating fatigue and supporting mental well-being. Preferably, the diet supplement is provided in a caplet form consumable several times per day, for causing rapid weight loss, controlling appetite, managing stress, supporting relaxation, combating fatigue and supporting mental well-being throughout the day. Additionally, the present invention relates to a method of promoting same by consuming the diet supplement. In addition, the present invention relates to a method of manufacturing the diet supplement. SUMMARY OF THE INVENTION [0003] The present invention provides for a diet supplement causing rapid weight loss, controlling appetite, managing stress, supporting relaxation, combating fatigue and supporting mental well-being. The diet supplement may include one or more of the Calcium and Potassium double salt of Garcinia Cambogia Extract standardized to about 60% Hydroxycitric Acid, Gymnema Sylvestre Leaf Extract, Rhodioia Rosea Root Extract, Theanine (gamma-glutamylethylamide). Astaxanthin, Chromium Polynicotinate, Hoodia Gordonii (e.g., an extract that does not contain any extract from the root of the plant), N-olyl-phosphatidyl ethanolamine (NOPE)/EGCG blend, Vinpocetine, Russian Tarragon Extract (Artemisia dracunculus L. plant). N-acetyl tyrosine and Withania Somnifera Root Extract. For example, in an embodiment, the present invention may provide a diet supplement comprising an extract of Hoodia Gordonii and Vinpocetine, wherein the Hoodia Gordonii extract does not contain any extract from the roots of the plant. The diet supplement may also include any one or more of an extract of Rhodiola Rosea, Theanine, an Astaxanthin extract of Algae, Chromium Polynicotinate, a blend of

N-olyl-phosphatidyl ethanolamine/EGCG Blend, an extract of Russian Tarragon, N-acetyl tyrosine, an extract of Withania Somnifera, an extract of Gymnema Sylvestre, and the Calcium and Potassium double salt of Garcinia Cambogia Extract supplying about 60% Hydroxycitric Acid. [0004] Advantageously, the diet supplement is provided in a caplet form, which may be consumed several times per day. For instance, in an embodiment, the diet supplement comprises a two caplet serving; each serving suitable for being consumed three times daily, e.g., before each one of three daily meals. In this manner, the diet supplement may cause rapid weight loss, control appetite, manage stress, support relaxation, combat fatigue and support mental well-being for an extended period of time, e.g., all day. [0005] The present invention also provides, by the consumption of the supplemental composition, a method for causing rapid weight loss, controlling appetite, managing stress, supporting relaxation, and supporting mental well-being. For example, in an embodiment, the present invention may provide a method for controlling appetite and promoting rapid weight loss, comprising the step of administering to a human or animal a diet supplement that comprises an extract of Hoodia Gordonii, wherein the Hoodia Gordonii extract does not contain any extract from the roots of the plant, and may also comprise one or more of the Calcium and Potassium double salt of Garcinia Cambogia Extract supplying 60% Hydroxycitric Acid. Gymnema Sylvestre, Chromium Polynicotinate, N-olyl-phosphatidyl Ethanolamine/EGCG Blend, an extract of Russian Tarragon and Vinpocetine. The method may include the step of administering the diet supplement to a human or animal at least once daily. [0006] In addition, the present invention relates to a method of manufacturing a diet supplement for causing rapid weight loss, controlling appetite, managing stress, supporting relaxation, combating fatigue and supporting mental well-being. In an embodiment, there is provided a method of manufacturing a diet supplement comprising one or more of the Calcium and Potassium double salt of Garcinia Cambogia Extract standardized to about 60% Hydroxycitric Acid, Gymnema Sylvestre Leaf Extract, Rhodiola Rosea Root Extract, Theanine (gamma-glutamyethylamide), Astaxanthin, Chromium Polynicotinate, Hoodia Gordonii (e.g., an extract that does not contain any extract from the root of the plant), N-olyl-phosphatidyl ethanolamine (NOPE/EGCG blend, Vinpocetine, Russian Tarragon Extract (Artemisia dracunculus L. plant), N-acetyl tyrosine and Withania Somnifera Root Extract. [0007] In addition, the present invention may relate to a method of managing stress comprising the step of administering to a human or animal a diet supplement that comprises an extract of Rhodiola Rosea, Theanine, N-acetyl Tyrosine and an extract of Withania Somnifera Root. In addition, the present invention may relate to a method of supporting relaxation comprising the step of administering to a human or animal a diet supplement that comprises Theanine and an extract of Russian Tarragon. In addition, the present invention may relate to a method of supporting mental well-being comprising the step of administering to a human or animal a diet supplement that comprises an extract of Rhodiola Rosea, Theanine, Astaxanthin extract of Algae, Vinpocetine, N-acetyl Tyrosine

and an extract of Withania Somnifera Root. In addition, the present invention may relate to a method of ameliorating mental performance comprising the step of administering to a human or animal a diet supplement that comprises Vinpocetine, an extract of Rhodiola Rosea, and N-acetyl Tyrosine. In addition, the present invention may relate to a method of regulating blood glucose levels comprising the step of administering to a human or animal a diet supplement that comprises an extract of Gymnema Sylvestre, Chromium Polynicotinate, and an extract of Russian Tarragon. In addition, the present invention may relate to a method of supplying antioxidants to a human or animal comprising the step of administering to a human or animal a diet supplement that comprises an extract of Rhodiola Rosea, Theanine, an extract of Astaxanthin, N-olyl-phosphatidyl Ethanolamine/EGCG Blend, and an extract of Withania Somnifera Root. DETAILED DESCRIPTION OF THE INVENTION [0008] The present invention, according to various embodiments thereof, is directed to a diet supplement for inducing rapid weight loss, controlling appetite, and managing stress, supporting relaxation, combating fatigue and supporting mental well-being. [0009] Hoodia Gordonii (wherein the extract does not contain any extract from the root of the plant). [0010] Hoodia is a cactus which has been used traditionally to ease hunger discomfort and as such, is used as an appetite suppressant. A suspected active compound isolated from Hoodia Root, termed P57, has been shown to reduce food intake in rats (MacLean D B. Luo L G. Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety, studies of the anorectic mechanism of a plant steroidal glycoside. Brain Res. 2004 Sep 10; 1020(1-2):1-11.). Furthermore, it was found that P57 countered the reduction in ATP normally expected from calorie restriction. Further studies in rats indicate that Hoodia is effective in reducing blood glucose and weight loss (Tulp O L, Harbl N A, Mihalov J, DerMarderosian A. Effect of Hoodia plant on food intake and body weight in lean and obese LA/Ntul//cp rats. FASEB J. 2001 Mar 7, 15(4):A404.: Tulp O L Harbi N A, DerMarderosian A. Effect of Hoodia plant on weight loss in congenic obese LA/Ntul//-cp rats FASEB J. 2002 Mar 20:16(4):A648.). [0011] In 2001, Phytopharm completed a double-blind, placebo-controlled trial comprised of a group of health yet overweight volunteers. Following two weeks of high doses of Hoodia, the treatment group showed a reaction in weight while being inactive, and further, their daily caloric intake was voluntarily reduced via appetite suppression by approximately 1000 calories. [0012] In an embodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include Hoodia Gordonii (e.g., an extract that does not contain any extract from the root of the plant). A serving of the diet supplement may include from about 1.0 mg to about 100 mg of Hoodia Gordonii (e.g., an extract that does not contain any extract from the root of the plant). The preferred dosage, in a serving of said diet supplement, comprises about 20 mg of Hoodia Gordonii (e.g., an extract that

does not contain any extract from the root of the plant). [0013] Vinpocetine [0014] Vinpocetine is an extract of Vinca minor, or periwinkle plant, used traditionally to improve circulation. Vinpocetine has been shown to prevent brain cell damage by increasing blood flow in a rat model of forebrain ischemia (2-vessel occlusion and hypotension) wherein the ischemia was maintained for 10 minutes (Sauer D, Rischke R, Beck T, Rossberg C, Mennel H D, Bielenberg G W, Kriegistein J, Vinpocetine prevents ischemic cell damage in rat hippocampus. Life Sci. 1998: 43(21).17333-9). Image analysis indicates that Vinpocetine can increase cerebral blood flow in stroke patients and thereby improving cerebral glucose uptake and metabolism in the brain (Szakail S, Boros I, Balkay L, Emri M, Fekete I, Kerenyi L, Lehel S, Marian T, Molnar T, Varga J, Galuska L, Tron L, Bereczki D, Csiba L, Gulyas B, Cerebral effects of a single dose of intravenous vinpocetine in chronic stroke patients; a PET study. J Neuroimaging. 1998 Oct;8(4):197-204: Szilagyi G, Nagy Z, Balkay L, Boros I, Emri M, Lehel S, Marian T, Moinar T, Szakail S, Tron L, Bereczki D, Csiba L, Fekete I, Kerenyi L, Galuska L, Varga J, Bonoczk P, Vas A, Gulyas B. Effects of vinpocetine on the redistribution of cerebral blood flow and glucose matabolism in chronic ischemic stroke patients; a PET study. J Neurol Sci 2005 Mar 15:229-230:275-84). Interestingly, Vinpocetine may exert its effect by blocking sodium channels in the brain (Moinar P, Erdo S L. Vinpocetine is as potent as phenyloin to block voltage-gated Na+ channels in rat cortical neurons. Eur J Pharmacol 1995 Feb 6:273(3):303-6), which is thought to be involved in neuroprotection (Bonoczk P, Gulyas B, Adam-Vizi V, Nemes A, Karpali E, Kiss B, Kapas M, Szantay C, Koncz I, Zelles T, Vas A, Role of sodium channel inhibition in neuroprotection effect of vinpocetine. Brain Res Bull, 2000 Oct: 53(3):245-54). The antioxidant activity of Vinpocetine may also contribute to protection of neural cells (Santos M S, Duarte A I, Moreira P I, Oliveira C R, Synaptosomal response to oxidative stress effect of vinpocetine. Free Radic Res. 2000 Jan; 32(1):57-66.). Furthermore, Vinpocetine may also prevent the accumulation of calcium, phosphorus and aluminum in the central nervous system, which has been suggested to be involved in atherosclerosis (Yasui M, Yano I, Ota K, Oshima A, Calcium phosphorus and aluminum concentrations in the central nervous system, liver and kidney of rabbits with experimental atherosclerosis preventive effects of vinpocetine on the deposition of these elements, J Int Med Res 1990 Mar-Apr: 18(2):142-52.). [0015] In human trials, Vinpocetine has been shown to be effective at treating a number of circulation-related disorders. In a double-blind clinical trial, Vinpocetine was shown to effect significant improvement in elderly patients with chronic cerebral dysfunction (Balestreri R, Fontana L, Astengo F. A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfuction. J Am Geriatr Soc 1987 May, 35(6):425-30). A single-blind randomized trial has demonstrated the feasibility of continued study of Vinpocetine to treat stroke patients (Feigin V L, Doronin B M, Popova T F, Gribatcheva E V, Tchervov D V. Vinpocetine treatment in acute ischaemic stroke; a pilot single-blind randomized clinical trial. Eur J Neurol 2001 Jan; 8(1):81-5.). Further to these studies, it was shown

that cognitive performance improved in patients with mild to moderate pychosyndromes such as dementia (Hindmarch I, Fuchs H H, Erzigkeit H. Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes Int Clin Psychopharmacol. 1991 spring;6(1):31-43.). An improvement in the memory of healthy woman due to a three-day supplementation with Vinpocetine has also been documented (Subhan Z, Hindmarch I. Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur J Clin Pharmacol. 1985:28(5):567-71). [0016] In an embodiment of the present invention which is set forth in greater detail in Example 1, include from about 0.1 mg to about 10 mg of Vinpocetine. The preferred dosage, in a serving of said diet supplement, comprises about 1 mg of Vinpocetine. [0017] Theanine (Gamma-Glutamylethylamide) [0018] Theanine is an amino acid found in green tea. It is however distinct from the polyphenols and Catechins that are typically associated with the beneficial effects of green tea. While Catechins are generally associated with antioxidant activity, Theanine is associated with anti-stress and cortisol control. [0019] In hypertensive rats, Theanine has been shown to lower blood pressure (Yokogoshi H, Kato Y, Sagesaka Y M, Takinara-Matsuura T, Kakuda T, Takeuchi N. Reduction effect of theanine on blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats. Biosci Biotechnol biochem. 1995 Apr;59(4):615-8). Moreover, Theanine possess neuroprotective effects in animal models of brain damage (Kakuda T, Yanase H, Utsunomlya K, Nozawa A, Unno T, Kataoka K. Protective effect of gamma-glutamylethylamide (Theanine) on ischemic delayed neuronal death in gerbils. Neurosci Lett. 2000 Aug 11;289(3):189-92.) which is thought to be due to inhibiting the ligand binding to glutamate receptors (Kakuda T, Nozawa A, Sugimoto A, Niino H. Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 glutamate receptors. Biosci Biotechnol Biochem. 2002 Dec:66(12):2683-6.). Glutamic acid signaling through its related glutamate receptor is involved in memory and learning. Excess glutamate receptor signaling, which may occur due to and following brain injury, can lead to neuronal cell death (Chol D W, Rothman S M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 1990:13:171-82.) via apoptotic cascade mechanisms. Furthermore, weight gain and fat accumulation have been suppressed in rats fed Theanine (Zheng G, Sayama K, Okubo T, Juneja L R, Oguni I, Anti-obesity effects of three major components of green tea, catechins, caffeine and theanine, in mice. In Vivo 2004 Jan-Feb:18(1):56-62.) relative to control animals. [0020] Clinical studies have been done examining effects of Theanine in humans. One study demonstrated a relaxing effect under non-stress conditions (Lu K, Gray M A, Oliver C, Liley D T, Harrison B J, Bartholomeusz C F, Phan K L, Nathan P J. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol, 2004 Oct;19(7):457-65.). [0021] In an embodiment of the present invention, which is set forth in greater detail in

Example 1, the diet supplement may include Theanine (gamma-glutamylethylamide). A serving of the diet supplement may include from about 1.0 mg to about 100 mg of Theanine (gamma-glutamylethylamide). The preferred dosage, in a serving of said diet supplement, comprises about 52 mg of Theanine (gamma-glutamylethylamide). [0022] Astaxanthin [0023] Astaxanthin is a red carontenoid pigment occurring naturally in many living organisms. Studies utilizing animals indicate that Astaxanthin can confer antioxidant activity that can altenuate exercise-induced muscle damage (Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Macka T, Toyokuni S, Oka S, Yasuhara M, Yoshikawa T. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Antioxid Redox Signal 2003 Feb:5(1):139-44), has anticancer activity (Jyonouchi H, Sun S, Lijima K, Gross M D. Antitumor activity of astaxanthin and its mode of action. Nutr Cancer. 2000:36(1):59-65). anti-inflammatory activity (Kurashige M, Okimasu E, Inoue M, Utsumi K. Inhibition of oxidative injury of biological membranes by astaxanthin. Physiol Chem Phys Med NMR 1990:22(1);27-38.). anti-diabetic activity (Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T. Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. Redox Rep 2002:7(5):290-3.), immunity-boosting properties (Okai Y, Higashi-Okai K. Possible immunomodulating activities of carotenoids in vitro cell culture experiments Int J Immunopharmacol. 1996 Dec;18(12):753-8.), and antihypertensive and neuroprotective properties (Hussein G, Nakamura M, Zhao Q, Iguchi T, Goto H, Sankawa U, Watanabe H. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. Biol Pharm Bull. 2005 Jan;28(1):47-52.). [0024] Studies have examined the effects of Astaxanthin in humans where it has been shown to be safe (Spiller G A, Dewell A. Safety of an astaxanthin-rich Haematococcus pluvialis algal extract, a randomized clinical trial. J Med Food 2003 spring;6(1);51-6.) and of potential benefit in cancer treatment by inhibiting 5-alpha-reductase (Anderson M L. A preliminary investigation of the enzymatic inhibition of 5alpha-reduction and growth of prostatic carcinoma cell line LNCap-FGC by natural astaxanthin and Saw Palmetto lipid extract in vitro. J Herb Pharmacother, 2005;5(1);17-26.). [0025] In an embodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include Astaxanthin. A serving of the diet supplement may include from about 1 mg to about 100 mg of Astaxanthin. The preferred dosage, in a serving of said diet supplement, comprises from about 5 mg of Astaxanthin. [0026] Chromium Polynicotinate [0027] Chromium is an essential trace mineral that is used to control blood sugar levels by aiding insulin binding, wherein it can aid in the control weight of reduction. Chromium, however, is poorly absorbed by the body and must therefore be combined with a more efficiently absorbed compound such as niacin (found in Polynicotinate). Chromium likely exerts its main function as a component of the glucose tolerance factor,

which is involved in insulin sensitivity. [0028] Chromium has been shown clinically to increase lean mass (Bahadori B, Wailner S, Schneider H, Wascher T C, Toplak H, Effect of chromium yeast and chromium picolinate on body composition of obese, non-diabetic patients during and after a formula diet. Acta Med Austriaca, 1997:24(5):185-7.) and reduce body fat when combined with exercise (Grant K E, Chandler R M, Castle A L, Ivy J L, Chromium and exercise training; effect on obese women, Med Sci Sports Exerc. 1997 Aug:29(8:992-8.). Chromium has also been shown to increase HDL, (`good`) cholesterol (Riales R, Albrink M J. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men Am J Clin Nutr 1981:34:2670-8.). [0029] In an embodiment of the present invention which is set forth in greater detail in Example 1, the diet supplement may include Chromium Polynicotinate. A serving of the diet supplement may include from about 0.01 mg to about 10 mg of Chromium Polynicotinate. The preferred dosage, in a serving of said diet supplement, comprises about 0.133 meg (0.000133 g) of Chromium Polynicotinate. [0030] N-olyl-Phosphatidyl Ethanolamine ("NOPE")/EGCG Blend [0031] NOPE is a naturally occuring lipid synthesized and released in the intestine, in vivo rat studies have shown that food deprivation results in decreased NOPE synthesis, while administration of NOPE causes appetite suppression and subsequent weight loss (Rodriguez de Fonseca F, Navarro M, Gomez R, Escuredo L, Nava F, Fu J, Munillo-Rodriguez E, Giuffrida A, LoVerme J, Gaetani S, Kathuria S, Gall C, Piomelli D. An anorexic lipid mediator regulated by feeding Nature 2001 Nov 8;414(6860):209012., Gaetani S, Oveisi F, Piomelli D. Modulation of meal pattern in the rat by the anorexic lipid mediator olecylethanolamide. Neuropsychopharmacology, 2003 Jul;28(70:1311-6.). Moreover, NOPE has been shown to lower body weight in obese rats (Fu J, Oveisi F, Gaetani S, Lin E, Piomelli D. Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology, 2005 Jun;48(8):1147-53.). This action is likely mediated through the NOPE binding of the peroxisome-proliferator-activated receptor-alpha (PPAR-alpha) (Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodriguez De Fonseca F, Rosengarth A, Luecke H, Di Giacomo B, Tarzia G, Piomelli D. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha Nature 2003 Sep 4;425(6953):90-3.). PPAR-alpha is involved in regulating lipid metabolism (Chawla A, Repa J J, Evans R M, Mangeisdorf D J. Nuclear receptors and lipid physiology: opening the X-files. Science 2001 Nov 30:294(5548):1866-70.). Furthermore, another possible mechanism of NOPE's action is through the 7-transmembrane spanning G protein-coupled receptor (GPCR) GPR119 found predominantly in human and rodent pancreas (Overton H A, Babbs A J, Doel S M, Fyfe M C, Gardner L S, Griffin G, Jackson H C, Procter M J, Rasamison C M, Tang-Christensen M, Widdowson P S, Williams G M, Reynet C, Deorphanization of a G protein-coupled receptor for oleoylethanoiamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006 Mar;3(3):167-75.) by which hypophagic signals may be conferred.

[0032] (-)-Epigallocatechin-3-gallate (EGCG) is the most active Catechin polyphenol compound found in Green Tea. EGCG has potent antioxidant activity and has been shown by laboratory tests to be greater than many well known and established antioxidants such as vitamin C and E (Pillar S P, Mitscher L A, Menon S R, Pillal C A. Shankel D M. Antimutagenic/antioxidant activity of green tea components and related compounds. J Environ Pathol Toxicol Oncol. 1999:18(3):147-58). Further to its antioxidant activity, EGCG was found to be effective at reducing food intake, body weight, cholesterol and triglycerides in both lean and obese rats (Kao Y H, Hipakka R A, Liao S. Modulation of endocrine systems and food intake by green tea epigailocatechin gailate. Endocrinology,2000 Mar;141(3):980-7.). In humans, Green Tea extracts rich in EGCG and other Catechins have been shown to result in a rapid increase in plasma antioxidant activity (Benzie I F, Szeto Y T, Strain J J, Tomlinson B. Consumption of green tea causes rapid increase in plasma antioxidant power in humans, Nutr Cancer 1999:34(1):83-7.) and further to aid in weight loss due to increased metabolism and fat oxidation (Chantre P, Lairon D. Recent findings of green tea extract AR25 (Exolise) and its activity for the treatment of obesity. Phytomedicine 2002 Jan;9(1):3-8. Dulico A G, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P, Vandermander J. Efficacy of a green tea extract rich in catachin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr. 1999 Dec;70(6):1040-5.). The associated mechanism of action may be, at least partially, due to an increase in norepinephrine. Catechins are also known to inhibit catechol-O-methyl-transferase (COMT), an enzyme that degrades norepinephrine (Borchardt R T, Huber J A, Catechol O-methyltransferase, 5. Structure-activity relationships for inhibition by flavonoids. J Med Chem, 1975 Jan;18(1):120-2.). EGCG is both a substrate of and, as a result an inhibitor of, COMT (Li C, Allen A, Kwagh J, Doliba N M, Qin W, Najafi H, Collins H W, Matschinsky F M, Stanley C A, Smith T J. Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. J Biol Chem. 2006 Apr 14:281(15:10214-21. Epub 2006 Feb 13). In turn, norepinephrine inhibits degradation of intracellular cyclic AMP (cAMP), an important signaling molecule involved in many metabolic processes including thermogenesis. Furthermore, EGCG has been shown to be an inhibitor of glutamate dehydrogenase, which regulates insulin secretion (Lu H, Meng X, Yang C S. Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (-)-epigallocatechin gailate. Drug Metab Dispos. 2003 May:31(5):572-9.). [0033] In an embodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include an N-olyl-phosphatidyl ethanolamine ("NOPE")/EGCG blend. A serving of the diet supplement may include from about 0.1 mg to about 10 mg of N-olyl-phosphatidyl ethanolamine (NOPR)/EGCG blend. The preferred dosage, in a serving of said diet supplement, comprises about 1 mg of N-olyl-phosphatidyl ethanolamine (NOPE)/EGCG blend. [0034] Russian Tarragon Extract [0035] Russian Tarragon (Artemisia dracunculus) is a perennial herb widely used in

cooking. Historically it has been use as a natural blood cleanser and as a treatment for headaches and dizziness. Current studies are examining the use of the ethanolic extract of Russian Tarragon called for the treatment of hyperglycemia associated with diabetes. The toxicology of this extract has been evaluated, and shown to be safe and non-toxic (Ribnicky D M, Poulev A, O'Neal J, Wnorowski G, Malek D E, Jager R, Raskin I. Toxicological evaluation of the ethanolic extract of Artemisia dracunculus L. for use as a dietary supplement and in functional foods. Food Chem Toxicol 2004 Apr;42(4):586-98). Furthermore, it has been demonstrated to reduce blood glucose levels in diabetic mice (Ribnicky D M, Poulev A, Watford M, Cefalu W T, Raskin I. Antihyperglycemic activity of Tarralin.TM., an ethanolic extract of Artemisia dracunculus L. Phytomedicine. In Press. Corrected Proof, Available online 2 November 2005). Additionally, an essential oil extracted from Artemisia dracunculus may have potential therapeutic effects as an anticonvulsant and mild sedative (Sayyah M, Nadjafnia L, Kamalinejad M. Anticonvulsant activity and chemical composition of Artemisia dracunculus L. essential oil J Ethnopharmacol 2004 Oct.94(2-3):283-7.). [0036] In an embodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include Russian Tarragon Extract (Artemisia dracunculus L. plant). A serving of the diet supplement may include from about 0.1 mg to about 10 mg of Russian Tarragon Extract (Artemisia dracunculus L. plant). The preferred dosage, in a serving of said diet supplement, comprises about 1 mg of Russian Tarragon Extract (Artemisia dracunculus L. plant). [0037] N-acetyl Tyrosine [0038] N-acetyl tyrosine is a stable form of the amino acid tyrosine. Tyrosine is a nonessential amino acid, meaning that it can be synthesized by the body. Amino acids are the building blocks of protein. Tyrosine can also function as a neurotransmitter precursor and is converted into neuronal signaling molecules such as dopamine, norepinephrine, and epinephrine. It is known that increasing levels of neurotransmitter precursors in the brain stimulates further neurotransmitter production (Wurtman R J, Hefti F, Melamed E. Precursor control of neurotransmitter synthesis. Pharmacol Rev. 1980 Dec:32(4)315-35). As such, Tyrosine levels in the brain and the subsequent conversion into neurotransmitter has been shown to increase in response to increased dietary Tryrosine (Fernstrom J D, Fernsstrom M H. Dietary effects on tyrosine availability and catecholamine synthesis in the central nervous system, possible relevance to the control of protein intake. Proc Nutr Soc. 1994 Jul:53(2):419-29.). Conversely. Tyrosine depletion in humans has been shown to have detrimental effects on mood (Leyton M, Young S N, Pihl R O, Elezadi S, Lauze C, Blier P, Baker G B, Benkelfat C. Effects on mood of acute phenylalanine/tyrosine depletion in healthy women. Neuropsychopharmacology 2000 Jan:22(1):52-63.) and cognitive performance (Grevet E H, Tietzmann M R, Shansis F M, Hasteripflugl C, Santana L C, Forster L, Kapczinskil F, Irquierdo I. Behavioural effects of acute phenylalanine and tyrosine depletion in healthy male volunteers. J Psychopharmacol, 2000 Mar;16(1:51-5.). [0039] Tyrosine supplementation has be used to successfully improve mood and

cognitive performance during periods of stress (Banderet L E, Liebeman H R Treatment with tyrosine a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull 1989 Apr:22(4):759-62). One study has demonstrated a reduction in blood pressure in addition to cognitive improvement (Deijen J B, Oriebeke J F. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull 1994:33(3):319-23.) via Tyrosine supplementation. Mental performance during fatigue has been shown to improve with increased Tyrosine (Neri D F, Wiegmann D, Stanny R R, Shappell S A, McCardie A, McKay D L. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med. 1995 Apr:68(4):313-9.) supplementation. [0040] In an embodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include N-acetyl tyrosine. A serving of the diet supplement may include from about 0.1 mg to about 10 mg of N-acetyl tyrosine. The preferred dosage, in a serving of said diet supplement, comprises about 1 mg of N-acetyl tyrosine. [0041] Gymnema Sylvestre [0042] Gymnema Sylvestre is a plant which is used in traditional Eastern medicine as a treatment for diabetes due to its ability to inhibit glucose absorption in addition to its ability suppress the taste of `sweetness`. [0043] Gymnema extract has been shown to be an effective diabetes treatment in rats (Okabayashi Y, Tani S, Fujisawa T, Koide M, Hasegawa H, Nakamura T, Fujii M, Otsuki M. Effects of Gymnema sylvestre R.Br on glucose homeostasis in rats Diabetes Res Clin Pract. 1990 May-Jun:9(2):143-8.). This is likely due to the ability of Gymnema to suppress glucose absorption in rat intestine (Shimizu K, Iino A, Nakajima J, Tanaka K, Nakalyo S, Urakawa N, Atsuchi M, Wada T, Yamashita C, Suppression of glucose absorption by some fractions extracted from Gymnema sylvestre leaves J Vet Med Sci. 1997 Apr:59(4):245-51); to lower glucose content in tissue of rats (Chattopadhyay R R. Possible mechanism of antihyperglycemic effect of Gymnema sylvestre leaf extract, part I Gen Pharmacol 1998 Sep;31(3):495-6.); and to suppress neural responses to sweet taste in rats and mice (Imoto T, Miyasaka A, Ishima R, Akasaka K. A novel peptide isolated from the leaves of Gymnema sylvestre-I. Characterization and its suppressive effect on the neural responses to sweet taste stimuli in the rat Comp Biochem Physiol A 1991;100(2):309-14. Ninomiya Y, Imoto T. Gurmarin inhibition of sweet taste responses in mice. Am J Physiol. 1995 Apr;268(4 Pt 2),R1019-25.). [0044] Moreover, Gymnema has further been shown to be effective in treating diabetes in humans by both lowering blood glucose along with increasing insulin levels (Shanmugasundaram E R, Rajeswari G, Baskaran K, Rajesh Kumar B R, Radha Shanmugasundaram K, Kizar Ahmath B. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes melitus J Ethnopharmacol 1990 Oct;30(3):281-94; Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, Shanmugasundaram E R. Antidiabetic effect of a leaf extract from Gymnema sylvestre in

non-insulin-dependent diabetes melitus patients. J Ethnopharmacol. 1990 Oct;30(3):295-300.). Gymnema Sylvestre extract can be combined with HCA to produce greater weight loss (Preuss H G, Garis R I, Bramble J D, Bagchi D, Bagchi M, Rao C V, Satyanarayana S. Efficacy of a novel calcium/potassium salt of (-)-hydroxycitric acid in weight control Int J Clin Pharmacol Res 2005;25(3):133-44.) as experimentally evidenced. [0045] In an emodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include Gymnema Sylvestre Leaf Extract. A serving of the diet supplement may include from about 1 mg to about 1000 mg of Gymnema Sylvestre Leaf Extract. The preferred dosage, in a serving of said diet supplement, comprises about 133 mg of Gymnema Sylvestre Leaf Extract. [0046] Withania Somnifera Root Extract [0047] Withania Somnifera (Ashwagandha Winter Cherry) is an herb used in traditional East Indian medicine. Withania Somnifera is reported to have a number of beneficial effects including antioxidant and antistress (Mishra L C, Singh B B, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha); a review Altern Med Rev. 2000 Aug:5(4):334-46) activities. It is also considered to be an adaptogen and therefore, may possess non-specific protective effects, wherein this has been demonstrated in animal studies (Dhuley J N. Asaptogenic and cardioprotective action of ashwagandha in rats and frogs J Ethnopharmacol. 2000 Apr;70(1):57-63.). In rats, Withania Somnifera has a positive effect on mood by reducing stress and anxiety (Bhattacharya S K, Bhattacharya A, Sairam K, Ghosal S. Anxiolytic-antidepressant activity of Witharia somnifera glycowithanolides, an experimental study. Phytomedicine 2000 Dec;7(6):463-9.). Moreover, Withania Somnifera has been shown to attenuate both age-associated and chemica-induced cellular and tissue oxidative damage in rats (Gupia S K, Dua A, Vohra B P. Withania somnifera (Ashwagandha) attenuates antioxidant defense in aged spinal cord and inhibits copper induced lipid peroxidation and protein oxidative modifications Drug Metabol Drug Interact, 2003:19(3):211-22.). [0048] Human clinical trials examining Withania Somnifera have been conducted. One clinical trial demonstrated potential for Withania Somnifera to treat arthritic (Kuikami R R, Patki P S, Jog V P, Gandage S G, Patwardhan B, Treatment of osteoarthritis with a herbomineral formulation, a double-blind, placebo-controlled, cross-over study J Ethnopharmacol, 1991 May-Jun;33(1-2):91-5). [0049] In an embodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include Withania Somnifera Root Extract. A serving of the diet supplement may include from about 0.1 mg to about 10 mg of Withania Somnifera Root Extract. The preferred dosage, in a serving of said diet supplement, comprising about 1 mg of Withania Somnifera Root Extract. [0050] Calcium and Potassium double salt of Garcinia Cambogis Extract (supplying about 60% Hydroxycitric Acid)

[0051] Hydroxycitric acid (HCA) is extracted from the fruit of the Garcinia Cambogia plant, it has been shown to inhibit fat production and suppress appetite and as such is used to control weight by virtue of these characteristics. [0052] U.S. Pat. No. 6,875,891, entitled "Process for Preparing Highly Water Soluble Double Salts of Hydroxycitric Acid Particularly Alkali and Alkaline Earth Metal Double Salts" describes a method for producing highly water-soluble Calcium and Potassium Hydroxycitric Acid salts which are odorless and essentially tasteless. The process involves the steps of precipitating sparingly soluble alkaline earth metal salts of Hydroxycitric acid from an aqueous extract of plants belonging to the Garcinia species, dissolving said alkaline earth metal salts in aqueous alkali and adjusting the pH of said alkaline solution by adding an extract of purified Garcinia fruit extract. From this process, the Calcium salt of Hydroxycitric Acid can be precipitated. Additionally, said Calcium salt can be treated with Potassium Hydroxide to form the Potassium and Calcium double salt of Hydroxycitric Acid which can further be purified by treatment with activated charcoal, filtered and spray dried. [0053] HCA has been shown to inhibit fatty acid synthesis and repress appetite in rats (Watson J A, Fang M, Lowenstein J M. Tricarballylate and hydroxycitrate: substrate and inhibitor of ATP citrate oxaloacetate lyase Arch Biochem Biophys 1969 Dec;135(1):209-17. Louter-van de Haar J, Wielinga P Y, Scheurink A J. Nieuwenhuizen A G. Comparison of the effects of three different (-)-hydroxycitric acid preparations on food intake in rats Nutr Metal (Lond), 2005 Sep 13:2:23.) and is known to be a competitive inhibitor or ATP citrate lyase, an enzyme necessary for the conversion of carbohydrates into fat. By its actions of competitive inhibition of ATP citrate lyase, it reduces that amount of storable fat. Garcinia Cambogia extract can also improve glucose metabolism in mice (Hayamizu K, Hirakawa H, Oikawa D, Nakanishi T, Takagi T, Tachibana T, Furuse M. Effects of Garcinia cambogia extract on serum leptin and insulin in mice, Fitoterapia, 2003 Apr:74(3:267-73). [0054] Several human clinical trials have demonstrated that the HCA extract of Garcinia Cambogia can be used safely and has beneficial effects in terms of weight management, Moreover, HCA has been shown to reduce caloric intake (Westerterp-Plantenga M S, Kovacs E M. The effect of (-)-hydroxycitrate on energy intake and safety in overweight humans Int J Obes Relat Metab Disord. 2002 Jun;26(6):870-2) and increase fat oxidation during exercise in untrained men and women (Lim K, Ryu S, Nho H S, Choi S K, kwon T, Suh H, So J, Tomita K, Okuhara Y, Shigematsu N. (-)-Hydroxycitric acid ingestion increases fat utilization during exercise in untrained women J Nutr Sci Vitaminol (Tokyo) 2003 Jun;49(3):163-7: Tomita K, Okuhara Y, Shigematsu N, Suh H, Lim K (-)-hydroxycitrate ingestion increases fat oxidation during moderate intensity exercise in untrained men. Biosci Biotechnol Biochem, 2003 Sep;67(9):1999-2001.). The results of a randomized controlled trial which combined data from two earlier trials demonstrated that daily HCA and chromium supplementation together with moderate exercise over an 8-week period resulted in increased weight loss as compared to placebo, as well as resulted in an improved blood cholesterol profile (Preuss H G, Garis R I, Bramble J D, Bagchi D, Bagchi M, Rao C V, Satyanarayana S. Efficiency of a novel

calcium/potassium salt of (-)-hydroxycitric acid in weight control Int J Clin Pharmacol Res 2005;25(3:133-44.). It was also noted that serotonin levels were significantly increased by HCA. Serotonin is a neurotransmitter which, when low, signals hunger and particularly carbohydrate cravings. [0055] In an embodiment of the present invention, which is set forth in greater detail in Example 1 below, The diet supplement may include the Calcium and Potassium double salt of Garcinia Cambogia Extract standardized to about 60% Hydroxycitric Acid. A serving of the diet supplement may include from about 100 mg to about 5 g of the Calcium and Potassium double salt of Garcinia Cambogia Extract standardized to about 60% Hydroxycitric Acid. The preferred dosage, in a serving of the diet supplement, comprises about 1.555 g of the Calcium and Potassium double salt of Garcinia Cambogia Extract standardized to about 60% Hydroxycitric Acid. [0056] Rhodiola Rosea [0057] Rhodiola Rosea is also known as `Golden root`, `Arctic root` and Crenulin. Typically, it is considered to be an `adaptogen` due to the observed ability of Rhodiola to confer increased resistance to multiple stresses, both mental and physical (Kelly G S, Rhodiola rosea: a possible plant adaptogen Altern Med Rev. 2001 Jan:6(3):293-302.). The mechanism of action for Rhodiola Rosea appears to be primarily its ability to increase the levels of monamine neurotransmitters such as serotonin, dopamine and norepinephrine (Stancheva S L, Mosharrof A, Effect of the extract of Rhodiola rosea L, on the content of the brain biogenic monamines, Med Physiol 1987:40:85-87.). In vivo experiments in rats show that Rhodiola possesses both cardioprotective (Lishmanov IuB, Maslova L V, Maslov L N, Dan'shina E N, [The anti-arrhythmia effect of Rhodiola rosea and its possible mechanism] Biull Eksp Biol Med. 1993 Aug:116(8):175-6.) and anticancer properties (Udinlsev S N, Shakhov V P. The role of humoral factors of regenerating liver in the development of experimental tumors and the effect of Rhodiola rosea extract on this process. Neoplasma 1991: 38(3):323-331.). Using in vitro studies on human cells, it was demonstrated that Rhodiola extract has marked protective and antioxidant activity (De Sanctis R, De Bellis R, Scesa C, Mancini U, Cucchianni L, Dacha M, in vitro protective effect of Rhodiola rosea extract against hypochlorous acid-induced oxidative damage in human erythrocytes Biofactors, 2004:20(3):147-59.). [0058] In human clinical trials, Rhodiola has been shown to improve mental performance (Darbinyan V, Kleyan A, Panossian A, Gabriellian E, Wikman G, Wagner H, Rhodiola rosea in stress induced fatigue--a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine, 2000 Oct:7(5):365-71.; Shevtsov V A, Zholus B I, Shervarly V I, Vol'skij V B, Korovin Y P, Khristich M P, Roslyakova N A, Wikman G. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine, 2003 Mar:10(2-3):95(105.) and reduce stress-induce fatigue without side-effects (Spasov A A, Wikman G K, Mandrikov V B, Mironova I A, Neumoin W. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on

the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine, 2000 Arr;7(2):85-9.). Furthermore, Rhodiola can also improve endurance exercise performance (De Beck K, Eijnde B O, Ramaekers M, Hespel P, Acute Rhodiola rosea intake can improve endurance exercise performance, Int J Sport Nutr Exerc Metab, 2004 Jun;14(3):298-307.). [0059] In an embodiment of the present invention, which is set forth in greater detail in Example 1, the diet supplement may include Rhodiola Rosea Leaf Extract. A serving of the diet supplement may include from about 1 mg to about 1 g of Rhodiola Rosea Leaf Extract. The preferred dosage, in a serving of said diet supplement, comprises about 124 mg of Rhodiola Rosea Leaf Extract. [0060] The diet supplement according to this invention provides a method for causing rapid weight loss, controlling appetite, managing stress, supporting relaxation, and supporting mental well-being. Advantageously, consumption of the diet supplement is combined with a reduced calorie diet and a program of regular exercise. [0061] According to various embodiments of the present invention, the diet supplement may be consumed in any form. For instance, the dosage form of the diet supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a tablet, a caplet, or as a dietary gel. The most preferred dosage form is a caplet. [0062] Preferably, the diet supplement is consumed by an individual in accordance with the following method: As a diet supplement, 2 caplets may be taken with an 8 oz. glass of water three times daily. Preferably each serving, comprised of 2 caplets may be consumed approximately 30 to 60 minutes before each meal, e.g., breakfast, lunch and dinner. In this manner, the diet supplement may cause rapid weight loss, control appetite, manage stress, support relaxation, combat fatigue and support mental well-being for an extended period of time, e.g., all day. [0063] Furthermore, the dosage form of the diet supplement may be provided in accordance with customary processing techniques for herbal and dietary supplements in any of the forms mentioned above. Furthermore, the diet supplement set forth in the example embodiments herein may contain any appropriate number and type of excipients, as is well known in the art. [0064] In addition, the present invention relates to a method of manufacturing a diet supplement for causing rapid weight loss, controlling appetite, and managing stress, supporting relaxation, combating fatigue and supporting mental well-being. For example, the method of manufacturing a diet supplement may include the step of mixing one or more of the Calcium and Potassium double salt of Garcinia Cambogia Extract, supplying 60% Hydroxycitric Acid, Gymnema Sylvestre Leaf Extract, Rhodiola Rosea Root Extract, Theanine (gamma-glutamylethylamide), Astaxanthin, Chromium Polynicotinate, Hoodia Gordonii (e.g., an extract that does not contain any extract from the root of the plant), N-olyl-phosphatidyl ethanolamine (NOPE)/EGCG blend, Vinpocetine, Russian

Tarragon Extract (Artemisia dracunculus L. PLANT), N-acetyl tyrosine, Withania Somnifera Root Extract, Microcrystalline Cellulose, Dicalcium Phosphate Dihydrate, Stearic Acid, Titanium Dioxide, Water, Propylene Glycol, Sodium Carboxymethylcellulose, Maltodextrin, Dextrose Monohydrate, Soy Lecithin, Polysorbate 80, Croscarmellose Sodium, Magnesium Stearate, Silicon Dioxide, Sucralose, and Ascorbic Acid. The method of manufacturing the diet supplement may also include the step of checking for uniformity/homogeneity. In addition, the method of manufacturing the diet supplement may include the step of aliquoting the mixture into a serving, e.g., for compression into a caplet. [0065] Although the following example illustrates the practice of the present invention in one of its embodiments, the example should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification of the following example. EXAMPLES Example 1 [0066] A diet supplement for promoting rapid weight loss, controlling appetite, managing stress, supporting relaxation, combating fatigue and supporting mental well-being is provided, the diet supplement comprising the Calcium and Potassium double salt of Garcinia Cambogia Extract standardized to about 60% Hydroxycitric Acid (1.55500 g), Gymnema Sylvestre Leaf Extract (0.133000 g) standardized to 25% Gymnemic Acids, Rhodiola Rosea Extract (0.124000 G) standardized to 3% Rosavins. Theanine (0.052000 g). Astaxanthin Algae Extract (0.00500 g), Chromium-Polynicotinate (0.000133 g), Hoodii Gordonii (0.020000 g) plant without the roots. N-olyl-phosphatidyl ethanolamine (NOPE)/EGCG blend (0.00100 g) standardized to 23% NOPE, 20% Polyphenols, 14% EGCG, Vinpocetine (0.00100 g). Russian Tarragon Extract (0.00100 g), N-acetyl tyrosine (0.00100 g), and Withania Somnifera Root Extract (0.00100 g) standardized to 1.5% Withanolides. [0067] Directions: As a diet supplement, 2 caplets are administered with an 8 oz. glass of water threee times daily. Preferably, each two caplet serving may be consumed approximately 30 to 60 minutes before each meal, e.g., breakfast, lunch and dinner.

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United States Patent Application 20070280996

Kind Code A1

Gardiner; Paul T. ; et al. December 6, 2007

Dietary supplement having improved efficacy at time of consumption

Abstract

A dietary supplement that includes a container having a first compartment and a second compartment. The first compartment includes an aqueous medium. The second compartment includes an ingredient that is stable when stored within the second compartment. The container is configured such that a user may selectively cause the first and second compartments to be in communication with each other such that the ingredient of the second compartment is mixed with the aqueous medium of the first compartment. The ingredient, which may be creatine or a derivative thereof, is less stable after being mixed with the aqueous medium of the first compartment.

Inventors: Gardiner; Paul T.; (Mississauga, CA) ; Heuer; Marvin A.;

(Mississauga, CA) ; Chaudhuri; Shan; (Mississauga, CA) ; Ramsbottom; James D.; (Mississauga, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 5100 SPECTRUM WAY MISSUSSAUGA ON L4W 5S2 US

Serial No.: 443656

Series Code: 11

Filed: May 30, 2006

U.S. Current Class: 424/439; 514/19; 514/440; 514/553; 514/554; 514/557; 514/563

U.S. Class at Publication: 424/439; 514/554; 514/440; 514/553; 514/557;

514/19; 514/563

Intern'l Class: A61K 47/00 20060101 A61K047/00; A61K 31/385 20060101 A61K031/385; A61K 31/185 20060101

A61K031/185; A61K 31/205 20060101 A61K031/205; A61K 31/19 20060101 A61K031/19;

A61K 31/198 20060101 A61K031/198

Claims

1. A dietary supplement comprising:a container having a first compartment and a second compartment, the first compartment including an aqueous medium, the second compartment including an ingredient that is stable when stored within the second compartment, the container being configured such that a user may selectively cause the first and second compartments to be in communication with each other such that the ingredient of the second compartment is mixed with the aqueous medium of the first compartment, the ingredient being less stable after being mixed with the aqueous medium of the first compartment. 2. The dietary supplement of claim 1, wherein the ingredient is creatine or a derivative thereof. 3. The dietary supplement of claim 2, wherein the creatine or a derivative thereof comprises at least one of creatine monohydrate, creatine alpha ketoglutarate, creatine ethyl ester HCl, tricreatine hydroxycitrate, creatine citrate, creatine pyruvate, creatine pyroglutamate, dicreatine malate, creatine anhydrous, creatine taurinate, creatine lipoate and creatine methyl ester. 4. The dietary supplement of claim 1, wherein the second compartment comprises a mixture of granular anhydrous creatine, calcium salt of ketoisocaproic acid, and trometamol salt of alpha lipoic acid. 5. The dietary supplement of claim 4, wherein the mixture includes about 2.5 g of granular anhydrous creatine, about 0.05 g of calcium salt of ketoisocaproic acid, and about 0.1 g of trometamol salt of alpha lipoic acid. 6. The dietary supplement of claim 1, wherein the second compartment comprises a mixture of creatine citrate, trometamol salt of alpha lipoic acid, creatine alpha ketoglutarate, creatine ethyl ester HCl, creatine methyl ester, dicreatine malate, granular anhydrous creatine, calcium salt of ketoisocaproic acid. 7. The dietary supplement of claim 6, wherein the mixture includes about 5.0170 g of creatine citrate, about 0.0510 g of trometamol salt of alpha lipoic acid, about 0.0010 g of creatine alpha ketoglutarate, about 0.0010 g of creatine ethyl ester HCl, about 0.0010 g of creatine methyl ester, about 0.0010 g of dicreatine malate, about 0.00094 g of granular

anhydrous creatine, about 0.00002 g of calcium salt of ketoisocaproic acid. 8. The dietary supplement of claim 1, wherein the second compartment comprises a mixture of creatine citrate, trometamol salt of alpha lipoic acid, granular anhydrous creatine, calcium salt of ketoisocaproic acid, creatine alpha ketoglutarate, creatine pyroglutamate, dicreatine malate, L-glutamine, and taurine. 9. The dietary supplement of claim 8, wherein the mixture includes about 4.994 g of creatine citrate, about 0.0510 g of trometamol salt of alpha lipoic acid, about 0.00094 g of granular anhydrous creatine, about 0.0002 g of calcium salt of ketoisocaproic acid, about 0.0010 g of creatine alpha ketoglutarate, about 0.0010 g of creatine pyroglutamate, about 0.0010 g of dicreatine malate, about 0.0010 g of L-glutamine and about 0.0010 g of taurine. 10. A dietary supplement that is provided in a container, comprising:a first compartment of the container including an aqueous medium; anda second compartment of the container including an ingredient, the ingredient being more stable when stored separately from the aqueous solution as compared to when dissolved in the aqueous solution,wherein, in a pre-use configuration of the container, the first and second compartments are not in communication with each other,and wherein, in a use configuration of the container, the first and second compartments are in communication with each other and the ingredient is mixed with the aqueous medium. 11. The dietary supplement of claim 10, wherein the ingredient is creatine or a derivative thereof. 12. The dietary supplement of claim 11, wherein the creatine or a derivative thereof comprises at least one of creatine monohydrate, creatine alpha ketoglutarate, creatine ethyl ester HCl, tricreatine hydroxycitrate, creatine citrate, creatine pyruvate, creatine pyroglutamate, dicreatine malate, creatine anhydrous, creatine taurinate, creatine lipoate and creatine methyl ester. 13. The dietary supplement of claim 10, wherein the second compartment comprises a mixture of granular anhydrous creatine, calcium salt of ketoisocaproic acid, and trometamol salt of alpha lipoic acid. 14. The dietary supplement of claim 13, wherein the mixture includes about 2.5 g of granular anhydrous creatine, about 0.05 g of calcium salt of ketoisocaproic acid, and about 0.1 g of trometamol salt of alpha lipoic acid. 15. The dietary supplement of claim 10, wherein the second compartment comprises a mixture of creatine citrate, trometamol salt of alpha lipoic acid, creatine alpha ketoglutarate, creatine ethyl ester HCl, creatine methyl ester, dicreatine malate, granular anhydrous creatine, calcium salt of ketoisocaproic acid. 16. The dietary supplement of claim 15, wherein the mixture includes about 5.0170 g of

creatine citrate, about 0.0510 g of trometamol salt of alpha lipoic acid, about 0.0010 g of creatine alpha ketoglutarate, about 0.0010 g of creatine ethyl ester HCl, about 0.0010 g of creatine methyl ester, about 0.0010 g of dicreatine malate, about 0.00094 g of granular anhydrous creatine, about 0.00002 g of calcium salt of ketoisocaproic acid. 17. The dietary supplement of claim 10, wherein the second compartment comprises a mixture of creatine citrate, trometamol salt of alpha lipoic acid, granular anhydrous creatine, calcium salt of ketoisocaproic acid, creatine alpha ketoglutarate, creatine pyroglutamate, dicreatine malate, L-glutamine, and taurine. 18. The dietary supplement of claim 17, wherein the mixture includes about 4.994 g of creatine citrate, about 0.0510 g of trometamol salt of alpha lipoic acid, about 0.00094 g of granular anhydrous creatine, about 0002 g of calcium salt of ketoisocaproic acid, about 0.0010 g of creatine alpha ketoglutarate, about 0.0010 g of creatine pyroglutamate, about 0.0010 g of dicreatine malate, about 0.0010 g of L-glutamine and about 0.0010 g of taurine. 19. A dietary supplement according to claim 1, wherein the ingredient being more stable when stored separately from the aqueous medium or solution is separated from the aqueous medium or solution having a pH less than or equal to 7. 20. A dietary supplement according to claim 1, wherein the ingredient being more stable when stored separately from the aqueous medium or solution is separated from the aqueous medium or solution having a pH greater than or equal to 7. 21. A dietary supplement according to claim 1, wherein the ingredient being more stable when stored separately from the aqueous medium or solution is separated from the aqueous medium or solution being more acidic than the unstable ingredient. 22. A dietary supplement according to claim 1, wherein the unstable ingredient is separated from an aqueous medium or solution being more basic than the unstable ingredient. 23. A dietary supplement according to claim 10, wherein the ingredient being more stable when stored separately from the aqueous medium or solution is separated from the aqueous medium or solution having a pH less than or equal to 7. 24. A dietary supplement according to claim 10, wherein the ingredient being more stable when stored separately from the aqueous medium or solution is separated from the aqueous medium or solution having a pH greater than or equal to 7. 25. A dietary supplement according to claim 10, wherein the ingredient being more stable when stored separately from the aqueous medium or solution is separated from the aqueous medium or solution being more acidic than the unstable ingredient. 26. A dietary supplement according to claim 10, wherein the ingredient being more stable

when stored separately from the aqueous medium or solution is separated from the aqueous medium or solution being more basic than the unstable ingredient.

Description

FIELD OF THE INVENTION [0001]The present invention relates to a dietary supplement, e.g., ready-to-drink supplements that include ingredients, e.g., creatine and derivatives thereof, which may be unstable if dissolved in an aqueous solution significantly before the dietary supplement is to be consumed. By improving the stability of such ingredients, the present invention may improve the efficacy of the ingredient at the time of consumption. SUMMARY OF THE INVENTION [0002]According to an embodiment of the present invention, there is provided a dietary supplement that includes a container having a first compartment and a second compartment. The first compartment includes an aqueous medium. The second compartment includes an ingredient that is stable when stored within the second compartment. The container is configured such that a user may selectively cause the first and second compartments to be in communication with each other such that the ingredient of the second compartment is mixed with the aqueous medium of the first compartment. The ingredient, which may be creatine or a derivative thereof, is less stable after being mixed with the aqueous medium of the first compartment. [0003]According to another embodiment of the present invention, there is provided a dietary supplement that is provided in a container. A first compartment of the container includes an aqueous medium. A second compartment of the container includes at least one ingredient. The ingredient may be more stable when stored separately from the aqueous solution as compared to when dissolved in the aqueous solution. In a pre-use configuration of the container, the first and second compartments are not in communication with each other. In a use configuration of the container, e.g., immediately prior to consumption of the dietary supplement by a user, the first and second compartments are in communication with each other and the ingredient is mixed with the aqueous medium. DETAILED DESCRIPTION OF THE INVENTION [0004]One of the ways that an ingredient of a dietary supplement may be provided to a user is by suspending or dissolving the ingredient in an aqueous solution. While some dietary supplements may provide an ingredient pre-mixed in the aqueous solution, there are some ingredients (for example, creatine and others discussed in greater detail below) for which the suspension or dissolution of the ingredient within a solution for longer than a given period of time may undesirably alter, e.g., degrade or otherwise transform, the

ingredient's molecular make-up and thus adversely effect the ingredient's function. Since the stability and/or efficacy of certain ingredients of a dietary supplement formulation can be compromised within a given amount of time after being dissolved in an aqueous solution, the present invention may improve the stability and/or efficacy of certain active ingredients by storing such ingredients in separate compartments of a single container. The separate compartments provide, prior to the consumption of the supplement, a physical barrier between the components of the dietary supplement, e.g., between the aqueous solution and the ingredient that may exhibit compromised stability and/or efficacy upon being, or within a given amount of time after being, dissolved in the aqueous solution. [0005]To consume the supplement, a user may selectively cause the contents of the separate compartments to mix. For example, the user may deform or otherwise manipulate the two compartments such that the ingredient stored in a first compartment is mixed with the aqueous solution in the second compartment. Since the user may perform this step, e.g., mixing the ingredient stored in the first compartment with the aqueous solution in the second compartment, at the time that the dietary supplement is to be consumed, any instability and/or inefficacy which may have resulted from the ingredient being dissolved in an aqueous solution for longer than a given period of time may be avoided. [0006]Various embodiments of the present invention may include creatine also know as (alpha-methyl) guandino-acetic acid. Creatine is one of the basic molecules involved with energy storage, particularly in fast twitch glycolytic fibres. Creatine loading is known to increase the creatine stored within muscle tissue. Moreover, creatine is able to reversibly bind phosphate. Therefore, if more creatine is present within a muscle tissue, there is more stored and donatable phosphate within the muscle tissue. When a muscle undergoes a contraction, it employs adenosine triphosphate (ATP) as an energy source. During this process a phosphate group is cleaved from ATP leaving the molecule adenosine diphosphate (ADP), which is devoid of energetic properties with respect to muscular contraction (Tortora G J, Grabowski S R. Principles of Anatomy and Physiology. 8th Ed. Addison Wesley Longman, Inc. Don Mills, ON. 1996). Creatine is able to pick-up a phosphate and reversibly bind it; forming Phospho-creatine. Phospho-creatine ultimately donates a phosphate to ADP, thus rendering ATP, which is able to be used in a subsequent muscular contraction immediately following intense muscle effort and provides enough energy for 15 seconds of maximal contraction. Therefore, creatine loading aids in the regeneration of ATP, leading to an increase in muscular output ability. (Tortora G J, Grabowski S R. Principles of Anatomy and Physiology. 8.sup.th Ed. Addison Wesley Longman, Inc. Don Mills, ON. 1996). [0007]Creatine converts to creatinine via an irreversible, pH-dependent, non-enzymatic reaction in aqueous medium. Aqueous and alkaline solutions contain a mixture of creatine and creatinine. In acidic solutions, 100% of creatine is converted to creatinine. While creatine plays an important role in storing high energy phosphate for muscle use, creatinine is inactive and is excreted by the kidneys (Mesa J L, Ruiz J R, Gonzalez-Gross M M, Gutierrez Sainz A, Castillo Garzon M J. Oral creatine supplementation and skeletal

muscle metabolism in physical exercise. Sports Med. 2002; 32(14):903-44. Review.). [0008]Creatine is also known as 2-(carbamimidoyl-methyl-amino) acetic acid, N-(aminoiminomethyl)-N-methylglycine, N-amidinosarcosine, (alpha-methylguanido) acetic acid, N-methyl-N-guanylgliycine and methylglycocyamine. Creatine as used herein may refer to creatine in any of its known forms, e.g., salts and/or esters thereof. Examples of creatine in its various forms include but are not limited to creatine monohydrate, creatine alpha ketoglutarate, creatine ethyl ester HCl, tricreatine hydroxycitrate, creatine citrate, creatine pyruvate, creatine pyroglutamate, dicreatine malate, creatine anhydrous, creatine taurinate, and creatine methyl ester. [0009]Tricreatine hydroxycitrate is another example of a creatine derivative which may be unstable in an aqueous medium. It is formed in an anionic-cationic reaction whereby three moles of creatine are bound to one mole of hydroxycitric acid. Applicant's co-pending U.S. patent application Ser. No. 11/349,960, for "Creatine Hydroxycitric Acid Salts and Methods for Their Production and Use in Individuals", which was filed on Feb. 7, 2006, and which is based upon U.S. Provisional Patent No. 60/651,049, filed on Feb. 7, 2005, discloses a method for producing tricreatine hydroxycitrate. [0010]As set forth above, the present invention, in accordance with various embodiments thereof, involves a dietary supplement that is disposed in a container that has at least two compartments. In order to improve the stability and/or efficacy of an ingredient of the dietary supplement, the ingredient may be maintained in a first compartment of the container until a user selectively causes, e.g., immediately prior to consumption, the ingredient to be mixed with an aqueous solution stored in a second compartment of the container. [0011]While the present invention envisions that any type of multi-compartmented container may be employed, some examples of two-part beverage containers are disclosed, for example, in U.S. Pat. Nos. 2,562,402, 2,753,990, 4,627,986 and 6,620,444. [0012]U.S. Pat. No. 2,562,402, discloses a two compartment container wherein the outer container is comprised of a flexible material which upon squeezing increases the internal pressure. The inner container or capsule is pressure-sensitive and upon an increase in the internal pressure of the outer container, the inner capsule ruptures and its contents are mixed with the contents of the outer container. [0013]U.S. Pat. No. 2,753,990, discloses a glass container having large and small-sized, separate compartments for the storage of the first and second liquids in the separate storage compartments. When the large compartment is opened, thus resulting in a drop in pressure below that of the small compartment leads to the opening of a valve in the wall separating the two compartments allowing for the mixing of the liquids in the two compartments. [0014]U.S. Pat. No. 4,627,986, discloses a container for the storage of a pressurized fluid, having a separate compartment therein for the segregated storage of a second material.

The mechanism is arranged such that it is sensitive to the rapid drop in pressure upon the opening of the container and that the contents of the segregated container are released into the fluid of the first container. [0015]U.S. Pat. No. 6,620,444, discloses a two compartment container under pressure wherein the inner compartment opens in response to pressure change upon the opening of the outer compartment. The contents of the inner container are thus released and mixed with the contents of the outer container immediately prior to consumption. [0016]While the preceding examples illustrate some of the types of containers that may be employed in the practice of the present invention, Examples 1 to 4 below illustrate some of the dietary supplements that may advantageously employ such containers. Generally, these dietary supplements include active ingredients that may irreversibly convert to inactive forms of the ingredient were the ingredients to be dissolved in the respective aqueous solution greater than a given period of time prior to a user consuming the dietary supplement. In this manner, the stability and/or efficacy of the ingredients may be increased by preventing the active molecules from dissolving or being suspended in the aqueous solution until a predetermined time period, e.g., immediately, prior to consumption. [0017]Although the following examples illustrate the practice of the present invention in five of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and the following examples. EXAMPLES Example 1 [0018]A dietary supplement is contained within a container comprising two compartments. Within a first compartment, a solute mixture of granular anhydrous creatine (2.5000 g), calcium salt of ketoisocaproic acid (0.0500 g), and trometamol salt of alpha lipoic acid (0.1000 g) is contained. Within a second compartment, a solvent is contained. At the time of opening the two-compartment container, the contents of the first compartment are emptied, e.g., automatically, into the second compartment such that the solutes contained within the first compartment are combined with the solvent in the second compartment to form a consumable solution. Example 2 [0019]A dietary supplement is contained within a container comprising two compartments. Within a first compartment, a solute mixture of creatine citrate (5.0170 g), trometamol salt of alpha lipoic acid (0.0510 g), creatine alpha ketoglutarate (0.0010 g), creatine ethyl ester HCl (0.0010 g), creatine methyl ester (0.0010 g), dicreatine malate (0.0010 g), granular anhydrous creatine (0.00094 g), calcium salt of ketoisocaproic acid (0.00002 g) is contained. Within a second compartment, a solvent is contained. At the

time of opening the two-compartment container, the contents of the first compartment are emptied, e.g., automatically, into the second compartment such that the solutes contained within the first compartment are combined with the solvent in the second compartment to form a consumable solution. Example 3 [0020]A dietary supplement is contained within a container comprising two compartments. Within a first compartment, a solute mixture of creatine citrate (4.9940 g), trometamol salt of alpha lipoic acid (0.0510 g), granular anhydrous creatine (0.00094 g), calcium salt of ketoisocaproic acid (0.00002 g), creatine alpha ketoglutarate (0.0010 g), creatine pyroglutamate (0.0010 g), dicreatine malate (0.0010 g), L-glutamine (0.0010 g), and taurine (0.0010 g) is contained. Within a second compartment, a solvent is contained. At the time of opening the two-compartment container, the contents of the first compartment are emptied, e.g., automatically, into the second compartment such that the solutes contained within the first compartment are combined with the solvent in the second compartment to form a consumable solution. Example 4 [0021]A dietary supplement is contained within a container comprising two compartments. Within a first compartment, a solute mixture comprising at least tricreatine hydroxycitric acid or a derivative thereof is contained. Within a second compartment, a solvent is contained. At the time of opening the two-compartment container, the contents of the first compartment are emptied, e.g., automatically, into the second compartment such that the solutes contained within the first compartment are combined with the solvent in the second compartment to form a consumable solution.

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United States Patent Application 20080152732

Kind Code A1

Heuer; Marvin A. ; et al. June 26, 2008

Compositions and methods for increasing adipose metabolism, lipolysis or lipolytic metabolism via thermogenesis

Abstract

A composition and method for promoting weight loss through the mutual and simultaneously to promotion lipolysis, the expenditure of energy stored in the body as fat, the inhibition of lipolysis as well as affording the body of an individual protection from reactive oxygen species resulting from the .beta.-oxidation of fats. The composition comprises at least a lipolytic substance, a thermogenic substance, a substance to inhibit the reformation of triglycerides in the bodily tissues of an individual and an antioxidant.

Inventors: Heuer; Marvin A.; (Oakville, CA) ; Clement; Ken; (Oakville, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 381 North Service Road West Oakville ON L6M 0H4 omitted

Serial No.: 985609

Series Code: 11

Filed: November 14, 2007

U.S. Current Class: 424/729; 514/263.34; 514/667

U.S. Class at Publication: 424/729; 514/263.34; 514/667

Intern'l Class: A61K 36/82 20060101 A61K036/82; A61K 31/522 20060101 A61K031/522; A61K 31/133 20060101

A61K031/133

Claims

1-9. (canceled) 10. A method to aid in the bodily fat loss of an individual, the method comprising the step of:administering to the individual a composition comprising:one or more lipolytic substances;one or more thermogenic substances; anda substance to inhibit the reformation of triglycerides in the bodily tissues of an individual. 11. The method of claim 10, wherein the one or more lipolytic substances, the one or more thermogenic substances, and the substance to inhibit the reformation of triglycerides in the body of an individual act mutually simultaneously to promote lipolysis. 12. The method of claim 10, wherein the one or more lipolytic substances, the one or more thermogenic substances, and the substance to inhibit the reformation of triglycerides in the body of an individual act mutually simultaneously to promote stored energy expenditure. 13. The method of claim 10, wherein the one or more lipolytic substances, the one or more thermogenic substances, and the substance to inhibit the reformation of triglycerides in the body of an individual act mutually simultaneously to inhibit lipogenesis. 14. The method of claim 10, further comprising an antioxidant whereby said antioxidant affords protection to the body of an individual from reactive oxygen species resulting from .beta.-oxidation of fats. 15. The method of claim 10, wherein said lipolytic substance is selected from the group consisting of an extract of green tea, caffeine anhydrous, an extract of Evodia rutaecarpia, deanol, and yohimbine. 16. The method of claim 10, wherein the thermogenic substance is selected from the group consisting of an extract of green tea, caffeine anhydrous, and deanol. 17. The method of claim 10, wherein the substance to inhibit the reformation of triglycerides is an extract of black pepper. 18. The method of claim 14, wherein said antioxidant is selected from the group consisting of green tea polyphenols, toxerutin, an extract of black pepper, Cissus Quadrangularis, and inositol hexaphosphate.

Description

RELATED APPLICATIONS [0001]The present application is related to and claims benefit of priority to U.S. Provisional Application No. 60/780,741 entitled "Compositions and Methods for Increasing Adipose Metabolism or Lipolysis or Lipolytic Metabolism via Thermogenesis" filed Mar. 8, 2006, the disclosure of which is hereby fully incorporated by reference. FIELD OF THE INVENTION [0002]The present invention is related to compositions and methods for increasing an individual's natural ability to utilize adipose tissue as an energy source via adipose metabolism. Specifically, the adipose metabolism occurs through mechanisms of lipolysis or lipolytic metabolism for the purposes of reducing body fat mass and fat loss. SUMMARY OF THE INVENTION [0003]The present invention is directed towards a diet supplement comprising a lipolytic substance, a thermogenic substance, a substance to inhibit the reformation of triglycerides in the bodily tissues of an individual and an antioxidant. The ingredients of the present composition act to mutually and simultaneously promote lipolysis, the expenditure of energy stored in the body as fat, inhibits lipolysis and affords the body of an individual protection from reactive oxygen species resulting from the .beta.-oxidation of fats. A method of providing same is also provided. BACKGROUND [0004]Obesity has become an increasingly widespread and predominant health concern. According to the World Health Organization (WHO) obesity is considered a multifactorial chronic disease which is increasing in frequency (Curioni C, Andre C, Veras R. Weight reduction for primary prevention of stroke in adults with overweight or obesity. Cochrane Database Syst Rev. 2006 Oct. 18; (4):CD006062). Obesity, a condition of excessive body fat, generally results from more energy (food) being consumed than is being used. Stemming from excessive body fat, several health-related concerns such as increased morbidity have linked to obesity and being overweight as well as hypertension, coronary heart disease, type 2 diabetes mellitus, stroke and even some forms of cancer (Curioni C, Andre C, Veras R. Weight reduction for primary prevention of stroke in adults with overweight or obesity. Cochrane Database Syst Rev. 2006 Oct. 18; (4):CD006062). [0005]One of the main contributing factors in obesity is overeating, which results in an excess of energy being consumed in relation to the amount of being energy expended by an individual. The excess energy is then stored largely as fat. A simplified determination of an individual's body weight is essentially governed by the net effect of energy

consumed versus energy expended. Daily energy expenditure consists of three components: basal metabolic rate, adaptive thermogenesis and physical activity (Westerterp K R. Diet induced thermogenesis. Nutr Metab (Lond). 2004 Aug. 18; 1(1):5). All of the aforementioned components must be in a balance of energy expenditure in an individual with energy or food intake such an individual does not gain nor lose body weight fat adipose issue reduction. Therefore, in order that person may lose body weight from a reduction in adipose tissue, more energy must be expended by the individual than in taken into the body. [0006]An undesired effect of increased accumulation of body fat is an increased oxidative stress through the generation of reactive oxygen species and the downregulation of antioxidative enzymes. This downregulation of antioxidative enzymes can contribute to the pathogenesis of diabetes, hypertension and atherosclerosis (Furukawa S, Fujita T. Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O. Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004 December; 114(12):1752-61). Thus it is desirable to provide to the body of an individual means to reduce stored body fat and simultaneously offer protection from reactive oxygen species. It is likely that the oxidative stress associated with obesity involves mechanisms distinct from those solely due to mitochondrial beta-oxidation of fats. Increased oxidative stress due to increased body fat is thought to be an early contributor to hypertension, coronary heart disease, type 2 diabetes mellitus, stroke and even some forms of cancer and is therefore an attractive target strategy for combating the negative effects of excessive body fat while aiming to reduce the volume of stored body in an individual. [0007]With the unprecedented rise in obesity throughout the world, here exists both a need and want from individuals for improved aids, methods and interventions directed to reducing body fat and maintaining lowered levels of body fat, while also supplying beneficial antioxidant activity. DETAILED DESCRIPTION OF THE INVENTION [0008]In the following description, for the purposes of explanations, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one skilled in the art that the present invention may be practiced without these specific details. [0009]The present invention, according to various embodiments thereof, provides a composition and method for increasing an individual's natural adipose metabolism occurring through mechanisms of lipolysis or lipolytic metabolism, thermogenesis and inhibition of the reformation of triglycerides for the purposes of reducing body fat mass and fat loss. In addition, in various embodiments, simultaneous means of affording protection to the body of individual from reactive oxygen species resulting from the .beta.-oxidation of fats is also provided by way of a compositions and methods. Preferably, the composition is that of a dietary supplement.

[0010]According to various embodiments of the present invention, compositions are provided which facilitate in the reduction of body fat mass, leading to fat loss; simultaneously affording protection to the body of an individual from reactive oxygen species resulting from the .beta.-oxidation of fats. DEFINITIONS [0011]The term `fat` as used herein is understood to represent lipids and includes related forms such as triglycerides, cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL) and fatty acids. [0012]Furthermore, as herein in the present disclosure, it is understood that cells that store fat are termed `adipocytes` and that adipose tissue is comprised of adipocytes. [0013]The term `adipocyte metabolism` as used herein is understood to represent any biological process which causes or leads to an impact on fat and includes but is not limited to anabolism or synthesis, catabolism or breakdown, degradation, lipolysis and forms of oxidation. [0014]Although not wishing to be bound by theory, in the present invention, free-circulating norepinephrine is understood to be responsible for the stimulation of .beta.-receptors on the cell surface of adipose cells. The stimulation of Preceptors via norepinephrine using cyclic adenosine monophosphate (CAMP) as a second messenger stimulates the release of fatty acids from adipose cells The released fatty acids then undergo a thermogenic metabolic process whereby the fat is converted into body heat and released. [0015]In one aspect of the present invention the composition comprises components that have been shown to induce lipolysis in adipose tissue. It is understood that the aforementioned combination of components will have an additive effect relating to lipolysis and energy expenditure. Lipolysis has been shown to lead to a decrease in both the lipid content of individual adipocytes as well as the number of adipocytes. [0016]In another aspect of the present invention the composition comprises components for the inhibition of phosphodiesterases. Phosphodiesterases are known to degrade intracellular CAMP. Therefore, the inhibition of phosphodiesterases allows for the continued release of fatty acids from adipose tissue and thermogenesis via a cAMP-dependant mechanism. [0017]Another aspect of the present invention comprises components which inhibit the breakdown of the norepinephrine via the inhibition of catechol-O-methyltransferase (COMT). COMT is the enzyme responsible for the degradation of norepinephrine. Inhibition of COMT leads to an elevated level of norepinephrine. [0018]Additionally, the present invention is designed to inhibit the stimulation of .alpha..sub.2-receptors on the cell of adipose cells. When stimulated, an .alpha..sub.2-

receptor stops the breakdown of fat and subsequently inhibits a reduction body fat mass (Kucio C, Jonderko K, Piskorske D. Does Yohimbine act as a slimming drug? Isr J Med Sci 1991; 27:550-556). To further ensure the inhibition of stimulation of .alpha..sub.2-receptors, the binding of norepinephrine to its .alpha.-receptor on nerve cell is inhibited by components of the composition. Since norepinephrine is released via a negative feedback loop, the present invention allows for the maintenance of circulating norepinephrine through the interruption of the negative feedback loop. Subjects consuming the components in a composition of the invention showed a 40% increase in norepinephrine relative to control subjects (Dulloo A G, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P, Vandermander J. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr 1999; 70:1040-1045). In studies on ingredients of the present invention; consumption of components in a composition of the invention in combination with an intense diet, subjects lost on average 60% more weight than the placebo group over the course of the study (Kucio C, Jonderko K, Piskorske D. Does Yohimbine act as a slimming drug? Isr J Med Sci 1991; 27:550-556). Moreover, in another study, subjects consuming the components in a composition of the invention showed a 7.9% reduction in total area of body fat as compared to control groups as determined by CT scan (Nagao T, Komine Y, Soga S, Meguro S, Hase T, Yukitaka T, Tokimitsu I. Ingestion of a tea rich in catechins leads to a reduction in body fat and malondialdehyde-modified LDL in men. Am J Clin Nutr 2005; 81:122-129). Green Tea Extract (ECGC, Catechins and Polyphenols) [0019]The active compounds of green tea are a family of polyphenols with tannins being the largest of the subgroups contained therein. The most active specific compound of the polyphenols is epigallocatechin gallate (ECGC) which comprises 10-50% of the total the catechins found in green ten. Furthermore, caffeine is also a major active component of green tea, however the percentage of caffeine contained in extracts of green tea fluctuates significantly owing to several different factors such as processing, for example. [0020]Green tea principally acts in a beneficial way through the polyphenols' antioxidant activities as evidenced by several laboratory studies. One clinical study has shown that the ingestion of an extract of green tea results in a rapid increase in plasma antioxidant activity (Benzie I F, Szeto Y T, Strain J J, Tomlinson B. Consumption of green tea causes rapid increase in plasma antioxidant power in humans. Nutr Cancer, 1999. 34(1):83-7). [0021]Moreover, green tea has also been shown to be effective in aiding weight loss. This effect may be due to two activities. Green tea both reduces fat digestion and increases energy expenditure (Berube-Parent S, Pelletier C, Dore J, Tremblay A. Effects of encapsulated green tea and Guarana extracts containing a mixture of epigallocatechin-3-gallate and caffeine on 24 h energy expenditure and fat oxidation in men. Br J Nutr, 2005, 94(3):432-6). Fat stores may provide the energy necessary for the increase in energy expenditure via the oxidation of fat, consequently leading to thermogenesis. The thermogenic activity of green tea may additionally be greatly enhanced by synergistic cooperation with additionally added caffeine. In the regard the .beta.-oxidation of fats

owing to green tea is a result of activities at adenosine receptors and their effect on and increase in cyclic adenosine monophosphate (cAMP). [0022]Additionally, the mechanism of action of green tea may also be, at least partially, due to an increase in norepinephrine. Catechins, found in green tea, are known to inhibit catechol-O-methyl-transferase (COMT), an enzyme which degrades norepinephrine. In turn, norepinephrine inhibits the degradation of cyclic adenosine monophosphate (cAMP). Furthermore, increasing norepinephrine levels by the inhibition of norepinephrine uptake results in increased weight loss in both lean and obese mice as evidenced in animal studies (Billes S K, Cowley M A. Inhibition of Dopamine and Norepinephrine Reuptake Produces Additive Effects on Energy Balance in Lean and Obese Mice. Neuropsychopharmacology. 2006 Jul. 12). Stemming from increased norepinephrine levels is the result of an increased interaction with adrenergic receptors which are known to regulate lipolysis, again acting to further aiding in the reduction of body fat. [0023]In an embodiment of the present invention which is set forth in greater detail in the examples below, the diet supplement includes an extract of green tea dry leaf (Camellia sinensis). A serving of the diet supplement includes from about 0.1 g to about 0.7 g of an extract of green tea dry leaf (Camellia sinensis). The preferred dosage in a serving of the diet supplement of the present invention comprises about 0.4600 g of an extract of green tea dry leaf (Camellia sinensis). Anhydrous Caffeine [0024]Caffeine is a naturally occurring xanthine alkaloid found in some plants where it serves as a natural pesticide. It is also common additive to food products, especially beverages for human consumption and as such, it has numerous beneficial effects, the most common of which uses caffeine as a supplement to the central nervous system. In this capacity, it is used as both a neuro-stimulant and performance enhancer. A meta-analysis compiled from forty double-blind studies supports the use of caffeine to increase physical endurance (Doherty M, Smith P M. Effects of caffeine ingestion on exercise testing: a meta-analysis. Int J Sport Nutr Exerc Metab, 2004. 14(6):626-46). [0025]Caffeine is also widely used to control weight, which may occur through multiple mechanisms. Significant weight loss related to caffeine supplementation has been observed in obese women (Yoshida T, Sakane N, Umekawa T, Kondo M. Relationship between basal metabolic rate, thermogenic response to caffeine, and body weight loss following combined low calorie and exercise treatment in obese women. Int J Obes Relat Metab Disord, 1994. 18(5):345-50), which may be, at least in part, due to increased lipolysis as fat is metabolized. Caffeine has additionally been shown to increase the basal metabolic rate in humans wherein this also adds to its weight-lowering effects via increased energy expenditure. [0026]Biochemically, caffeine, as it is structurally similar to adenosine, binds to, but does not activate, adenosine receptors which are normally activated by adenosine to induce

sleep. Thus, caffeine acts as a stimulant through having the opposite effect of the receptor's natural ligand, adenosine. By antagonizing certain adenosine receptors, caffeine has the effect of increasing levels of intracellular cAMP, which is an important signaling molecule involved in many metabolic processes including thermogenesis (Ramkumar V, Bumgamer J R, Jacobson K A, Stiles G L. Multiple components of the A1 adenosine receptor-adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion. J Clin Invest. 1988, 82(1):242-7). As an additional function with respect to CAMP, caffeine also enables the increase CAMP levels through the inhibition of phosphodiesterases which specifically degrade CAMP. The ensuing actions of caffeine with respect to the CAMP system lead to an increase in the release of epinephrine and norepinephrine. Since epinephrine and norepinephrine use CAMP for signaling, increased levels of CAMP will yield increased adrenergic signaling thereby inducing lipolysis, where thermogenesis can expend energy leading to body fat loss. [0027]In an embodiment of the present invention which is set forth in greater detail in the examples below, the diet supplement includes an effective amount of anhydrous caffeine. A serving of the diet supplement includes from about 0.1 g to about 0.5 g of anhydrous caffeine. In the preferred dosage of the present invention, a serving of the diet supplement comprises about 0.3000 g of anhydrous caffeine. Cissus quadrangularis Extract (from Stem and Leaf) [0028]Cissus quadrangularis is a plant indigenous to India where it is largely used in traditional medicine. Extracts of Cissus quadrangulans have additionally been shown to be effective as a weight loss agents. Clinical studies have shown that in a randomized double-blind trial, a group taking an extract of Cissus quadrangularis for 6-weeks lost more weight, had lower cholesterol, as well as reduced LDL and fasting blood glucose levels as compared to the control groups. The experimental group also displayed increased HDL levels as compared to a placebo group (Oben J E, Mandob D, Fomekong G, Momo C. The effect of an extract of Cissus quadranguaris (Cylaris.TM.) on weight and serum lipids in obese patients in Cameroon: a randomized double-blind clinical trial. Presented at Paris Anti-Obesity Therapies. May 2006), suggesting an additional effect on cholesterol. [0029]Moreover, for the purposes of the present invention, extracts of Cissus quadrangularis contain sterols, vitamin C, and tannins, which have antimicrobial and antoxidant activity (Chidambara Murthy K N, Vanitha A, Mahadeva Swamy M, Ravishankar G A. Antioxidant and antimicrobial activity of Cissus quadrangularis L, J Med Food, 2003. 6(2):99-105). The antioxidant activity of Cissus quadrangularis has been proposed to be one of the mechanisms by which it shows protection against tissue injury in animal models (Jainu M, Mohan K V, Devi C S. Protective effect of Cissus quadrangularis on neutrophil mediated tissue injury induced by aspirin in rats. J Ethnopharmacol, 2006. 104(3):302-5). [0030]In an embodiment of the present invention which is set forth in greater detail in the examples below, the diet supplement includes an extract of Cissus quadrangularis. A

serving of the diet supplement includes from about 0.05 g to about 0.3 g of an extract of Cissus quadrangularis. In the preferred dosage of the present invention, in a serving of said diet supplement comprises about 0.1500 g of Cissus quadrangularis extract. Evodia rutaecarpia Extract [0031]Evodia species of plants are a source of many chemicals with a variety of potentially beneficial actions. One specific chemical is evodiamine, which has been shown to increase the secretion of adrenergic signaling molecules and stimulate the sympathetic nervous system (Yoshizumi M, Houchi H, Ishimura Y, Hirose M, Kitagawa T, Tsuchiya K, Minakuchi K, Tamaki T. Effect of evodiamine on catecholamine secreton from bovine adrenal medulla. J Med Invest. 1997 August; 44(1-2):79-82 Abstract). Evodiamine has also been shown to increase energy expenditure and lipid mobilization and decrease body fat in mice (Kobayashi Y, Nakano Y, Kizaki M, Hoshikuma K Yokoo Y, Kamiya T. Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med. 2001 October; 67(7):628-33 Abstract), through the increase in adrenergic signaling molecule secretions. [0032]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the nutritional supplement includes Evodia rutaecatpia extract. A serving of the nutritional supplement includes from about 0.005 g to about 0.02 g of Evodia rutaecarpia extract. In the preferred dosage of the present invention, a serving of the diet supplement comprises about 0.01 g of Evodia rutaecarpia extract. Deanol [0033]Deanol is an organic compound also commonly known by the synonyms: dimethylaminoethanol, dimethylethanolamine or DMAE. Deanol is involved in synthesis of the neurotransmitter acetylcholine via involvement in choline metabolism. The cholinergic system pertains to any aspect affecting the function of acetylcholine. Furthermore, digestion and energy conservation at periods of rest are exclusively governed by acetylcholine signaling in the parasympathetic nervous system. Moreover, the cholinergic system has been implicated in several disease conditions including obesity. In an elaborate experiment by Myers and Yaksh using primates, acetylcholine was demonstrated to be involved in thermoregulation (Myers R D, Yaksh T L. Control of body temperature in the unanaesthetized monkey by cholinergic and aminergic systems in the hypothalamus. J Physiol. 1969 June; 202(2):483-500). In addition to thermoregulation, cholinergic signaling has been linked to food intake and satiety (Di Marco A, Demartis A, Gloaguen I, Lazzaro D, Delmastro P, Ciliberto G, Laufer R. Leptin receptor-mediated regulation of cholinergic neurotransmitter phenotype in cells of central nervous system origin. Eur J Biochem. 2000 May; 267(10):2939-44) and lipolysis in human adipocytes (Andersson K, Amer P. Systemic nicotine stimulates human adipose tissue lipolysis through local cholinergic and catecholaminergic receptors. Int J Obes Relat Metab Disord. 2001 August; 25(8):1225-32). A further role cholinergic signaling may play in obesity is suggested by it's involvement in insulin secretion in obese individuals (Del Rio G, Procopio M, Bondi M, Marrama P, Menozzi R, Oleandri S E,

Grottoli S, Maccario M, Velardo A, Ghigo E. Cholinergic enhancement by pyridostigmine increases the insulin response to glucose load in obese patients but not in normal subjects. Int J Obes Relat Metab Disord. 1997 December; 21(12):1111-4 Abstract). [0034]One of the most important sources of choline is through the diet and deanol which has been shown to be capable of conversion into choline-containing compounds (Andriamampandry C, Freysz L, Kanfer J N, Dreyfus H, Massarelli R. Conversion of ethanolamine, monomethylethanolamine and dimethylethanolamine to choline-containing compounds by neurons in culture and by the rat brain. Biochem J. 1989 Dec. 1; 264(2):555-62). Treatment of mice with deanol has been shown to increase plasma and tissue levels of choline, at least in part, by inhibiting the metabolism of choline (Haubnch D R, Gerber N H, Pflueger A B. Deanol affects choline metabolism in peripheral tissues of mice. J Neurochem. 1981 August; 37(2):476-82 Abstract). [0035]In an embodiment of the present invention which is set forth in greater detail in the examples below, the diet supplement includes deanol bitartrate. A serving of the diet supplement includes from about 0.05 g to about 0.2 g of deanol bitartrate. The present invention, in a preferred dosage of said dietary supplement comprises about 0.1 g of deanol bitartrate per serving. Xanthinol Nicotinate [0036]Xanthinol nicotinate is one of several forms of the vitamin Niacin (vitamin B3 or nicotinic acid). It easily passes through the cell membrane and is considered the most potent form of Niacin. Pharmaceutically, xanthinol nicotinate is classified as a vasodilator and presents in human with a "flushed" to the skin. [0037]In patients with peripheral arterial obliterative disease, xanthinol nicotinate was found to have anti-platelet and thrombolytic actions accompanied by an increase in the release of NO (Bieron K, Swies J, Kostka-Trabka E, Gryglewski R J. Thrombolytic and antiplatelet action of xanthinol nicotinate (Sadamin): possible mechanisms. J Physiol Pharmacol. 1998 June; 49(2):241-9). Xanthinol nicotinate may also have the effects of enhancing cellular metabolism and increasing oxygen supply to tissues. This may be the mechanism by which improvements in both short- and long-term memory associated with the administration of xanthinol nicotinate three times per day for eight weeks in a double blind study (Loriaux S M, Deijen J B, Orlebeke J F, De Swart J H. The effects of nicotinic acid and xanthinol nicotinate on human memory in different categories of age. A double blind study. Psychopharmacology (Berl). 1985; 87(4):390-5) were realized. [0038]In a comparative study of 117 individuals, 63 treated with Niacin and 54 treated with a placebo, active treatment resulted in an increase in high-density lipoprotein cholesterol (HDL-C), a decrease in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels (Squires R W, Allison T G, Gau G T, Miller T D, Kottke B A. Low-dose, time-release nicotinic acid: effects in selected patients with low concentrations of high-density lipoprotein cholesterol. Mayo Clin Proc. 1992 September;

67(9):855-60). Niacin achieves the aforementioned results by reducing lipoprotein synthesis in the liver. [0039]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement includes xanthinol nicotinate. A serving of the dietary supplement includes from about 0.02 g to about 0.1 g of xanthinol nicotinate. The preferred dosage of a serving of the dietary supplement comprises about 0.0500 g of xanthinol nicotinate or derivatives thereof. Inositol Hexaphosphate [0040]Inositol hexaphosphate, also commonly known as phytic acid, is the main storage form of phosphorous in cereals and legumes. Most mammalian cells contain inositol hexaphosphate which serves as an important signaling molecule involved in anti-cancer and antioxidant activities (Vucenik 1, Shamsuddin A M. Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic. J Nutr. 2003 November; 133(11 Suppl 1):3778S-3784S) which is understood to be related to the ability of inositol hexaphosphate to chelate metal ions that can produce free-radicals. [0041]Dietary Inositol hexaphosphate has been shown to improve parameters of blood-lipids. Rats fed a high sucrose diet displayed a dose-dependent response to inositol hexaphosphate (0.02%, 0.1%, 0.5%, 2.5%, 5% and 10% phytic acid) in terms of reducing triglycerides, cholesterol and lipogenic enzymes (Onomi S, Okazaki Y, Katayama T. Effect of dietary level of phytic acid on hepatic and serum lipid status in rats fed a high-sucrose diet. Biosci Biotechnol Biochem. 2004 June; 68(6):1379-81). At the highest dose (10% phytic acid) there was also a reduction in food intake and growth. Similar improvements were also found with rats fed a high-cholesterol diet (Koba K, Liu J W, Bobik E Jr, Mills D E, Sugano M, Huang Y S. Effect of phytate in soy protein on the serum and liver cholesterol levels and liver fatty acid profile in rats. Biosci Biotechnol Biochem. 2003 January; 67(1):15-22). Inositol phosphate also has an effect on insulin secretion from beta-cells via the release of calcium (Barker C J, Leibiger I B, Leibiger B, Berggren P O. Phosphorylated inositol compounds in beta-cell stimulus-response coupling. Am J Physiol Endocrinol Metab. 2002 December; 283(6):E1113-22). [0042]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the dietary supplement includes inositol hexaphosphate. A serving of the dietary supplement includes from about 0.01 g to about 0.04 g of inositol hexaphosphate. The preferred dosage of a serving of the dietary supplement comprises about 0.0200 g of inositol hexaphosphate. Sophora japonica [0043]Sophora japonica is a small tree native to Asia that has been introduced to most parts of the world and is an ingredient in Traditional Chinese Medicine. Toxerutin is a derivative of ruin, which is a natural bioflavinoid extracted from Sophora japonica.

[0044]Oral administration of Sophora japonica to chemically-induced diabetic rats (Jung C H, Zhou S, Ding G X, Kim J H, Hong M H, Shin Y C, Kim G J, Ko S G. Antihyperglycemic activity of herb extracts on streptozotocin-induced diabetic rats. Biosci Biotechnol Biochem. 2006 October; 70(10):2556-9) and radiation-exposed rats (Maurya D K, Salvi V P, Krishnan Nair C K. Radioprotection of normal tissues in tumor-bearing mice by troxerutin. J Radiat Res (Tokyo). 2004 June; 45(2):221-8) improved measures of lipid peroxidation by reactive oxygen species and to scavenge damaging free-radicals which are known to cause complications diabetes. Indeed, toxerutin, an active antioxidant of Sophora japonica, has been shown to show promise as a treatment for diabetic retinopathy in rat models (Chung H K, Choi S M, Ahn B O, Kwak H H, Kim J H, Kim W B. Efficacy of troxerutin on streptozotocin-induced rat model in the early stage of diabetic retinopathy. Arzneimittelforschung. 2005; 55(10):573-80 Abstract) and as a liver protectant from lipid peroxidation (Adam B S, Pentz R, Siegers C P, Strubelt O, Tegtmeier M. Troxerutin protects the isolated perfused rat liver from a possible lipid peroxidation by coumarin. Phytomedicine. 2005 January; 12(1-2):52-61 Abstract). [0045]In an embodiment of the present invention which is set forth in greater detail in the examples below, the diet supplement includes an extract of Sophora japonica. A serving of the diet supplement includes from about 0.01 g to about 0.04 g of an extract of Sophora japonica. The preferred dosage in a serving of said diet supplement comprises about 0.02 g of Sophora japonica extract Black Pepper Extract [0046]Black pepper, also known as Piper nigrum, is a flowering vine cultivated for its fruit which is usually dried for use as a spice and seasoning. Many of the active constituents of black pepper contribute to it's high antioxidant activity, which rivals that of potent synthetic antioxidants. Black pepper also appears to be beneficial for weight reduction through the inhibition of diacylglycerol acyltransferase (DGAT) (Lee S W, Rho M C, Park H R, Choi J H, Kang J Y, Lee J W, Kim K, Lee H S, Kim Y K. Inhibition of diacylglycerol acyltransferase by alkamides isolated from the fruits of Piper longum and Piper nigrum. J Agric Food Chem. 2006 Dec. 27; 54(26):9759-63 Abstract), an enzyme involved in triglyceride synthesis, which provides another anti-obesity therapeutic strategy. [0047]In an embodiment of the present invention which is set forth in greater detail in the examples below, the diet supplement includes an extract of black pepper. A serving of the diet supplement includes from about 0.001 mg to about 0.008 mg of black pepper extract. The present invention, in a preferred dosage said diet supplement comprises about 0.005 g of black pepper extract per serving. Yohimbine Hydrochloride [0048]Yohimbine is a naturally occurring alkaloid derived from the African tree, Pausinysatlia yohimbe. Furthermore, yohimbine has been shown through research to increase the amount of non-esterified fatty acids (NEFAs) in the bloodstream, as a

product of lipolysis in both lean and obese individuals (Berlan M, Galitzky J, Riviere D, Foureau M, Tran M A, Flores R, Louvet J P, Houin G, Lafontan M. Plasma catecholamine levels and lipid mobilization induced by Yohimbine in obese and non-obese women. Int J, Obes. 1991 May; 15(5):305-15; Galitzky J, Taouis M, Berlan M, Riviere D, Garrigues M Lafontan M. Alpha 2-antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect of oral Yohimbine in healthy male volunteers. Eur J Clin Invest. 1988 December; 18(6):587-94.). Additionally this effect persists for upwards of 14 days, indicating that a rapid tolerance, as seen with several other known lipolytic agents, to yohimbine does not develop (Galitzky J, Taouis M, Berlan M, Riviere D, Garrigues M Lafontan M. Alpha 2-antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect of oral Yohirnbine in healthy male volunteers. Eur J Clin Invest. 1988 December; 18(6):587-94.). In addition to its effects on lipolysis, Yohimbine is also an appetite suppressant, and has been shown to decrease energy intake in both lean and obese mice (Currie P J, Wilson L M. Yohimbine attenuates clonidine-induced feeding and macronutrient selection in genetically obese (ob/ob) mice. Pharmacol Biochem Behav. 1992 December; 43(4):1039-46.) Researchers also found that in a 3-week study utilizing 20-obese-female subjects wherein the subjects were restricted to a 1000 calories per day diet, that 20 mg of yohimbine administered daily increased weight loss by an additional 3 pounds over the placebo group (Kucio C, Jonderko K, Piskorska D. Does Yohimbine act as a slimming drug? Isr J Med Sci. 1991 October; 27(10):550-6.). [0049]In an embodiment of the present invention which is set forth in greater detail in the examples below, the diet supplement includes Yohimbine H Cl. A serving of the diet supplement includes from about 0.001 mg to about 0.008 mg of Yohimbine HCl. The present invention, in a preferred dosage said diet supplement comprises about 0.0045 g of Yohimbine HCl per serving. [0050]The aforementioned ingredients in embodiments of the present invention, are combined to form several embodiments. Specific embodiments of the present invention are understood by the inventors to function in the capacity of a dietary supplement to aid in body fat loss, lipolysis while affording protection against reactive oxygen species resulting from the .beta.-oxidation of fats are set forth below. [0051]In one embodiment of the present invention, the composition includes a combination of one or more of the following, but not limited to an extract of green tea, Caffeine anhydrous, Deanol, and extract of Aspidosperma quebracio-blanco, yohimbine, an extract of Cnidium monnieri, an extract of Evodia rutaecarpa fruit and Inositol Hexaphosphate. The composition of the present invention is in the nature of a dietary supplement wherein the dietary supplement may be consumed by an individual in any acceptable form. For example, the dosage form of the supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a tablet, a caplet, a liquid caplet, or as a dietary gel. The most preferred mode of delivery of the present embodiment is that of a liquid capsule. [0052]In a second embodiment of the present invention, the composition includes a

combination of one or more of the following, but not limited to an extract of green tea, caffeine anhydrous, and extract of black tea, an extract of oolong tea, an extract of red tea (rooibos tea), and extract of white tea, vinpocetne, Coleus foskohlii, cocoa seed and an extract of Evodia ruteecarpa. The composition of the present invention is in the nature of a dietary supplement, wherein the dietary supplement may be consumed in any acceptable form. For example, the dosage form of the supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a tablet, a caplet, a liquid caplet, or as a dietary gel. The most preferred mode of delivery of the present invention is that of a liquid capsule. [0053]In a third embodiment of the present invention comprises a combination of one or more of an extract of green tea, caffeine anhydrous, and extract of Cissus quadrangularis, niacin, and extract of white willow bark, and extract of black pepper. The composition of the present invention is in the nature of a dietary supplement, wherein the dietary supplement may be consumed in any acceptable form. For example, the dosage form of the supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a tablet, a caplet, a liquid caplet, or as a dietary gel. The most preferred mode of delivery of the present embodiment is that of a liquid capsule. [0054]Furthermore, the dosage form of the dietary supplement composition of embodiments of the present invention may be provided in accordance with any of the known customary processing techniques for herbal and/or dietary supplements in any of the aforementioned forms. [0055]In an compositional example embodiment of the present invention, which is set forth in greater detail in Example 1, a dietary supplement comprised of green tea dry leaf extract (Camellia sinensis), anhydrous caffeine, Cissus quadrangularis extract, deanol, xanthinol nicotinate, inositol hexaphosphate, troxerutin (as Sophora japonica), Evodia rutaecarpa extract (Teradium ruticarpum), Inula racemosa extract (from root), Cnidium monnieri extract (seed), black pepper extract (Piper nigrum L), yohimbine hydrochloride (methyl 17-alpha-hydroxy-yohimban-16 alpha-arboxylate hydrochloride), Aspidosperma quebracho-blanco extract (bark), Codonopsis pilosula extract (root), and white willow bark extract (Salix alba) is provided for increasing individual's natural adipose lipolytic metabolism via adipose metabolism by way of lipolysis or lipolytic metabolism, and thermogenic means while simultaneously affording protection to the body of individual from reactive oxygen species resulting from the .beta.-oxidation of fats and inhibiting the reformation of triglycerides in the body. [0056]In a second compositional example embodiment of the present invention, which is set forth in greater detail in Example 2, is a dietary supplement comprised of green tea dry leaf extract (Camellia sinensis), anhydrous caffeine, banaba leaf extract (Lagerstroemia speciosa L.), black tea leaf extract (Camelila sinensis L.), about white tea leaf extract (Camella sinensis), oolong tea dry leaf extract (Camellia sinensis), rooibos tea extract (Aspalathus linearis), vinpocetine, Coleus forskholli extract, Theobroma cacao extract (from seed), and Evodia rutaecarpa fruit extract (Tetradium ruticarpum) is

provided for increasing individual's natural adipose lipolytic metabolism via adipose metabolism by way of lipolysis or lipolytic metabolism, and thermogenic means while simultaneously affording protection to the body of individual from reactive oxygen species resulting from the .beta.-oxidation of fats and inhibiting the reformation of triglycerides in the body. [0057]A third compositional example embodiment of the present invention, which is set forth in greater detail in Example 3, is a dietary supplement comprised of anhydrous caffeine, green tea dry leaf extract, Cissus quadrangularis extract (from stem and leaves), (Camellia sinensis), soy albumin bean extract powder, vitamin B-6 (pyridoxine hydrochloride), picamilon HCl, L-selenomethionine, Niacin, vitamin B-12 (cyanocobalamin), chromium polynicotinate, white pepper powder, oolong tea dry leaf extract (Camellia sinensis), quercetin dihyrdrate (citrus bioflavanoid), white willow bark extract (Salix alba), rooibos tea extract (Aspalathus linearis), black tea leaf extract (Camellia sinensis L.), and folic acid is provided for increasing individual's natural adipose lipolytic metabolism via adipose metabolism by way of lipolysis or lipolytic metabolism, and thermogenic means while simultaneously affording protection to the body of individual from reactive oxygen species resulting from the .beta.-oxidation of fats and inhibiting the reformation of triglycerides in the body. [0058]The present invention may be utilized for increasing an individual's natural adipose metabolism by way of lipolysis or lipolytic metabolism, thus leading to a desired body fat composition while promoting stored energy utilization manifesting in thermogenesis in an individual and simultaneously affording protection to the body of individual from reactive oxygen species resulting from the .beta.-oxidation of fats while Inhibiting the reformation of triglycerides in the body. The compositions of the present invention are of particular interest and advantageous to those seeking to lose body fat mass, such as bodybuilders and athletes or those suffering from excess body fat. The amount of the composition administered to the athlete and/or person is variable dependant upon the desired effect, body mass, and the individual characteristics of the athletes and/or persons as well as the like. For example, in various embodiments, the subject compositions are administered to the diet of the athlete and/or bodybuilder and/or person on a daily basis. [0059]In addition to compositions, the present invention, also provides various methods of increasing an individual's natural adipose burning metabolism lipolysis or lipolytic metabolism, thus leading to a desired body fat composition while promoting stored energy utilization manifesting in thermogenesis in an individual and simultaneously affording protection to the body of individual from reactive oxygen species resulting from the .beta.-oxidation of fats while inhibiting the reformation of triglycerides in the body. Preferably, the method of the present invention provides a manner of consuming a composition of the present invention in the form of a dietary supplement. According to at least one embodiment of the present invention, the method provides for the consumption of a composition that reduces body fat mass leading to change in body mass composition according to the aforementioned parameters. For example, the consumption of the composition in accordance with the method will allow an individual's body to burn more stored body fat than they would otherwise burn, leading to hardcore fat loss.

[0060]As aforementioned, the diet supplement compositions according to the present invention may be employed in methods for increasing an individual's natural adipose metabolism. The methods of the present invention are of particular interest and advantageous to those seeking to lose body fat mass, such as hardcore bodybuilders and/or athletes or those suffering from an elevated body mass. The methods may involve a determination, and an administration of an amount of a composition in accordance with factors such as the desired effect, the body weight and the characteristics of the athlete and/or bodybuilder and/or person and the like. For example, in preferred embodiments, the method includes the administration of the aforementioned compositions to the diet of the athlete and/or bodybuilder and/or person on a daily basis. [0061]Although the following examples illustrate the practice of the present invention according to various embodiments thereof, the examples should not be construed as limiting the scope of the invention. Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the specification and examples. EXAMPLE 1 [0062]A dietary supplement comprising the following ingredients per serving is prepared for consumption as a caplet: about 0.46 g of green tea dry leaf extract (Camellia sinensis) which is standardized for 90% polyphenols, 75% catechins, 45% epigallocatechin gallate, about 0.3 g of anhydrous caffeine, about 0.15 g of Cissus quadrangularis extract (from stem and leaves) which is standardized for 2.5% phytosterols, about 0.1 g of deanol bitartrate, about 0.05 g of xanthinol nicotinate, about 0.02 g of inositol hexaphosphate, about 0.02 g of troxerutin (as Sophora japonica) which is standardized for 97% trihydroxyethylrutoside, about 0.01 g of Evodia rutaecarpa extract (Teradium ruticarpum) from fruit which is standardized for 10% evodiamine, about 0.01 g of Inula racemosa extract (from root) which is standardized for 2% alantolactone, about 0.01 g of Cnidium monnieri extract (seed) which is standardized for 20% osthole, about 0.005 g of black pepper extract (Piper nigrum L) from fruit which is standardized for 95% piperine, about 0.0045 g of yohimbine hydrochloride (methyl 17-alpha-hydroxy-yohimban-16 alpha-carboxylate hydrochloride), about 0.001 g of Aspidosperma quebracho-blanco extract (bark) which is standardized for 0.3% alkaloids, about 0.001 g of Codonopsis pilosula extract (root), and about 0.001 g of white willow bark extract (Salix alba) which is standardized for 25% salicin. [0063]Preferably, the nutritional composition is consumed in accordance with the following directions: Directions: As a dietary supplement, take 3 capsules with an 8 oz. glass of water 2 times daily, approximately 30 to 60 minutes before meals. On days of wherein the individual undertakes a physical workout, take 1 of aforementioned servings before the workout.

EXAMPLE 2 [0064]A dietary supplement comprising the following ingredients per serving is prepared for consumption as a tablet: about 0.2 g of green tea dry leaf extract (Camellia sinensis) which is standardized for 90% polyphenols, 75% catechins, 45% epigallocatechin gallate, about 0.2 g of anhydrous caffeine, about 0.024 g of banaba leaf extract (Lagerstroemia speciosa L.) which is standardized for 3% corosolic acid, about 0.001 g of black tea leaf extract (Camellia sinensis L.) which is standardized for 70% polyphenols, 50% catechins, 25% epigallocatechin gallate, about 0.001 g of white tea leaf extract (Camellia sinensis) which is standardized for 50% polyphenols, 35% catechins, 15% epigallocatechin gallate, about 0.001 g of oolong tea dry leaf extract (Camellia sinensis) which is standardized for 50% polyphenols, 25% catechins, 15% epigallocatechin gallate, about 0.001 g of rooibos tea extract (Aspalathus linearis) from leaf and stem which is standardized for 20% polyphenols, about 0.001 g of vinpocetine, about 0.001 g of Coleus forskholli extract (from root) which is standardized for 10% forskolin, about 0.001 g of Theobroma cacao extract (from seed) which is standardized for 6% theobromine, and about 0.001 g of Evodia rutaecarpa fruit extract (Tetradium ruticarpum) which is standardized for 10% evodiamine. [0065]Preferably, the nutritional composition is consumed in accordance with the following directions: Directions: As a dietary supplement, take 2 capsules with an 8 oz. glass of water, 2 times daily. On days of wherein the individual undertakes a physical workout, take 1 of aforementioned servings before the workout. EXAMPLE 3 [0066]A dietary supplement comprising the following ingredients per serving is prepared for consumption as a liquid gel capsule: about 0.25 g of anhydrous caffeine, about 0.15 g of Cissus quadrangularis extract (from stem and leaves) which is standardized for 2.5% phytosterols, about 0.1222 g of green tea dry leaf extract (Camellia sinensis) which is standardized for 90% polyphenols, 45% epigallocatechin gallate, about 0.05 g of soy albumin bean extract powder (glycine max), about 0.05 g of vitamin B-6 (pyridoxine hydrochloride), about 0.05 g of picamilon HCl, about 0.012 g of L-selenomethionine, about 0.005 g of Niacin, about 0.005 g of vitamin B-12 (cyanocobalamin), about 0.015 g of chromium polynicotinate, about 0.001 g of white pepper powder, about 0.001 g of oolong tea dry leaf extract (Camellia sinensis) which is standardized for 50% polyphenols, 25% catechins, 15% epigallocatechin gallate, about 0.001 g of quercetin dihyrdrate granular (citrus bioflavanoid), about 0.001 g of white willow bark extract (Salix alba) which is standardized for 25% salicin, about 0.001 g of rooibos tea extract (Aspalathus linearis) from leaf and stem which is standardized for 20% polyphenols, about 0.001 g of black tea leaf extract (Camellia sinensis L.) which is

standardized for 70% polyphenols, 50% catechins, 25% epigallocatechin gallate, and about 0.0004 g of folic acid. [0067]Preferably, the nutritional composition is consumed in accordance with the following directions: Directions: As a dietary supplement, take 2 liquid gel capsules with a glass of water 2 times daily, before meals. For best results; use for 8 weeks in conjunction with a sensible diet and a regular exercise program. On days of wherein the individual undertakes a physical workout, take 1 of aforementioned servings before the workout. EXTENSIONS AND ALTERNATIVES [0068]In the foregoing specification, the invention has been described with specific embodiments thereof, however, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.

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( 11 of 15 )

United States Patent Application 20080166434

Kind Code A1

Heuer; Marvin A. July 10, 2008

Diet supplement for burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus

Abstract

A diet supplement comprising at least Green Tea Extract and Oolong Tea Extract may be in a time-release mechanism for sustained all-day energy, burning of calories, supporting weight loss, and improving mental focus. A method for providing sustained all-day energy, burning of calories, weight loss support, and improved mental focus by consumption of the diet supplement is also provided.

Inventors: Heuer; Marvin A.; (Mississauga, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 381 North Service Road West Oakville ON L6M 0H4 omitted

Serial No.: 075835

Series Code: 12

Filed: March 14, 2008

U.S. Current Class: 424/729

U.S. Class at Publication: 424/729

Intern'l Class: A61K 36/82 20060101 A61K036/82; A61P 43/00 20060101 A61P043/00

Claims

1. A diet supplement comprising Green Tea Extract and Oolong Tea Extract. 2. The diet supplement of claim 1, further comprising White Tea Extract. 3. The diet supplement of claim 2, wherein the Green Tea Extract is Green Tea Dry Leaf Extract, the White Tea Extract is White Tea Dry Leaf Extract, and the Oolong Tea Extract is Oolong Tea Dry Leaf Extract. 4. The diet supplement of claim 3, further comprising Anhydrous Caffeine. 5. The diet supplement of claim 4, further comprising a time-release mechanism. 6. The diet supplement of claim 5, wherein the time-release mechanism provides for up to and including 12 hours active compound release. 7. The diet supplement of claim 4, wherein the Green Tea Dry Leaf Extract is present in amounts from about 0.01 g to about 2 g, the Anhydrous Caffeine is present in amounts from about 0.001 g to about 1 g, the White Tea Dry Leaf Extract is present in amounts from about 0.0001 g to about 0.01 g and the Oolong Tea Dry Leaf Extract is present in amounts from about 0.0001 to about 0.01 g per serving. 8. The diet supplement of claim 4, wherein the Green Tea Dry Leaf Extract, Anhydrous Caffeine, White Tea Dry Leaf Extract and Oolong Tea Dry Leaf Extract are present in amounts effective for at least one of burning calories, providing sustained energy, supporting weight loss and improving mental focus in a human or animal. 9. A method for at least one of burning calories, providing sustained energy, supporting weight loss and improving mental focus in a human or animal, comprising the step of administering to the human or animal a diet supplement that comprises Green Tea Extract and Oolong Tea Extract. 10. The method of claim 9, wherein the diet supplement further comprises White Tea Extract. 11. The method of claim 10, wherein the Green Tea Extract is Green Tea Dry Leaf Extract, the White Tea Extract is White Tea Dry Leaf Extract, and the Oolong Tea Extract is Oolong Tea Dry Leaf Extract. 12. The method of claim 11, wherein the diet supplement further comprises Anhydrous Caffeine. 13. The method of claim 12, wherein the diet supplement is provided in a time release mechanism.

14. The method of claim 13, wherein the time-release mechanism provides for up to and including 12 hours active compound release. 15. The method of claim 12, wherein the diet supplement is administered to the human or animal within at least one hour of waking in the morning.

Description

RELATED APPLICATIONS [0001]This application is a continuation of U.S. Ser. No. 11/447,476, filed Jun. 5, 2006, which claims the benefit of U.S. Provisional Patent Application No. 60/688,420, filed Jun. 7, 2005, entitled "Diet Supplement for Burning Additional Calories, Providing Sustained Energy, Supporting Weight Loss, and/or Improving Mental Focus", the disclosure of which is hereby fully incorporated by reference. FIELD OF THE INVENTION [0002]The present invention relates to a diet supplement for burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus. Preferably, the diet supplement is provided in a time-release form for burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus for an extended period of time throughout the day, e.g., an entire work day. In addition, the present invention relates to a method of promoting same by consuming the diet supplement. SUMMARY OF THE INVENTION [0003]The present invention provides for a diet supplement that burns additional calories, provides sustained energy, supports weight loss, and/or improves mental focus. The diet supplement may include Caffeine Anhydrous. In addition or alternatively, the diet supplement may include one or more of Green Tea Dry Leaf Extract, White Tea Dry Leaf Extract and/or Oolong Tea Dry Leaf Extract. In one embodiment of the present invention, the diet supplement includes Green Tea Dry Leaf Extract and Caffeine Anhydrous in equal quantities. Advantageously, the diet supplement is provided in a time-release form, for burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus for an extended period of time, e.g., up to 12 hours, so as to be an all-work day formula, after being consumed by an individual. [0004]The present invention also provides, by the consumption of the supplemental composition, a method of burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus. DETAILED DESCRIPTION OF THE INVENTION

[0005]The present invention, according to various embodiments thereof, is directed to a diet supplement that burns additional calories, provides sustained energy, supports weight loss, and/or improves mental focus. [0006]Advantageously, the diet supplement is provided in a time-release form, for burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus for an extended period of time after being consumed by an individual. For example, in an example embodiment, the diet supplement is provided in a time-release form that has a time release of approximately eight hours. Thus, for an embodiment that includes caffeine having a half-life of approximately 4 hours, each serving of the diet supplement may burn additional calories, provide sustained energy, support weight loss, and/or improve mental focus for up to 12 hours after being consumed by an individual. In this manner, the diet supplement may provide an all-work day formula in that it may burn additional calories, provide sustained energy, support weight loss, and/or improve mental focus throughout an entire "work-day" of a typical individual. [0007]Green Tea Dry Leaf Extract [0008]All teas of which the diet supplement of the present invention may be comprised, for example e.g., Green Tea, White Tea and Oolong Tea, are derived from the same plant namely Camellia sinensis. However, through the use of different processing methods, different proportions of active compounds result in each of the respective teas. White Tea undergoes very little processing, as does Green Tea, thereby leaving a relatively large amount of active compounds. Unlike green tea however, white tea is harvested before the leaves are fully opened. The processing of Oolong Tea is typically more involved than that of green tea. The active compounds of tea are a family of polyphenols, particularly the Catechins. The most active specific compound is the Catechin, epigallocatechin gallate (ECGC) which comprises from about 10 to about 50% of the total Catechins (Kao Y H, Hiipakka R A, Liao S. Modulation of endocrine systems and food intake by green tea epigallocatechin gallate. Endocrinology. 2000 March; 141(3):980-7). Furthermore, Green Tea also contains caffeine, although typically significantly less than Black Tea. Green tea and the active compounds isolated from Green Tea are the most widely studied teas to date. [0009]The principal beneficial activity of Green Tea imparted by polyphenols is its antioxidant activity as evidenced by several studies. One clinical study has shown that ingestion of green tea extract results in a rapid increase in plasma antioxidant activity (Benzie I F, Szeto Y T, Strain J J, Tomlinson B. Consumption of green tea causes rapid increase in plasma antioxidant power in humans. Nutr Cancer. 1999; 34(1):83-7). Green tea has also been shown to be effective in aiding weight loss (Chantre P, Lairon D. Recent findings of green tea extract AR25 (Exolise) and its activity for the treatment of obesity. Phytomedicine. 2002 January; 9(1):3-8). This effect may be due to two activities. Firstly, Green Tea reduces fat digestion and secondly it increases energy expenditure (Berube-Parent S, Pelletier C, Dore J, Tremblay A. Effects of encapsulated green tea and

Guarana extracts containing a mixture of epigallocatechin-3-gallate and caffeine on 24 h energy expenditure and fat oxidation in men. Br J Nutr. 2005 September; 94(3):432-6). The increase in energy expenditure may be derived from fat stores via the oxidation of fat, resulting in thermogenesis (Choo J J. Green tea reduces body fat accretion caused by high-fat diet in rats through beta-adrenoceptor activation of thermogenesis in brown adipose tissue. J Nutr Biochem. 2003 November; 14(11):671-6; Dulloo A G, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P, Vandermander J. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr. 1999 December; 70(6):1040-5). The thermogenic activity of Green Tea may additionally be greatly enhanced by its synergistic cooperation with caffeine (Dulloo A G, Seydoux J, Girardier L, Chantre P, Vandermander J. Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity. Int J Obes Relat Metab Disord. 2000 February; 24(2):252-8). Moreover, an inverse relationship has also been demonstrated with respect to Green Tea consumption and total cholesterol levels (Kono S, Shinchi K, Ikeda N, Yanai F, Imanishi K. Green tea consumption and serum lipid profiles: a cross-sectional study in northern Kyushu, Japan. Prev Med. 1992 July; 21(4):526-31). [0010]The mechanism of action for fat loss resulting from Green Tea consumption may be, at least partially, due to an increase in norepinephrine. Catechins are known to inhibit catechol-O-methyl-transferase (COMT), an enzyme that degrades norepinephrine (Borchardt R T, Huber J A. Catechol O-methyltransferase. 5. Structure-activity relationships for inhibition by flavonoids. J Med Chem. 1975 January; 18(1):120-2). In turn, norepinephrine inhibits degradation of intracellular cyclic AMP (cAMP), an important signaling molecule involved in many metabolic processes including thermogenesis. EGCG has been shown to be an inhibitor of glutamate dehydrogenase, which regulates insulin secretion (Li C, Allen A, Kwagh J, Doliba N M, Qin W, Najafi H, Collins H W, Matschinsky F M, Stanley C A, Smith T J. Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. J Biol Chem. 2006 Apr. 14; 281(15):10214-21. Epub 2006 Feb. 13). The Anticancer activities associated with Green Tea may be related to its antioxidant activity and inhibition of vascular endothelial growth factor (VEGF) receptor signaling, which plays a role in tumor angiogenesis (Lamy S, Gingras D, Beliveau R. Green tea catechins inhibit vascular endothelial growth factor receptor phosphorylation. Cancer Res. 2002 Jan. 15; 62(2):381-5; Lee Y K, Bone N D, Strege A K, Shanafelt T D, Jelinek D F, Kay N E. VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. Blood. 2004 Aug. 1; 104(3):788-94. Epub 2004 Mar. 2). [0011]The diet supplement may include Green Tea Dry Leaf Extract. In one embodiment of the present invention, which is set forth in greater detail in Example 1 below, the diet supplement may comprise Green Tea Dry Leaf Extract wherein a serving includes from about 1 mg to about 2000 mg of Green Tea Dry Leaf Extract. The preferred dosage of a serving of the diet supplement comprises about 600 mg of Green Tea Dry Leaf Extract. [0012]Additionally, in a second embodiment of the present invention, which is set forth

in greater detail in Example 2 below, the diet supplement may comprise Green Tea Dry Leaf Extract wherein a serving includes from about 1 mg to about 2000 mg of Green Tea Dry Leaf Extract. The preferred dosage of a serving of the diet supplement comprises about 598 mg of Green Tea Dry Leaf Extract. [0013]In an embodiment of the present invention, the diet supplement comprises Green Tea Dry Leaf Extract, wherein the Green Tea Dry Leaf Extract comprises about 90% polyphenols. In one such embodiment of the present invention, the diet supplement includes Green Tea Dry Leaf Extract, wherein the Green Tea Dry Leaf Extract comprises about 75% Catechins. Furthermore, in one such embodiment of the present invention, the diet supplement comprises Green Tea Dry Leaf Extract, wherein the Green Tea Dry Leaf Extract comprises about 45% epigallocatechin gallate ("EGCG"). [0014]In a second embodiment of the present invention, the diet supplement comprises Green Tea Dry Leaf Extract, wherein the Green Tea Dry Leaf Extract comprises about 98% polyphenols. In one such embodiment of the present invention, the diet supplement includes Green Tea Dry Leaf Extract, wherein the Green Tea Dry Leaf Extract comprises about 75% Catechins. Furthermore, in one such embodiment of the present invention, the diet supplement comprises Green Tea Dry Leaf Extract, wherein the Green Tea Dry Leaf Extract comprises about 45% epigallocatechin gallate ("EGCG"). [0015]White Tea Dry Leaf Extract [0016]White Tea is reported to have the same health benefits of green tea. However, White Tea has been reported to impart these benefits to an even greater extent (Santana-Rios G, Orner G A, Amantana A, Provost C, Wu S Y, Dashwood R H. Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay. Mutat Res. 2001 Aug. 22; 495(1-2):61-74). White Tea has further been shown to possess anticarcinogenic properties in rats (Santana-Rios G, Orner G A, Xu M, Izquierdo-Pulido M, Dashwood R H. Inhibition by white tea of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced colonic aberrant crypts in the F344 rat. Nutr Cancer. 2001; 41(1-2):98-103). A 6-month double blind, placebo controlled, randomized study on healthy post-menopausal females demonstrated that a supplement containing white tea improved skin condition, structure and firmness (Skovgaard G R, Jensen A S, Sigler M L. Effect of a novel dietary supplement on skin aging in post-menopausal women. Eur J Clin Nutr. 2006 May 3). White tea, as shown by a bacterial virus inactivation assay, has been reported to be more effective than Green Tea and to also possess anti-fungal properties (Dr. Schiffenbauer, Pace University, 104th General Meeting of the American Society for Microbiology on May 23, 2004, New Orleans, La.). [0017]In addition or alternatively to the ingredients set forth above, the diet supplement may include White Tea Dry Leaf Extract. In an embodiment of the present invention, which is set forth in greater detail in Example 1 below, the diet supplement may comprise White Tea Dry Leaf Extract wherein a serving includes from about 0.1 mg to about 1000 mg of White Tea Dry Leaf Extract. The preferred dosage of a serving of the diet supplement comprises about 1.56 mg of White Tea Dry Leaf Extract.

[0018]In addition or alternatively to the ingredients set forth above, the diet supplement, in a second embodiment may include White Tea Dry Leaf Extract. In an embodiment of the present invention, which is set forth in greater detail in Example 2 below, the diet supplement may comprise White Tea Dry Leaf Extract wherein a serving includes from about 0.1 mg to about 1000 mg of White Tea Dry Leaf Extract. The preferred dosage of a serving of the diet supplement comprises about 1.00 mg of White Tea Dry Leaf Extract. [0019]In both embodiments of the present invention, the diet supplement comprises White Tea Dry Leaf Extract, wherein the White Tea Dry Leaf Extract comprises about 50% polyphenols. In one such embodiment of the present invention, the diet supplement comprises White Tea Dry Leaf Extract, wherein the White Tea Dry Leaf Extract comprises about 35% Catechins. Furthermore, in one such embodiment of the present invention, the diet supplement comprises White Tea Dry Leaf Extract, wherein the White Tea Dry Leaf Extract comprises about 15% EGCG. [0020]Oolong Tea Dry Leaf Extract Oolong Tea has also been specifically studied for beneficial activities. The chemopreventative activity has been demonstrated in rats (Matsumoto N, Kohri T, Okushio K, Hara Y. Inhibitory effects of tea catechins, black tea extract and oolong tea extract on hepatocarcinogenesis in rat. Jpn J Cancer Res. 1996 October; 87(10):1034-8) has been experimentally shown. Employing a comparative study in rats, it was found that Oolong Tea was superior in controlling weight as compared to Green Tea, while Green Tea was more effective at lowering total cholesterol (Kuo K L, Weng M S, Chiang C T, Tsai Y J, Lin-Shiau S Y, Lin J K. Comparative studies on the hypolipidemic and growth suppressive effects of oolong, black, pu-erh, and green tea leaves in rats. J Agric Food Chem. 2005 Jan. 26; 53(2):480-9). As a method of weight control, clinical trials in humans have shown that Oolong Tea increases metabolic rate and energy expenditure (Rumpler W, Seale J, Clevidence B, Judd J, Wiley E, Yamamoto S, Komatsu T, Sawaki T, Ishikura Y, Hosoda K. Oolong tea increases metabolic rate and fat oxidation in men. J Nutr. 2001 November; 131(11):2848-52; Komatsu T, Nakamori M, Komatsu K, Hosoda K, Okamura M, Toyama K, Ishikura Y, Sakai T, Kunii D, Yamamoto S. Oolong tea increases energy metabolism in Japanese females. J Med Invest. 2003 August; 50(3-4):170-5). Clinical trials have further demonstrated the potential therapeutic benefit of Oolong Tea as a treatment for diabetes (Hosoda K, Wang M F, Liao M L, Chuang C K, Iha M, Clevidence B, Yamamoto S. Antihyperglycemic effect of oolong tea in type 2 diabetes. Diabetes Care. 2003 June; 26(6):1714-8) and coronary artery disease (Shimada K, Kawarabayashi T, Tanaka A, Fukuda D, Nakamura Y, Yoshiyama M, Takeuchi K, Sawaki T, Hosoda K, Yoshikawa J. Oolong tea increases plasma adiponectin levels and low-density lipoprotein particle size in patients with coronary artery disease. Diabetes Res Clin Pract. 2004 September; 65(3):227-34). [0021]In addition or alternatively to the ingredients set forth above, the diet supplement may include Oolong Tea Dry Leaf Extract. In an embodiment of the present invention, which is set forth in greater detail in Example 1 below, the diet supplement may comprise Oolong Tea Dry Leaf Extract wherein a serving includes from about 0.1 mg to about 1000 mg of Oolong Tea Dry Leaf Extract. The preferred dosage of a serving of the diet

supplement comprises about 1.56 mg of Oolong Tea Dry Leaf Extract. [0022]In addition or alternatively to the ingredients set forth above, the diet supplement, a second embodiment may include Oolong Tea Dry Leaf Extract. In an embodiment of the present invention, which is set forth in greater detail in Example 2 below, the diet supplement may comprise Oolong Tea Dry Leaf Extract wherein a serving includes from about 0.1 mg to about 1000 mg of Oolong Tea Dry Leaf Extract. The preferred dosage of a serving of the diet supplement comprises about 1.00 mg of Oolong Tea Dry Leaf Extract. [0023]In both embodiments of the present invention that are set forth above, the diet supplement comprises Oolong Tea Dry Leaf Extract, wherein the oolong tea dry leaf extract comprises about 50% polyphenols. In one such embodiment of the present invention, the diet supplement comprises Oolong Tea Dry Leaf Extract, wherein the Oolong Tea Dry Leaf Extract comprises about 25% Catechins. Furthermore, in one such embodiment of the present invention, the diet supplement comprises Oolong Tea Dry Leaf Extract, wherein the Oolong Tea Dry Leaf Extract comprises about 15% EGCG. [0024]Anhydrous Caffeine [0025]Anhydrous Caffeine is a naturally occurring xanthine alkaloid found in some plants, where it acts as a natural pesticide. In humans, however, it may have numerous beneficial effects, the most common of which uses caffeine as a supplement to the central nervous system. In this capacity, it is used as a stimulant and performance enhancer. Biochemically, caffeine which is structurally similar to adenosine receptors, binds to, but does not activate, adenosine receptors which are normally activated by adenosine to induce sleep (Shi D, Nikodijevic O, Jacobson K A, Daly J W. Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain. Cell Mol Neurobiol. 1993 June; 13(3):247-61). This antagonism of adenosine receptors leads to increased levels of neurotransmitters. [0026]A meta-analysis compiled from forty double-blind studies support the use of Caffeine to increase physical endurance (Doherty M, Smith P M. Effects of caffeine ingestion on exercise testing: a meta-analysis. Int J Sport Nutr Exerc Metab. 2004 December; 14(6):626-46; Graham T E, Hibbert E, Sathasivam P. Metabolic and exercise endurance effects of coffee and caffeine ingestion. J Appl Physiol. 1998 September; 85(3):883-9; Kovacs E M, Stegen J H C H, Brouns F. Effect of caffeinated drinks on substrate metabolism, caffeine excretion, and performance. J Appl Physiol. 1998 August; 85(2):709-15). Furthermore, Caffeine is also widely used to control weight, which may occur through multiple mechanisms. Significant weight loss has been observed in obese women related to caffeine supplementation (Yoshida T, Sakane N, Umekawa T, Kondo M. Relationship between basal metabolic rate, thermogenic response to caffeine, and body weight loss following combined low calorie and exercise treatment in obese women. Int J Obes Relat Metab Disord. 1994 May; 18(5):345-50) which may be, at least in part, due to increased lipolysis as fat is metabolized (Jung R T, Shetty P S, James W P, Barrand M A, Callingham B A. Caffeine: its effect on catecholamines and metabolism in

lean and obese humans. Clin Sci (Lond). 1981 May; 60(5):527-35). Caffeine has also been shown to increase metabolic rate in both lean and obese individuals (Roberts A T, de Jonge-Levitan L, Parker C C, Greenway F. The effect of an herbal supplement containing black tea and caffeine on metabolic parameters in humans. Altern Med Rev. 2005 December; 10(4):321-5; Astrup A, Toubro S, Cannon S, Hein P, Breum L, Madsen J. Caffeine: a double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers. Am J Clin Nutr. 1990 May; 51(5):759-67; Dulloo A G, Geissler C A, Horton T, Collins A, Miller D S. Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers. Am J Clin Nutr. 1989 January; 49(1):44-50) wherein this adds to its weight-lowering effects. Furthermore, caffeine additionally improves cognitive performance following physical activity (Hogervorst E, Riedel W J, Kovacs E, Brouns F, Jolles J. Caffeine improves cognitive performance after strenuous physical exercise. Int J Sports Med. 1999 August; 20(6):354-61). [0027]In addition or alternatively to the ingredients set forth above, the diet supplement may include Caffeine Anhydrous. In an embodiment of the present invention, which is set forth in greater detail in Examples 1 and 2 below, the diet supplement may comprise Caffeine Anhydrous wherein a serving includes from about 1 mg to about 2000 mg of Caffeine Anhydrous. The preferred dosage of a serving of the diet supplement comprises about 400 mg of Caffeine Anhydrous. Furthermore, in an embodiment of the present invention, the diet supplement includes green tea dry leaf extract and caffeine anhydrous in equal quantities. [0028]The present invention, according to various embodiments thereof, provides a method of burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus by the consumption of the diet supplement. Advantageously, consumption of the diet supplement is combined with a program of diet and exercise. [0029]According to various embodiments of the present invention, the diet supplement may be consumed in any form. For instance, the dosage form of the diet supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a tablet, a caplet, or as a dietary gel. The most preferred dosage form is a caplet. [0030]Preferably, the diet supplement is consumed by an individual in accordance with the following: As a diet supplement, 2 caplets may be taken with an 8 oz. glass of water within one hour after waking up in the morning. More than two caplets should not be consumed by an individual in a 24-hour period. To assess individual tolerance, an individual may consume, on Day 1 to Day 3, 1 caplet daily. Thereafter, an individual may consume two caplets daily. [0031]Furthermore, the dosage form of the diet supplement may be provided in accordance with customary processing techniques for herbal and/or dietary supplements in any of the forms mentioned above.

[0032]The diet supplement of the present invention may be provided in a time release mechanism. U.S. Pat. No. 5,445,826, entitled "Delivery System Containing a Gel-Forming Fiber and a Drug" discloses a prolonged-release dosage formulation preferably in a tablet form. The patent purports to describe a composition that includes a gel-forming fiber, preferably hydrocolloid-coated, a biologically-absorbable drug, or other active therapeutic agent which is also preferably hydrocolloid-coated, and a mineral salt such as mineral carbonate or bicarbonate which releases a physiologically-acceptable gas such as carbon dioxide upon ingestion. The composition may optionally also contain phosphoric acid and a dextrose or similar sugar. The aforementioned fiber-containing coating, when in the form of a tablet or other unit dosage form together with the drug or agent, provides a controllable prolonged action drug-delivery system. [0033]U.S. Pat. No. 5,292,518, entitled "Prolonged-Release Drug Table Formulations" discloses a prolonged-release unit dosage formulation or pharmaceutical composition. Preferably, the unit dosage is in the form of a table wherein the composition consists of a gel-forming dietary fiber, a biologically-absorbable drug or other active therapeutic agent, and a disintegrant such a mineral salt e.g. mineral carbonate or bicarbonate, which releases a physiological acceptable gas such as carbon dioxide upon ingestion, and advantageously dextrose or similarly soluble sugar. Furthermore, a physiologically-acceptable acid may optionally be included in the composition to further facilitate the disintegration of the tablet. The dietary fiber-containing composition, when compressed into a table together with the drug and specific disintegrant, provides a prolonged-action drug-delivery system. [0034]U.S. Pat. No. 5,096,714 entitled "Prolonged-release Drug Tablet Formulations" purports to describe a composition to provide a prolonged-action drug-delivery system. The invention comprises a composition consisting of a gel-forming dietary fiber, a biologically-absorbable drug or other active therapeutic agent, disintegrants such as physiological-acceptable edible acids and mineral salts; which upon ingestion release a physiological acceptable gas such as carbon dioxide, as well as dextrose or a similarly soluble sugar. The unit dosage according to the present invention is a tablet. [0035]A study designed to assess the effectiveness of the pharmacokinetics of extended release Caffeine tablets was performed. The study was a single-site, open label, phase 1 study involving 30 healthy subjects with no known allergies or hypersensitivity to Caffeine. Subjects first visited the study site for an initial screening and to consent to the study and on a second occasion to the clinic for Caffeine dosing. According to the dosage schedule, subject was asked to refrain from Caffeine intake for 48 hours prior to the second visit. [0036]Subjects were dosed with 600 mg Caffeine in extended-release capsules and blood sample were taken at 0, 0.5, 1, 2, 3, 6, 8, 10, 11, and 12 hours via an 18-gauge arm-inserted catheter. Urine was collected at 0, 6, and 12 hours. [0037]The half-life of the extended-release Caffeine capsule for the pooled subjects was

7.09 hours. Five subjects had kinetic that did not allow for a calculation of the half-life and were excluded from the pooled subjects. As a comparison, the accepted half-life for Caffeine in a non-extended release format is 3.5 to 5 hours. Utilizing the extend-release format, the release period is approximately 70% longer that the non-extended release format. Furthermore, the maximum concentration of the Caffeine in the serum was 5.76 mg/l with a T.sub.max median and mode of 3 hours. [0038]In the present invention, two examples of which are set forth in greater detail in Examples 1 and 2 below, a diet supplement is provided for burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus. In this manner, consumption by an individual of the supplemental composition provides for a method for burning additional calories, providing sustained energy, supporting weight loss, and/or improving mental focus. According to the example embodiment set forth below, the diet supplement is provided and consumed in the form of a time-release tablet. [0039]The diet supplement set forth in the example embodiment below may contain one or more of the following excipients: guar gum, dicalcium phosphate, calcium carbonate, microcrystalline cellulose, stearic acid, vegetable stearin, citrus pectin, magnesium stearate, silica and film coating (hypromellose, hydroxypropyl cellulose, and polyethylene glycol). [0040]Although the following examples illustrate the practice of the present invention in two of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification of the following examples. EXAMPLES Example 1 [0041]A diet supplement formula for promoting the burning of additional calories, providing sustained energy, supporting weight loss, and/or improves mental focus is provided comprising Green Tea Dry Leaf Extract (0.60000 g) standardized to 45% EGCG, 75% Catechins, 90% Polyphenols, Anhydrous Caffeine (0.40000 g), White Tea Dry Leaf Extract (0.00156 g) standardized to 15% EGCG, 35% Catechins, 50% Polyphenols, and Oolong Tea Dry Leaf Extract (0.00156 g) standardized to 15% EGCG, 25% Catechins, 50% Polyphenols. The present embodiment, taken as a daytime supplement, may provide sustained energy, improve mental focus as well as support weight loss by adding in the burning of additional calories. [0042]Directions: As a dietary supplement, 2 caplets may be taken with an 8 oz. glass of water within one hour following waking in the morning. Example 2 [0043]A diet supplement formula for promoting the burning of additional calories,

providing sustained energy, supporting weight loss, and/or improves mental focus is provided comprising Green Tea Dry Leaf Extract (0.59800 g) standardized to 45% EGCG, 75% Catechins, 90% Polyphenols, Anhydrous Caffeine (0.40000 g), White Tea Dry Leaf Extract (0.00100 g) standardized to 15% EGCG, 35% Catechins, 50% Polyphenols, and Oolong Tea Dry Leaf Extract (0.00100 g) standardized to 15% EGCG, 25% Catechins, 50% Polyphenols. The present embodiment, taken as a daytime supplement, may provide sustained energy, improve mental focus as well as support weight loss by adding in the burning of additional calories. [0044]Directions: As a dietary supplement, 2 caplets may be taken with an 8 oz. glass of water within one hour following waking in the morning.

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United States Patent Application 20080254110

Kind Code A1

HEUER; MARVIN ; et al. October 16, 2008

Composition For Enhancing Immunity and Reducing Inflammation Related to Infections

Abstract

A composition and method for enhancing immunity and reducing or inhibiting inflammation related innate immune system activation while affording the body of a user protection against known detrimental byproducts of immune-response is provided. The composition comprises at least a therapeutically effective amount of vitamin C and extract of Andrographis paniculata. The present invention may additionally comprise vitamin A (Retinyl palmitate), an extract of blackberry, garlic, and an extract of cranberry. A method of same is also provided.

Inventors: HEUER; MARVIN; (MISSISSAUGA, CA) ; CLEMENT; KEN;

(MISSISSAUGA, CA) ; SHAN; CHAUDHURI; (MISSISSAUGA, CA) ; THOMAS; MEGAN; (MISSISSAUGA, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 381 North Service Road West Oakville ON L6M 0H4 CA

Serial No.: 733510

Series Code: 11

Filed: April 10, 2007

U.S. Current Class: 424/451; 424/466; 424/732; 424/754; 424/765; 424/774; 514/168; 514/474

U.S. Class at Publication: 424/451; 424/466; 424/732; 424/754; 424/765;

424/774; 514/168; 514/474

Intern'l Class: A61K 9/48 20060101 A61K009/48; A61K 31/07 20060101 A61K031/07; A61K 31/34 20060101

A61K031/34; A61K 36/00 20060101 A61K036/00; A61K 36/45 20060101 A61K036/45; A61P 29/00

20060101 A61P029/00; A61K 36/73 20060101 A61K036/73; A61K 36/8962 20060101

A61K036/8962; A61K 9/20 20060101 A61K009/20

Claims

1. A composition comprising an effective amount of vitamin C and an extract of Andrographis paniculata wherein the composition inhibits an inflammatory response and substantially simultaneously protects against immune response byproducts and maintains immune cell populations in a user. 2. The composition of claim 1 wherein the vitamin C and the extract of Andrographis paniculata act synergistically through differing molecular mechanisms to inhibit inflammation and enhance immunity. 3. The composition of claim 2 wherein the extract of Andrographis paniculata inhibits the binding of NF-.kappa.B transcription factor to DNA. 4. The composition of claim 2 wherein the vitamin C acts to increase the infiltration of leukocytes and simultaneously protect cells from reactive oxygen species produced during immune responses. 5. The composition of claim 1, further comprising and extract of blackberry. 6. The composition of claim 5 wherein the extract of blackberry acts to inhibit the NF-.kappa.B pathway through a C3G-dependent mechanism. 7. The composition of claim 6 wherein the inhibition of the NF-.kappa.B pathway inhibits inflammation. 8. The composition of claim 1, further comprising an effective amount of garlic. 9. The composition of claim 8 wherein the garlic acts to inhibit TNF-.alpha. mediated T cell adhesion. 10. The composition of claim 9 wherein the inhibition of TNF-.alpha. mediated T cell adhesion effectively reduces immune-mediated cellular damage. 11. The composition of claim 1, further comprising an extract of cranberry.

12. The composition of claim 11 wherein the cranberry extract acts to limit production leukotrienes and prostaglandins through the inhibition of arachidonic acid metabolism. 13. The composition of claim 12 wherein the limited production of leukotrienes and prostaglandins aids in inhibiting inflammation. 14. The composition of claim 1, further comprising vitamin A. 15. The composition of claim 14 wherein the vitamin A acts to inhibit the production of pro-inflammatory cytokines and substantially simultaneously increase production of immune modulating cytokines. 16. A method of inhibiting inflammation in a mammal and substantially protect the mammal from undesired immune-response byproducts, the method comprising the step of administering to said mammal a composition comprising a effective amount of vitamin C and an extract of Andrographis paniculata. 17. The method of claim 16 wherein the vitamin C and the extract of Andrographis paniculata act synergistically through differing molecular mechanisms to inhibit inflammation and enhance immunity. 18. The method of claim 17 wherein the extract of Andrographis paniculata inhibits the binding of NF-.kappa.B transcription factor to DNA. 19. The method of claim 17 wherein the vitamin C acts to increase the infiltration of leukocytes and simultaneously protect cells from reactive oxygen species that are produced during immune responses. 20. The method of claim 16, further comprising the step of administering of an extract of blackberry. 21. The method of claim 20 wherein the extract of blackberry acts to inhibit the NF-.kappa.B pathway through a C3G-dependent mechanism. 22. The method of claim 21 wherein the inhibition of the NF-.kappa.B pathway inhibits inflammation. 23. The method of claim 16 further comprising the step of administering a effective amount of garlic. 24. The method of claim 23 wherein the garlic acts to inhibit TNF-.alpha. mediated T cell adhesion. 25. The method of claim 24 wherein inhibition of TNF-.alpha. mediated T cell adhesion effectively reduces immune-mediated cellular damage.

26. The method of claim 16, further comprising the step of administering an extract of cranberry. 27. The method of claim 26 wherein the cranberry extract acts to limit production leukotrienes and prostaglandins through the inhibition of arachidonic acid metabolism. 28. The method of claim 27 wherein the limited production leukotrienes and prostaglandins aids in inhibiting inflammation. 29. The method of claim 16, further comprising the step of administering a effective amount of vitamin A. 30. The method of claim 29 wherein the vitamin A acts to inhibit the production of pro-inflammatory cytokines and substantially simultaneously increase production of immune modulating cytokines. 31. The composition of claim 1 wherein the composition is provided in an capsule. 32. The method of claim 16 wherein the composition is provided in an effervescent capsule. 33. The composition of claim 1 wherein the composition is provided in an orally acceptable dosage format selected from the group consisting of a tablet, a caplet, a dietary gel and effervescent tablet. 34. The method of claim 16 wherein the composition is provided in an orally acceptable dosage format selected from the group consisting of a tablet, a caplet, a dietary gel and effervescent tablet.

Description

FIELD OF THE INVENTION [0001]The present invention relates to immunity enhancing, anti-inflammatory compounds. More specifically, the present invention relates to a composition comprising a synergistic combination of vitamin C and plant extracts. BACKGROUND OF THE INVENTION [0002]Inflammation, also called the innate immune cascade, is the result of a complex series of molecular signals involving the immune system, usually in response to infection or cellular or tissue damage. Inflammation normally constitutes the body's initiation of healing, however when it is not properly regulated inflammation can result in chronic

diseases such as arthritis. On its own, inflammation is neither good nor bad for the body since inflammation does fight disease. It does, however, indirectly affect the body of an individual at a cost to normal immune and catabolic processes. [0003]The innate cascade, or the innate immune response, is the non-specific response mounted by the immune system and is characterized by the infiltration of cells such as leukocytes such as natural killer cells, mast cells, eosinophils and basophils as well as phagocytes such as neutrophils, macrophages and dendritic cells in response to chemotatic signaling at the site of injury or infection. Molecules secreted by these aforementioned cells such as histamine and various cytokines; and the complement system of circulating proteins assist several aspects of the immune response, however contributing to inflammation through the cellular signaling for infiltration of immune cells to the cell of injury or infection. There are several common clinical symptoms associated with inflammation and the innate immune system including pain, localized redness, swelling and heat at the site of inflammation. [0004]When inflammation persists, pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-.alpha.), are released, which act upon cell-surface receptors, causing increased migration of neutophils, monocytes, activated T-helper and T-cytotoxic cells to the area. The expression of pro-inflammatory cytokines is regulated by a group of transcription factors, belonging to the Nuclear Factor kappa B (NF-.kappa.B) family, which are found in nearly all cells (Guijarro C, Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int. 2001 February;59(2):415-24). NF-.kappa.B activity is stimulated by any number of stimuli including various cytokines, stress, pathogens or chemicals. [0005]What is currently known regarding both the up-stream and down-stream NF-.kappa.B signaling is complex, however the general consensus that the NF-.kappa.B activation pathway is summarized as follows. In the unstimulated state NF-.kappa.B resides, as a dimer, in the cytoplasm sequestered by inhibitor proteins termed `inhibitor of kappa B` (IkB). These IkB proteins mask the domain of NF-.kappa.B that binds to the promoter region of specific target genes, thereby blocking the ability of NF-.kappa.B to initiate transcription. Upon activation by any number of stimuli such as various cytokines, stress, pathogens or chemicals, the NF-.kappa.B portion of the dimer is liberated from IkB via the phosphorylation of IkB via IkB kinases (IKK 1 and 2) through degradation signaling of IkB. The activity of these IKK factors is essential for NF-.kappa.B activity as evidenced by the finding that mice deficient in IKK1 and IKK2 lack all NF-.kappa.B activity (Li Q, Estepa G, Memet S, Israel A, Verma I M. Complete lack of NF-.kappa.B activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev. 2000 July 15;14(14):1729-33). Also, in human cell cultures, blocking the interaction of IKKgamma/NEMO with a specific peptide inhibits NF-.kappa.B activity (May M J, D'Acquisto F, Madge L A, Glockner J, Pober J S, Ghosh S. Selective inhibition of NF-.kappa.B activation by a peptide that blocks the interaction of NEMO with the I.kappa.B kinase complex Science. 2000 September 1;289(5484):1550-4), further solidifying the actions of IKK 1 and IKK 2.

[0006]The liberation of NF-.kappa.B from the dimer allows it to rapidly translocate into the nucleus and commence initiation of transcription by high affinity binding to regulatory .kappa.B motifs in target genes (Blackwell T S, Christman J W. The role of nuclear factor-kappa B in cytokine gene regulation. Am. J. Respir. Cell Mol. Biol. 1997 July;17(1):3-9). [0007]Although it is desirable to reduce the severity of inflammation, some inflammation will naturally occur as a result of the innate immune system mounting a defense against pathogens. During an attack on pathogens, reactive oxygen species, and other byproducts are produced which can be potentially harmful to the body. Therefore, it is desirable to afford the body protection from reactive oxygen species during an immune response. [0008]Furthermore, it is also desirable to increase or maintain the quantity of various types of cells involved in immune responses. [0009]A composition to inhibit inflammation and protect against harmful byproducts of an immune response is disclosed henceforth. A method is same is also presented. SUMMARY OF THE INVENTION [0010]The present invention is directed towards an orally administered anti-inflammatory, immune-cell enhancing and immune-response byproduct protective composition comprising an effective amount of vitamin C and an extract of Andrographis paniculata. In additional aspects of the present invention, one or more of vitamin A (Retinyl palmitate), an extract of blackberry, garlic, ginger (dry rhizome), and an extract of cranberry are added to the composition to provide further synergistic benefits. Both a composition and a method are provided by the present disclosure. DETAILED DESCRIPTION OF THE INVENTION [0011]In the following description, for the purposes of explanations, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one of ordinary skill in the art that the present invention may be practiced without these specific details. [0012]The present invention is directed towards an orally administrable anti-inflammatory composition, comprising an effective amount of vitamin C and a plant extract with known antioxidant properties. The present invention comprises at least vitamin C and an extract of Andrographis paniculata. According to various embodiments, the present invention may further comprise vitamin A (Retinyl palmitate), an extract of blackberry, garlic, ginger (dry rhizome), and an extract of cranberry. Vitamin C [0013]Vitamin C, or L-ascorbic acid, is an essential nutrient required in small amounts in order to allow a range of essential metabolic reactions in animals and plants. The human

body does not make or store vitamin C, therefore they are required to ingest it as part of their daily diests. In addition to the being a strong antioxidant and helping to protect the body from oxidative stress, Ascorbic acid is acts as a coenzyme in necessary enzymatic reactions as well as providing anti-inflammatory benefits (Wannamethee S G, Lowe G D, Rumley A, Bruckdorfer K R, Whincup P H. Associations of vitamin C status, fruit and vegetable intakes, and markers of inflammation and hemostasis. Am J Clin Nutr. 2006 March;83(3):567-74). [0014]Vitamin C concentrations in plasma and leukocytes rapidly decline during infections and stress, therefore supplementation during periods of infection is desired in order to maintain essential metabolic reactions. Furthermore, supplementation of vitamin C is known to improve antimicrobial and natural killer cell activities, in addition to increasing lymphocyte proliferation. Studies of the role of vitamin C in immune response situations have concluded that ascorbic acid helps to protect cells from reactive oxygen species that are produced during immune responses (Wintergerst E S, Maggini S, Hornig D H. Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann Nutr Metab. 2006;50(2):85-94. Epub 2005 Dec. 21. Review). [0015]In a meta-analysis it was concluded that daily supplementation of ascorbic acid, in amounts greater than 100 mg, lowers the incidence, severity and integrated morbidity of the common cold (Pauling L. The significance of the evidence about ascorbic acid and the common cold. Proc Nat Acad Sci USA 1971 November;68(11):2678-81). It is herein understood by the inventors that the incorporation of ascorbic acid in an immune system enhancing supplement will effectively reduce incidence, severity and duration of cold related infections as well as help to maintain vitamin C levels in an individual during infections. [0016]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the immune enhancing, anti-inflammatory composition comprises vitamin C. A serving of the immune enhancing, anti-inflammatory composition comprises from about 0.100 g to about 2.000 g of vitamin C. The preferred dosage of a serving of the immune enhancing, anti-inflammatory composition comprises about 1.100 g of vitamin C. Andrographis Paniculata [0017]Andrographis paniculata is a medicinal herb used traditionally throughout Asia used to treat a number of conditions. Clinical studies have demonstrated an immunity-enhancing benefit of Andrographis paniculata supplementation by reducing the occurrence and severity of common cold symptoms (Caceres D D, Hancke J L, Burgos R A, Sandberg F, Wikman G K. Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study. Phytomedicine. 1999 October;6(4):217-23) as well as upper-respiratory tract infections (Melchior J, Spasov A A, Ostrovskij O V, Bulanov A E, Wikman G. Double-blind, placebo-controlled pilot and phase III study of activity of standardized Andrographis paniculata Herba Nees

extract fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infection. Phytomedicine. 2000 October;7(5):341-50). [0018]One of the active components of Andrographis paniculata extracts is the diterpene, andrographolide. (Shen Y C, Chen C F, Chiou W F. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol. 2002 January;135(2):399-406). Andrographolide is known to inhibit expression of intercellular adhesion molecule-1 which is activated by tumor necrosis factor-alpha (TNF-.alpha.). Furthermore, it has been shown that andrographolide specifically affects the binding of nuclear factor kappa B (NF-.kappa.B) to the DNA, thus inhibiting pro-inflammatory cytokine expression (Hidalgo MA, Romero A, Figueroa J, Cortes P, Concha I I, Hancke J L, Burgos R A. Andrographolide interferes with binding to nuclear factor-.kappa.B to DNA in HL-60-derived neutrophilic cells. Br J Pharmacol. 2005 March;144(5):680-6). Although the previously mentioned research is specific to HL-60-derived neutrophic cell, nuclear Factor kappa B (NF-.kappa.B) is a family of transcription factors found in nearly all cells and is involved with regulating immune responses (Guijarro C, Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int. 2001 February;59(2):415-24). Thus, it is understood by the inventors that andrographolide will confer NF-.kappa.B inhibitory properties in several other cell types as found in the body of an individual. [0019]It is understood by the inventors that the incorporation of an inhibitor of the NF-.kappa.B pathway in an anti-inflammatory composition will attenuate the production of pro-inflammatory cytokines, thus resulting in a reduction in relation to the intensity and duration of inflammation-related symptoms. [0020]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the immune enhancing, anti-inflammatory composition comprises Andrographis paniculata. A serving of the immune enhancing, anti-inflammatory composition comprises from about 0.0001 g to about 1.0 g of Andrographis paniculata. The preferred dosage of a serving of the immune enhancing, anti-inflammatory composition comprises about 0.001 g of Andrographis paniculata. Vitamin A (Retinyl palmitate) [0021]Retinol, the animal form of vitamin A, is a fat soluble, antioxidant that is an essential human nutrient, important for the health of the mucus lining of the nose, mouth, sinuses, and stomach. Vitamin A plays an important role in the maintenance of epithelial tissues which provide a physical barrier for the body to pathogens which can lead to infection. It is also involved in maintaining various immune cell types from both the innate and the acquired immune systems, including the lymphocytes, such as B-cells, T-cells, and natural killer cells, as well as many myelocytes such as neutrophils, macrophages, and myeloid dendritic cells. [0022]A metabolite of vitamin A, all trans-retinoic acid (atRA), has been shown to lower the production of pro-inflammatory cytokines (e.g. IL-12 and TNF-.alpha.) while enhancing the production of the immune modulating cytokine, IL-10 (Wang X, Allen C,

Ballow M. Retinoic Acid Enhances the Production of IL-10 While Reducing the Synthesis of IL-12 and TNF-alpha from LPS-Stimulated Monocytes/Macrophages. J Clin Immunol. 2007 Jan. 26; [Epub ahead of print] (Abstract)). [0023]IL-12 is a cytokine that is naturally produced by macrophages in response to antigenic stimulation. This cytokine stimulates the production of TNF-.alpha. from both T and natural killer cells and mediates the enhancement of the cytotoxic activity of natural killer cells and cytotoxic T lymphocytes. IL-10, on the other hand, is an anti-inflammatory cytokine that inhibits the synthesis of pro-inflammatory cytokines (interferon-gamma, IL-2, IL-3 and TNF-.alpha.), which are produced by macrophages and T helper cells. IL-10 is often released by cytotoxic T-cells to inhibit the action of natural killer cells during the acquired immune response to viral infections. [0024]It is understood by the inventors that incorporation of vitamin A in an anti-inflammatory composition will attenuate the production of pro-inflammatory cytokines while at the same time increasing the production of anti-inflammatory cytokines thus resulting in a decrease in severity and duration of inflammation. [0025]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the immune enhancing, anti-inflammatory composition comprise vitamin A. A serving of the immune enhancing, anti-inflammatory composition comprises from about 1000 IU to about 10000 IU of vitamin A. The preferred dosage of a serving of the immune enhancing, anti-inflammatory composition comprises about 5010 1 U of vitamin A. Blackberry Extract [0026]The blackberry is a widespread and well known shrub; commonly called a bramble in the eastern United States and Europe. Blackberry contains the water-soluble flavonoid, cyanidin-3-glucoside (C3G), which has been shown to be the active compound responsible for blackberries' antioxidant benefits. [0027]In a study of the effects of blue honeysuckle extract on lipopolysaccharide-induced (LPS), a commonly known and used initiator of innate immune responses, inflammation (Jin X H, Ohgami K, Shiratori K, Suzuki Y, Koyama Y, Yoshida K, llieva I, Tanaka T, Onoe K, Ohno S. Effects of blue honeysuckle (Lonicera caerulea L.) extract on lipopolysaccharide-induced inflammation in vitro and in vivo. Exp Eye Res. 2006 May;82(5):860-7. [Epub 2005 Nov. 23] (Abstract)), C3G was shown to inhibit the NF-.kappa.B dependent signaling pathway, thereby reducing the production of pro-inflammatory mediators. [0028]It is understood by the inventors that the incorporation of a known inhibitor of the NF-.kappa.B dependent signaling pathway in an anti-inflammatory composition will effectively reduce production of pro-inflammatory mediators. This lessening of pro-inflammatory cytokine production will result in a lowering of inflammation observed during infections or injury.

[0029]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the immune enhancing, anti-inflammatory composition comprises an extract of blackberry. A serving of the immune enhancing, anti-inflammatory composition comprises from about 0.0001 g to about 1.000 g of an extract of blackberry. The preferred dosage of a serving of the immune enhancing, anti-inflammatory composition comprises about 0.0010 g of an extract of blackberry. Garlic [0030]Garlic is the common name for a species of onion, Allium sativum L. Allium sativum has been found to regulate blood sugar levels and posses some cancer-fighting properties. Moreover, garlic is known to stimulate the body's immune system, particularly through enhancing the macrophages and lymphocytes. Allicin is a powerful antibiotic and anti-fungal compound that is obtained from uncooked, freshly cut garlic cloves. [0031]A study conducted in East Sussex, showed treatment with a garlic supplement, containing allicin, decreased the likelihood of catching a cold in more then half of the volunteers (Josling P. Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey. Adv Ther. 2001 July-August;18(4):189-93 (Abstract)), as well as a decrease the average duration of infections in those whom became afflicted. [0032]Additionally, treatment of mice with allicin was shown to significantly reduced NF-.kappa.B binding to the nucleus (Bruck R, Aeed H, Brazovsky E, Noor T, Hershkoviz R. Allicin, the active component of garlic, prevents immune-mediated, concanavalin A-induced hepatic injury in mice. Liver Int. 2005 June;25(3):613-21 (Abstract)). This reduction in binding was also accompanied with an inhibition of TNF-.alpha. mediated T cell adhesion to the extracellular matrix components as wells as to endothelial cells. It is herein understood by the inventors that the incorporation of an inhibitor of NF-.kappa.B-transcription binding and TNF-.alpha. mediated T cell adhesion, in an anti-inflammatory composition, will effectively reduce immune-mediated cellular damage. [0033]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the immune enhancing, anti-inflammatory composition comprises garlic. A serving of the immune enhancing, anti-inflammatory composition comprises from about 0.0001 g to about 1.0000 g g of garlic. The preferred dosage of a serving of the immune enhancing, anti-inflammatory composition comprises about 0.0010 g of an garlic. Cranberry Extract [0034]Cranberries are the fruit from a species of evergreen dwarf scrubs found in acidic bogs throughout the cooler parts of the Northern Hemisphere. Cranberries are a major commercial crop in the United States and Canada where they are processed into consumer products, like juices and sauces. They are also a source of flavonoids,

chemicals which are known to provide certain health benefits to the immune system. More specifically cranberries provide an abundant source of proanthocyanidins, which are polymers made from multiple anthocyanidin-like molecules known as flavanols. These are called proanthocyanidins because under acidic conditions they are broken apart to yield their constituent anthocyanidins. Proanthocyanidins are also known as leucoanthocyanins, leucodelphinins, leucocyanins, anthocyanogens, epicatechin-catechin polymers or procyanins. [0035]Procyanidin B(2), epicatechin-epicatechin dimer, has been shown to strongly inhibit arachidonic acid inflammatory reactions (Chen D M, Cai X, Kwik-Uribe C L, Zeng R, Zhu X Z. Inhibitory effects of procyanidin B(2) dimer on lipid-laden macrophage formation. J Cardiovasc Pharmacol. 2006 August;48(2):54-70 (Abstract)). Arachidonic acid is metabolized by the cells of the body to produce potent mediators of inflammation, leukotrienes and prostaglandins. [0036]Leukotrienes are secreted lipid mediators of the inflammation response produced by leukocytes from arachidonic acid, which is a precursor for several mediators involved in inflammation. The production of leukotrienes is increased during inflammation and can produce and sustain the symptoms of inflammation (Hedqvist P, Gautam N, Lindbom L. Interactions between leukotrienes and other inflammatory mediators/modulators in the microvasculature. Am J Respir Crit Care Med. 2000 February;161(2 Pt 2):S117-9). It is herein understood by the inventors that the incorporation of an inhibitor of leukotriene biosynthesis in an anti-inflammatory composition will effectively reduce inflammation observed as a result of infection or injury. [0037]In an embodiment of the present invention, which is set forth in greater detail in the examples below, the immune enhancing, anti-inflammatory composition comprises an extract of cranberry. A serving of the immune enhancing, anti-inflammatory composition comprises from about 0.0001 g to about 1.0000 g of an extract of cranberry. The preferred dosage of a serving of the immune enhancing, anti-inflammatory composition comprises about 0.0010 g of an extract of cranberry. [0038]In an embodiment of the present invention, which is set forth in greater detail Example 1, the immune enhancing, anti-inflammatory composition comprises vitamin C, an extract of Andrographis paniculata, vitamin A (Retinyl palmitate), an extract of blackberry, garlic, and an extract of cranberry. The composition is provided in any acceptable and suitable oral dosage form as known in the art to attenuate the intensity and duration of inflammatory reaction as a result of infection or injury, as well as reduce the immune-mediated cell damage associated with infections. The composition may also be provided in a prolonged or extended release format. [0039]While, not wishing to be bound by theory, the present invention is comprised of components that have been shown to inhibit the binding of NF-.kappa.B to the promoter regions of specific target genes, thus reducing the expression of pro-inflammatory cytokines, such as TNF-.alpha. and IL-1. It is herein understood by the inventors that attenuation of the production of pro-inflammatory cytokines will result in decreased

intensity and duration of inflammation-related symptoms. [0040]Furthermore, the present invention comprises components that have been shown to lower the production of pro-inflammatory cytokines, such as IL-12 and TNF-.alpha., while at the same time enhancing the production of the immune modulating cytokine, IL-10 (Wang X, Allen C, Ballow M. Retinoic Acid Enhances the Production of IL-10 While Reducing the Synthesis of IL-12 and TNF-alpha from LPS-Stimulated Monocytes/Macrophages. J Clin Immunol. 2007 Jan. 26; [Epub ahead of print] (Abstract)). It is herein understood by the inventors that limiting the production of pro-inflammatory mediators through various mechanisms while simultaneously increasing immune modulating cytokines, will result more controlled and less severe inflammatory response to injury and infection. The present invention additionally comprises components which are known to afford the body protection against reactive oxygen species. It is herein understood by the inventors that by reducing the severity of an inflammatory response and substantially simultaneously affording the body protection against byproducts of an immune response further cellular damage as a result of an insult will be reduced. The insult may be in the form of a physical insults, or a of a pathogenic nature. [0041]Additionally, as the present invention comprises components that have been shown to significantly reduce the binding of the transcription factor NF-.kappa.B to the promoter region of specific target genes, as well as inhibition of TNF-.alpha. mediated T-cell adhesion to the extracellular matrix components and to endothelial cells, it is herein understood by the inventors that inhibition of NF-.kappa.B-binding and TNF-.alpha. mediated T-cell adhesion, will effectively reduce immune-mediated cell damage. [0042]Further to the aforementioned functions, the present invention comprises components that inhibit arachidonic acid metabolization by the cells of the body to produce potent mediators of inflammation, such as leukotrienes and prostaglandins. It is herein understood by the inventors that this action will effectively reduce inflammation observed as a result of infection or injury. [0043]The present invention is understood by the inventors to inhibit inflammation resulting from stimulation of the innate immune system of an individual by pathogens by substantially simultaneously affecting several mechanisms in the body pertaining to inflammation. Furthermore, the present invention affords the body of a user protection from byproducts of an immune-response which are known to be detrimental to the body of an afflicted mammal. The mechanisms are herein disclosed. [0044]According to various embodiments of the present invention, the nutritional supplement may be consumed in any form. For instance, the dosage form of the nutritional supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid capsule, a tablet, a caplet, an effervescent tablet, or as a dietary gel. The preferred dosage form of the present invention is as a capsule.

[0045]Furthermore, the dosage form of the nutritional supplement is provided in accordance with customary processing techniques for herbal and nutritional supplements in any of the forms mentioned above. Additionally, the nutritional supplement set forth in the example embodiment herein disclosed may contain any appropriate number and type of excipients, as is well known in the art. [0046]Although the following example illustrates the practice of the present invention in one of its illustrative compositional embodiments, the example should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one of skill in the art from consideration of the specifications and example. EXAMPLES [0047]An immune enhancing, anti-inflammatory supplement comprising the following ingredients per serving is prepared for consumption as a effervescent tablet: [0048]about 1.100 g of vitamin C, about 0.001 g of an extract of Andrographis paniculata, about 5010 IU of vitamin A (Retinyl palmitate), about 0.001 g of an extract of blackberry standardized flavonoids, about 0.001 g of garlic, and about 0.0010 g of an extract of cranberry standardized to proanthocyanidins. Extensions and Alternatives [0049]In the foregoing specification, the invention has been described with a specific embodiment thereof; however, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.

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United States Patent Application 20080249063

Kind Code A1

Heuer; Marvin A. ; et al. October 9, 2008

Composition for promoting the maintenance and function of muscle-specific progenitor cells

Abstract

The biological function of skeletal muscle precursor cells in the repair and growth of skeletal muscle in response to exercise is promoted by providing a supplemental composition comprising at least creatine and fucoidin to reinforce biochemical pathways involved in the maintenance of skeletal muscle satellite cells and other myogenic precursors. The composition and method of the present invention induce muscle hypertrophy via satellite cells fusion to muscle fibres and induce a substantially simultaneous replenishment of myogenic precursor cells in response to exercise in a mammal.

Inventors: Heuer; Marvin A.; (Mississauga, CA) ; Clement; Ken; (Mississauga,

CA) ; Chaudhuri; Shan; (Mississauga, CA) ; Molino; Michele; (Mississauga, CA) ; Apong; Philip; (Mississauga, CA) ; Peters; Jason; (Mississauga, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 381 North Service Road West Oakville ON L6M 0H4 CA

Serial No.: 784098

Series Code: 11

Filed: April 4, 2007

U.S. Current Class: 514/54; 514/563; 514/736

U.S. Class at Publication: 514/54; 514/563; 514/736

Intern'l Class: A61K 31/195 20060101 A61K031/195; A61K 31/05 20060101 A61K031/05; A61K 31/715 20060101

A61K031/715; A61P 21/00 20060101 A61P021/00

Claims

1. A composition comprising creatine or derivatives thereof and a source of fucoidan in amounts effective to induce muscle hypertrophy and to induce a substantially simultaneous replenishment of myogenic precursor cells in a mammal. 2. The composition of claim 1, wherein muscle hypertrophy is induced via satellite cells fusion to muscle fibres in a mammal. 3. The composition of claim 1, further comprising a source of sphingolipids. 4. The composition of claim 3, wherein the source of sphingolipids is provided in an amount effective to promote the synthesis of sphingosine 1-phosphate in a mammal. 5. The composition of claim 3, further comprising a source of resveratrol. 6. The composition of claim 5, wherein the source of resveratrol is provided in an amount effective to increase the production of nitric oxide in a mammal. 7. A method comprising at least the step of administering to a mammal a composition comprising creatine or derivative thereof and a source of fucoidan wherein said composition induces muscle hypertrophy and substantially simultaneously induces a replenishment of myogenic precursor cells in said mammal in response to physical exercise. 8. The method of claim 7, wherein the composition further comprises a source of sphingolipids. 9. The method of claim 8, wherein the source of sphingolipids promote the synthesis of sphingosine 1-phosphate in the mammal. 10. The method of claim 7, wherein the composition further comprises a source of resveratrol. 11. The method of claim 10, wherein the source of resveratrol increases the production of nitric oxide in the mammal.

Description

FIELD OF THE INVENTION [0001]The present invention is directed towards a composition and method for inducing muscle hypertrophy via satellite cells fusion to muscle fibres and for inducing a substantially simultaneous replenishment of myogenic precursor cells in response to exercise. BACKGROUND OF THE INVENTION [0002]Body composition, including muscle, is influenced both by genetic factors and environmental stimuli. Important environmental factors or stimuli which effect muscle metabolism include food intake and exercise (Rennie M J. Body maintenance and repair: how food and exercise keep the musculoskeletal system in good shape. Exp Physiol. July 2005;90(4):427-36). Gene and protein expression patterns change in response to stimuli. This results in muscle adaptations such as muscle atrophy (loss) or muscle hypertrophy (gain). The determination of muscle loss or gain is the net effect of both positive and negative factors governing muscle development. [0003]True` muscle hypertrophy can be defined as "as an increase in fiber diameter without an apparent increase in the number of muscle fibers, accompanied by enhanced protein synthesis and augmented contractile force" (Sartorelli V, Fulco M. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE. Jul. 27, 2004;2004(244):re 11). However, postnatal muscle growth is known to involve both myofiber hypertrophy and increased numbers of myonuclei--the source of which are satellite cells (Olsen S, Aagaard P, Kadi F, Tufekovic G; Verney J, Olesen J L, Suetta C, Kjaer M. Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol. Jun. 1, 2006;573(Pt 2):525-34). The growth in the size of muscles after birth is, in reality, a combination of an increase in the actual diameter of a given muscle fiber and an increase in the number of mononuclei. [0004]Satellite cells are a small population of quiescent muscle precursor cells that occupy a "satellite" position immediately outside of muscle fibers (Mauro A. Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol. February 1961;9:493-5). They are normally maintained in a quiescent state and become activated to fulfill roles of routine maintenance, repair and hypertrophy. Satellite cells are thought to be muscle-specific stem cells which are capable of producing large numbers of differentiated progeny as well as being capable of self-renewal (Collins C A, Partridge T A. Self-renewal of the adult skeletal muscle satellite cell. Cell Cycle. October 2005;4(10):1338-41). In order that satellite cells can fulfill their biological role, they must become activated, proliferate, differentiate and fuse to existing muscle cells (Anderson J E. The satellite cell as a companion in skeletal muscle plasticity: currency, conveyance, clue, connector and colander. J Exp Biol. June 2006;209(Pt 12):2276-92). In this way, multinucleate muscle fibers are maintained or increased in size in response to stimuli.

[0005]Activation of satellite cells is essential for their proper function and is defined as "an entry into G1 from quiescence and mobilization" (Anderson J E, Wozniak A C. Satellite cell activation on fibers: modeling events in vivo--an invited review. Can J Physiol Pharmacol. May 2004;82(5):300-10). One of the main factors which has been associated with the activation of satellite cells is nitric oxide (NO) (Anderson J E, Wozniak A C. Satellite cell activation on fibers: modeling events in vivo--an invited review. Can J Physiol Pharmacol. May 2004;82(5):300-10). NO is a small, freely diffusible signaling molecule produced in muscle by neuronal NO-synthase. NO release is regulated by stretching in skeletal muscle and is thought to be responsible for early satellite cell activation in response to muscle injury in proximal and distal muscle fibers (Anderson J E. A role for nitric oxide in muscle repair: nitric oxide-mediated activation of muscle satellite cells. Mol Biol Cell. May 2000;11(5):1859-74). [0006]NO activity is largely controlled by regulating the enzymes responsible for synthesizing NO--Nitric Oxide Synthases (NOSs). All major nitric oxide synthase (NOS) isoforms and splice variants, including a muscle-specific splice variant, are expressed in the skeletal muscles of all mammals (Stamler J S, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev. January 2001;81(1):209-237). Furthermore, the inner lining, or endothelium, of blood vessels uses NO to signal the surrounding smooth muscle to relax. This has the effect of dilating the artery thereby increasing blood flow in the affected region. [0007]NO has also been shown to play an important role in myoblast and satellite cell fusion (Pisconti A, Brunelli S, Di Padova M, De Palma C, Deponti D, Baesso S, Sartorelli V, Cossu G, Clementi E. Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated signaling pathway that controls myoblast fusion. J Cell Biol. Jan. 16, 2006;172(2):233-44) thereby contributing to muscle maintenance and growth. Myoblast fusion is itself a complex process involving migration, recognition and adhesion, each involving several mechanisms and factors. [0008]If stem cells are to function properly, their pools must be maintained. Therefore, a defining feature of stem cells is their ability of self-renewal in addition to being able to produce differentiated cells (Collins C A, Partridge T A. Self-renewal of the adult skeletal muscle satellite cell. Cell Cycle. October 2004;4 (10):1338-41). Research has shown that the pool of satellite cells is maintained not only by self-renewal but also by contributions from the hematopoietic, i.e. blood, system (Doyonnas R, LaBarge M A, Sacco A, Chariton C, Blau H M. Hematopoietic contribution to skeletal muscle regeneration by myelomonocytic precursors. Proc Natl Acad Sci USA. Sep. 14, 2004;101(37):13507-12). [0009]In the case where hematopoietic stem cells contribute to muscle maintenance, the cells must migrate to the area at which they are required for repair or maintenance. This directed migration of stem/progenitor cells is termed `mobilization`. A main mechanism for the mobilization of stem cells is through the release of signaling molecules at the site of the stem cell requirement wherein the stem cells express the corresponding cell surface

receptors (Papayannopoulou T. Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood. Mar. 1, 2004;103(5):1580-5). An important receptor-ligand system for the relationship between the hematopoietic and muscle systems is the CXCR-4 receptor and the secreted chemokine, SDF-1 (Ratajczak M Z, Majka M, Kucia M, Drukala J, Pietrzkowski Z, Peiper S, Janowska-Wieczorek A Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells. 2003;21 (3):363-71). [0010]The foregoing disclosure describes a composition and method for stimulating the aforementioned for purposes of muscle hypertrophy in a mammal. SUMMARY OF THE INVENTION [0011]The present invention comprises, in accordance with an embodiment therof, the administration, to a mammal, of a composition comprising at least creatine or pharmaceutically acceptable derivatives of creatine such as salts and esters of creatine and a source of fucoidan, to induce muscle hypertrophy via satellite cell fusion to muscle fibres and to provide substantially coincident support for the replenishment of myogenic precursor cells in response to exercise. DETAILED DESCRIPTION OF THE INVENTION [0012]In the following description, for the purposes of explanations, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one of ordinary skill in the art that the present invention may be practiced without these specific details. [0013]The present invention is directed towards inducing muscle hypertrophy via satellite cell fusion to muscle fibres and provide substantially coincident support for the replenishment of myogenic precursor cells in response to exercise. The composition and method of the present invention accomplishes said support by encouraging multiple distinct aspects of muscle-specific progenitor cell biology. [0014]As used herein, the term "muscle-specific progenitor cell" refers to any undifferentiated cell that is, or will be, at any time, capable of differentiating into any cell type which contributes to mature, functional adult skeletal muscle. This, for the purposes of the present disclosure, includes satellite cells and any other multi-potent cells such as hematopoietic stem cells which have the potential to contribute to skeletal muscle hypertrophy and growth, development or maintenance. It is herein understood that, despite a lack of consensus regarding nomenclature, there exists a continuum of cell types that lie between a classical pluripotent `embryonic stem cell` capable of giving rise to all cell types on one extreme and a terminally-differentiated cell on the other extreme. It is herein understood that a number of undifferentiated cell types having increasingly limited developmental potential progressing from an embryonic stem cell toward a terminally-

differentiated cell exist between said extremes. Furthermore, it is herein understood that such undifferentiated cells with limited, yet still multiple, developmental possibilities are generally termed `tissue-specific stem cells`. However, undifferentiated cells with only one developmental possibility are generally termed `progenitor cells`. [0015]Ingredients of the present composition may also be fine-milled in order to improve the immediacy of absorption, and thus the rate of bioavailability upon consumption by an individual. The fine-milling techniques and the immediacy of absorption employed in the present invention are disclosed in U.S. patent application Ser. No. 11/709,526, entitled "Method For Increasing The Rate And Consistency Of Bioavailability Of Supplemental Dietary Ingredients" and U.S. patent application Ser. No. 11/709,525, entitled "Method for a Supplemental Dietary Composition Having a Multi-Phase Dissolution Profile," both herein incorporated fully by reference. Briefly, rate of bioavailability is increased via a narrowing of particle size range and a concomitant reduction in the average particle size, improving the immediacy of absorption of said supplemental dietary ingredient. Furthermore, the consistency of dissolution, and thus the absorption of orally administered supplemental dietary ingredients, is improved by the fine-milled process. [0016]As used herein, the term "fine-milled" and/or "fine-milling" refers to the process of micronization. Micronization is a mechanical process that involves the application of force to a particle, thereby resulting in a reduction in the size of the particle. The force, in the case of micronization may be applied in any manner such as, e.g., the collision of particles at high rates of speed, grinding, or by an air-jet micronizer. In a preferred embodiment, fine-milled particles are obtained by jet-milling with nitrogen and compressed air. [0017]As used herein, the term "particle size" refers to the diameter of the particle. The term "average particle size" means that at least 50% of the particles in a sample will have the specified particle size. Preferably, at least 80% of the particles in a sample will have the specified particle size, and more preferably, at least 90% of the particles in a given sample will have the specified particle size. For the purposes of the present invention, the preferred particle size range for fine-milled particles is between 2 and 50 microns. [0018]The size of a particle can be determined by any of the methods known within the art. Methods for particle size determination which may be employed are, for example, sieves, sedimentation, electrozone sensing (Coulter counter), microscopy, and/or Low Angle Laser Light Scattering. The preferred methods for the particle size determination of the present invention are the methods which are most commonly used in the pharmaceutical industry, such as laser diffraction, e.g., via light scattering Coulter Delsa 440SX. [0019]The fine-milling process may be employed in the processing of one or more of the ingredients of the present invention in the dosage forms of tablets, e.g., immediate-release film coated, modified-release and fast-dissolving; capsules, e.g., immediate-release and modified-release; liquid dispersions; powders; drink mixes, etc.

[0020]Creatine [0021]Creatine use has been thoroughly studied and is well-established as a beneficial dietary supplement for replenishing energy stores in working muscle cells (Greenhaff P L, Bodin K, Soderlund K, Hultman E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol. May 1994;266(5 Pt 1):E725-30). The resultant increase in muscular energy stores from creatine supplementation in an individual, combined with physical exercise leads to increased strength, and a reduction in fatigue resulting from high-intensity exercise (Greenhaff P L, Casey A, Short A H, Harris R, Soderlund K, Hultman E. Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci (Lond). May 1993;84(5):565-71) as well as increasing muscle growth (Volek J S, Duncan N D, Mazzetti S A, Staron R S, Putukian M, Gomez A L, Pearson D R, Fink W J, Kraemer W J. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Med Sci Sports Exerc. August 1999;31(8):1147-56). [0022]More recently however, creatine supplementation has been shown to augment the increase in satellite cell numbers in response to exercise (Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen J L, Suetta C, Kjaer M. Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol. Jun. 1, 2006;573(Pt 2):525-34). Furthermore, it was suggested by the results of Olsen et al., that the rate of fusion of satellite cells was also increased in response to creatine supplementation and exercise, adding to an observed increase in the size of muscle fibers. [0023]In various embodiments of the present invention, which are set forth in greater detail in Examples 1 to 4 below, the supplemental composition comprises creatine or derivatives thereof. A serving of the supplemental composition comprises from about 1.00 g to about 10.00 g of creatine or derivatives thereof. The preferred dosage of a serving of the supplemental composition of the present invention comprises about 3.50 g of creatine or pharmaceutically acceptable derivatives of creatine such as salts and esters of creatine. [0024]For example, the creatine may be present in various embodiments of the present invention as creatine salts of malate, maleate, fumarate, tartrate, citrate, succinate, pyruvate, pyroglutamate, glutamate or any other pharmaceutically acceptable salt as known in the art. [0025]Additionally or alternatively, the creatine may be present in various embodiments of the present invention as creatine esters of phosphate, sulphate or any other pharmaceutically acceptable esters as known in the art. [0026]The present invention, as set forth in greater detail in Example 4 below, may further comprise creatine pyroglutamate as a pharmaceutically acceptable derivative of creatine. A serving of the supplemental composition may comprise from about 0.005 g to about 0.10 g of creatine pryoglutamate. The preferred dosage of a serving of the

supplemental composition comprises about 0.01 g of creatine pyroglutamate. [0027]The present invention may further comprise at least a portion of the creatine or pharmaceutically acceptable salts or esters thereof in a fine-milled format. In various embodiments of the present invention, the supplemental composition comprises fine-milled creatine or pharmaceutically acceptable salts or esters of said creatine. A serving of the supplemental composition comprises from about 0.005 g to about 0.05 g of fine-milled creatine or pharmaceutically acceptable salts or esters of said creatine. The preferred dosage of a serving of the supplemental composition comprises about 0.02 g of fine-milled creatine or pharmaceutically acceptable salts or esters of said creatine. [0028]Fucoidan [0029]Fucoidans are naturally-occurring sulfated sugar polymers. They are constituents of edible seaweed and have been consumed by humans for centuries. The specific type of fucoidan differs dependent upon the source. Brown seaweed, in particular, is a source of branched-chain Fucoidans and several species have been used experimentally as a source of Fucoidans including Fucus vesiculosus, Undaria pinnatifida and Laminaria japonica. One of the main and earliest mechanisms elucidated for the activity of Fucoidans has been the binding with L- and P-selectin, members of a family of cell surface receptors involved in the inflammatory response. The selectins mediate the binding and adhesion of cells expressing the selectins to other cells such as those on the endothelium upon cytokine activation (Bevilacqua M P, Nelson R M. Selectins. J Clin Invest. February 1993;91(2):379-87). [0030]A number of potential beneficial uses have been suggested for Fucoidan (Berteau O, Mulloy B. Sulfated fucans, fresh perspectives: structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology. June 2003;13(6):29R-40R). Fucoidan has been shown to have immunomodulating effects by stimulating lymphocytes and macrophages (Choi E M, Kim A J, Kim Y O, Hwang J K. Immunomodulating activity of arabinogalactan and fucoidan in vitro. J Med Food. 2005 Winter;8(4):446-53). As well, Herpes virus reactivation can be inhibited by treatment with Fucoidan (Cooper R, Dragar C, Elliot K, Fitton J H, Godwin J, Thompson K. G F S, a preparation of Tasmanian Undaria pinnatifida is associated with healing and inhibition of reactivation of Herpes. BMC Complement Altern Med. Nov. 20, 2002;2:11). Importantly, orally administered Fucoidan in humans has been shown to increase the number of CXCR-4-expressing stem cells which can replenish the pool of satellite cells (Irhimeh M R et al. Fucoidan and CXCR4+ hemopoietic progenitor stem cell population, 2004, The Sydney Convention Centre North, Darling Harbour, Australian StemCell Centre). Furthermore, fucoidan can induce the mobilization of these stem cells to muscles (Sweeney E A, Priestley G V, Nakamoto B, Collins R G, Beaudet A L, Papayannopoulou T. Mobilization of stem/progenitor cells by sulfated polysaccharides does not require selectin presence. Proc Natl Acad Sci USA. Jun. 6, 2000;97(12):6544-9). This effect is most likely due to the observed effect of increasing SDF-1 plasma levels (Sweeney E A, Lortat-Jacob H, Priestley G V, Nakamoto B, Papayannopoulou T. Sulfated polysaccharides increase

plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood. Jan. 1, 2002;99(1):44-51). [0031]In a preferred embodiment of the present invention, the supplemental composition comprises fucoidan. A serving of the supplemental composition comprises from about 0.01 g to about 0.1 g of fucoidan. The preferred dosage of a serving of the supplemental composition of the present invention comprises about 0.024 g of fucoidan. [0032]In various embodiments of the present invention, which are set forth in greater detail in Examples 1 to 4 below, the supplemental composition comprises Laminaria japonica extract as a source of fucoidan. [0033]Sphinoglipids [0034]Sphingolipids are important constituents of eukaryotic organisms. Complex sphingolipids and their metabolic products are highly bioactive molecules which are involved in the regulation of many important biological functions including cell growth, differentiation and apoptosis (Vesper H, Schmelz E M, Nikolova-Karakashian M N, Dillehay D L, Lynch D V, Merrill A H Jr. Sphingolipids in food and the emerging importance of sphingolipids to nutrition. J Nutr. July 1999;129(7):1239-50). Sphingolipid metabolism and biological function can be modulated by dietary intake of sphingolipids. Supplying supplemental sphingolipids promotes the synthesis of sphingosine 1-phosphate. [0035]Sphingosine 1-phosphate is a bioactive sphingolipid metabolite that has been shown to regulate a number of important biological functions including satellite cell activation (Nagata Y, Partridge T A, Matsuda R, Zammit P S. Entry of muscle satellite cells into the cell cycle requires sphingolipid signaling. J Cell Biol. Jul. 17, 2006;174(2):245-53) and myogenic differentiation (Donati C, Meacci E, Nuti F, Becciolini L, Farnararo M, Bruni P. Sphingosine 1-phosphate regulates myogenic differentiation: a major role for S1P2 receptor. FASEB J. March 2005;19(3):449-51), both of which are processes important for increasing muscle hypertrophy. [0036]In embodiments of the present invention, which are set forth in greater detail in Examples 2 to 4 below, the supplemental composition comprises a source of sphingolipids. A serving of the supplemental composition of the present invention comprises from about 0.005 g to about 0.05 g of a source of sphingolipids. The preferred dosage of a serving of the supplemental composition of the present invention comprises about 0.014 g of a source of sphingolipids. [0037]Resveratrol [0038]Resveratrol is a polyphenol found in many plant sources, most notably in grape skins, grape juice and red wine. One of the most abundant sources is from the roots of Polygonum cuspidatum. In plants, the biological function of resveratrol is as an antibiotic to fight infection. However, as a component of the diet, either as a constituent of plant-

based foods or as a nutritional supplement, resveratrol has been reported to confer many health benefits. The main beneficial function of polyphenols from plant sources is generally attributed to antioxidant activity. However, resveratrol has been shown to increase NO production by tissue-specific induction of NOSs (Das S, Alagappan V K, Bagchi D, Sharma H S, Maulik N, Das D K. Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrol preconditioning of the heart. Vascul Pharmacol. April-May 2005;42(5-6):281-9 Abstract). [0039]In various embodiments of the present invention, which are set forth in greater detail in Examples 3 and 4 below, the supplemental composition of the present invention comprises Polygonum cuspidatum as a source of resveratrol. A serving of the supplemental composition of the present invention comprises from about 0.001 g to about 0.01 g of Polygonum cuspidatum as a source of resveratrol. The preferred dosage of a serving of the supplemental composition of the present invention comprises about 0.004 g of Polygonum cuspidatum as a source of resveratrol. [0040]In a preferred embodiment of the present invention, the composition of the present invention comprises at least creatine or pharmaceutically acceptable derivatives of creatine such as salts and esters of creatine and a source of fucoidan. [0041]In another embodiment of the present invention, the composition of the present invention comprises creatine or pharmaceutically acceptable derivatives of creatine such as salts and esters of creatine, a source of fucoidan and a source of sphingolipids. [0042]In yet another embodiment of the present invention, the composition of the present invention comprises creatine or pharmaceutically acceptable derivatives of creatine such as salts and esters of creatine, a source of fucoidan, a source of sphinoglipids and a source of resveratrol. [0043]The compositions of the present invention may also comprise, in addition to the aforementioned constituents, any number of amino acids in sufficient quantities to be effective in inducing muscle hypertrophy, or salts or esters of said amino acids. For example, proteins, such as whey protein, casein protein, milk proteins, or soy protein, may further be included in the compositions of the present invention in quantities effective to induce muscle hypertrophy. Amino acids and proteins are well known in the art to aid in the generation and repair of muscle protein. [0044]Not wishing to be bound by theory, it is believed that the various components of the present invention will act via multiple, distinct biological pathways to aid in the maintenance and function of myogenic precursor cells in repair and growth of skeletal muscle. The composition of the present invention, when used in conjunction with the method provided herein, induces muscle hypertrophy via satellite cells fusion to muscle fibres and induces the substantially simultaneous replenishment of myogenic precursor cell in response to exercise.

[0045]Additionally, by way of ingestion of the composition of the present invention, a method for enhancing the effectiveness of the immune system in an individual is provided. The method of the present invention comprises at least the step of administering to an individual a therapeutically effective and acceptable amount of the composition of the present invention. [0046]According to additional methods, the compositions of the present invention may be administered to a mammal via any therapeutically acceptable format. For example, the compositions of the present invention may be administered to a mammal intravenously, intramuscularly, or interperitoneally as routes of administration distinct from the aforementioned oral method. These instantly disclosed routes of administration may also be combined with an oral administration of the composition of the present invention as an additional method of administration to a mammal. [0047]According to various embodiments of the present invention, the nutritional supplement may be consumed in any form. For instance, the dosage form of the nutritional supplement may be provided as, e.g., a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid capsule, a tablet, a caplet, or as a dietary gel. The preferred dosage forms of the present invention are as a caplet or as a liquid capsule. The present composition may also be provided in various time-release formats, e.g. a slow-release format, a quick-release format, or a phase-release format, as are known in the art as well. [0048]Furthermore, the dosage form of the nutritional supplement may be provided in accordance with customary processing techniques for herbal and nutritional supplements in any of the forms mentioned above. Additionally, the nutritional supplement set forth in the example embodiments herein may contain any appropriate number and type of excipients, as is well known in the art. [0049]The present nutritional composition or those similarly envisioned by one of skill in the art, may be utilized in methods to support the biological function of muscle-specific progenitor cells required for skeletal muscle recovery and growth in response to exercise. Specifically, the present compositions and method disclosed herein are provided to induce muscle hypertrophy via satellite cell fusion to muscle fibres and induce a substantially coincident replenishment of myogenic precursor cell in response to exercise. [0050]Although the following examples illustrates the practice of the present invention in several of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one of skill in the art from consideration of the specifications and examples. EXAMPLES Example 1 [0051]A nutritional supplement for inducing muscle hypertrophy via satellite cell fusion

to muscle fibres and inducing a substantially simultaneous replenishment of myogenic precursor cell in response to exercise is provided. The nutritional supplement is in the form of caplets. One serving of the nutritional supplement is 7 caplets and each serving comprises: [0052]about 3.5 g of creatine monohydrate (fine-milled), and about 0.024 g of Laminaria japonica extract (standardized to 85% fucoidan). Example 2 [0053]A nutritional supplement for inducing muscle hypertrophy via satellite cells fusion to muscle fibres and inducing a substantially simultaneous replenishment of myogenic precursor cell in response to exercise is provided. The nutritional supplement is in the form of caplets. One serving of the nutritional supplement is 7 caplets and each serving comprises: [0054]about 3.5 g of creatine monohydrate (fine-milled), about 0.024 g of Laminaria japonica extract (standardized to 85% fucoidan), and about 0.0145 g of soy/milk sphingolipids. Example 3 [0055]A nutritional supplement for inducing muscle hypertrophy via satellite cells fusion to muscle fibres and inducing a substantially simultaneous replenishment of myogenic precursor cell in response to exercise is provided. The nutritional supplement is in the form of caplets. One serving of the nutritional supplement is 7 caplets and each serving comprises: [0056]about 3.5 g of creatine monohydrate (fine-milled), about 0.024 g of Laminaria japonica extract (standardized to 85% fucoidan), about 0.0145 g of soy/milk sphingolipids, and about 0.004 g of Polygonum cuspidatum. Example 4 [0057]A nutritional supplement for inducing muscle hypertrophy via satellite cells fusion to muscle fibres and inducing a substantially simultaneous replenishment of myogenic precursor cell in response to exercise is provided. The nutritional supplement is in the form of caplets. One serving of the nutritional supplement is 7 caplets and each serving comprises: [0058]about 2.00 g of creatine monohydrate (fine-milled), about 0.02 g of creatine monohydrate (nanodiffuse), about 0.01 g of creatine pyroglutamate, about 1.30 g of creatine citrate, about 0.001 g of creatine malate, about 0.02 g of creatine pyruvate, about 0.024 g of Laminaria japonica extract (standardized to 85% fucoidan), about 0.0145 g of soy/milk sphingolipids, about 0.004 g of Polygonum cuspidatum, about 0.05 g of L-glycine ethyl ester, about 2.9 g of L-tyrosine, about 0.001 g of L-tyrosine methyl ester, and about 0.002 g of Yohimbe. [0059]Extensions and Alternatives [0060]In the foregoing specification, the invention has been described with specific embodiments thereof. However, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.

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United States Patent Application 20080268075

Kind Code A1

Samuel; Philip ; et al. October 30, 2008

Herbal Composition Weight Management

Abstract

Herbal extracts composition suitable for weight management in mammals is disclosed. The composition comprises a mixture of Garcinia extract, Green tea extract, Green coffee extract and Banaba extract. The method of reducing weight, and treating diabetes in mammals involve oral administration of the composition. The invention further relates to a method of producing and standardizing the individual extract useful for human health.

Inventors: Samuel; Philip; (Bangalore, IN) ; Pescatore; Fred; (New York, NY)

Correspondence Name and Address:

FITZPATRICK CELLA HARPER & SCINTO 30 ROCKEFELLER PLAZA NEW YORK NY 10112 US

Assignee Name and Adress:

IOVATE T. & P. INC. Oakville, Ontario CA

Serial No.: 092161

Series Code: 12

Filed: November 3, 2006

PCT Filed: November 3, 2006

PCT NO: PCT/US2006/042943

371 Date: June 10, 2008

U.S. Current Class: 424/729; 514/299; 514/574

U.S. Class at Publication: 424/729; 514/299; 514/574

Intern'l Class: A61K 36/82 20060101 A61K036/82; A61K 31/437 20060101 A61K031/437; A61K 31/194 20060101

A61K031/194

Claims

1. An oral herbal composition comprising Garcinia extract, Green tea extract, Green coffee extract and Banaba extract, wherein none of the Garcinia extract, Green tea extract, Green coffee extract and Banaba extract are identical, said composition further comprising a comestible excipient. 2. The herbal composition of claim 1, wherein the Garcinia extract is a complex metal salt of (-)hydroxycitric acid. 3. The herbal composition of claim 1, wherein the Green tea extract comprises catechin polyphenols, caffeine and L-theanine. 4. The herbal composition of claim 1, wherein the green coffee extract comprises chlorogenic acids, caffeine and polyphenols. 5. The herbal composition of claim 1, wherein the Banaba extract comprises colosolic acid. 6. The herbal composition of claim 2, wherein the complex metal salt of Garcinia contains greater than 60% (-)hydroxycitric acid. 7. The herbal composition of claim 2, wherein complex metal salt is calcium, magnesium, potassium or zinc salt of (-)hydroxycitric acid. 8. The herbal composition of claim 7, wherein the complex metal salt comprises calcium and the content of calcium is 20 to 80 mg per gram of complex metal salt. 9. The herbal composition of claim 7, wherein the complex metal salt comprises magnesium and the content of magnesium is 60 to 100 mg per gram of complex metal salt. 10. The herbal composition of claim 7, wherein the complex metal salt comprises potassium and the content of potassium is 20 to 100 mg per gram of complex metal salt. 11. The herbal composition of claim 7, wherein the complex metal salt comprises zinc and the content of zinc is 2 to 6 mg per gram of complex metal salt. 12. The method of claim 27, wherein the mammal is an adult human and a daily dose of

the composition comprises 1950 mg to 4875 mg of Garcinia extract. 13. The method of claim 12, wherein the mammal is an adult human and a daily dose of the composition comprises 225 mg to 600 mg of Green tea extract. 14. The method of claim 13, wherein the mammal is an adult human and a daily dose of the composition comprises 345 mg to 865 mg of Green coffee extract. 15. The method of claim 14, wherein the mammal is an adult human and a daily dose of the herbal composition comprises 75 mg to 190 mg of Banaba extract. 16. The method of claim 15, wherein the mammal is an adult human and a daily dose of the herbal composition comprises about 3900 mg Garcinia extract, about 450 mg Green coffee extract, about 600 mg Green tea extract, and about 150 mg of Banaba extract. 17. (canceled) 18. The herbal composition of claim 17, comprising 975 mg of Garcinia extract. 19. The herbal composition of claim 17, comprising 150 mg of Green tea extract. 20. The herbal composition of claim 17, comprising 112 mg of Green coffee extract. 21. The herbal composition of claim 17, comprising 37 mg of Banaba extract. 22. The herbal composition of claim 24, which is selected from the group consisting of a pill, a tablet, and a capsule. 23. (canceled) 24. The herbal composition of claim 1, wherein the excipient is selected from the group consisting of a starch, pre-gelatinized starch, dicalcium phosphate, polyvinyl povidine, magnesium stearate, talc, isopropyl alcohol, carboxymethyl cellulose, hydroxymethylcellulose, ethyl cellulose, isopropyl alcohol and mixtures thereof. 25. The herbal composition of claim 24, further comprising a preservative. 26. The herbal composition of claim 25, wherein the preservative is selected from the group consisting of propylparaben, methylparaben, 2-bromo-2-nitropropane-1,3-diol, salts thereof, and mixtures thereof. 27. A method for reducing body weight in a mammal by orally administering an herbal composition comprising Garcinia extract, Green tea extract, Green coffee extract and Banaba extract, wherein none of the Garcinia extract, Green tea extract, Green coffee extract and Banaba extract are identical.

28. The method of claim 27, wherein the Garcinia extract is a complex metal salt of (-)hydroxycitric acid. 29. The method of claim 27, wherein the Green tea extract is a full spectrum extract containing catechin polyphenols, caffeine and L-theanine. 30. The method of claim 27, wherein the Green coffee extract is a full spectrum extract containing chlorogenic acids, caffeine and polyphenol. 31. The method of claim 27, wherein the Banaba extract contains colosolic acid. 32. (canceled) 33. The method of claim 34, which is selected from the group consisting of a pill, a tablet, and a capsule. 34. The method of claim 32, wherein the orally administered form further comprises an excipient. 35. The method of claim 34, wherein the excipient is selected from the group consisting of a starch, pre-gelatinized starch, dicalcium phosphate, polyvinyl povidine, magnesium stearate, talc, isopropyl alcohol, carboxymethyl cellulose, hydroxymethylcellulose, ethyl cellulose, isopropyl alcohol and mixtures thereof. 36. The method of claim 32, wherein the herbal composition further comprises a preservative. 37. The method of claim 36, wherein the preservative is selected from the group consisting of propyl paraben sodium, methyl paraben sodium, bronopol, and mixtures thereof. 38. The method of claim 16, wherein the orally administered form comprises about 975 mg of Garcinia extract. 39. The method of claim 38, wherein the orally administered form comprises about 150 mg of Green tea extract. 40. The method of claim 39, wherein the orally administered form comprises about 112 mg of Green coffee extract. 41. The method of claim 40, wherein the orally administered form comprises about 37 mg of Banaba extract. 42. The method of claim 16, wherein the herbal composition is administered between 30 and 60 minutes before a meal.

43. The method of claim 16, wherein the herbal composition is administered between 2 hours and 30 minutes before one or more meals within a day. 44. (canceled)

Description

CROSS REFERENCE TO RELATED APPLICATION [0001]This is a non-provisional application of provisional application No. 60/733,924 filed on Nov. 4, 2005, the entire disclosure of which is hereby incorporated by reference and to which application priority is claimed under 35 USC .sctn.120. BACKGROUND OF THE INVENTION [0002]Obesity and overweight are risk factors for type 2 diabetes, hypertension and coronary heart disease that cause morbidity, mortality and high health-care expenditure. [0003]Obesity is the number one nutritional problem in the U.S. An estimated one third of Americans are overweight, with an additional 25 percent being classified as obese. Being overweight significantly increases a person's risk of developing diabetes, heart disease, stroke, and other diseases. The clustering of hyperinsulinemia, dyslipidemia, type 2 diabetes mellitus and hyper tension is called insulin resistance syndrome or metabolic syndrome, and syndrome X. Accordingly, evaluation of obesity for the prevention of syndrome X must be conducted using not only body weight or Body Mass Index (BMI) but also Visceral Fat Accumulation (VFA) [Hayamizu et al. 2003]. [0004]Type 2 diabetes is a chronic disease associated with high rates of morbidity and premature mortality [Nathan et al. 1993]. An alarming increase in the prevalence of type 2 diabetes is expected [Wild et al. 2004] and the need for preventive action is widely acknowledged. While increased physical activity and restriction of energy intake can substantially reduce the incidence of type 2 diabetes [Tuomilehto et al. 2001; Knowler et al. 2002] insight into the role of other lifestyle factors may contribute to additional prevention strategies for type 2 diabetes. [0005]The objective of the present invention is to provide a simultaneous multi approach way to control weight gain by providing a herbal extracts composition which can increase metabolism, thermogenesis, and control diabetes mellitus. Furthermore, it has been established that full spectrum herbal extract has more biological activity than the purified herbal extracts which is devoid of other important micronutrient essential for synergistic effect. As a result the present invention strives to give each component of the herbal extracts composition as a full spectrum extract containing all the biologically active compounds present in the herb.

SUMMARY OF THE INVENTION [0006]The present invention provides a means for weight management in the form of a herbal composition comprising Garcinia cambogia extract, Green tea extract, Green coffee extract and Banaba extract. This composition can be made easily for human consumption to give desired weight loss. The reduction in weight can be achieved through normalized blood sugar levels, decreased fat synthesis, enhanced metabolism, lowering the risk of type 2 diabetes mellitus and antihypertension. BRIEF DESCRIPTION OF DRAWINGS [0007]FIG. 1. is a graphical representation of the change in mean fat mass between baseline and end of study for all three groups. [0008]FIG. 2. is a graphical representation of the change in mean body weight between baseline and end of study for all three groups. [0009]FIG. 3. is a graphical representation of the change in weight from baseline to end of study at each two-week interval for all three groups. [0010]FIG. 4. is a graphical representation of the change in girth from baseline to end of study at each two-week interval for all three groups. [0011]FIG. 5. is a graphical representation of the change in BMI from baseline to end of study at each two-week interval for all three groups. DETAILED DESCRIPTION [0012]Various embodiments of the present invention will be described in detail with reference to the tables and figures, wherein like reference numerals represent like parts throughout the several views. Reference to various embodiments does not limit the scope of the invention, which is limited only by the scope of the claims attached hereto. Additionally, any examples set forth in this specification are not intended to be limiting and merely set forth some of the many possible embodiments for the claimed invention. [0013]The invention relates to herbal extracts composition for weight management and treating diabetes in humans. The invention further relates to a method for producing and standardizing the herbal extracts composition useful for human health. [0014]The herbal composition of the present invention comprises Garcinia extract, Green tea extract, Green coffee extract and Banaba extract. The four extracts are known for their weight control and or other health benefits by different mechanisms but individually none provide all the desired weight control and health benefits. Indeed there arise a need to provide an improved composition for weight control and other preferred health benefits. The purpose of the present invention is to get all the desired benefits using a single herbal composition comprising Garcinia cambogia extract, Green tea extract, Green coffee

extract and Banaba extract. 1. Garcinia Cambogia [0015]Garcinia Cambogia is an exotic fruit grown in South India and has been used for centuries to impart a distinctive sour flavor to Indian cooking. The active ingredient extracted from the Garcinia Cambogia (Indica) is (-)hydroxycitric acid that acts as an appetite suppressant and a lipid-lowering agent, as well as a fat burning agent. One way hydroxycitrate (HCA) present in the fruit rind of Garcinia species reduces weight gain is by competitively inhibiting ATP-citrate lyase, the enzyme responsible for catalyzing the extramitochondrial cleavage of citrate to oxaloacetate and acetyl-CoA, a building block of fatty acid synthesis [U.S. Pat. No. 3,764,692]. The mode of action of HCA appears to center on its ability to slow the regeneration of acetyl CoA--the citrate cleavage enzyme outside the mitochondria in hepatic cells. The effect is to reduce the major source of carbon atoms available for the synthesis of triglycerides, cholesterol and storage of fat without reduction in energy output. Carbon atoms are instead directed to glycogen in the muscles and liver, resulting in more stamina and increased endurance, but not increased body weight. Therefore, HCA is considered to be an effective herbal medicine for controlling obesity and cholesterol by inhibiting lipogenesis in the body. [0016]HCA has also been demonstrated to cause weight loss in rodents by a reduction in food intake rather than through a direct effect on fatty acid synthesis. HCA improves synthesis of glycogen. Increased glycogen levels in the liver and muscles result in reduced appetite and food intake. In an animal study it was concluded that treatment with Garcinia cambogia fruit extract resulted in reduction of both serum and liver lipid to near normalcy. This hypolipidemic property of Garcinia cambogia in turn reduces the peroxidative damage, enhanced by ethanol [Mahendran et al 2001]. In a double-blind, Randomized, Placebo-Controlled trial it was observed that Garcinia cambogia extract had significantly reduced visceral, subcutaneous and total fat areas compared with placebo group [Hayamizu et al 2003]. Therefore, Garcinia cambogia extract is also considered a fat burning agent. [0017]The sodium salt of hydroxycitric acid was studied by the Roche company in the 1970's and was shown to reduce food intake and cause weight loss in rodents. [Sullivan C, 1977] Subsequently, Heymsfield et al. evaluated the calcium salt of hydroxycitric acid in a human clinical trial and found it to be ineffective for weight loss, but failed to measure blood levels. [Heymsfield, S B et al. 1998] The calcium salt of hydroxycitric acid used by Heymsfield may dissociate poorly and may not be absorbed and if so, poor absorption would explain the lack of efficacy in the Heymsfield study. Preuss et al. have published an abstract in which a mixture of calcium and potassium hydroxycitrate was used in a human clinical weight loss trial and was shown to be effective. [Preuss H. G., et al. 2002] Blood levels confirmed absorption of this hydroxycitrate compound. [Loe Y C et al. 2001, Loe Y C et al. 2001] [0018]In various embodiments, the Garcinia extract used in the weight loss composition described herein includes tri-, tetra-, or penta-metal complex salts of hydroxycitric acid.

In an embodiment, the present invention provides a composition comprising a complex metal salt of (-)hydroxycitric acid either alone or in combination with the lactone of HCA and citric acid, wherein the salt comprises mineral supplements such as sodium, potassium, calcium, magnesium and zinc. The HCA complex metal salt is advantageously highly soluble in water, non-hygroscopic and stable in solution. Thereby avoiding problems with poor disassociation and absorption. In alternative embodiments, single complex salts of HCA, such as (Ca, K, Mg, Zn) HCA are included in the composition in alternative to or in addition to the tri-, tetra-, or penta-metal complex salts of hydroxycitric acid. [0019]In another embodiment, the complex metal salt of HCA can be manufactured by keeping the pH of the final product below 4, in which case the product will contain a combination of HCA and the lactone of HCA. This low pH embodiment can be formulated in carbonated beverages in which the pH is maintained below 4 for stability and is suitable for use in food products without affecting their flavor or taste. [0020]The complex metal salt of (-)hydroxycitric acid is prepared from water extract of Garcinia and a mixture of bases selected from oxides, bicarbonates, carbonates, hydroxides of sodium, potassium, calcium, magnesium and zinc. Hydroxycitric acid is a tricarboxylic acid and therefore each HCA molecule can have only up to three different cations. However, some cations (such as the divalent cations Ca.sup.++ and Mg.sup.++) can bond with two different molecules of hydroxycitric acid. Therefore, complex tetra or penta salts can be created using various cations and hydroxycitric acid. In some embodiments, the complex metal salt of hydroxycitric acid consists of two classes of cations, at least one bivalent ion--selected from Calcium (Ca), Magnesium (Mg) and Zinc (Zn) and at least one univalent ion--selected from Potassium (K) and Sodium (Na). [0021]Embodiments of the complex metal salt of HCA can be prepared conveniently as highly soluble, partially soluble, or insoluble salt in water. [0022]A representative general structure of complex salt of HCA is [0023]where (X,X) is selected from (Ca), (Mg), (Zn), (K,K), (Na, Na), (K, Na). [0024]One particular representative example of four salt of Hydroxycitric acid is [0025]One particular representative example of three salt of Hydroxycitric acid is [0026]Five salt of Garcinia acid occurs when the terminal acid groups are bound with one univalent ion and one bivalent ion thereby giving room to the binding of third HCA molecule to the vacant bivalent ion. [0027]One embodiment of complex metal salt of HCA that is essentially non-hygroscopic and stable in solutions includes (by weight percent) 40-75% (-)hydroxycitric acid (HCA) and/or 0.1-30% lactone of (-)hydroxycitric acid, 1-5% citric acid, 1-10% sodium (or alternatively less than 1%), 1-35% Potassium, 1-2-% Calcium, 1-15%

Magnesium, and 0.1-10% Zinc. [0028]Embodiments of the complex metal salt of (-)hydroxycitric acid and/or its lactone can be manufactured by an economically viable process. In one embodiment, the Garcinia rind is extracted with demineralized water at room temperature. In contrast, the boiling or hot extraction used in the art gives an extract liquid that is enriched with unwanted water soluble components. In an embodiment, the unwanted soluble matter is minimized by extracting the rind at room temperature. The extract liquid is treated with a calcium base to neutral pH to get insoluble calcium hydroxycitrate. The HCA content of this insoluble material is approximately 70%. If the neutralization is done at pH more than 7, the HCA content in the resulting insoluble salt will be 50-60%. [0029]The insoluble calcium salt of HCA is mixed with water and 10% sulphurous acid. This step removed the calcium as insoluble calcium sulphite. The pH is maintained at 3.0 to 3.5 during this operation. The art employs phosphoric acid in which case calcium cannot be removed as insoluble salt because both HCA and phosphoric acids are weak acids and an exchange reaction will not take place. The filtrate liquid, light brown in color, is treated with the preferred mixture of metal bases to neutral pH, treated with activated charcoal, filtered and spray dried to get white to off-white complex metal salt of HCA with or without the lactone of HCA. The resulting product is highly soluble in water (more than 20%), non-hygroscopic and stable in solution. Additional description for preparation of complex metal salt HCA from Garcinia is presented in U.S. Application Publication No. US 2004-0259937 A1, herein incorporated by reference. [0030]In an embodiment, the Garcinia extract is a multimineral salt of hydroxy citric acid (4-salt HCA), which is obtained from water extract of Garcinia Cambogia fruit. In one embodiment, the Garcinia extract (4-salt HCA) contains 60 to 65% HCA bound to Ca, K, Mg and Zn moieties. The 4-salt HCA is non-toxic, tasteless, and odorless powder. 2. BANABA (5% COROSOLIC ACID) [0031]Banaba whose botanical name is Lagerstroemia speciosa is a plant that is found in India, The Philippines, and parts of South East Asia. The plant has been traditionally used in the Philippines to treat diabetes and obesity. Banaba extracts have been found to assist in weight loss. In an animal study conducted by Suzuki, et al. it was shown that Banaba extracts induced weight loss and reduced adipose tissue weight. [Suzuki Y et al. 1999] Additionally, a significant drop of up to 65% in hepatic lipids was observed. Extracts of Banaba leaves containing a triterpene compound called Corosolic acid (2-hydroxyursolic acid) have demonstrated the capability to increase glucose uptake and lower blood sugar levels. Murakami et al. showed that Corosolic acid extracted from Banaba leaves stimulate significant glucose transport activity in vitro in Ehrlich ascites tumor cell studies. [Murakami C et al. 1993] Tommasi et al. reported the hypoglycemic action of Corosolic acid. [Tommasi N D et al. 1991] In an 8-week human clinical study conducted in Japan with 26 subjects, it was confirmed by Ikeda et al. that Corosolic acid improved glucose tolerance and improved blood sugar levels. [Ikeda Y et al. 1999] The same study also found that intake of Banaba extract was not harmful to any of the subjects.

3. EXTRACT OF GREEN COFFEE (COFFEE ROBUSTA 25% CHLOROGENIC ACID) [0032]Green Coffee containing phenolic compounds called Chlorogenic acids may have the ability to assist in weight loss by blocking the uptake of carbohydrates. In a human clinical trial Johnston K L et al. evaluated Chlorogenic acids and found that they have an antagonistic effect on glucose absorption in the intestine. [Johnston K L et al. 2003] Chlorogenic acids may also induce weight loss inhibiting glucose creation from the metabolism of carbohydrates, thus inducing higher rates of metabolism in the body. In support of this hypothesis, Arion W J et al. and Hemmerle H et al. showed that Chlorogenic acids inhibit glucose-6-phosphate thereby curtailing the formation of glucose that is formed from gluconeogenesis and glycogenolysis. [Arion W J, et al. 1997, Hemmerle H, et al. 1997] [0033]Tea and coffee are the most widely consumed beverages in the world next to water [Schaefer et al 2004]. Caffeine present in tea and coffee has been shown to increase energy expenditure in humans, and weight loss has reduced risk factors for diabetes in clinical trials [Dulloo et al 1999; Bracco et al 1995]. Caffeine ingestion can acutely reduce glucose storage, but beneficial effects of caffeine on lipid oxidation and uncoupling protein-3 expression have also been suggested. [0034]Coffee contains numerous substances; among them, caffeine, chlorogenic acids, quinides, and magnesium have been shown to affect glucose metabolism in animal or metabolic studies. In a Dutch study, it has been shown that higher coffee consumption was associated with a substantially lower risk of type 2 diabetes. Coffee is the major source of the chlorogenic acids. Intake of chlorogenic acids have been shown to reduce glucose concentrations in rats, and intake of quinides, degradation products of chlorogenic acids, increased insulin sensitivity in rats. Chlorogenic acids contribute to the antioxidant effects of coffee, may reduce hepatic glucose output through inhibition of glucose-6-phosphatase, and may improve tissue mineral distribution through its action as a metal chelator. In addition, chlorogenic acids act as a competitive inhibitor of glucose absorption in the intestine. [0035]Recently, coffee consumption and type 2 diabetes has been reviewed by R. M. van Dam et al [R M Van Dam et al 2005]. The authors systematically reviewed all available epidemiological evidence on the relation between habitual coffee consumption and risk of type 2 diabetes. The authors conclude that their systematic review supports the hypothesis that habitual coffee consumption is associated with a substantially lower risk of type 2 diabetes. 4. EXTRACT OF GREEN TEA (20% L-THEANINE, 35% POLYPHENOLS, 15% EGCG) [0036]Green Tea leaves contain 1-2% by weight of an L-enantiomer stereoisomer of an amino acid. This amino acid is called Theanine and the L-enantiomer stereoisomer is

referred to as L-Theanine. Extracts of Green Tea (Camellia sinensis) containing higher concentrations of L-Theanine may have the ability to assist in weight loss by reducing stress. L-Theanine's stress reducing capabilities are well documented. In human clinical trials, Mason R et al. found that L Theanine stimulates the production of alpha brain waves thereby creating a sense of alertness and relaxation. [Mason R. 2001] It was also found that L-Theanine is involved in the formation of gamma amino butyric acid (GABA). This leads to a relaxation effect as GABA influences the levels of the neurotransmitters, dopamine and serotonin. In another clinical trial Juneja L R et al. confirmed that L-Theanine increase alpha brain wave activity. [Juneja L R 1999] [0037]Oral administration of green tea extract rich in catechin polyphenol and caffeine stimulates thermogenesis and fat oxidation and thus has the potential to influence body weight and body composition via changes in both energy expenditure and substrate utilization. In particular, tea polyphenol have been suggested to play a role in lowering the oxidation of low density cholesterol (LDL), with a consequent decreased risk of heart disease [Weisburger, 1999]. In a cross-cultural correlation study of sixteen cohorts, known as the Seven Countries Study, the average flavanol intake was inversely correlated with mortality rates of coronary heart disease after 25 years of follow-up. [Hertog et al., 1995; Hollman et al., 1999] 5. SAFETY OF Garcinia EXTRACT 4-SALT HCA AND THE OTHER EXTRACTS [0038]Garcinia has been used in foods as a seasoning for many years. There have been several clinical trials showing it to be safe in acute administration at doses as high as 6-30 times the dose used in diet supplements and in extended doses in obese and overweight subjects. [Preuss, H. G. et al. 2004, van Loon, L. et al. 2000, and Heymsfield, S. 1998] Cantox Health Sciences International, Missisauga, ON Canada, was commissioned by Indfrag Limited to do a safety assessment of HCA. After reviewing all the pertinent scientific literature Cantox found no relevant safety issues at doses in the range of 1 to 5 grams a day. HCA has been used for many years in supplements without significant adverse effects. [0039]The safety of Banaba extract is reinforced by the fact that it has been traditionally used in the Philippines for many years. Shirai et al. confirmed Banaba's safety in an in vivo mouse model. [Shirai M. et al. 1994] Green Coffee extract has a history of safe usage as a food ingredient. L-Theanine has a history of safe usage as a dietary supplement. 6. HERBAL COMPOSITION [0040]One embodiment of the herbal composition of the present invention is presented in Table 1. The herbal composition may additionally comprise pharmaceutically acceptable excipients. TABLE-US-00001 TABLE 1 An Embodiment of the Herbal Composition of Present Invention Expressed as Range of Proportion of Extracts Approx. wt % in Name of the

botanical extract Daily Adult Dose composition Garcinia extract 1950 mg to 4875 mg 55% to 88% Green tea extract 225 mg to 600 mg 4% to 19% Green coffee extract 345 mg to 865 mg 6% to 28% Banaba extract 75 mg to 190 mg 1% to 7% [0041]One embodiment of the herbal composition includes a daily dose of about 3900 mg Garcinia 4 salt-HCA, 450 mg Green coffee extract (25% chlorogenic acids), 600 mg Green Tea extract (25% L-Theanine and 35% Polyphenols: 15% EGCG), 150 mg Banaba extract (5% Corosolic acid). [0042]The composition of the present invention, in addition to the active ingredients noted in Table 1 above, may also contain pharmaceutical excipients that are usually employed to prepare any oral dosage form such as powder, tablets, capsules, syrups, and liquids etc. [0043]The excipients, such as starch, pre-gelatinized starch, dicalcium phosphate, polyvinyl povidine, magnesium stearate, talc, ethanol, isopropanol, or other alcohols, carboxymethyl cellulose, hydroxymethylcellulose, ethyl cellulose or other cellulose materials or a mixture thereof may be used. A suitable amount of excipient is employed for formation of the selected oral delivery form. The composition may also contain preservatives, which may be selected from parabens, including paraben salts such as propylparaben sodium and methyl paraben sodium, or 2-bromo-2-nitropropane-1,3-diol (BRONOPOL) or a mixtures thereof. [0044]The Daily Adult Dose presented in Table 1 may be divided into multiple doses administered at time intervals throughout a 24 hour interval. In various embodiments, the daily dose is divided for administration as one, two, three, four, five, or six doses per day. In a further embodiment, the daily dose is orally administered in two divided doses of 2 caplets per dose. In an embodiment, the herbal composition is administered 30-60 minutes before a meal. [0045]Table 2 gives the proportion of the extracts in one embodiment of a tablet or capsule made by mixing the herbal extracts. Two to five tablets or capsules illustrated in Table 2 would provide an adult daily dose. The tablets or capsules are administered in one or more divided doses. In one embodiment, the divided doses are administered from between 2 hours to 30 minutes before one or more meals within a day. TABLE-US-00002 TABLE 2 An Embodiment of the Herbal Composition of Present Invention Expressed as Specific Proportion of Extracts mg per tablet Approx. % by weight of Name of the botanical extract or capsule active ingredients Garcinia extract 975 mg 76.5% Green tea extract 150 mg 11.8% Green coffee extract 112 mg 8.8% Banaba extract 37 mg 2.9% Excipients q.s. -- [0046]The compositions provided above are dependent on the content of the individual extracts, as described below. As is understood, the quantity of an extract included in the present herbal composition is adjusted based on the potency of the individual extract. Alternatively, an extract is standardized according to the contents described below for use

in the present herbal composition. [0047]Garcinia extract contains greater than 60% (-)hydroxycitric acid, less than 5% lactone of (-)hydroxycitric acid, less than 5% citric acid, 4-6% calcium, 4-6% potassium, 8-10% magnesium, 0.4-0.6% zinc and less than 1% sodium. A unique (-)hydroxycitric acid composition is described and claimed in published US patent application US 2004/0259937 herein incorporated by reference. The (-)hydroxycitric acid composition contains 40-75% (-)hydroxycitric acid, 0.1-30% lactone of (-)hydroxycitric acid, 1-5% citric acid, 1-10% sodium, 1-35% potassium, 1-20% calcium, 1-15% magnesium and 0.1-10% zinc. [0048]In one embodiment of the invention, the content of calcium in the Garcinia extract is 20-80 mg per gram of complex metal salt of HCA. In another embodiment, the content of magnesium is 60-100 mg per gram of complex metal salt of HCA. In yet another embodiment, the content of potassium is 20-100 mg per gram of complex metal salt of HCA. In yet another embodiment, the content of zinc is 2-6 mg per gram of complex metal salt of HCA. [0049]The active ingredients in the full spectrum Green tea extract are catechin polyphenols, caffeine, L-theanine and other amino acids. The compositions provided herein utilize a unique full spectrum green tea extract containing greater than 35% polyphenols in which greater than 15% is EGCG, as well as containing approximately 11-13% Caffeine, L-theanine 21-23%. [0050]The active ingredients in the full spectrum extract of green coffee are chlorogenic acids, caffeine and polyphenols. The present invention utilizes a unique full spectrum coffee extract containing a minimum of 25% chlorogenic acids, 1-2% caffeine and greater than 40% polyphenols. [0051]Banaba extract in the present invention contains 5% corosolic acid along with other biologically active constituents. [0052]All the extracts are produced using water or aqueous methanol as solvent. The extract are mixed in the above said proportion along with excipients appropriate for the selected delivery form, in a high speed blender to get uniformity in terms of color and active ingredient. The resulting blend is then tableted, encapsulated or provided in powdered or liquid/syrup form. [0053]In an embodiment consistent with that presented in Table 2 above, the active ingredient contents per tablet is summarized in table 3. TABLE-US-00003 TABLE 3 Active Ingredients Per Tablet Name of the active ingredient mg of active ingredient per tablet (-)Hydroxycitric acid 600-660 mg Polyphenol 90-100 mg EGCG 23-30 mg Caffeine 18-22 mg L-theanine 35-40 mg Chlorogenic acids 25-35 mg Colosolic acid 2-3 mg Calcium 55-65 mg

[0054]HCA, EGCG, Caffeine, L-theanine, Chlorogenic acids and Colosolic acid present in the composition are estimated using High pressure Liquid chromatography (HPLC). Polyphenols are estimated by UV method. [0055]The present invention is described in further detail in the following clinical experiments, which are merely exemplary and are not intended to limit the scope of the invention. 7. EXAMPLE EFFICACY AND SAFETY STUDY OF ACTIVE HCA AND ACTIVE HCA 7.1 Summary [0056]A three-group, parallel, double-blind, randomized, prospective, placebo-controlled, efficacy and safety study was completed to test the weight-reduction effects of Garcinia extract 4-salt HCA (active HCA), and a combination of Garcinia extract 4-salt HCA, Banaba extract, Green Coffee extract, and Green Tea extract (herbal composition) in healthy overweight and obese adults over a 12-week period. Products evaluated during this study are shown in Table 4. [0057]The per-protocol patient population consisted of 91 subjects of Asian ethnicity with BMI values between 28 and 40 kg/m.sup.2. Two-thirds of the patient population were male. One-third of the patient population was female. The ages of the patient population varied from 19 to 58 years of age with a mean age in the mid-to-late thirties. The patients activity level at work ranged from sedentary to heavy. [0058]Patients were randomized between three treatment arms (1:1:1 ratio) and received either Herbal Composition, Active HCA or Placebo for 12 weeks. Study endpoints were evaluated at weeks 0, 2, 4, 6, 8, 10, and 12. [0059]The following products were evaluated. The composition was developed by Indfrag Ltd. with technical assistance from Dr. Fred Pescatore, MD, MPH, CCN. The supplements used in the trial were produced and certified to contain the active ingredients, in the dose specified, by the manufacturer and sponsor of the trial, Indfrag Limited, 1320, 12 Cross, Indiranagar II Stage, Bangalore 560-038, India. Each lot that was individually assayed and the quality of the extracts was ensured by Certificates of Analysis provided by Indfrag Ltd TABLE-US-00004 TABLE 4 Products Evaluated During Study Product Active Formula Active HCA Placebo Contents Garcinia extract 4-salt Garcinia extract 4-salt Cellulose HCA HCA Maltodextrin Banaba Extract Green Coffee Extract Green Tea Extract [0060]The primary efficacy endpoint of the study was reduced fat mass on the dual energy x-ray absorptiometry (DEXA) scan between baseline and 12 week visit and loss of 5% or more of body weight at 12 weeks.

[0061]The secondary efficacy endpoints of the study were: improved body composition, increase lean mass and improved bone density measured by dual energy x-ray absorptiometry (DEXA) scan; reduced abdominal girth; improved lipid profiles; reduced insulin resistance calculated by the HOMA-IR method, ability to maintain a weight loss diet and/or diminished appetite; and improved quality of life based on a quality of life questionnaire (QLQ). [0062]The primary safety endpoints were physical examination (HR, SBP, DBP) and safety laboratory values (Complete Blood count (CBC), BUN, electrolytes, glucose, creatinine, calcium, AST, ALT, Alkaline Phosphatase, total bilirubin, uric acid, urine analysis, cholesterol, triglycerides, TSH, HbA1c, pregnancy test (females), amylase). The secondary safety endpoint was adverse events. [0063]It was found that the significant reduction in body fat and significant body weight loss of 6.18% by the active formula group met the primary efficacy objectives of the study. [0064]On analyzing the efficacy data for the active HCA it was found that body fat reduced significantly thus meeting a primary efficacy objective. Though body weight reduced significantly, the reduction of only 2.91% was not enough to meet the primary efficacy objective of a 5% body weight reduction. [0065]In addition, the active formula group and active HCA groups also showed a significant reduction in abdominal girth which was listed as a secondary efficacy objective. [0066]Furthermore, both active groups also showed a decrease in diastolic blood pressure and AST broadly indicating an improving metabolic profile. [0067]No serious adverse events were noted in this study. 7.2 Efficacy Analysis [0068]7.2.1 Changes in Efficacy Variables from Baseline to End of Study (Per-Protocol Analysis) [0069]Tables 5-13 and FIGS. 1 and 2 (graphs plotted for Primary efficacy variables of fat mass and body weight only) summarize the change in efficacy variables from baseline to end of study (week 12) for each product group. Baseline is defined as the average of available values from the screening and/or randomization visit (prior to dispensation of study product). [0070]Variables are summarized in the format: Mean .+-. Standard Deviation

[0071]Referring to Tables 5-13, the p-values at the row titled `significance (Baseline-12.sup.th week)` of each table indicates whether that product group had a significant average change from baseline--this was calculated using the paired student t test with Bonferroni correction. The p-values in the last column of the table with the heading `Significance comparisons` indicates whether the amount of change was significantly different between the active and placebo groups calculated by ANCOVA (Pre values are the covariates and the significance is calculated on the difference of post values). Nominally significant p-values (p<0.05) are highlighted in bold text. The significance data between active groups and the placebo group is indicated in the row titled `Significance of Active Group compared with Placebo`. For the lipid profile table non-identical superscripts are significant at p<0.05, identical superscripts are not significant using the Student t test with Bonferroni correction. [0072]The estimate of effect size was computed using the partial Eta square method for all groups for all primary efficacy variables and selected secondary efficacy variables. The effect size for each group is indicated in the row titled `Estimate of Effect` for each respective table. [0073]The graphs represent the change in means in all three groups from the baseline to the end of study. The standard deviations were calculated for all the means displayed here, and the standard deviation bars are displayed on the graphs. [0074]This summary is based on the per-protocol population, consisting of all subjects who kept all scheduled visits and who were at least 75% product compliant over the 12-week course of the study. A per-protocol analysis addresses the scientific question of whether the product works in those people who use it as directed. Subjects who do not take the product as directed, or who drop out of the protocol, have not really given the product a "fair chance" of working. Evaluating whether the product is efficacious, a per-protocol analysis therefore looks only at data from those subjects who were compliant with the protocol. Changes in Efficacy Variables (Per-Protocol Population) Primary Efficacy Variables TABLE-US-00005 [0075]TABLE 5 Fat Mass (see related FIG. 1.) Fat mass in gms Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline 32810.37 .+-. 7024.79 30942.46 .+-. 5916.88 33399.41 .+-. 8457.21 End of 12.sup.th week 31107.42 .+-. 7068.24 30245.18 .+-. 6188.14 33697.18 .+-. 8437.30 Difference in Fat mass loss 1702.95 697.28 -297.77 (grams) Significance p < 0.001 p < 0.01 p = 0.293 (Baseline-12.sup.th week) Significance of Active p < 0.001 p = 0.011 -- Group compared with Placebo by ANCOVA Estimate of Effect 67.7% 19.6% 3.9% TABLE-US-00006 TABLE 6 Body Weight (see related FIG. 2.) Body Weight in kg Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline

84.20 .+-. 11.64 83.07 .+-. 10.92 87.63 .+-. 12.14 End of 12.sup.th week 78.99 .+-. 11.95 80.65 .+-. 10.80 87.98 .+-. 12.26 Difference in weight 5.21 2.42 -0.35 loss (kg) Significance p < 0.001 p < 0.001 p = 0.222 (Baseline-12.sup.th week) Significance of Active p < 0.001 p < 0.001 -- Group compared with Placebo Estimate of Effect 76.1% 53.2% 4.5% Secondary Efficacy Variables TABLE-US-00007 [0076]TABLE 7 Lean Mass Lean mass in gms Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline 46388.46 .+-. 9334.98 47389.06 .+-. 10755.03 49707.05 .+-. 8748.72 End of 12.sup.th week 45668.29 .+-. 9255.95 46769.06 .+-. 10049.42 49077.05 .+-. 8446.49 Difference in Lean 720.17 620 630.00 mass loss (grams) Significance p = 0.075 p = 0.044 p = 0.087 (Baseline-12.sup.th week) Significance of p = 0.651 p = 0.729 -- Active Group compared with Placebo TABLE-US-00008 TABLE 8 Bone Density Bone Density in gms Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline 1.144 .+-. 0.102 1.154 .+-. 0.119 1.205 .+-. 0.143 End of 12.sup.th week 1.154 .+-. 0.087 1.151 .+-. 0.111 1.203 .+-. 0.131 Difference in Bone -0.01 0.003 0.002 Density (gms) Significance p = 0.549 p = 0.487 p = 0.747 (Baseline-12.sup.th week) Significance of p = 0.692 p = 0.377 -- Active Group compared with Placebo TABLE-US-00009 TABLE 9 Abdominal Girth Abdominal girth in cms Active Active formula HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline 98.90 .+-. 13.40 99.28 .+-. 12.17 100.50 .+-. 13.39 At 12 weeks 94.50 .+-. 13.07 95.73 .+-. 11.61 99.78 .+-. 13.67 Difference in Girth 4.40 3.55 0.72 change (cm) at 12 weeks Significance p < 0.001 p < 0.001 p = 0.529 (Baseline-12.sup.th week) Significance of p < 0.001 p = 0.002 -- Active Group compared with Placebo Estimate of Effect 42.7% 38.4% 3% TABLE-US-00010 TABLE 10 Lipid Profile Active formula Active HCA Placebo Lipid Parameters (n = 30) (n = 32) (n = 29) Total cholesterol Baseline 181.97 .+-. 25.64.sup.a 172.00 .+-. 29.52.sup.a 183.93 .+-. 30.68.sup.a At 12 weeks 185.43 .+-. 25.69.sup.a 182.35 .+-. 27.32.sup.b 192.79 .+-. 31.81.sup.a Triglycerides Baseline 155.30 .+-. 40.42.sup.a 155.25 .+-. 45.19.sup.a 164.41 .+-. 62.39.sup.a At 12 weeks 157.90 .+-. 52.02.sup.a 150.87 .+-. 51.21.sup.a 164.21 .+-. 83.83.sup.a LDL Baseline 112.33 .+-. 18.87.sup.a 103.94 .+-. 25.71.sup.a 113.07 .+-. 26.77.sup.a At 12 weeks 114.17 .+-. 20.95.sup.a 115.39 .+-. 25.95.sup.b 122.14 .+-. 27.62.sup.a VLDL Baseline 30.78 .+-. 8.03.sup.a 30.95 .+-. 9.05.sup.a 32.71 .+-. 12.47.sup.a At 12 weeks 38.30 .+-. 10.40.sup.a 30.33 .+-. 10.16.sup.a 32.52 .+-. 15.89.sup.a HDL Baseline 38.30 .+-. 7.06.sup.a 35.93 .+-. 8.14.sup.a 37.83 .+-. 6.16.sup.a At 12 weeks 38.37 .+-. 7.34.sup.a 36.45 .+-. 7.25.sup.a 36.59 .+-. 6.14.sup.a TABLE-US-00011 TABLE 11 HOMA-IR HOMA-IR Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline 4.22 .+-. 2.33 4.15 .+-. 2.37 4.26 .+-. 3.03 End of 12.sup.th week 4.71 .+-. 2.79 4.18 .+-. 2.59 5.85 .+-. 3.60 Difference in 1.68 0.16 1.59 HOMA-IR Significance p = 0.238 p = 0.951 p = 0.009 (Baseline-12.sup.th

week) Significance of p = 0.107 p = 0.030 -- Active Group compared with Placebo TABLE-US-00012 TABLE 12 Appetite Test Appetite Test (VAS) Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline 7.47 .+-. 3.87 8.58 .+-. 3.83 8.94 .+-. 3.98 End of 12.sup.th week 5.87 .+-. 2.37 6.69 .+-. 3.63 7.90 .+-. 4.19 Difference in 1.6 1.51 1.04 Appetite test (VAS) Significance p < 0.001 p < 0.001 p = 0.077 (Baseline-12.sup.th week) Significance of p = 0.080 p = 0.301 Active Group compared with Placebo TABLE-US-00013 TABLE 13 Quality of Life (Total Score) Quality of Life (total score) Active formula Active HCA Placebo Study Period (n = 30) (n = 32) (n = 29) Initial 34.50 .+-. 16.94 35.22 .+-. 25.55 32.41 .+-. 22.86 At the End of 12.sup.th 28.43 .+-. 12.88 29.88 .+-. 27.01 28.33 .+-. 21.65 week Difference in 6.07 5.34 4.08 Quality of Life (Total score) Significance p = 0.043 p = 0.051 p = 0.116 (Baseline-12.sup.th week) Significance of p = 0.684 p = 0.808 -- Active Group compared with Placebo [0077]When examining the baseline data it was found that the groups when compared with each other did not show any significant differences as calculated by ANOVA. At the end of the study the tables were analyzed again using ANCOVA to see if there were any differences from the baseline for all three groups. The data from this analysis is displayed below: [0078]a. Fat Mass--F=15.309 and p<0.001 [0079]b. Body Weight--F=118.03 and p<0.001 [0080]Thus, it can be concluded that there were significant changes in the primary efficacy variables between all three groups from baseline to the end of study. [0081]On analyzing the variables in each group it was found that four of the primary efficacy variables underwent statistically significant changes from baseline to end of study: [0082]a. 1702.95 gms decrease in fat mass in Active formula group [0083]b. 697.28 gms decrease in fat mass in Active HCA group [0084]c. 5.21 kg or 6.18% decrease in body weight in Active formula group [0085]d. 2.42 kg or 2.91% decrease in body weight in Active HCA group [0086]The active formula group as well as the active HCA group showed a significant reduction in fat mass and body weight when compared with the placebo group. [0087]The placebo group showed slight but statistically insignificant increases in fat mass and body weight. [0088]Looking at the estimate of effect analysis for fat mass it was found that the active formula had the best reliability factor (67.7%) followed by the active HCA (19.6%) and placebo (3.9%). Thus it can be concluded that the active formula has a higher chance for inducing fat mass loss than the active HCA and placebo. It can also be concluded that the active HCA has a higher chance for inducing fat mass loss than the placebo. [0089]Similarly, looking at the estimate of effect analysis for body weight it was found

that the active formula had the best reliability factor (76.1%) followed by the active HCA (53.2%) and placebo (4.5%). Thus it can be concluded that the active formula has a higher chance for inducing weight loss than the active HCA and placebo. It can also be concluded that the Active HCA has a higher chance for inducing weight loss than the placebo. [0090]Further analysis was carried out on the body weight variable as data was collected at 2 week intervals and not only at the baseline and end of study. This was also tabulated and represented in table 13 below. It was found that the change in body weight was linear for the active formula and active HCA groups while it was non-linear for the placebo group as calculated by Repeated Measures ANOVA. [0091]When examining the baseline data it was found that the groups when compared with each other did not show any significant differences as calculated by ANOVA. At the end of the study the tables were analyzed again using ANCOVA to see if there were any differences from the baseline for all three groups (as the lipid profile variables did not show changes of clinical significance the ANCOVA analysis was not done for these variables). The data from this analysis is displayed below: [0092]a. Lean Mass--F=0.176 and p=0.839 [0093]b. Body Density--F=0.632 and p=0.534 [0094]c. Abdominal Girth--F=8.574 and p<0.001 [0095]d. HOMA-IR--F=3.23 and p=0.049 [0096]e. Appetite test--F=1.089 and p=0.19 [0097]f. Quality of Life Questionnaire--F=0.097 and p=0.908 [0098]Thus, it can be concluded that there was a significant change in the abdominal girth and the HOMA-IR variables between all three groups from baseline to the end of study. None of the other secondary efficacy variables showed any significance between all three groups from baseline to the end of the study. [0099]On analyzing the variables in each group it was found that nine of the secondary efficacy variables underwent statistically significant changes from baseline to end of study: [0100]a. 620 gms decrease in Lean Mass in Active HCA Group [0101]b. 4.40 cms decrease in abdominal girth in Active formula group [0102]c. 3.55 cms decrease in abdominal girth in Active HCA group [0103]d. 10.35 mg/dL increase in total cholesterol in Active HCA group [0104]e. 11.45 mg/dL increase in LDL in Active HCA group [0105]f. 1.59 increase in HOMA-IR in placebo group [0106]g. 1.6 unit decrease in the appetite test (VAS) in the Active formula group [0107]h. 1.89 unit decrease in the appetite test (VAS) in the Active HCA group [0108]i. 6.07 unit decrease in the Quality of Life Questionnaire in Active formula group [0109]The active Formula group showed a significant reduction in abdominal girth when compared with the placebo group. [0110]Even though there was a significant decrease in the Quality of Life score (indicative of a better quality of life) and the Appetite test score (indicative of a reduced appetite) for the active formula group, when compared with placebo group this change was not significant.

[0111]The active HCA group showed a significant decrease in lean mass and appetite test score (Indicative of a reduced appetite), however when compared with the placebo group the changes were not significant. [0112]The active HCA group also showed a significant reduction in abdominal girth when compared with the placebo group. [0113]Finally, the active HCA group also showed an increase in Total Cholesterol and LDL. These changes observed were not clinically significant as the mean values for the Total Cholesterol and LDL are within the NCEP ATP III [National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), NIH Publication No. 02-5215, September 2002] guidelines for all three groups at the end of the study and furthermore, the comparison between these variables and the corresponding placebo variables were not statistically significant. [0114]Even though the active HCA group did not show a significant change in HOMA-IR when compared with placebo there was a significant change. The active HCA has shown a relatively smaller increase in HOMA-IR (Increase of 0.03) than the placebo (Increase of 1.59), thus it can be concluded there is a possibility that the active HCA may arrest increases in HOMA-IR. [0115]Looking at the estimate of effect analysis for abdominal girth it was found that the active formula had the best reliability factor (42.7%) followed by the active HCA (38.4%) and placebo (3%). Thus it can be concluded that the active formula has a higher chance for inducing a decrease in abdominal girth than the active HCA and placebo. It can also be concluded that the active HCA has a higher chance for inducing a decrease in abdominal girth than the placebo. [0116]Further analysis was carried out on the abdominal girth variable as data was collected at 2 week intervals and not only at the baseline and end of study. This was also tabulated and represented in Table 15 below. It was found that the change in abdominal girth was linear for the active formula and active HCA groups while it was non-linear for the placebo group as calculated by Repeated measures ANOVA. 7.2.2 Time-Course of Selected Efficacy Variables and Derived Efficacy Variables (Per-Protocol Population) [0117]Tables 14-16 and related FIGS. 3-5 display the visit-by-visit values of those efficacy variables that were collected at baseline (screening and/or randomization), two week intervals and end of the study. The change in Body Mass Index (BMI) was derived from the body weight and height data and the results are shown in Table 16 with inference and graph shown in FIG. 5. [0118]Such tables and graphs are meaningful only for subjects who had values at all of theses time points, and were therefore based on the per-protocol population.

TABLE-US-00014 TABLE 14 Change in Weight from Baseline to End of Study at Each Two-Week Interval for All Three Groups (see related FIG. 3.) Weight in kg Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Baseline 84.20 .+-. 11.64 83.07 .+-. 10.92 87.63 .+-. 12.14 At 2 weeks 82.86 .+-. 11.86 82.44 .+-. 10.78 87.64 .+-. 12.59 At 4 weeks 82.19 .+-. 11.94 81.88 .+-. 10.67 87.82 .+-. 12.56 At 6 weeks 81.64 .+-. 11.79 81.61 .+-. 11.07 87.41 .+-. 12.32 At 8 weeks 80.89 .+-. 12.03 81.28 .+-. 11.19 87.26 .+-. 12.47 At 10 weeks 80.08 .+-. 12.09 81.32 .+-. 11.16 87.26 .+-. 12.75 At 12 weeks 78.99 .+-. 11.95 80.65 .+-. 10.80 87.98 .+-. 12.26 Difference in weight 5.21 2.42 -0.35 loss (kg) at 12 weeks TABLE-US-00015 TABLE 15 Change in Girth from Baseline to End of Study at Each Two-Week Interval for All Three Groups (see related FIG. 4.) Abdominal girth in cms Active formula Active HCA Placebo Study Period (n = 30) (n = 32) (n = 29) Baseline 98.90 .+-. 13.40 99.28 .+-. 12.17 100.50 .+-. 13.39 At 2 weeks 97.81 .+-. 12.79 98.44 .+-. 12.15 98.29 .+-. 13.65 At 4 weeks 97.07 .+-. 13.38 97.52 .+-. 11.87 99.19 .+-. 12.69 At 6 weeks 96.55 .+-. 13.38 96.82 .+-. 11.55 98.65 .+-. 13.45 At 8 weeks 96.10 .+-. 13.37 96.34 .+-. 11.48 99.16 .+-. 13.75 At 10 weeks 95.45 .+-. 13.41 96.26 .+-. 111.46 98.88 .+-. 14.07 At 12 weeks 94.50 .+-. 13.07 95.73 .+-. 11.61 99.78 .+-. 13.67 Difference in 4.40 3.55 0.72 Girth change (cm) at 12 weeks TABLE-US-00016 TABLE 16 Change in BMI from Baseline to End of Study at Each 2 Week Interval for All Three Groups (see related FIG. 5.) BMI in kg/m.sup.2 Active formula Active HCA Placebo Study Period (n = 30) (n = 32) (n = 29) Baseline 32.99 .+-. 2.68 32.77 .+-. 2.83 33.36 .+-. 3.72 At 2 weeks 32.44 .+-. 2.67 32.55 .+-. 2.87 33.24 .+-. 3.77 At 4 weeks 32.19 .+-. 2.78 32.33 .+-. 2.84 33.30 .+-. 3.74 At 6 weeks 31.98 .+-. 2.78 32.22 .+-. 2.89 33.14 .+-. 3.64 At 8 weeks 31.78 .+-. 2.73 32.09 .+-. 2.98 33.17 .+-. 3.79 At 10 weeks 31.47 .+-. 2.83 32.11 .+-. 2.92 33.09 .+-. 3.79 At 12 weeks 30.96 .+-. 2.79 31.89 .+-. 2.92 33.49 .+-. 3.72 Difference in BMI 2.06 0.88 -0.13 change (kg) at 12 weeks Significance p < 0.001 p < 0.001 p = 0.216 (Baseline-12.sup.th week) Estimate of Effect 65.3% 48.5% 4.8% Interpretation for BMI [0119]The active formula showed a significant drop in BMI of 2.06 kg/m.sup.2. The active HCA showed a significant drop in BMI of 0.88 kg/m.sup.2 and the placebo showed a slight but insignificant increase in BMI. The active formula and active HCA showed a significant change from baseline when compared with placebo as calculated by ANCOVA. [0120]Looking at the estimate of effect analysis for BMI it was found that the Active formula had the best reliability factor (65.3%) followed by the Active HCA (48.5%) and placebo (4.8%). Thus it can be concluded that the Active formula has a higher chance for inducing a decrease in BMI than the Active HCA and placebo. It can also be concluded that the Active HCA has a higher chance for inducing a decrease in BMI than the placebo.

[0121]Further analysis was carried out on the BMI variable as data was collected at 2 week intervals and not only at the baseline and end of study. It was found that the change in BMI was linear for the active formula and active HCA groups while it was non-linear for the placebo group as calculated by Repeated measures ANOVA. 7.2.3 Efficacy Conclusions [0122]It was found that the significant reduction in body fat and significant body weight loss of 6.18% by the active formula group met the primary efficacy objectives of the study. [0123]On analyzing the efficacy data for the active HCA it was found that body fat reduced significantly thus meeting a primary efficacy objective. Though body weight reduced significantly, the reduction of only 2.91% was not enough to meet the primary efficacy objective of a 5% body weight reduction. [0124]In addition, the active formula group and active HCA groups also showed a significant reduction in abdominal girth which was listed as a secondary efficacy objective. [0125]Furthermore, the both active groups also showed a decrease in diastolic blood pressure and AST broadly indicating an improving metabolic profile. 7.3 Study Population and Baseline 7.3.1 Disposition of Subjects and Analytical Populations [0126]Out of 165 subjects who were screened, 49 were screen failures and 116 were randomized into the study. [0127]These 116 subjects were randomized into three groups, using a randomization schedule supplied by the sponsor, The disposition of these subjects is shown in Table 17. TABLE-US-00017 TABLE 17 Disposition of Enrolled Subjects Status of subjects Active formula Active HCA Placebo Total Lost to follow up 1 (2.56%) -- 3 (7.89%) 4 (3.45%) Early Terminate, due to -- -- -- -- Adverse Event(s) Early Terminate, for Other 8 (20.51%) 7 (17.95%) 6 (15.78%) 21 (18.1%) Reasons Completed Study 30 (76.92%) 32 (82.05%) 29 (76.32%) 91 (78.4%) Total 39 (100.0%) 39 (100.0%) 38 (100.0%) 116 (100.0%) p Value .chi..sup.2 = 3.216, p = 0.522 [0128]While the active HCA group had less non-completers than the placebo group (7 vs 9, respectively), these differences are not statistically significant. The Active formula had the same number of non-completers as the placebo group (9 vs 9). [0129]The per-protocol population consists of 91 subjects (78.4%) who were randomized

into three arms (30-Active formula Vs 32-Active HCA Vs 29-Placebo) 7.3.2 Baseline and Demographic Characteristics of the Subjects [0130]As a check on the even randomization of subjects, the demographic, safety and efficacy variables were compared between the Active formula, Active HCA and placebo groups. Table 18 summarizes the characteristics of the subjects at baseline (defined as the average of the values at the screening and randomization visits). [0131]Numeric variables are summarized in the format: [0132]Mean .+-. Standard Deviation [0133]Median (Minimum-Maximum) [0134]Categorical variables are shown as counts and percentages of total within product group. P-values in the last column of the table indicated whether there is a significant difference between the active and placebo groups as calculated by ANOVA. Nominally significant p-values (p<0.05) are highlighted in bold text. TABLE-US-00018 TABLE 18 Baseline and Demographic Characteristics of Subjects (Completed Subjects) Active formula Active HCA Placebo Variable (n = 30) (n = 32) (n = 29) p-value Demographic Variables Age in years 36.73 .+-. 8.34 37.59 .+-. 7.92 34.66 .+-. 8.41 0.321 37 (19-55) (38 (20-50) 33 (20-58) Gender Female 8 (26.6%) 10 (31.3%) 13 (44.8%) 0.310 Male 22 (73.3%) 22 (68.7%) 16 (55.2%) Ethnicity White -- -- -- -- Black -- -- -- -- Asian 30 (100.0%) 32 (100.0%) 29 (100.0%) -- American -- -- -- -- Indian Others -- -- -- Exercise at work Sedentary 7 (23.3%) 6 (18.8%) 10 (34.5%) Light 18 (60.0%) 14 (43.8% 10 (34.5%) 0.272 Moderate 5 (16.7%) 10 (31.3%) 9 (31.0%) -- Heavy -- 2 (6.3%) -- Physical Examination and Vital Signs Height (m) 1.59 .+-. 0.09 1.59 .+-. 0.08 1.62 .+-. 0.08 0.303 1.58 (1.46-1.80) 1.60 (1.45-1.75) 1.63 (1.48-1.78) BMI 32.88 .+-. 2.73 32.77 .+-. 2.83 33.23 .+-. 3.81 0.157 (Kg/m.sup.2) 32.39 (28.5-8.75) 32.93 (27.7-38.8) 32.9 (28.02-38.65) HR 79.10 .+-. 9.27 79.09 .+-. 10.68 80.28 .+-. 8.34 0.860 (beats/min) 76 (66-104) 78 (59-100) 80 (66-100) Systolic BP 123.87 .+-. 13.77 122.19 .+-. 12.63 123.26 .+-. 11.81 0.871 mm Hg 120 (95-154) 120 (104-160) 120 (106-160) Diastolic BP 83.63 .+-. 8.87 83.00 .+-. 9.91 80.34 .+-. 9.29 0.365 mm Hg 80 (69-100) 80 (60-100) 80 (65-100) ECG Normal 30 (100%) 32 (100%) 29 (100%) Abnormal -- -- -- Safety laboratory values Hematocrit 39.71 .+-. 3.69 39.24 .+-. 3.71 40.45 .+-. 3.64 0.442 38 (34.1-47.2) 39.2 (31.5-46.6) 40 (34.50-51.30) Hemoglobin 13.07 .+-. 2.02 13.14 .+-. 1.74 13.80 .+-. 2.01 0.279 12.4 (10.7-17.1) 13.5 (9.9-16.8) 13.8 (11.20-18.4) Na 141.07 .+-. 3.20 141.81 .+-. 2.78 140.21 .+-. 3.74 0.162 142 (127-145) 142 (135-149) 140 (130-148) K 4.53 .+-. 0.38 4.51 .+-. 0.39 4.55 .+-. 0.36 0.920 4.5 (3.8-5.3) 4.6 (3.70-5.30) 4.5 (4.0-5.40) Cl 105.30 .+-. 7.32 105.72 .+-. 4.39 106.14 .+-. 4.43 0.845 101.5 (99-135) 105.5 (100-113) 107.0 (98-113) Creatinine 0.87 .+-. 0.17 0.87 .+-. 0.19 0.89 .+-. 0.21 0.949 0.9 (0.4-1.1) 0.9 (0.50-1.20) 0.9 (0.4-1.30) BUN 17.44 .+-. 5.22 17.48 .+-. 3.87 18.34 .+-. 7.19 0.778 16.5 (6.28-32) 17.5 (9.30-26.0) 16 (10.0-36.0) Ca 9.01 .+-. 0.35 9.25 .+-. 1.46 9.03 .+-. 0.49 0.460 9.1 (8.2-9.6) 9.1 (8.10-17.0) 9.0 (8.10-10.00) AST 27.87 .+-. 10.69 27.41 .+-. 6.76 28.17 .+-. 6.98 0.936 27 (12-69) 27 (17-40) 29 (12-43) ALT 31.42 .+-. 12.30 34.72 .+-. 12.14 42.07 .+-. 17.16 0.016 28 (19-63) 32 (17-71) 38 (17-82) Alk Phos 95.63 .+-. 21.91 95.41 .+-. 21.02 90.45 .+-. 19.03 0.555 101.5 (48-152)

100.0 (45-123) 96 (52-122) Total 0.43 .+-. 0.32 0.36 .+-. 0.25 0.67 .+-. 0.65 0.018 Bilirubin 0.23 (0.1-1.0) 0.21 (0.1-1.20) 0.6 (0.10-3.20) Uric acid 4.78 .+-. 0.91 4.62 .+-. 1.06 5.10 .+-. 1.36 0.241 4.45 (3.8-7.3) 4.3 (3.3-7.6) 4.8 (1.8-8.3) TSH 1.72 .+-. 1.33 2.18 .+-. 1.47 2.19 .+-. 1.24 0.299 1.60 (0.15-5.53) 1.78 (0.3-6.4) 1.78 (0.3-5.2) Amylase 45.21 .+-. 13.17 45.31 .+-. 15.09 45.79 .+-. 14.69 0.986 42 (30-81) 41.5 (30-89) 42 (23-87) WBC 8993.33 .+-. 1364.81 9034.38 .+-. 1580.45 8951.72 .+-. 1452.98 0.976 8900 (6800-13200) 8500 (7000-13700) 8800 (5900-13100) Primary Efficacy Variables Weight 84.20 .+-. 11.64 83.07 .+-. 10.92 87.63 .+-. 12.14 0.285 Kg 83.37 (68.8-106.9) 82.38 (66.57-112.0) 85.46 (68.10-109.8) Fat Mass 32810.37 .+-. 7024.79 30942.46 .+-. 5916.88 33399.41 .+-. 8457.21 0.376 In Gms 32364.5 (19908.0-46185.0) 31180.35 (16682.5-42065.5) 33355.9 (17978.0-47647.30) Secondary Efficacy Variables Lean Mass 46388.46 .+-. 9334.98 47389.06 .+-. 10755.03 49707.05 .+-. 8748.72 0.407 In Gms 43496.6 (33651.0-62982) 44565.5 (30390-69278.10) 50189.40 (38870.0.67210.0) Bone 1.144 .+-. 0.102 1.154 .+-. 0.119 1.205 .+-. 0.143 0.133 Density 1.15 (0.985-1.307) 1.17 (0.934-1.382) 1.18 (0.956-1.597) Abdominal 98.90 .+-. 13.40 99.28 .+-. 12.17 100.50 .+-. 13.39 0.945 girth 99.75 (72.5-130) 99.75 (81.0-127.0) 99.0 (75.50-129.0) Total 181.97 .+-. 25.64 172.00 .+-. 29.52 183.93 .+-. 30.68 0.220 cholestrol 183 (117-256) 177 (108-221) 183 (126-249) Triglycerides 155.30 .+-. 40.42 155.25 .+-. 45.19 164.41 .+-. 62.39 0.719 145 (82-269) 146.5 (69-274) 143 (59-319) LDL 112.33 .+-. 18.87 103.94 .+-. 25.71 113.07 .+-. 26.77 0.256 108.5 (67-161) 106 (51-168) 109 (78-170) VLDL 30.78 .+-. 8.03 30.95 .+-. 9.05 32.71 .+-. 12.47 0.713 28.5 (16.4-53.8) 29.1 (13.80-54.80) 32.0 (11.80-63.80) HDL 38.30 .+-. 7.06 35.93 .+-. 8.14 37.83 .+-. 6.16 0.395 41.5 (21-48) 40.0 (15.0-44.0) 41.0 (26.0-46.0) Blood 83.90 .+-. 19.38 87.09 .+-. 8.22 87.72 .+-. 10.51 0.909 Glucose 85.5 (70-124) 85.0 (70-106) 87.0 (70-113) Insulin 19.47 .+-. 9.59 19.19 .+-. 10.53 19.86 .+-. 13.74 0.974 17.50 (6.8-45) 17.25 (6.20-47.0) 15.70 (4.40-54.0) HOMA-IR 4.22 .+-. 2.21 4.15 .+-. 2.37 4.26 .+-. 3.03 0.987 3.83 (1.39-10.98) 3.61 (1.25-11.11) 3.18 (1.00-13.04) Appetite 7.47 .+-. 3.87 8.20 .+-. 4.05 8.94 .+-. 3.98 0.370 (VAS-score) 7.10 (1-12) 8.80 (0-12) 12.20 (1-12) Quality of 34.50 .+-. 16.94 35.22 .+-. 25.55 32.41 .+-. 22.86 0.879 life score 36.0 (2-72) 35.0 (0-76) 35.0 (0-74) (Total) 7.3.3 Interpretation [0135]Since no product had been administered at either of the baseline evaluations, we would expect baseline subject characteristics to be similar between groups, and this is generally what was found. [0136]The only significant differences between product groups were slightly lower ALT and Total Bilirubin in the active groups compared to the placebo Group (Active formula ALT 31.42 U/L and Total Bilirubin 0.43 mg/dL, Active HCA ALT 34.72 U/L and Total Bilirubin 0.36 mg/dL, Placebo ALT 42.07 U/L and Total Bilirubin 0.67 mg/dL, p=0.016 and 0.018 respectively). This difference may be due to random fluctuations--2 differences would not be an unexpected occurrence in 41 significant tests. [0137]Active groups had a lower body weight (Active Formula 84.20 kg, Active HCA 83.07 Kg and Placebo 87.63 Kg), but the difference was not statistically significant (P=0.285).

7.4 Safety Analysis 7.4.1 Adverse Events [0138]No serious adverse events were noted in this study. [0139]Table 19 lists each of the adverse events reported during this study for completed subjects. Tables 20, 21, and 22 list the severity and probable relationship to each group of each adverse event. TABLE-US-00019 TABLE 19 Adverse Events Reported by Each Group for Completed Subjects Active Active ADVERSE EVENTS formula HCA Placebo Total Constipation 1 1 Headache earlier 1 1 Ankle and foot pain 1 1 Back pain 1 1 2 Boils on his legs due to heat 1 1 Constipation 1 1 Dry cough, severe cold and nose 1 1 block Dryness of mouth 1 1 Fever for 2 days 1 1 Gastric problem 1 1 Gastritis 1 1 Gastritis, back pain 1 1 Increased appetite 1 1 Irregular periods 1 1 Irritation in the chest 1 1 Joint pain, gastritis 1 1 Knee pain 1 1 Leg and back pain 1 1 Leg pain 1 1 2 Leg pain, giddiness 1 1 Loose motion 2 2 Loose motion and stomach upset 1 1 Neck pain 1 1 Palpitation 5-10 minutes every day in 1 1 the morning Skin irritation, asthma 1 1 Tiredness 1 1 2 Tiredness, headache, giddiness 2 2 Tiredness, tension, gastritis 1 1 Weakness 1 1 TABLE-US-00020 TABLE 20 Adverse Events, by Product Group - Active Formula Sl. No Sub No Event Description Severity Relationship 1 49 Leg and back pain Mild Unrelated 2 6 Tiredness Mild Probable 3 13 Gastritis, back pain Severe Certain 4 39 Neck pain Moderate Unrelated 5 40 Skin irritation, asthma Severe Unrelated 6 41 Back pain Moderate Probable 7 87 Palpitation 5-10 minutes Mild Certain every day in the morning and constipation 8 97 Leg pain Moderate Probable 9 111 Leg pain, giddiness Mild Probable TABLE-US-00021 TABLE 21 Adverse Events, by Product Group - Active HCA Sl. No Sub No Event Description Severity Relationship 1 48 Irritation in the chest Moderate Probable 2 50 Gastritis Moderate Probable 3 12 Fever for 2 days Moderate Unrelated 4 14 Loose motion Moderate Unrelated 5 16 Loose motion Moderate Unrelated 6 42 Back pain Moderate Probable 7 47 Tiredness, tension, gastritis Severe Probable 8 44 Dry cough, severe cold and Severe Unrelated nose block 9 110 Constipation Severe Probable 10 83 Increased appetite Moderate Probable TABLE-US-00022 TABLE 22 Adverse Events, by Product Group - Placebo Sl. Sub No No Event Description Severity Relationship 1 8 Weakens Moderate Unrelated 2 7 Irregular periods Moderate Unrelated 3 37 Dryness of mouth Moderate Probable 4 46 Ankle and foot pain Severe Unrelated 5 86 Tiredness Mild Probable 6 53 Knee pain Very Severe Probable 7 80 Joint pain, gastritis Moderate Probable 8 89 Gastric problem Moderate Probable 9 98 Leg pain Moderate Probable 10 74 Constipation Moderate Probable 11 77 Tiredness, headache, giddiness Mild Probable 12 78 Tiredness, headache, giddiness Mild Probable 13 75 Loose motion and stomach upset Moderate Probable 14

76 Headache earlier Moderate Unrelated 15 85 Boils on his legs due to heat Severe Probable [0140]A total of 34 adverse events were experienced by the subjects in the per protocol population. Of this, the placebo group reported 15 adverse events. The Active formula group reported 9 adverse events and the Active HCA group reported 10 adverse events. There was no significance between the three groups (p=0.193) nor was there significance when comparing the Active formula group with placebo (p=0.089) and Active HCA with placebo (p=0.179). [0141]Even though there was no significant difference between the three groups, a general trend was observed whereby the adverse events can be grouped into two main categories--joint pain and gastritis. However, these events appeared across all three groups and could not be attributed to any one group. [0142]Adverse events were not responsible for any early terminations for any of the subjects for any of the groups. 7.4.2 Safety Laboratory Values and Vital Signs [0143]Tables 23, 24, 25, and 26 summarize the change in safety lab values from baseline to end of study (week 12) for each product group. Baseline is defined as the average of available values from the screening and/or randomization visit (prior to dispensation of study product). [0144]Variables are summarized in the format: [0145]Mean .+-. Standard Deviation [0146]For the tables corresponding to Physical examination and vital signs the significance data is represented at the bottom most row of the tables--this has been calculated by repeated measures ANOVA. For the tables corresponding to safety lab values non-identical superscripts are significant at p<0.05, identical superscripts are not significant using the Student t test with Bonferroni correction. [0147]This summary is based on the completed subjects. TABLE-US-00023 TABLE 23 Hemodynamics (Pulse Rate) Active formula Active HCA Placebo Time Period (n = 30) (n = 32) (n = 29) Baseline 79.10 .+-. 9.27 79.09 .+-. 10.68 80.28 .+-. 8.35 At 2 weeks 77.27 .+-. 10.80 77.75 .+-. 10.06 78.76 .+-. 9.03 At 4 weeks 77.37 .+-. 10.93 80.44 .+-. 8.36 79.32 .+-. 9.81 At 6 weeks 76.80 .+-. 7.85 76.75 .+-. 7.91 77.52 .+-. 7.51 At 8 weeks 76.33 .+-. 8.21 76.28 .+-. 10.89 77.75 .+-. 10.05 At 10 weeks 76.17 .+-. 8.29 76.78 .+-. 8.85 75.97 .+-. 8.66 At 12 weeks 75.20 .+-. 7.22 74.06 .+-. 7.93 74.76 .+-. 6.25 Significance by p = 0.582 p = 0.031 p = 0.115 Repeated Measures ANOVA TABLE-US-00024 TABLE 24 Hemodynamics (Systolic Blood Pressure) Active formula Active HCA Placebo Time Period (n = 30) (n = 32) (n = 29) Baseline 123.87 .+-. 13.77

122.19 .+-. 12.64 123.28 .+-. 11.81 At 2 weeks 121.97 .+-. 10.89 122.56 .+-. 10.56 122.38 .+-. 12.01 At 4 weeks 122.27 .+-. 11.41 121.13 .+-. 10.05 124.04 .+-. 12.82 At 6 weeks 119.30 .+-. 12.15 118.63 .+-. 12.32 119.41 .+-. 11.66 At 8 weeks 118.43 .+-. 11.05 118.66 .+-. 12.79 121.71 .+-. 9.06 At 10 weeks 118.80 .+-. 9.41 118.56 .+-. 12.06 120.00 .+-. 11.51 At 12 weeks 122.53 .+-. 12.83 117.97 .+-. 9.23 120.45 .+-. 12.05 Significance by p = 0.125 p = 0.302 p = 0.158 Repeated Measures ANOVA TABLE-US-00025 TABLE 25 Hemodynamics (Diastolic Blood Pressure) Active formula Active HCA Placebo Time Period (n = 30) (n = 32) (n = 29) Baseline 83.63 .+-. 8.86 83.00 .+-. 9.91 80.34 .+-. 9.29 At 2 weeks 78.73 .+-. 9.68 79.88 .+-. 7.62 80.28 .+-. 10.94 At 4 weeks 83.13 .+-. 9.41 79.06 .+-. 9.19 81.79 .+-. 8.49 At 6 weeks 79.87 .+-. 9.83 79.22 .+-. 9.85 79.24 .+-. 9.25 At 8 weeks 78.00 .+-. 9.63 78.31 .+-. 10.16 79.11 .+-. 8.49 At 10 weeks 78.27 .+-. 8.58 78.31 .+-. 10.16 78.41 .+-. 7.82 At 12 weeks 79.63 .+-. 9.81 77.00 .+-. 6.85 78.41 .+-. 10.64 Significance by p = 0.012 p = 0.016 p = 0.755 Repeated Measures ANOVA TABLE-US-00026 TABLE 26 Safety Lab Values Active formula Active HCA Placebo Variable/time period (n = 30) (n = 32) (n = 29) Hematocrit Baseline 39.71 .+-. 3.69.sup.a 39.24 .+-. 3.71.sup.a 40.45 .+-. 3.64.sup.a At 12 weeks 40.88 .+-. 4.01.sup.b 40.33 .+-. 3.60.sup.a 41.84 .+-. 4.02.sup.a FBS Baseline 83.90 .+-. 19.38.sup.a 87.09 .+-. 8.22.sup.a 87.72 .+-. 10.51.sup.a At 12 weeks 86.27 .+-. 7.79.sup.a 83.94 .+-. 7.81.sup.a 85.17 .+-. 8.22.sup.a Insulin Baseline 19.47 .+-. 9.59.sup.a 19.19 .+-. 10.53.sup.a 19.86 .+-. 13.74.sup.a At 12 weeks 21.73 .+-. 12.31.sup.a 21.07 .+-. 12.04.sup.a 28.17 .+-. 17.99.sup.b Bone Density Baseline 1.144 .+-. 0.102.sup.a 1.154 .+-. 0.119.sup.a 1.205 .+-. 0.143.sup.a At 12 weeks 1.154 .+-. 0.087.sup.a 1.151 .+-. 0.111.sup.a 1.203 .+-. 0.131.sup.a HOMA-IR Baseline 4.22 .+-. 2.21.sup.a 4.15 .+-. 2.37.sup.a 4.26 .+-. 3.03.sup.a At 12 weeks 4.71 .+-. 2.79.sup.a 4.18 .+-. 2.59.sup.a 5.85 .+-. 3.60.sup.b Hemoglobin Baseline 13.07 .+-. 2.02.sup.a 13.14 .+-. 1.74.sup.a 13.80 .+-. 2.01.sup.a At 12 weeks 13.24 .+-. 1.94.sup.a 13.09 .+-. 1.68.sup.a 13.67 .+-. 2.01.sup.a WBC Baseline 8993.33 .+-. 1364.81.sup.a 9034.38 .+-. 1580.45.sup.a 8951.72 .+-. 1452.98.sup.a At 12 weeks 8590.00 .+-. 1176.01.sup.a 8125.81 .+-. 855.17.sup.b 8803.45 .+-. 1868.82.sup.a Na Baseline 141.07 .+-. 3.20.sup.a 141.81 .+-. 2.78.sup.a 140.21 .+-. 3.74.sup.a At 12 weeks 138.87 .+-. 2.32.sup.b 139.26 .+-. 2.76.sup.b 140.00 .+-. 2.66.sup.a K Baseline 4.53 .+-. 0.38.sup.a 4.51 .+-. 0.39.sup.a 4.55 .+-. 0.36.sup.a At 12 weeks 4.48 .+-. 0.27.sup.a 4.43 .+-. 0.38.sup.a 4.53 .+-. 0.35.sup.a CI Baseline 105.30 .+-. 7.32.sup.a 105.72 .+-. 4.39.sup.a 106.14 .+-. 4.43.sup.a At 12 weeks 104.53 .+-. 4.04.sup.a 104.45 .+-. 3.92.sup.a 104.28 .+-. 3.37.sup.b Creatinine Baseline 0.87 .+-. 0.17.sup.a 0.87 .+-. 0.19.sup.a 0.89 .+-. 0.21.sup.a At 12 weeks 0.89 .+-. 0.16.sup.a 0.84 .+-. 0.19.sup.a 0.93 .+-. 0.17.sup.a BUN Baseline 17.44 .+-. 5.22.sup.a 17.48 .+-. 3.87.sup.a 18.34 .+-. 7.19.sup.a At 12 weeks 16.73 .+-. 3.52.sup.a 17.05 .+-. 4.16.sup.a 16.14 .+-. 4.49.sup.a AST Baseline 27.87 .+-. 10.69.sup.a 27.41 .+-. 6.76.sup.a 28.17 .+-. 6.98.sup.a At 12 weeks 24.40 .+-. 6.45.sup.a 23.29 .+-. 7.26.sup.b 25.07 .+-. 7.29.sup.a ALT Baseline 31.42 .+-. 12.30.sup.a 34.72 .+-. 12.14.sup.a 42.07 .+-. 17.16.sup.a At 12 weeks 30.71 .+-. 12.74.sup.a 31.61 .+-. 11.29.sup.a 39.00 .+-. 17.41.sup.a Alk Phos Baseline 95.63 .+-. 21.91.sup.a 95.41 .+-. 21.02.sup.a 90.45 .+-. 19.03.sup.a At 12 weeks 95.06 .+-. 16.94.sup.a 93.58 .+-. 17.29.sup.a 93.03 .+-. 18.18.sup.a Total Baseline 0.43 .+-.

0.32.sup.a 0.36 .+-. 0.25.sup.a 0.67 .+-. 0.65.sup.a Bilirubin At 12 weeks 0.38 .+-. 0.30.sup.a 0.34 .+-. 0.24.sup.a 0.60 .+-. 0.47.sup.a Uric Acid Baseline 4.78 .+-. 0.91.sup.a 4.62 .+-. 1.06.sup.a 5.10 .+-. 1.36.sup.a At 12 weeks 4.76 .+-. 1.11.sup.a 4.56 .+-. 1.04.sup.a 4.89 .+-. 1.40.sup.a TSH Baseline 1.72 .+-. 1.33.sup.a 2.18 .+-. 1.47.sup.a 2.19 .+-. 1.24.sup.a At 12 weeks 1.65 .+-. 0.83.sup.a 1.92 .+-. 0.76.sup.a 1.94 .+-. 0.84.sup.a Amalyse Baseline 45.21 .+-. 13.17.sup.a 45.31 .+-. 15.09.sup.a 45.79 .+-. 14.69.sup.a At 12 weeks 43.72 .+-. 15.48.sup.a 46.13 .+-. 19.54.sup.a 45.55 .+-. 16.22.sup.a [0148]Three of the physical examination variables underwent statistically significant changes from baseline to end of study: [0149]a. 3.9 beats/min decrease in pulse rate in active formula group [0150]b. 4 mm Hg decrease in Diastolic Blood Pressure in active Formula group [0151]c. 6 mm Hg decrease in Diastolic Blood Pressure in active HCA group [0152]The change observed in the pulse rate was not clinically significant as the mean values are within the normal range for all three groups at the end of the study. Even though there was a significant decrease in the pulse rate of the active HCA this can be attributed to random fluctuations. From a safety perspective, there were no clinically significant changes in the diastolic blood pressure in the active formula group and the active HCA group. [0153]Furthermore, the comparison between the above variables to the corresponding placebo variables were not statistically significant. [0154]Eight of the safety laboratory variables underwent statistically significant changes from baseline to end of study: [0155]a. 2.2 mEq/L decrease in Na in active formula group [0156]b. 2.55 mEq/L decrease in Na in active HCA group [0157]c. 1.86 mEq/L decrease m Cl in placebo group [0158]d. 4.12 U/L decrease in AST in active HCA group [0159]e. 1.17% increase in Hematocrit in active formula group [0160]f. 8.31 .mu.u/ml increase in Insulin in placebo group [0161]g. 1.59 increase in HOMA-IR in placebo group [0162]h. 908.57 thousands/.mu.l decrease in WBC in Active HCA group [0163]When comparing the above variables to the corresponding placebo variables it was found that there was no statistical significance for Na, Cl, Hematocrit, or AST. However, the active HCA group showed a significant decrease in WBC. [0164]From a safety perspective the changes observed were not clinically significant as the mean values for the Na, Cl, AST and WBC are within the normal range for all three groups at the end of the study. The increase in Hemocrit in the active formula group can be attributed to intra-inter observer variability and therefore is also not clinically significant from a safety perspective. [0165]The increase in Insulin and the consequent increase in HOMA-IR in the placebo group can be attributed to a few outliers in the placebo group. Three outliers have been identified and their details are as follows: [0166]a. Subject No. 54 had a baseline Insulin value of 31 .mu.u/ml and an end of study insulin value of 66 .mu.u/ml [0167]b. Subject

No. 89 had a baseline Insulin value of 14.2 .mu.u/ml and an end of study insulin value of 49.2 .mu.u/ml [0168]c. Subject No. 113 had a baseline Insulin value of 20 .mu.u/ml and an end of study insulin value of 46 .mu.u/ml [0169]If these outliers are dropped then the insulin and HOMA-IR increases will also become insignificant for the placebo group. 7.4.3 Safety Conclusions [0170]Four safety values showed nominally significant average changes from baseline to end of study in the active formula group (Decrease in Pulse, Diastolic blood pressure, Na, and an increase in Hematocrit). [0171]Four safety values showed nominally significant average changes from baseline to end of study in the active HCA group (Decrease in Diastolic blood pressure, AST, Na and WBC). [0172]Three safety values showed nominally significant average changes from baseline to end of study in the placebo group (increase in Insulin and HOMA-IR and a decrease in Cl). [0173]There were no significant differences between the Active groups and placebo for all variables except WBC. The Active HCA group did show a decrease in WBC as compared to placebo. However, this change was not of a clinically important magnitude. [0174]Generally, this study provided no reason for safety concerns. 7.4.4 Efficacy Analysis [0175]In addition, the active formula group and active HCA groups also showed a significant reduction in abdominal girth which was listed as a secondary efficacy objective. [0176]Furthermore, the both active groups also showed a decrease in diastolic blood pressure and AST broadly indicating an improving metabolic profile. 7.5 Compliance [0177]Compliance was analyzed from baseline to the end of study and for every two week period as well. Percentage compliance for the total and 2 week time period (Baseline to end of study) was calculated in the following manner: [0178]a. The number of pills returned was divided by the total pills dispensed during the corresponding period. [0179]b. The above number was then subtracted from the number 1 and the resulting number was multiplied by 100.Table 27 summarizes these compliance measures and compares them between product groups. Numerical data is presented in the format: [0180]Mean .+-. Standard Deviation

TABLE-US-00027 [0180]TABLE 27 Compliance (%) by Product (from Returned - Product Count) Active formula Active HCA Placebo Study period (n = 30) (n = 32) (n = 29) Week 2 84.53 .+-. 17.71 84.11 .+-. 10.64 85.68 .+-. 16.45 Week 4 84.44 .+-. 17.57 86.02 .+-. 8.27 88.36 .+-. 10.97 Week 6 79.39 .+-. 22.49 84.67 .+-. 11.97 89.60 .+-. 10.92 Week 8 90.74 .+-. 7.34 88.88 .+-. 8.86 89.89 .+-. 9.71 Week 10 87.22 .+-. 10.17 85.89 .+-. 16.99 94.06 .+-. 6.85 Week 12 90.16 .+-. 15.85 90.75 .+-. 11.33 88.50 .+-. 21.04 Baseline to 86.08 .+-. 6.10 86.72 .+-. 5.88 89.35 .+-. 7.60 end of study [0181]All the three groups had a high level of compliance on a 2 week basis. This was also observed when considering the baseline to end-of-study time period. [0182]Overall, compliance was very good and adequate for the purposes of this study. 7.6 Additional Information About the Study [0183]This section describes the design of the study, the data management methods, the parameters studied, and the statistical methods used. It presents results in the form of summary tables and graphs with significance levels, effect size and interpretations. 7.6.1 Description of the Study Design 7.6.1.1 Purpose, Objective and Endpoints of the Study [0184]The Purpose of this study is to test the Efficacy and Safety of two experimental Weight loss products as compared to placebo over a 12-week period in healthy overweight and obese adults. [0185]The Specific objectives and corresponding endpoints are summarized here. All effects that are defined as 12 week changes from baseline to end of the study. All Efficacy and Safety objectives involve comparing the active supplements to placebo, with regard to each of the following endpoints. Primary Efficacy Endpoints [0186]Reduced fat mass on the dual energy x-ray absorptiometry (DEXA) scan between baseline and 12 week visit and loss of 5% or more of body weight at 12 weeks Secondary Efficacy Endpoints [0186] [0187]Improved body composition, increase lean mass and improved bone density measured by dual energy x-ray absorptiometry (DEXA) scan [0188]Reduced abdominal girth [0189]Improved lipid Profiles [0190]Reduced Insulin resistance calculated by the HOMA-IR method. [0191]Ability to maintain a weight loss diet and/or diminished appetite [0192]Improved quality of Life based on a Quality of life questionnaire (QLQ)

Primary Safety Endpoints [0192] [0193]Physical Examination (HR, SBP, DBP) [0194]Safety laboratory values (Complete Blood count (CBC), BUN, electrolytes, glucose, creatinine, calcium, AST, ALT, Alkaline Phosphatase, total bilirubin, uric acid, urine analysis, cholesterol, triglycerides, TSH, IIbA1c, pregnancy test (females), amylase) Secondary Safety Parameters [0194] [0195]Adverse Events 7.6.1.2 Structure of the Study [0196]This is a three-group, prospective, parallel, randomized, double blind placebo-controlled clinical trial. 7.6.1.3 Description of the Study [0197]The study enrolled healthy adult males and females in the age group 18 to 60 years, who had BMI values between 28 and 40 kg/m.sup.2. [0198]All the subjects were pre-screened at site visits; Potential candidates were called in for a screening and baseline evaluation after obtaining informed consent. Acceptable subjects were enrolled and randomized for the three arms (1:1:1 ratio) to receive active formula, active HCA or placebo for 12 weeks. As per the protocol, efficacy and safety evaluations were performed at baseline, week 2, week 4, week 6, week 8, week 10 and week 12. [0199]The respective IRB/Ethics committees of the centres where the study was carried out approved this study: 1. St. Johns Medical College Hospital, Bangalore, India, and 2. M. S. Ramiah Medical College Hospital, Bangalore, India. 7.6.1.4 Testing Protocol [0200]Table 28 summarizes the activities performed at each visit of the study. A complete description of each visit's activities is provided in the protocol. TABLE-US-00028 TABLE 28 Activities Performed at Each Visit Screening Baseline Week Week Week Week Week Week Week -1 Week 0 +2 +4 +6 +8 +10 +12 Consent x Demographics x Exclusion/Inclusion x x History/concomitant medication x Physical Exam x x EKG x x Dietician instructions x Weight, girth, BMI, BP, pulse (BMI) x x x x x x x DEXA x x Routine lab.sup.1 x x Lipid profile x x Insulin/glucose x x Appetite/satiety VAS x x Quality of life (QOL) x x Excersice level x x x x x x x Diary review/compliance x x x x x x Adverse events/concomitant x x x x x x medications Pill Counts x x x x x x Dispense study compound x x x x x x Visits after the screening visit will have a window of +/- 7 days .sup.1Complete Blood count (CBC), BUN, electrolytes,

glucose, creatinine, calcium, AST, ALT, Alkaline Phosphatase, total bilirubin, uric acid, urine analysis, cholesterol, triglycerides, TSH, HbAlc, pregnancy test (females), amylase. 7.6.2 Data Management Methods [0201]All data elements recorded during the study period were entered and validated by K. P. Suresh (Statistician) in Microsoft Excel. Definitions of the data elements entered are shown in Table 29. The randomization key was transmitted electronically by the vendor to the statistician and each subject's supplement product group assignment was transferred electronically into the data spreadsheet on the basis of the subjects' randomization numbers. [0202]Body mass index was calculated from height and weight. All variables and changes were transferred into the SPSS, SYSTAT statistical software, summarized (Counts, Minimum, Maximum, Mean, Median, Standard Deviation) within each treatment group, transferred to the statistical report and then reformatted. Suitable graphs were generated to depict the changes in key efficacy parameters and then transferred to the statistical report. 7.6.3 Data Elements, Efficacy and Safety Parameters TABLE-US-00029 [0203]TABLE 29 Data Elements Data Elements Definition Initial Subject Initial Code Assigned Randomization number Visit Which visit the data was collected, per protocol Gender Male or Female Age Age in years Race Which Ethnicity the subject circled on the demographics or other related sheet Height Height in meters Weight Weight in kilograms BMI Weight in Kilograms/Height in Meters squared Body fat Total body fat as measured by DEXA in gms Lean Mass Total body lean mass as measured by DEXA in gms Cholesterol Total Cholesterol mg/dL Triglycerides Total Triglycerides mg/dL LDL Low Density Lipoprotein mg/dL VLDL Very Low Density Lipoprotein mg/dL HDL High Density Lipoprotein mg/dL Glucose Fasting Blood sugar mg/dL Insulin Fasting Insulin .mu.u/ml Hemocrit Hemocrit level % Hemoglobin Hemoglobin level g/dL White Cell Count White Blood Cells Count thousands/micro litre Creatinine Creatinine level mg/dL BUN Blood Urea Nitrogen mg/dL Na Fasting Sodium --electrolyte value, mEq/L K Fasting Potassium electrolyte value, mEq/L Cl Fasting Chloride electrolyte value, mEq/L Ca Fasting Calcium, mg/dL AST Aspartate Amino Transaminase, U/L ALT Alanine Amino Transferase, U/L Alk Phos Alkaline Phosphatase, U/L Total Bilirubin Fasting Total Bilirubin, mg/dL Uric Acid Fasting Uric Acid, mg/dL TSH Thyroid Stimulating Hormone, .mu.lu/ml Amylase Fasting Amylase, U/L Kcal Food intake at appetite test, Kcals Appetite Measured on visual analogue scale. 0-12.2 Blood Pressure Systolic/Diastolic blood pressure, mm Hg Pulse Resting pulse, beats/min QOL Weight Loss quality of life questionnaire Symptom Measure Weight related Symptom Measure Compliance % Compliance with taking assigned product 7.6.4 Statistical Methods 7.6.4.1 Definition of Study Population

[0204]The per protocol population is defined as all enrolled subjects who completed all scheduled visits and an overall product compliance rate of at least 75%. Safety and efficacy analysis was performed on this population, 7.6.4.2 Descriptive Statistics [0205]Descriptive statistics for each numerical variable was summarized as the mean and standard deviations for all the subjects at each time interval in each study group. 7.6.4.3 Changes over Time [0206]One-way Repeated Measures ANOVA assessed changes over time from baseline to each subsequent visit within each product group. [0207]Pair wise significance with Bonferroni Correction assessed changes over two points (baseline to end of study) for each study group, [0208]Treatment Effects were assessed by comparing the week-12 parameters between Active products and Placebo keeping the baseline values as covariates by the Analysis of Covariance (ANCOVA). 7.6.4.4 Adverse Events [0209]All the adverse events/complications were recorded for every visit for each product and the obtained frequencies were tabulated and tested for significance with Placebo by Chi-square/Fisher Exact Test. 7.6.4.5 Control of Type-1 Error [0210]All statistical tests were conducted at the 0.05 alpha level, meaning that P.ltoreq.0.05 was considered "nominally significant". The Adjustment for multiple tests was made by applying Bonferroni correction to the p-values. The p-value for the comparison of the primary efficacy endpoints between active and placebo group was considered to be conclusive. 7.6.4.6 Software [0211]The Statistical software namely SPSS 11.0 and Systat 8.0 were used for the analysis of the data and Microsoft word and Excel were used to generate graphs and tables. [0212]The specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended.

[0213]All publications and patent applications cited in this specification are indicative of the level of ordinary skill in the art to which this invention pertains and are incorporated herein by reference in their entireties. [0214]The various embodiments described above are provided by way of illustration only and should not be construed to limit the invention. Those skilled in the art will readily recognize various modifications and changes that may be made to the present invention without following the example embodiments and applications illustrated and described herein, and without departing from the true spirit and scope of the present invention without following the example embodiments and applications illustrated and described herein, and without departing from the true spirit and scope of the present invention, which is set forth in the following claims. TABLE-US-00030 REFERENCES CITED 3,764,692 October 1973 Lowenstein et al 424/279 6,399,089 April 2002 Yegorova, et al 424/439 6,784,206 August 2004 Udell, et al 514/557 6,830,765 December 2004 Rombi 424/729 2004/0259937 April 2000 Samuel et al 514/460 WO/2005/014020 July 2005 KROTKIEWSKI et al WO/2005/067952 February 2005 BAGCHI et al [0215]Arion W J, et al. (1997) Chlorogenic Acid Analogue S 3483: A Potent Competitive Inhibitor of the Hepatic and Renal Glucose-6-Phosphatase Systems. Archives of Biochemistry and Biophysics; 339(2):315-322. [0216]Hayamizu, K., Ishii Y., Knaeko, I., Shen, M., Okuhara, Y., Shigematsu, N., Tomi, H., Furuse, M., Yohsino, G., and Shimasaki, H.; (2003) Effects of Garcinia cambogia (Hydroxycitric acid) on Visceral fat accumulation: A double blind, randomized, placebo controlled trial, Curr Ther Res Clin Exp. 64: 551-567 [0217]Hemmerle H, et al. (1997) Chlorogenic acid and synthetic chlorogenic acid derivatives: novel inhibitors of hepatic glucose-6-phosphate translocase. Journal of Medicinal Chemistry 40(2):137-145. [0218]Hertog, M. G., Kromhout, D., Aravanis, C., Blackburn, H., Buzina, R., Fidanza F, Giampaoli, S., Jansen, A., Menotti, A., Nedeljkovic, S., Pekkarinen, M., Simic, B. S., Toshima, H., Feskens, E. J. M., Hollman, P. C. H., Katan, M. B. (1995) Flavonoid intake and long-term risk of coronary heart disease and cancer in the Seven Countries Study. Arch. Intern. Med., 155, 381-386 [abstract] [0219]Heymsfield, S. B., Allison, D., Vasselli, J. Pietrobelli, A, Greenfield, D. and Nunez, C. (1998) Garcinia cambogia (Hydroxycitric Acid) as a Potential Antiobesity Agent: A Randomized Controlled Trial. JAMA: The Journal of the American Medical Association, 280(18): 1596-1600. [0220]Heymsfield, S B, Allison, D B, Vasselli, J R, Pietrobelli, A, Greenfield, D, and Nunez, C. (1998) Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial. JAMA. 280, 1596-600. [0221]Hollman, P. C. H., Feskens, E. J. M. & Katan, M. B. (1999) Tea flavonols in cardiovascular disease and cancer epidemiology. Proc. Soc. Exp. Biol. Med., 220, 198-202 [0222]Ikeda Y et al. (1999) Effectiveness and safety of Banabamin tablets containing an extract from banaba in patients with mild type 2 diabetes. Japan Pharmacol Ther 27:67-73. [0223]Johnston K L et al. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine. Am J Clin Nutr. October; 78(4):728-33, 2003

[0224]Juneja L R, Chu D-C, Okubo T, et al. (1999) L-theanine a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Tech. 10:199-204. [0225]Knowler W C, Barrett-Connor E, Fowler S E, et al. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or Metformin. New England Journal of Medicine. 346:393-403 [0226]Loe Y C et al. (2001) Gas chromatography/mass spectrometry method to quantify blood hydroxycitrate concentration." Annal Biochem 292, 1:148-54. [0227]Loe Y C et al. (2001) Time course of hydroxycitrate clearance in fasting and fed humans. FASEB J 15, 4:632, Abs. 501.1. [0228]Mahendran, P., Shymala Devi, C. S. (2001) The Modulating effect of Garcinia cambogia extract on ethanol induced peroxidative damage in rats, Indian J of Pharmacology, 33: 87-91 [0229]Mason R. (2001) 200 mg of Zen; L-theanine boosts alpha waves, promotes alert relaxation. Alternative & Complementary Therapies, April; 7:91-9. [0230]Murakami C et al. (1993) Screening of plant constituents for effect on glucose transport activity in Ehrlich ascites tumour cells. Chem and Pharm Bulletin (Tokyo) December; 41(12):2129-31. [0231]Nathan D M. (1993) Long-term complications of diabetes mellitus. New England Journal of Medicine, 328:1676-1685. [0232]National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), NIH Publication No. 02-5215, September 2002. [0233]Preuss H. G., D. Bagchi, C. V. S. Rao, B. W. Echard, S. Satyanarayana, and M. Bagchi (2002) Effect of hydroxycitric acid on weight loss, body mass index and plasma leptin levels in human subjects. FASEB J, 16(5):A 1020. [0234]Preuss, H. G. (2004) Bagchi, D., Bagchi, M., Rao, C. V. S, Satyanarayana, S., Dey, D. K. Efficacy of a novel, natural extract of (-)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX, niacin-bound chromium and Gymnema sylvestre extract in weight management in human volunteers: A pilot study. Nutrition Research 24 45-58. [0235]Schaefer B. Coffee consumption and type 2 diabetes mellitus [letter]. (2004) Ann Intern Med. 141:321 [0236]Shirai M. et al. (1994) Single Forced Oral Administration Toxicity Test on Mouse by Banaba Extract Jpn Pharmacol Ther, 22(11): 119 121. [0237]Sullivan C., and Triscari J. (1977) Metabolic regulation as a control for lipid disorders. I. Influence of (--)-hydroxycitrate on experimentally induced obesity in the rodent. Am J Clin Nutr 30:767-76. [0238]Suzuki Y et al. (1999) Antiobesity activity of extracts from Lagerstroemia speciosa L. leaves on female KK-Ay mice. J Nutr Sci Vitaminol (Tokyo) 45(6):791-5. [0239]Tommasi N D et al. (1991) Hypoglycemic effects of sesquiterpene glycosides and polyhydroxylated triterpenoids of Eriobotrya japonica. Planta Medica 57: 414-416. [0240]Tuomilehto J, Lindstrom J, Eriksson J G, et al. (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine. 344:1343-1350 [0241]van Dam, R. M. and F. B. Hu (2005) Coffee Consumption and Risk of Type 2 Diabetes A Systematic Review; J. Am. Med. Assoc. 294: 97 [0242]van Loon, Luc J C, Johannes J M van Rooijen, Bas Niesen, Hans Verhagen, Wim H M Saris, and Anton J M (2000 Wagenmakers. Effects of acute (--)-hydroxycitrate supplementation on substrate metabolism at rest and during exercise in humans. Am J Clin Nutr 72; 1445-50. [0243]Weisburger, J. H. (1999) Tea and health: the underlying mechanisms. Proc. Soc. Exp. Biol. Med., 220, 271-275 [0244]Wild S, Roglic G, Green A, Sicree R, King H. (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 27:1047-1053

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United States Patent Application 20080254121

Kind Code A1

Clement; Ken ; et al. October 16, 2008

Multi-layer melatonin composition

Abstract

A multi-layered solid dosage form for oral administration for a multi-phasic controlled release of Melatonin is described. The solid dosage form is useful as a composition to promote and maintain a state of sleep in an individual.

Inventors: Clement; Ken; (Oakville, CA) ; Chaudhuri; Shan; (Brampton, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 381 North Service Road West Oakville ON L6M 0H4 CA

Assignee Name and Adress:

Iomedix Sleep International SRL Belleville BB

Serial No.: 099427

Series Code: 12

Filed: April 8, 2008

U.S. Current Class: 424/472; 424/464; 514/415

U.S. Class at Publication: 424/472; 514/415; 424/464

Intern'l Class: A61K 9/24 20060101 A61K009/24; A61K 31/4045 20060101 A61K031/4045; A61K 9/20 20060101

A61K009/20; A61P 43/00 20060101 A61P043/00

Claims

1. A solid orally administrable dosage form comprising:a first-layer comprising melatonin;a second-layer comprising melatonin, wherein the second-layer is disposed immediately adjacent the first-layer; andan inner-core comprising melatonin, wherein the inner-core is disposed immediately adjacent at least one of the group consisting of the first-layer and the second-layer. 2. The dosage form of claim 1, wherein the first-layer, second-layer and inner-core comprise different amounts of melatonin. 3. The dosage form of claim 1, wherein the inner-core is disposed immediately adjacent to the first-layer. 4. The dosage form of claim 1, wherein the inner-core us disposed immediately adjacent to the second-layer. 5. The dosage form of claim 1, wherein the inner-core is disposed immediately adjacent to each of the first-layer and the second-layer. 6. The dosage form of claim 1 further comprising an immediate release outer coating comprising fine-milled melatonin. 7. The dosage for of claim 6, wherein the outer coating comprises about 1.0 mg of fine-milled melatonin. 8. The dosage form of claim 1, wherein the first-layer comprises from about 0.1 mg to about 5.0 mg of melatonin. 9. The dosage form of claim 1, wherein the first-layer comprises about 2.0 mg of melatonin. 10. The dosage form of claim 1, wherein the second-layer comprises from about 0.1 mg to about 5.0 mg of melatonin. 11. The dosage form of claim 1, wherein the second-layer comprises about 1.5 mg of melatonin. 12. The dosage form of claim 1, wherein the inner-core comprises from about 0.1 mg to about 5.0 mg of melatonin. 13. The dosage form of claim 1, wherein the inner-core contains about 0.5 mg of melatonin.

14. A solid orally administrable dosage form comprising:an inner-core adjacently flanked on opposite sides by a first-layer and a second-layer;said inner-core comprises from about 0.1 mg and about 5 mg of melatonin in a delayed- and slow-release format;said first-layer comprises from about 0.1 mg to about 5 mg of melatonin in a slow-release format; andsaid second-layer comprises from about 0.1 mg to about 5 mg of melatonin in a delayed-release format. 15. A multilayer solid orally administrable dosage form, comprising:an inner-core comprising from about 0.1 mg to about 5 mg of melatonin, which is sequentially over coated with a second-layer comprising from about 0.1 mg to about 5 mg of melatonin; anda first-layer comprising from about 0.1 mg to about 5 mg of melatonin;wherein the first-layer, second-layer and inner-core contain different amounts of melatonin.

Description

RELATED APPLICATIONS [0001]The present application is related to and claims benefit of priority to U.S. Provisional Patent Application Ser. No. 60/911,010, entitled "Mutli-layer melatonin composition," filed Apr. 10, 2007, the disclosure of which is hereby fully incorporated by reference. Additionally, the instant application is related to the applicant's co-pending U.S. patent application Ser. No. 11/696,960 entitled "Composition for a Feeling of Relaxation", Ser. No. 11/696,948 entitled "Composition for Supporting Restful Sleep", and Ser. No. 11/696,945 entitled "Composition for a Feeling of Calmness", all of which were filed on Apr. 5, 2007. The abovementioned co-pending U.S. Patent Applications are hereby fully incorporated by reference. FIELD OF THE INVENTION [0002]The present invention relates to a multi-layered solid dosage form comprising Melatonin for oral administration for use as a sleep aid. In one aspect of the present invention, the arrangement of the individual layer is such that a temporally controlled and multi-phasic release of active ingredients results. In an additional aspect of the present invention the individual layers each provide distinct and differing dissolution characteristics to facilitate a temporally controlled and multi-phasic release of active ingredients. BACKGROUND OF THE INVENTION [0003]Sleep occupies about one-third of our life and is necessary for mental and physical well-being. It additionally affects mood, behavior and physiology. Sleep and the control of sleep is a complex process involving multiple neuro-chemical pathways and associated brain structures. It is a dynamic process involving a shift in the balance of distinct physiological changes, involving both positive and negative neural signaling. The

regulation of sleep in humans is governed by three processes--each influenced by hormonal and environmental factors: a daily sleep-wake cycle influenced by a circadian rhythm (24 hour cycle) tied to light-dark cycles. [0004]The need for sleep is a biological drive similar to thirst or hunger. Interestingly though, the function of sleep is largely unknown, however some evidence indicates that sleep is required for learning. In North America, insomnia is estimated to affect a significant portion of the population every year and is associated with health problems and concomitant economic loss to society. It is clear that the impairment of sleep is detrimental to one's health. In humans, mild sleep deprivation results in indications of impaired immune system function. Prolonged sleep deprivation is even known to result in death. It has been determined by many that an individual can survive longer without food than one can without sleep; thus indicating the importance of sleep. [0005]Strategies to improve sleep are beneficial, not only in terms of physical health, but also in terms of emotional health. Furthermore, reinforcement of sleep of adequate quantity and quality positively impacts most aspect of daily life. SUMMARY OF THE INVENTION [0006]The foregoing needs and other needs and objectives that will become apparent for the following description are achieved in the present invention, which comprises Melatonin in a multi-layered solid dosage format for oral administration by an individual for the promotion and maintenance of sleep. In one embodiment, the individual layers are arranged such that a temporally controlled release of active ingredients results. In an additional embodiment, the individual layers each provide distinct and differing dissolution characteristics to facilitate a temporally controlled release of active ingredients. BRIEF DESCRIPTION OF DRAWINGS [0007]FIG. 1A sagittal view of a caplet of an example embodiment. [0008]FIG. 2 A sagittal view of a caplet of an example embodiment. DETAILED DESCRIPTION OF THE INVENTION [0009]In the following description, for the purposes of explanations, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one of ordinary skill in the art that the present invention may be practiced without these specific details. [0010]The present invention is directed towards multi-layered solid dosage forms comprising Melatonin for oral administration acting to promote and maintain a state of sleep in an individual. Advantageously, the use of a solid dosage form comprised of multiple, distinct layers with distinct properties or sequential arrangement, allows for the

manipulation and control of the release of constituents contained within the various layers. [0011]As used herein the term "unmodified-release" format is understood to be defined as pertaining to the dissolution and bioavailability profile of an ingested dietary ingredient wherein no additional modifications, be it chemical or physical, have been made to the ingredient with the specific intent to alter the dissolution or bioavailability profile from that of ingredient in a naturally occurring form. It is also understood that unmodified-release is, essentially, immediate-release of active ingredients. This is further understood to be a traditional- or conventional-release format where no slow-, delayed- or extended-release modifiers are therein incorporated. [0012]As used herein the term "controlled-release" format is understood to be defined as a formulation and/or the physical arrangement of active ingredients and appropriate excipients in a specific format to facilitate a controlled- or non-immediate-release of active ingredients. The components of a controlled-release format may have been subjected to additional modifications, be it chemical or physical, with the specific intent to alter the dissolution or bioavailability profile from that of ingredient in a naturally occurring form. [0013]As used herein the term "slow-release" format is understood to be defined as a controlled-release format wherein the release of active ingredients are delayed for a period of time or gradually released over an extended period of time. This is accomplished through the use of specific excipients and may include structural features designed to facilitate controlled-release. It is further understood that a slow-release format releases active ingredients at a rate slower than immediate-release. [0014]As used herein the term "delayed-release" format is understood to be defined as a controlled-release format wherein the components of the delayed-release format have undergone specific modifications, be it physical or chemical, to facilitate the release of active ingredients at a specific time after ingestion. It is further understood that delayed-release formats, release active ingredients at a period of time later than unmodified release. [0015]As used herein the term "quick-release" format is understood to be defined essentially as "unmodified-release", as defined above. However, the term "quick-release" may further include components having modifications, chemical or physical, to enhance the rate of dissolution or bioavailability of active ingredients. [0016]In all cases herein, the term "release" is relative to ingestion or administration by the individual as it is herein understood that the process of digestion instigates the dissolution of oral solid dosage forms such as the present invention. [0017]Melatonin [0018]Melatonin is a hormone produced by the pineal gland and is derived from the

amino acid tryptophan. While possibly being involved in multiple biological processes, melatonin has largely been studied for its involvement in sleep regulation with respect to the circadian rhythm of an individual. Levels of melatonin cycle in the body based on lighting conditions--i.e. low melatonin levels during the day, higher levels at night. Typically, melatonin levels peak in the middle of the night and diminish thereafter. Melatonin has further been explored as a method to treat sleep disorders such as insomnia and `jet lag` due to its apparent involvement the regulation of circadian rhythms. Melatonin supplementation in humans has been found to be efficacious for treating jet lag as well as hastening the onset of sleep. [0019]In the preferred embodiment of the present invention, the solid dosage form is comprised of at least two distinct layers being positioned between an inner-most core and an outer-most coating. Each layer, the core and the coating contains an effective amount of Melatonin. The Melatonin will be released in a pre-determined manner according to the characteristics of the layer, the core or the coating as set forth below. [0020]In the preferred embodiment the coating contains from about 1 mg to 5 mg of Melatonin available for an immediate release having a time period of about less than sixty-seconds. The preferred amount of Melatonin in the coating is about 1 mg. A portion of the Melatonin contained in the coating may be fine-milled to facilitate quick release. As used herein, the terms "fine-milled" and/or "fine-milling" refer the process of micronization. U.S. application Ser. No. 11/709,526 entitled "Method for Increasing the Rate and Consistency of Bioavailability of Supplemental Dietary Ingredients", filed Feb. 21, 2007, which is herein fully incorporated by reference, discloses a method of improving the rate of bioavailability of compounds by increasing the rate of solubility. The increased rate of bioavailability of a compound or ingredients is achieved via a reduction in particle size using a "fine-milling" technique. Additionally, U.S. application Ser. No. 11/709,525 entitled "Method for a Supplemental Dietary Composition Having a Multi-Phase Dissolution Profile", filed Feb. 21, 2007, which is herein fully incorporated by reference discloses a method of providing a multi-phasic dissolution profile of a composition. Any acceptable fine-milling technique will result in the fine-milled particles having an average particle size of between about 50 microns to about 2 microns. The reduction in size of the particle increases the surface area-to-volume ratio of each particle, thus increasing the rate of dissolution, thereby improving the rate of absorption. [0021]As used herein, the terms "fine-milled" and/or "fine-milling" refer to the process of micronization. Micronization is a mechanical process which involves the application of force to a particle, thereby resulting in a reduction in the size of said particle. [0022]As used herein, the term "particle size" refers to the diameter of the particle. The term "average particle size" means that at least 50% of the particles in a sample will have the specified particle size. Preferably, at least 80% of the particles in a given sample will have the specified particle size, and more preferably, at least 90% of the particles in a given sample will have the specified particle size. [0023]As used herein, the term "solid dosage form" is defined as being a tablet or caplet

or other means suitable to comprise a solid layered format wherein each layer has a different temporal dissolution profile, thus leading to the release of the active ingredients at specific time periods. [0024]As used herein, the term "excipients" is defined as being any added material to the composition not considered to be an active component. Excipients may be used in the present invention as are commonly known in the art and may be employed for the purposes of fillers and binding agents. Excipients are also used herein to affect the dissolution profile of the individual components of the disclosed composition of the present invention. Examples of excipients which may be used in the present invention include, but are not limited to silicon dioxide, croscarmelose sodium, carboxymethyl cellulose, cross-linked povidone, starch, sodium starch glycolate, microcrystalline cellulose, hydropropylmethyl cellulose, and lactose. Other suitable excipients will be apparent to one of ordinary skill in the art. [0025]With reference to FIG. 1, the solid dosage form comprises a plurality of components sequentially arranged in layers from the outmost to the innermost of said solid dosage form; an outer coating 10, a first-layer 12, a second-layer 14 and an inner-core 16. Each of the layers containing a dosage of melatonin and excipients. The density of the first-layer 12, second-layer 14, and the inner core 16 are determined by the excipients and the compression applied during manufacturing to each of the layers 12, 14, and inner-core 16. The outer coating 10 as applied to the solid dosage form dissolves within 1 minute following oral administration, thus constituting an immediate-release profile. The first layer 12 begins to dissolve within about 60 seconds following administration to a mammal and is completely dissolved within about 2-hours following administration. The second-layer 14 begins to dissolve following the dissolution of the first-layer 12 at about 2-hours from the point of administration and is completely dissolved within about 4-hours following administration. The inner-core 16, begins to dissolve following the second-layer 14 at 4-hours following administration and is completely dissolved within about 6-hours following oral administration to a mammal. The interconnection of the dissolution profiles of the components of the present invention in this embodiment forms a multi-phase temporal release profile. [0026]Another embodiment of the present invention is shown in FIG. 2. According to FIG. 2, an inner-core 22 is adjacently flanked to the opposite sides by a first-layer 20 and a second-layer 24, along the inner-core's 22, width, forming a solid dosage form 26. The first-layer 20 and the second-layer 24 are bonded to the inner-core 22 by the use of pharmaceutically acceptable binding agents suitable to maintain the aforementioned in contact as they are dissolved following ingestion by a mammal. The density of the first-layer 20, second-layer 24, and the inner core 22 are determined by the excipients and the compression applied during manufacturing to each of the layers 20, 24, and inner-core 22. Encompassing all the components, said first-layer 20, said second-layer 24 and said inner-core 22 is an outer-coating 18. The outer coating 18 dissolves within about 60 seconds following oral administration, thus constituting an immediate-release profile. The first layer 20 begins to dissolve within about 60 seconds, after the dissolution of the outer-coating 18, and is completely dissolved within about 2-hours following

administration. The second-layer 24 begins to dissolve following the dissolution of the outer-coating 18, however the majority of said second-layer 24 dissolves from about 2-hours from the point of administration to said mammal and is completely dissolved within about 4-hours following administration. The inner-core 16, being adjacently flanked on opposite sides by said first-layer 20 and said second-layer 24 begins to dissolve following the dissolution of the outer-coating 18, however the majority the dissolution of said inner-corer 22 taking place about 4-hours from the point of administration and being completely dissolved within about 6-hours following administration. The interconnection of the dissolution profiles of the components of the present invention in this embodiment form a multi-phase temporal release profile. [0027]According to one embodiment herein disclosed each of the outer-coating, first-layer, second-layer and inner-core contain melatonin. The outer-coating of the solid dosage form of the present invention comprises from about 0.1 mg to about 5 mg of melatonin. Preferably the outer coating comprises about 1 mg of melatonin which is released immediately following oral administration to a mammal. The first-layer of the solid dosage form of the present invention comprises from about 0.1 mg to about 5 mg of melatonin. Preferably, the first-layer comprises about 2 mg of melatonin to promote sleep as well as aid in maintaining sleep in a mammal during the period of 1 minute to 2-hours following oral administration to said mammal. The second-layer of the solid dosage form of the present invention comprises from about 0.1 mg to about 5.0 mg of melatonin. Preferably, the second layer comprises about 1.5 mg of melatonin to aid in maintaining sleep in a mammal during the period of 2-hours to 4-hours following oral administration to said mammal. The inner-core of the solid dosage form of the present invention comprises from about 0.1 mg to about 5.0 mg of melatonin. Preferably, the inner-core comprises about 0.5 mg of melatonin to aid in maintaining sleep in a mammal during the period of 4-hours to 6-hours following oral administration to said mammal. [0028]The dissolution rate of the outer-coating, the first-layer, the second-layer and the inner-core, is determined by a combination of one or more excipients and the compression applied during manufacturing to each of the first-layer, second-layer and inner-core. The density of the layers, for the purposes of the present invention is achieved by varying the viscosity of the hydroxypropylmethyl cellulose used such that different dissolution profiles of each layer and the inner-core results. In the case of both embodiments presented herein, the inner-core 16 of FIG. 1 and the inner-core 24 of FIG. 2, the active ingredient, melatonin, binding agent excipients such as those selected from the group consisting of microcrystalline cellulose, hydroxypropylmethyl cellulose, and starch are compressed together at a force between 15 to 25 kN such that the majority of the dissolution occurs between 4-hours and 6-hours following oral administration. Furthermore, with reference to the second-layer 14 of FIG. 1 and the second-layer 24 of FIG. 2, the active ingredient, melatonin, and binding agent excipients such as those selected from the group consisting of microcrystalline cellulose, hydroxypropylmethyl cellulose, and starch are compressed together at a force between 15 to 25 kN such that the majority of the dissolution respective of said layer occurs between 2-hours and 4-hours following oral administration. Referring to the first-layer 12 of FIG. 1 and the first-layer 20 of FIG. 2, the active ingredient, melatonin, and binding agent excipients such as those

selected from the group consisting of microcrystalline cellulose, hydroxypropylmethyl cellulose, and starch are compressed together at a force between 15 to 25 kN such that the majority of the dissolution occurs between 60-seconds and 2-hours following oral administration. In one embodiment, the different dissolution rates are achieved by sequential arrangement of layers from the outmost to the innermost of the solid dosage form. In an additional embodiment, the different dissolution rates are achieved in the present invention through the use of various excipients or erosion polymers combined with the degree of compression. [0029]With reference to FIG. 2, said first-layer 20 is bonded to the inner-core 22 using one or more binding excipients in combination with compression sufficient for affixation as are known in the art. The resultantly bound first-layer 20 and inner-core 22 are bonded to said second-layer 24 using one or more binding excipients in combination with compression sufficient for affixation as is known in the art. The resultant multi-layered solid dosage 26 form is then coated with an outer-coating 18. [0030]The present invention or those similarly envisioned by one of skill in the art may be utilized in methods to promote and maintain a state of sleep in an individual. As such, the present invention may be utilized as a sole method, or alternatively may be used in conjunction with other methods known to promote and maintain a state of sleep. Additionally, the present invention may incorporate additional ingredients known to promote and maintain a state of sleep. [0031]In a preferred embodiment of the present invention, melatonin may be provided in a solid dosage form having specific controlled release characteristics. Advantageously, the composition may be provided in a layered solid dosage form. In such a form, each individual layer will provide unique dissolution characteristics. In this way a controlled release of the composition can be achieved. In one aspect of this embodiment, each layer contains a homogeneous mixture of ingredients whereby the release of all ingredients is dependent upon the characteristics of each given layer. In an alternative aspect of this embodiment, each layer contains a distinct set of specific ingredients which differ according to the layers such that different specific ingredients are released from the solid dosage form at different times according to a predetermined schedule. In all aspects of this embodiment, a temporally controlled release of ingredients is achieved. [0032]It is herein understood that the immediate-release of Melatonin from the coating of the multi-layered solid dosage form of the present invention will promote the onset of a state of sleep. Additionally, it is herein understood that a further release of Melatonin up to about 2-hours will aid in the promotion of sleep. Furthermore, it is herein understood that the release of Melatonin, to a lesser degree than used to promote the onset of sleep from about 2-hours to about 4-hours will act to maintain a state of sleep. It is furthermore herein understood that the release of Melatonin throughout a period of about 4-hours to about 6-hours will act to further maintain a state of sleep. [0033]The dosage form of the nutritional supplement may be provided in accordance with customary processing techniques for herbal and nutritional supplements in any of

the forms mentioned above. Additionally, the nutritional supplement set forth in the example embodiment herein may contain any appropriate number and type of excipients, as is well known in the art. [0034]Although the following examples illustrate the practice of the present invention in two of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one of skill in the art from consideration of the specifications and example. EXAMPLES Example 1 [0035]A nutritional supplement to aid in achieving a restful night's sleep in the form of a caplet to be consumed before bedtime. The nutritional supplement consists of the following: [0036]An outer-coating comprising about 3 mg fine-milled Melatonin for immediate release; a first-layer comprising about 0.5 mg Melatonin for slow-release up to about 45-minutes; a second-layer comprising about 0.5 mg Melatonin for delayed-release for about 2-hours; and an inner-core comprising about 1.0 mg Melatonin for delayed- and slow-release from about 4-hours to about 6-hours. Example 2 [0037]A nutritional supplement to aid in achieving a restful night's sleep in the form of a caplet to be consumed before bedtime. The nutritional supplement consists of the following: [0038]An outer-coating comprising about 3 mg fine-milled Melatonin for immediate release; a first-layer comprising about 0.5 mg Melatonin, about 1.0 mg Catnip flower powder, about 1.0 mg Piscidia piscipula and about 25.0 mg deodorized Valerian root extract for slow-release up to about 45-minutes; a second-layer comprising about 0.5 mg Melatonin, about 75.0 mg deodorized Valerian root extract, 0.006 mg Methylcobalamin, about 5.0 mg Eclipta alba whole plant extract and about 1.0 mg Nardostachys jatamansi for delayed-release for about 2-hours; and an inner-core comprising about 1.0 mg Melatonin, about 100 mg Lemon balm extract and about 2.0 mg Mesua ferrea plant powder for delayed- and slow-release from about 4-hours to about 6-hours. Example 3 [0039]A nutritional supplement to aid in achieving a restful night's sleep in the form of a caplet to be consumed before bedtime. The nutritional supplement consists of the following: [0040]An outer-coating comprising about 1.0 mg fine-milled Melatonin for immediate release; a first-layer comprising about 2.0 mg Melatonin for slow-release for up to about 2-hours after administration; a second-layer comprising about 1.5 mg Melatonin for delayed-release between about 2-hours and 4-hours after administration; and an inner-core comprising about 0.5 mg Melatonin for delayed- and slow-release between about 4-hours to about 6-hours after administration.

Example 4 [0041]A nutritional supplement to aid in achieving a restful night's sleep in the form of a caplet to be consumed before bedtime. The nutritional supplement consists of the following: [0042]An outer-coating comprising about 1.0 mg fine-milled Melatonin for immediate release; a first-layer comprising about 2.0 mg Melatonin, about 300 mg of lemon balm extract (Melissa officinalis), about 500 mg of Tryptophan, about 120 mg of Hops extract (Humulus iupulus), and about 50 mg of Griffonia simplicfolia for slow-release for up to about 2-hours after administration; a second-layer comprising about 1.5 mg Melatonin, about 2.0 mg of Mesua ferrea plant powder, and about 1.0 mg Nardostachys jatamansi for delayed-release between about 2-hours and 4-hours after administration; and an inner-core comprising about 0.5 mg Melatonin, about 30 mg of methylcobalamin and about 1.0 mg of Catnip flower powder (Nepeta cataria) for delayed- and slow-release between about 4-hours to about 6-hours after administration. [0043]Extensions and Alternatives [0044]In the foregoing specification, the invention has been described with a specific embodiment thereof, however, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.

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United States Patent Application 20080281113

Kind Code A1

MacDougall; Joseph November 13, 2008

Preparation of amino acid-fatty acid anhydrides

Abstract

The present invention describes compounds produced from an amino acid molecule and a fatty acid molecule. The compounds being in the form of amino-fatty acid compounds being bound by an anhydride linkage, or mixtures thereof made by reacting amino acids or derivatives thereof with an appropriate fatty acid previously reacted with a thionyl halide. The administration of such molecules provides supplemental amino acids with enhanced bioavailability and the additional benefits conferred by the specific fatty acid.

Inventors: MacDougall; Joseph; (Oakville, CA)

Correspondence Name and Address:

IOVATE HEALTH SCIENCE RESEARCH INC. 381 North Service Road West Oakville ON L6M 0H4 CA

Assignee Name and Adress:

Multi Formulations Ltd Oakville CA

Serial No.: 099306

Series Code: 12

Filed: April 8, 2008

U.S. Current Class: 554/108; 564/468

U.S. Class at Publication: 554/108; 564/468

Intern'l Class: C07C 227/14 20060101 C07C227/14; C07C 209/14

20060101 C07C209/14

Claims

1. A method for producing amino acid fatty acids comprising at least the steps of:reacting an excess of a thionyl halide with a fatty acid to form an acyl halide;neutralizing the carboxylic acid of an amino acid with an inorganic base to form an amino acid salt;reacting the acyl halide with the amino acid salt to form an amino acid fatty acid. 2. The method of claim 1 further comprising the step of:isolating the amino acid fatty acid. 3. The method of claim 1 wherein the halide of the thionyl halide is selected from the group consisting of fluorine, chlorine, bromine and iodine. 4. The method of claim 1 wherein the fatty acid comprises between 4 and 22 carbons. 5. The method of claim 1 wherein the acyl halide is produced at temperatures from about 35.degree. C. to about 50.degree. C. 6. The method of claim 1 wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide and sodium carbonate. 7. The method of claim 1 wherein the amino acid is selected from the group consisting of Glycine, Alanine, Valine, Leucine, Isoleucine, Asparagine, Glutamine, Lysine and Arginine. 8. The method of claim 2 wherein the amino acid fatty acid is isolated by distillation. 9. The method of claim 1 wherein the amino acid fatty acid has the general structure of:wherein R is selected from the group consisting of alkanes and alkenes;said alkanes and alkenes comprise between 3 and 21 carbons;wherein R.sub.2 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, butyl-1-amine, and 1-butylguanidine.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001]The present application is a Continuation of U.S. patent application Ser. No. 11/747,203, filed May 10, 2007, which is a Continuation-in-Part of U.S. patent

application Ser. No. 11/676,623 entitled "Creatine-Fatty Acids," filed Feb. 20, 2007, now U.S. Pat. No. 7,314,945, and claims benefit of priority thereto; the disclosures of which are all hereby fully incorporated by reference. FIELD OF THE INVENTION [0002]The present invention relates to structures and synthesis of amino acid-fatty acid compounds bound via an anhydride linkage. Specifically, the present invention relates to a compound comprising an amino acid bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid and bound to the amino acid via an anhydride linkage. BACKGROUND OF THE INVENTION [0003]Participation in sports at any level either professional or amateur requires an athlete to strive to bring their bodies to a physical state which is considered optimum for the sport of interest. One of the factors that correlate positively with successful participation in a sport is a high degree of development of the aerobic capacity and/or strength of skeletal muscle. Consequently, it is important that nutrients and other requirements of muscles be readily available and that they be transported to areas where they are needed without obstructions. [0004]Strength and aerobic capacity are both functions of training and of muscle mass. As such, an athlete who can train harder and longer is often considered to be the most effective at participation in the sport of interest. Strenuous exercise is an effective stimulus for protein synthesis. However, muscle requires a large array of nutrients, including amino acids, in order to facilitate this increased level of protein synthesis. [0005]Following periods of strenuous exercise, muscle tissue enters a stage of rapid nitrogen absorption in the form of amino acids and small peptides. This state of increased nitrogen absorption is a result of the body repairing exercise-induced muscle fiber damage as well as the growth and formation of new muscle fibers. It is important that muscles have sufficient levels of nitrogen, in the form of amino acids and small peptides, during this period of repair and growth. When an athlete is participating in a strenuous exercise regime and fails to ingest enough nitrogen, e.g. amino acids, the body often enters a state of negative nitrogen balance. A negative nitrogen balance is a state in which the body requires more nitrogen, to facilitate repair and growth of muscle, than is being ingested. This state causes the body to catabolize muscle in order to obtain the nitrogen required, and thus results in a decrease in muscle mass and/or attenuation of exercise-induced muscle growth. Therefore, it is important that athletes ingest adequate amounts of amino acids in order to minimize the catabolism of muscle in order to obtain the results desired from training. [0006]Although supplementation with amino acids are quite common, the uptake of amino acids by cells is limited or slow since amino acid residues are not soluble or only slightly soluble in nonpolar organic solution, such as the lipid bilayer of cells. As a result amino acids must be transported into cells via transport mechanisms which are specific to

the charges that the amino acid bears. It is therefore desirable to provide, for use in individuals, e.g. animals and humans, forms and derivatives of amino acids with improved characteristics that result in increased stability and increased uptake by cells. Furthermore, it would be advantageous to do so in a manner that provides additional functionality as compared to amino acids alone. [0007]Fatty acids are carboxylic acids, often containing a long, unbranched chain of carbon atoms and are either saturated or unsaturated. Saturated fatty acids do not contain double bonds or other functional groups, but contain the maximum number of hydrogen atoms, with the exception of the carboxylic acid group. In contrast, unsaturated fatty acids contain one or more double bonds between adjacent carbon atoms, of the chains, in cis or trans configuration [0008]The human body can produce all but two of the fatty acids it requires, thus, essential fatty acids are fatty acids that must be obtained from food sources due to an inability of the body to synthesize them, yet are required for normal biological function. The fatty acids which are essential to humans are linoleic acid and .alpha.-linolenic acid. [0009]Examples of saturated fatty acids include, but are not limited to myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic or octadecanoic acid, arachidic or eicosanoic acid, behenic or docosanoic acid, butyric or butanoic acid, caproic or hexanoic acid, caprylic or octanoic acid, capric or decanoic acid, and lauric or dodecanoic acid, wherein the aforementioned comprise from at least 4 carbons to 22 carbons in the chain. [0010]Examples of unsaturated fatty acids include, but are not limited to oleic acid, linoleic acid, linolenic acid, arachidonic acid, palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid and erucic acid, wherein the aforementioned comprise from at least 4 carbons to 22 carbons in the chain. [0011]Fatty acids are capable of undergoing chemical reactions common to carboxylic acids. Of particular relevance to the present invention are the formation of anhydrides and the formation of esters. SUMMARY OF THE INVENTION [0012]In the present invention, compounds are disclosed, where the compounds comprise an amino acid bound to a fatty acid, via an anhydride linkage, and having a structure of Formula 1: where: [0013]R.sub.1 is an alkyl group, preferably saturated, and containing from about 3 to a maximum of 21 carbons. [0014]R.sub.2 is hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, butyl-1-amine, or 1-butylguanidine. [0015]Another aspect of the invention comprises the use of a saturated fatty acid in the production of compounds disclosed herein.

[0016]A further aspect of the present invention comprises the use of an unsaturated fatty in the production of compounds disclosed herein. DETAILED DESCRIPTION OF THE INVENTION [0017]In the following description, for the purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one skilled in the art that the present invention may be practiced without these specific details. [0018]The present invention relates to structures and synthesis of amino acid-fatty acid compounds bound via an anhydride linkage. In addition, specific benefits are conferred by the particular fatty acid used to form the compounds in addition to, and separate from, the amino acid substituent. [0019]As used herein, the term `fatty acid` includes both saturated, i.e. an alkane chain as known in the art, having no double bonds between carbons of the chain and having the maximum number of hydrogen atoms, and unsaturated, i.e. an alkene or alkyne chain, having at least one double or alternatively triple bond between carbons of the chain, respectively, and further terminating the chain in a carboxylic acid as is commonly known in the art, wherein the hydrocarbon chain is greater than four carbon atoms. Furthermore, essential fatty acids are herein understood to be included by the term `fatty acid`. [0020]As used herein, "amino acid" refers a compound consisting of a carbon atom to which are attached a primary amino group, a carboxylic acid group, a side chain, and a hydrogen atom. For example, the term "amino acid" includes, but is not limited to, Glycine, Alanine, Valine, Leucine, Isoleucine, Asparagine, Glutamine, Lysine and Arginine. Additionally, as used herein, "amino acid" also includes derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form. [0021]According to the present invention, the compounds disclosed herein comprise an amino acid bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid. Furthermore, the amino acid and fatty acid are bound via an anhydride linkage and having a structure according to that of Formula 1. The aforementioned compound being prepared according to the reaction as set forth for the purposes of the description in Scheme 1: [0022]With reference to Scheme 1, in Step 1 an acyl halide (4) is produced via reaction of a fatty acid (2) with a thionyl halide (3). [0023]In various embodiments of the present invention, the fatty acid of (2) is selected from the saturated fatty acid group comprising butyric or butanoic acid, caproic or hexanoic acid, caprylic or octanoic acid, capric or decanoic acid, lauric or dodecanoic

acid, myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic or octadecanoic acid, arachidic or eicosanoic acid, and behenic or docosanoic acid. [0024]In alternative embodiments, of the present invention, the fatty acid of (2) is selected from the unsaturated fatty acid group comprising oleic acid, linoleic acid, linolenic acid, arachidonic acid, palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and erucic acid. [0025]Furthermore, the thionyl halide of (3) is selected from the group consisting of fluorine, chlorine, bromine, and iodine, the preferred method using chlorine or bromine. [0026]The above reaction proceeds under conditions of heat ranging between from about 35.degree. C. to about 50.degree. C. and stirring over a period from about 0.5 hours to about 2 hours during which time the gases sulfur dioxide and acidic gas, wherein the acidic gas species is dependent on the species of thionyl halide employed, are evolved. Preferably, the reaction proceeds at 45.degree. C. for 1.5 hours. [0027]Step 2 of Scheme 1 entails the neutralization of the carboxylic acid of the amino acid portion through the addition of an inorganic base. The inorganic base is selected from the group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, sodium carbonate. Preferred inorganic bases for the purposes of the present invention are sodium hydroxide and potassium hydroxide. [0028]Neutralization, as described above, is followed by the evaporation of water, resulting in the isolation of the corresponding salt. For example, using the amino acid, Arginine and the inorganic base potassium hydroxide, results in the production of the potassium Arginine salt. [0029]Step 3 of Scheme 1 involves the drop wise addition of the prepared acyl halide (4) to the amino acid salt (6) in a cooled flask and subsequent purification by two rounds of distillation to yield the desired anhydride compound (1), the anhydride compound being an amino acid-fatty acid compound of the present invention. [0030]In various embodiments, according to the aforementioned, using the saturated fatty acids, a number of compounds are produced; examples include, but are not limited to: 2-amino-3-methylbutanoic butyric anhydride, 2-amino-3-methylpentanoic hexanoic anhydride, 2,4-diamino-4-oxobutanoic octanoic anhydride, 2,4-diamino-4-oxobutanoic decanoic anhydride, 2-amino-5-guanidinopentanoic dodecanoic anhydride, 2,6-diaminohexanoic tetradecanoic anhydride, 2-amino-5-guanidinopentanoic palmitic anhydride, 2-amino-4-methylpentanoic stearic anhydride, 2-aminopropanoic icosanoic anhydride, and 2-aminoacetic docosanoic anhydride. [0031]In additional embodiments, according to the aforementioned, using the unsaturated fatty acids, a number of compounds are produced; examples include, but are not limited to: 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride, 2,5-diamino-5-oxopentanoic oleic anhydride, 2,4-diamino-4-oxobutanoic (9Z,12Z,15Z)-octadeca-

9,12,15-trienoic anhydride, 2-aminoacetic (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoic anhydride, 2-amino-5-guanidinopentanoic (Z)-hexadex-9-enoic anhydride, 2-amino-3-methylpentanoic (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic anhydride, 2-amino-4-methylpentanoic (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexenoic anhydride, and 2-amino-3-methylbutanoic (Z)-docos-13-enoic anhydride. [0032]The following examples illustrate specific amino acid-fatty acid anhydrides and routes of synthesis thereof. One of skill in the art may envision various other combinations within the scope of the present invention, considering examples with reference to the specification herein provided. EXAMPLE 1 2-amino-3-methylbutanoic butyric anhydride [0034]In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 8.75 ml (120 mmol) of thionyl chloride, and a water condenser, is placed 9.05 ml (100 mmol) of butanoic acid. Addition of the thionyl chloride is completed with heating to about 40.degree. C. over the course of about 30 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 30 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, butyryl chloride. [0035]Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 5.86 g (50 mmol) of Valine is dissolved in 200 ml of water. To this is added 55 ml of 1M sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-amino-3-methylbutanoate, shown below. [0036]Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 6.39 g (60 mmol) of the prepared butyryl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 9.18 g (66 mmol) of sodium 2-amino-3-methylbutanoate. The round bottomed flask is placed in an ice bath and the butyryl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-3-methylbutanoic butyric anhydride. EXAMPLE 2 2-amino-3-methylpentanoic hexanoic anhydride [0038]In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 6.97 ml (90 mmol) of thionyl bromide, and a

water condenser, is placed 5.68 ml (45 mmol) of hexanoic acid. Addition of the thionyl bromide is completed with heating to about 50.degree. C. over the course of about 50 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, hexanoyl bromide. [0039]Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 6.56 g (50 mmol) of Isoleucine is dissolved in 200 ml of water. To this is added 55 ml of 1M sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-amino-3-methylpentanoate, shown below. [0040]Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81 g (60 mmol) of the prepared hexanoyl bromide, and side arm water condenser fixed with a dry receiving flask, is placed 11.03 g (72 mmol) of sodium 2-amino-3-methylpentanoate. The round bottomed flask is placed in an ice bath and the hexanoyl bromide is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-3-methylpentanoic hexanoic anhydride. EXAMPLE 3 2-amino-5-guanidinopentanoic dodecanoic anhydride [0042]In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 5.85 ml (80 mmol) of thionyl chloride, and a water condenser, is placed 10.02 g (50 mmol) of dodecanoic acid. Addition of the thionyl chloride is completed with heating to about 45.degree. C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, dodecanoyl chloride. [0043]Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 10.45 g (60 mmol) of Arginine is dissolved in 300 ml of water. To this is added 78 ml of 1M ammonium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, ammonium 2-amino-5-guanidinopentanoate, shown below. [0044]Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 15.31 g (70 mmol) of the prepared dodecanoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 16.06 g (84 mmol) of ammonium 2-amino-5-guanidinopentanoate. The round bottomed flask is placed in an ice bath and the

dodecanoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-5-guanidinopentanoic dodecanoic anhydride. EXAMPLE 4 2-amino-4-methylpentanoic stearic anhydride [0046]In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 4.81 ml (66 mmol) of thionyl chloride, and a water condenser, is placed 15.65 g (55 mmol) of stearic acid. Addition of the thionyl chloride is completed with heating to about 45.degree. C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 45 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, stearoyl chloride. [0047]Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 7.87 g (60 mmol) of Leucine is dissolved in 300 ml of water. To this is added 72 ml of 1M potassium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, potassium 2-amino-4-methylpentanoate, shown below. [0048]Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27 g (70 mmol) of the prepared stearoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 13.03 g (77 mmol) of potassium 2-amino-4-methylpentanoate. The round bottomed flask is placed in an ice bath and the stearoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-4-methylpentanoic stearic anhydride. EXAMPLE 5 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride [0050]In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35 ml (128 mmol) of thionyl chloride, and a water condenser, is placed 24.90 ml (80 mmol) of linoleic acid. Addition of the thionyl chloride is completed with heating to about 40.degree. C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, (9Z,12Z)-

octadeca-9,12-dienoyl chloride. [0051]Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 5.34 g (60 mmol) of Alanine is dissolved in 200 ml of water. To this is added 78 ml of 1M ammonium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, ammonium 2-aminopropanoate, shown below. [0052]Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 17.93 g (60 mmol) of the prepared (9Z,12Z)-octadeca-9,12-dienoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 7.64 g (72 mmol) of ammonium 2-aminopropanoate. The round bottomed flask is placed in an ice bath and the (9Z,12Z)-octadeca-9,12-dienoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride. [0053]Thus while not wishing to be bound by theory, it is understood that reacting an amino acid or derivative thereof with a fatty acid or derivative thereof to form an anhydride can be used enhance the bioavailability of the amino acid or derivative thereof by improving stability of the amino acid in terms of resistance to hydrolysis in the stomach and blood and by increasing solubility and absorption. Furthermore, it is understood that, dependent upon the specific fatty acid, for example, saturated fatty acids form straight chains allowing mammals to store chemical energy densely, or derivative thereof employed in the foregoing synthesis, additional fatty acid-specific benefits, separate from the amino acid substituent, will be conferred. Extensions and Alternatives [0054]In the foregoing specification, the invention has been described with a specific embodiment thereof; however, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.

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