hayer et al . ( 45 ) date of patent : * oct . 17 , 2017 · u . s . c . 154 ( b ) by 0 days . this...

T he ARN THE AREA THAT THE US009789152B2

( 12 ) United States Patent Hayer et al .

( 10 ) Patent No . : US 9 , 789 , 152 B2 ( 45 ) Date of Patent : * Oct . 17 , 2017

FOREIGN PATENT DOCUMENTS ( 54 ) COMPOSITIONS AND METHODS TO INHIBIT KIDNEY STONE GROWTH RO 80051 A2 10 / 1982

( 71 ) Applicant : KIDNEY STONE RESEARCH COMPANY , INC . , Fort Lauderdale , FL ( US )

( 72 ) Inventors : Gregory K . Hayer , Fort Lauderdale , FL ( US ) ; Brendan Magrab , Westfield , NJ ( US ) ; Henry R . Wolfe , Jr . , Glenmoore , PA ( US )

( 73 ) Assignee : KIDNEY STONE RESEARCH COMPANY , INC . , Fort Lauderdale , FL ( US )

( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 U . S . C . 154 ( b ) by 0 days . This patent is subject to a terminal dis claimer .

( 21 ) Appl . No . : 15 / 487 , 735 ( 22 ) Filed : Apr . 14 , 2017

( 65 ) Prior Publication Data US 2017 / 0216388 A1 Aug . 3 , 2017

( 60 ) Related U . S . Application Data

Continuation of application No . 15 / 266 , 464 , filed on Sep . 15 , 2016 , now Pat . No . 9 , 623 , 066 , which is a division of application No . 15 / 059 , 644 , filed on Mar . 3 , 2016 , now Pat . No . 9 , 492 , 491 , which is a continuation - in - part of application No . 14 / 960 , 692 , filed on Dec . 7 , 2015 , which is a continuation of application No . 14 / 845 , 612 , filed on Sep . 4 , 2015 , now Pat . No . 9 , 233 , 135 .

OTHER PUBLICATIONS “ Highlights of Prescribing Information : Urocit - K ( Potassium Citrate ) " ; Mission Pharmacal Company ; Dec . 2009 ; 2 pages . “ Kidney stones ” ; Magnesium online resource center ; 2007 2008 ; [ retrieved Aug . 19 , 2015 from http : / / www . mg12 . info / articles / kidney - stones . html ] ; 2 pages . Abirami J et al . ; “ Evaluation of Toxicity Profiles of Musa paradisiaca L ( Pseudostem ) Juice ” ; International Journal of Pharmacy and Pharmaceutical Sciences ; vol . 6 , Sup . 1 ; 2014 ; pp . 9 - 11 . Devi et al . ; “ Biochemical Effects in Normal and Stone Forming Rats Treated With the Ripe Kernel Juice of Plantain ( Musa paradisiaca ) " ; Ancient Science of Life , vol . XII , Nos . 3 & 4 ; 1993 ; pp . 451 - 461 . Duan ; " Changes in urinary nanocrystallites in calcium oxalate stone formers before and after potassium citrate intake " ; International Journal of Nanomedicine , vol . 8 ; 2013 ; pp . 909 - 918 . Ebisuno et al . , “ Results of long - term rice bran treatment on stone recurrence in hypercalciuric patients ” ; Br J Urol . ; vol . 67 , No . 3 ; 1991 ; pp . 237 - 240 ( Abstract Only ) . Ebisuno et al . ; “ Rice - bran Treatment for Calcium Stone Formers with Idiopathic Hypercalciuria " ; British Journal of Urology ; vol . 58 , No . 6 ; 1986 ; pp . 592 - 595 ( Abstract Only ) . Grases et al . ; " Influence of Concomitant Food Intake on the Excretion of Orally Administered myo - Inositol Hexaphosphate in Humans ” ; J Med Food vol . 9 , No . 1 ; 2006 ; pp . 72 - 76 . Jha U et al . , “ Pharmacological Screening of Musa Paradisica Linn Against Ethylene Glycol Induced Renal Calculi ” ; Interntional Journal of Research in Ayurveda & Pharmacy , vol . 2 , No . 3 ; 2011 ; pp . 995 - 998 . Kalpana et al . ; " Inhibition of Calcium Oxalate Crystallization In Vitro by Extract of Banana Cultivar Monthan ” ; International Journal of Pharmacy and Pharmaceutical Sciences , vol . 5 , No . 4 ; 2013 ; pp . 649 - 653 . Khan et al . , “ Antiurolithic activity of Origanum vulgare is mediated through multiple pathways " ; BMC Complementary and Alternative Medicine ; vol . 11 , No . 96 ; 2011 ; 16 pages . Lindberg et al . , “ Magnesium Bioavailability from Magnesium Citrate and Magnesium Oxide ” ; Journal of the American College of Nutrition , vol . 9 , No . 1 ; 1990 ; pp . 48 - 55 . Massey ; “ Magnesium therapy for nephrolithiasis ” ; Magnesium Research , vol . 18 , No . 2 ; 2005 , pp . 123 - 126 . McNally et al . ; “ Empiric use of potassium citrate reduces kidney stone incidence with the ketogenic diet ” ; Pediatrics ; vol . 124 , No . 2 ; Aug . 2009 ; pp . 300 - 304 ( Abstract Only ) . Ogawa et al . , “ Effects of sodium citrate , potassium citrate , and citric acid in preventing experimental calcium oxalate urolithiasis in rats ” ; Acta Urol . Jpn . , vol . 33 , No . 11 ; 1987 ; pp . 1772 - 1777 . Patankar et al . ; " A Prospective , Randomized , Controlled Study to Evaluate the Efficacy & Tolerability of Ayurvedic Formulation Varuna and Banana Stem ” in the Management of Urinary Stones ; J . of Alternative & Complementary Medicine ; vol . 14 , No . 10 ; 2008 ; 4pgs .

( Continued ) Primary Examiner — Qiuwen Mi ( 74 ) Attorney , Agent , or Firm — Cantor Colburn LLP ( 57 ) ABSTRACT An oral dosage form or plurality of oral dosage forms comprising as active ingredients combinations of citric acid , magnesium citrate , phytin , pyridoxine , and musa is dis closed . The oral dosage form ( s ) is useful for inhibiting calcium oxalate crystal growth and for treating or inhibiting growth of kidney stones . Methods of inhibiting calcium oxalate crystal growth and of treating or preventing kidney stones are also disclosed .

19 Claims , 78 Drawing Sheets

( 51 )

( 52 )

Int . Ci . A61K 36 / 00 ( 2006 . 01 ) A61K 36 / 88 ( 2006 . 01 ) A61K 31 / 194 ( 2006 . 01 ) A61K 31 / 6615 ( 2006 . 01 ) A6IK 31 / 4415 ( 2006 . 01 ) A61K 9 / 00 ( 2006 . 01 ) U . S . CI . CPC . . . . . . . . . . . . A61K 36 / 88 ( 2013 . 01 ) ; A61K 9 / 0053

( 2013 . 01 ) ; A61K 31 / 194 ( 2013 . 01 ) ; A61K 31 / 4415 ( 2013 . 01 ) ; A61K 31 / 6615 ( 2013 . 01 )

Field of Classification Search None See application file for complete search history .

( 58 )

( 56 ) References Cited U . S . PATENT DOCUMENTS

2009 / 0068255 Al 2013 / 0302448 A1 2013 / 0337057 Al 2014 / 0272068 AL

3 / 2009 Yu et al . 11 / 2013 Parc 12 / 2013 Patankar

9 / 2014 Prakash et al .

US 9 , 789 , 152 B2

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Chow et al . ; “ A stone farm : development of a method for simultane ous production of multiple calcium oxalate stones in vitro " ; Urol Res , vol . 32 ; 2004 ; pp . 55 - 60 . Coe ( 2015 ) ; “ Citrate to Prevent Calcium and Uric Acid Stones ” ; University of Chicago Kidney Stone Evaluation and Treatment Program : http : / / kidneystones . uchicago . edu / citrate - to - prevent stones / [ retrieved on Aug . 19 , 2015 ] ; 8 pages . Coe et al . ; “ The Pathogenesis and Treatment of Kidney Stones ” ; N Engl J Med , vol . 327 ; 1992 ; pp . 1141 - 1152 ( abstract only ) . Costa - Bauza et al . , “ Factors affecting calcium oxalate dihydrate fragmented calculi regrowth ” BMC Urology , vol . 6 , No . 16 , 2006 ; 7 pages . Ettinger et al . , “ Potassium - magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis ” ; J Urol . , vol . 158 ; 1997 ; pp . 2069 - 2073 . Fabris et al . ; “ Long - Term Treatment with Potassium Citrate and Renal Stones in Medullary Sponge Kidney ” ; Clin J Am Soc Nephrol . , vol . 5 , No . 9 , 2010 ; pp . 1663 - 1668 . Forbes et al . ; “ Effects of Dietary Phytate , Calcium and Magnesium Levels on Zinc Bioavailability to Rats ” ; J . Nutr . , vol . 114 ; 1984 ; pp . 1421 - 1425 Foster et al . ; “ Emergency Department Visits and Hospital Admis sions for Kidney Stone Disease , 2009 ” ; Healthcare Cost and Utiliza tion Project ; Statistical Brief # 139 , Jul . 2012 , Agency for Healthcare Research and Quality , Rockville , MD . Available at http : / / www . hcup - us . ahrq . gov / reports / statbriefs / sb139 . pdf [ retrieved on Aug . 19 , 2015 ] ; 10 pages . Gershoff et al . ; “ Effect of Daily MgO and Vitamin B6 Administra tion to Patients with Recurring Calcium Oxalate Kidney Stones " The American Journal of Clinical Nutrition ; vol . 20 , No . 5 ; 1967 ; pp . 393 - 399 . Goldberg et al . ; “ Urine citrate and renal stone disease ” ; Canadian Medical Association Journal ; vol . 141 , No . 3 ; 1989 , pp . 217 - 221 . Grases et al . , “ Effects of Phytic Acid on Renal Stone Formation in Rats ” ; Scandinavian Journal of Urology and Nephrology ; vol . 32 , No . 4 ; 1998 ; pp . 261 - 265 ( Abstract Only ) . Grases et al . ; “ Phytate ( IP6 ) is a Powerful Agent for Preventing Calcifications in Biological Fluids : Usefulness in Renal Lithiasis Treatment ” ; Anticancer Research , vol . 19 ; 1999 ; pp . 3717 - 3722 . Grases et al . ; “ Study of Potassium Phytate Effects on Decreasing Urinary Calcium in Rats ” ; Urol Int ; vol . 72 ; 2004 ; pp . 237 - 243 . Grases et al . , “ Phytate acts as an inhibitor in formation of renal calculi ” ; Frontiers in Bioscience , vol . 12 ; 2007 ; pp . 2580 - 2587 . Grubbs ; “ Procedures for Detecting Outlying Observations in Samples " ; Technometrics ; vol . 11 , No . 1 ; Feb . 1969 ; 22 pages . Hess ; " Citrate determines calcium oxalate crystallization kinetics and crystal morphology - studies in the presence of Tamm - Horsfall protein of a healthy subject and a severely recurrent calcium stone former " , Nephrol Dial Transplant , vol . 15 ; 2000 ; 366 - 374 . Hughes et al . ; “ Diet and calcium stones ” ; Can Med Assoc J , vol . 146 , No . 2 ; 1992 , pp . 137 - 143 . Jahnen et al . ; “ Dietary fibre : the effectiveness of a high bran intake in reducing renal calcium excretion ” ; Urol Res ; vol . 20 , No . 1 ; 1992 ; pp . 3 - 6 ( Abstract Only ) . Johri et al . ; “ An Update and Practical Guide to Renal Stone Management ” ; Nephron Clinical Practice , vol . 116 ; published online Jul . 2010 ; pp . 159 - 171 . Leumann et al . , “ Efficacy of oral citrate administration in primary hyperoxaluria ” Nephrol Dial Transplant , vol . 10 , No . 8 ; 1995 ; pp . 14 - 16 . Lojanapiwat et al . ; “ Alkaline citrate reduces stone recurrence and regrowth after shockwave lithotripsy and percutaneous nephrolithotomy " ; International Braz J Urol , vol . 37 , No . 5 ; Sep . Oct . 2011 ; pp . 611 - 616 . López - González ; “ Phytate ( myo - Inositol Hexaphosphate ) and Risk Factors for Osteoporosis ” ; J Med Food , vol . 11 , No . 4 ; 2008 , pp . 747 - 752 . Massey ; “ Dietary influences on urinary oxalate and risk of kidney stones ” ; Frontiers in Bioscience ; vol . 8 , Sections 584 - 594 ; 2003 ; 8 pages . Mitwalli et al . ; “ Control of hyperoxaluria with large doses of pyridoxine in patients with kidney stones ” ; Int Urol Nephrol . , vol . 20 , No . 4 ; 1988 ; pp . 353 - 359 ( Abstract Only ) .

US 9 , 789 , 152 B2

( 56 ) References Cited OTHER PUBLICATIONS

Monico et al . , “ Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele ” ; Kidney International , vol . 67 ; 2005 ; pp . 1704 - 1709 . Nakagawa et al . ; “ Purification and Characterization of a Calcium Oxalate Monohydrate Crystal Growth Inhibitorfrom Human Kidney Tissue Culture Medium ” ; The Journal of Biological Chemistry , vol . 256 , No . 8 ; 1981 ; pp . 3936 - 3944 . Ortiz - Alvarado ; “ Pyridoxine and Dietary Counseling for the Management of Idiopathic Hyperoxaluria in Stone - forming Patients ” ; Urology , vol . 77 , No . 5 ; May 2011 ; pp . 1054 - 1058 — ( Abstract Only ) . Pak et al . ; “ Long - Term Treatment of Calcium Nephrolithiasis With Potassium Citrate ” ; The Journal of Urology , vol . 134 ; 1985 ; pp . 11 - 19 . Penniston ; “ Citric Acid and Kidney Stones ” ; Department of Clinical Nutrition Services , UW Hospital and Clinics ; Accessed Aug . 31 , 2015 ; https : / / www . uwhealth . org / files / uwhealth / docs / pdf / kidney _ citric _ acid . pdf ; 2 pages . Qiu et al . , Molecular modulation of calcium oxalate crystallization by osteopontin and citrate ; P . N . A . S , vol . 101 , No . 7 ; 2004 ; pp . 1811 - 1815 . Rao et al . , “ In - vitro Chemodissolution of Urinary Stones by Some Chelating Natural Acids ” ; Asian Journal of Chemistry , vol . 16 , No . 1 ; 2004 ; pp . 59 - 66 .

Riley et al . ; “ Effect of Magnesium on Calcium and Oxalate Ion Binding " ; J Endourol . , vol . 27 , No . 12 , Dec . 2013 ; pp . 1487 - 1492 . Scales et al . ; “ Prevalence of Kidney Stones in the United States ” ; European Urology , vol . 62 ; 2012 ; pp . 160 - 165 . Shang et al . ; " Concave Urinary Crystallines : Direct Evidence of Calcium Oxalate Crystals Dissolution by Citrate In Vivo ” ; Bioinorg Chem Appl . , DOI : 10 . 1155 / 2013 / 637617 [ retrieved Aug . 19 , 2015 ) ; 2013 ( Abstract Only ) . Smith ; “ Application of Physical , Chemical , and Metabolic Factors to the Management of Urolithiasis ” ; in Urolithiasis Research ; Fleisch , H ( Ed ) ; Springer US , 1976 ; pp . 199 - 211 ( Abstract Only ) . Soygür ; “ Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis : a randomized controlled trial ” ; J Endourol ; vol . 16 , No . 3 ; Apr . 2002 ; 7 pages . Tiselius ; “ Epidemiology and medical management of stone disease ” ; BJU International , vol . 91 , Issue 8 ; 2003 , pp . 758 - 767 . Tomson ; “ Prevention of recurrent calcium stones : a rational approach ” ; British Journal of Urology , vol . 76 ; 1995 ; 419 - 424 ( Abstract Only ) . Türk et al . ; Guidelines on Urolithiasis ; European Association of Urology ; 2014 ; [ retrieved Aug . 19 , 2015 from http : / / uroweb . org / wp - content / uploads / 22 - Urolithiasis _ LR . pdf ; 98 pages . Watts et al . ; " Studies on Some Possible Biochemical Treatments of Primary Hyperoxaluria ” ; QJM ( 1979 ) 48 ( 2 ) : 259 - 272 DOI : http : / / dx . doi . org / 259 - 272 Published Online Apr . 1 , 1979 ( Abstract Only ) . Yasui et al . ; “ Effects of citrate on renal stone formation and osteopontin expression in rat urolithiasis model " ; Urol Res , vol . 29 ; 2001 ; pp . 50 - 56 ( Only pp . 50 - 51 ) .

U . S . Patent atent Oct . 17 , 2017 Sheet 1 of 78 US 9 , 789 , 152 B2

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Test 3 - 41 Test3 - # 2 Test 3 . 3 Test 3 - 04 Test 3 - 5

Fig . 12

- - - - - - - - - - - - - - Inhibition of Calcum oxalate Formation by Test Solution 3 - Slope Tests - -

- - - - - -

. . . . . . . 730 . 0027x10 . 0246 . * 0 . 36

- - - - - - - - - - - - - - - - - -

Wwwwwwwwwwwwww Y * 0 . 0039x * 0 . 011 - - 0 . 8029 4

- - - - - - - - -

Absortance ( 620 . 6 mm minutes . . . 8

. . . . . . . . . . . . . . . . en permangana mane yang

- - - - - - - - - - - - - - - - - - - - - - - * GOMO - 0 . 00776 - 0 . 005

- 0 . 9743 - 0 . 0036K 0 , 001 . 7 .

92 = 0 . 8637 V : 0 . 0014x + 0 . 0037

22 - 0 : 4991 hungen aningen en ontvang ng mga magnetom in

- -

2 . 5 Time min . )

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - * o Test 3 - # 1 O tex3 - 42 . X Test 3 - 5 www . Unear ( Test 3 - # 1 )

aminaari Test Swa n eer ( Test 3 - 55 )

Test 3 - 3 near Text 3 - # 21

Test 3 - 4 Linear ( Test 3 - # 3 }


Fig . 13

inhibition of Calcium Oxalate formation - Vehice Runs

Absorbance ( 620 , 6 mm . . . . . . . . . . . . . . . . . . . . .

10

Time in Venice 6 vehicle 7 Vance &

Fig . 14

Inhibition of Calcium Oxalate Formation - Vehice Runs , Slope Tests

0 . 05

0 . 046 0 . 04 00164 * 0 . 0115

R = 0 . 9822 0 . 055

Absorbance ( 6x0 . 6 am 0 . 08 0 . 025 0 . 02 ng VE 0 . 0046x0 . 0025

a = 0 . 9588 20 . 05 0 : 01

0 . 005 mennesseren omenantiye

m nge andre som a y = 0 . 0099x * 0 . 002 - 0 . 9086

OS S N

Tirsia sin : )

o Vehce 6 Veticie ? Venide # 8 linear Vehicles * * * * * * * * * Unear ( Vehicle 16 ) Unear ( Vehicle 7


Fig . 15

Inhibition of Caicium Oxalate Formation - Test Solution 4

Absorbance 620 . 6 . ami

C

0

6 Ime min . )

Tex4 - 91 Tas 4 - 2 Test 4 - 13 Test 4 . - * 4 • Test 4 - Test 5 - 86

Fig . 16

Inhibition of Calcium Oxalate Formation - Test Solution 4 , Slope Test

0 : 04

0 . 035 . . . . . . . . . . . . . . . . . . . . . .

= 0 . 0026x * 0 . 0191 - 0 . 7774

- 0 . 0075 % - 0 . 019 . . 00439 . . . 0 . 03

Absorbancs ( 630 . 6 mm ) 19 : 42 w Ooh agemang nggunakan mengan 0 . 0006X · 00153 .

20 : 1439 - 35 - 05x + 0 . 0132 22 0 . 0005 w ww . Ex

g . grace . Ag 0 . 005 .

Y - 00001 + 0 . 0129 . . . . . . . . . 82 - 0 . 0052

= 0 . 0007x + 0 . 0091 vs 0 , 407

25 .

0 . 5 1 . 5 Tirne ( mirs .

0 Test 4 . 1

Test 4 - 1 . . . Linear Test 4 - 5 )

os4 - 72 Test 4 - * Test 4 - 4 0 Tests - # s < < near Test 4 - 1 ) . . . . Linear ( Test4 . . 21

www inear ( Test 4 - 841 . . . . . . Dnear ( Test 4 . 45 . . . . . . . . . Linear ( Test 5 - 61


Fig . 17

Inhibition of Calcium Oxalate formation Vehicle Runs

W9 029 ) oueduosey S . . . . . .

rrrr

Time ( mm )

Vahide 49 Verýcle 10 vende $ 11

Fig . 18

. M

2 SSS m Inhibition of Caloum Oxalate Formation - Vehicle Runs , Slope Tests

O O v = 0 . 05SIX + 0 : 104 ) A O O . . . . - 0 . 7729 occa Absorbance 620 . 6 cm )

. V00533x40022 Om0 . 9499

v = 0 . 04672 0 . 0202 072 30 . 9653 . . . . .

. . . . . .

:

Q 0 . 5 2 . 5 ne ( min .

Vende Vehicle 10 & Vehicle 211 w - linear ( Venice - - - - Unear Wehide # 10 ) Unear ( Venice $ 13 )


Fig . 19

Inhibition of Calcium Oxalate formation by Test Solution 5

????

bscbe { 52

. . . . . . . . . . . . . . . . . . . . .

- - - - - - - - - . . . . . . . . . . . . . 0

8 10 12 Time ( min .

Test 5 . 1 Test 5 - 62 Test 5 . 53 Tests - - 4 .

Fig . 20

Inhibition of Calcium Oxalate Formation by Test Solutions - Slope Tests

0 . 028 0 . 027

y = 0 . 000 $ X + 0025 * * B = 0 . 2013

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . Absorbance ( €20 . 6 cm . . . . . . . . . . . . . . . . . . . . . . . . . 0 . 025 . . . . . . Ay = 0 . 0003x40 . 0259

* * K = 0 . 107

0 . 024

y = 0 . 0007X00221 : 82 = 0 . 5801

0 . 022 . . . . . .

OS 15 1 : 5 2 2 . 5 ime ( min . )

Test 5 - 2 Tes : S - $ 3 A Tests - $ 4 Bear Test 5 . 42 ) * * * * Unicar ( Test 5 - 3 e Unear fasts - 24

U . S . Patent Oct . 17 , 2017 Sheet 11 of 78 US 9 , 789 , 152 B2

Fig . 21

Inhibition of Calcium Oxalate Formation - Vehide Runs

W gozel audioso

0 .

Time ( min .

ovaticemi vehica # 2 # venice 43 # venica 14 vehicle 5 Vehics * 6

Fig . 22

inhibition of Calcium Oxalate Formation - Vehicle Runs , Siope Test

ROLLERLEIHILISHLARININ

0 0 . . . ( Wu g ' azal ozuegosay

. 0

may 00717 % * 0 . 0923 R 0 . 801

y = 0 . 0898x 0 . 0507 . . . . . . 2 - 0 . 8733

W = 0 . 008 * * 0 . 0102 . . 820 . 9677

- 0 . 0013X * 00238 . . - 02 . 0 3031

0 . 0037 * * 00115 20 : 5437

y = - 0 . 0068x0 , 000

. . . . . . . . . . . . . . . . . . . . . . . . . . . . fine . .

. W . . . . . . . . . . .

. . . . . . . . . . .

XU tunggang co 0 . 5 29

Time min . )

o Venice 63 vehide 82 * Vehicles Vebide 66

e ar ( Venice ) manunun Linear vahide * * Bnear Vehicle to

& Vehicle # 3 wwwwww Lineer ( Vehicle # 1 . . . . Lingar ( Veticie 45 ) .

* Vehicles Linear ( Vehicle $ 2 ) Wear ( Vehicla # 6 ) L


Fig . 23

Inhibition of Calcium Oxalate Formation - Test Solution 6 0 . 99 . . .

. . . . . &

Absorbance ( 620 . 5 nm ) o

9

2 $ 20 12 Time ( min . )

Tesi ö $ Test 6 - # 2 Test & # 3 Test 6 - 45 Test & - $ 5 Test 5 - 45

Fig . 24

inhibition of Caloum Oxalate Formation - Test Soluton

009 = 3 : 0012x * 016778 0 . 3 . 271

. . . . . . . . .

L X . . . . . . . . . .

0 : 3389X . 0463 . . R 01 51

. . . . . . . . . . . . . . . . . . . . . . . . Absorsange ( 620 . 5 cm annyiuntinify bandydamgangna gawaing yenesfarsi forma transformationen

. . XXXXXX 0

= 0 . 0045x 0 . 9423 RE : 0 . 7005

2 - 20035x * 0 , 0838 7 .

0 . 01 . . . . . . . .

0003 0 . 0294 2 . 07207

= - 0 . 00286 + 0 . 0269 . . . . . . . . . . R - 0 . 5334 . . . . . . . . . .

7 . 5 . . . . . . . . . . . . . . - . . . . .

05 1 . S Time min )

Test 6 - 41 Test 6 - # 2 Text 6 - 13 * Tests - 14 X Test 65 Testa - 26 * * * * * * * * linear Kesto ) . Unear Test 6 - 82 ;

wce . . . Linear Test & - 43 ) . . . Uness ( Test 6 - 41 . . . . . . ungai Test 5 - 4S ) . . . . . . . Dnear ( Test 6 - 61


Fig . 25

Inhibition of Calcium Oxalate Formation - Venice Runs

. . . . . . . . . . . . . . . . . . . . . . . . . . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . . : . : . : . : . : . : . : . : . : . : . : . : . : . :

WU9 079 ) Boucquosay

? . .

O venice 1 Venice # 2 Vercie 53 vehide 4 Valice # 5 vehice to veices ?

Fig . 26

inhibiton of Calcun Oxalate Formation - Vehicle Runs , Slope Test

. . . . . . . . . . . . . . . . . . . . . .

* * * * * * * * * * snovu wey 0 . 3045 % * 00327 R = 0 . 882

3 . 000X - 0 . 0028 R2 - 0 . 9951

. . . * * * . . . . * 0 02€2x = 0 . 0025

24 - 0 . 9868 Absorbance ( 6206 mm * * * * * *

* * * . * * *

. . * * * y : 0 : 0195x 0 . 0034 . . 9 . 09926

* * * * * * * * * * * Y00204x - Down *

S Y

w w OS . 3 5

0 . 0034x - 0 . 0046 . . . . . . . 0 : 9705 . . .

4 = 0 . 0054 - 0 . 000325 = 0 9673 . . . na o Time ( min .

* Venica * Velxde 13 o Verde ? KRAINA Linear Vahice 11 )

0 Vehícek1 . a vehiice 2 Ventes vehice to

scos . . Unear Venice x2 i mear Venice 13 . . . Unear Venice 15 . . . . . . . . - Unear Verilce # 6 )

winear ( Venice 83 ) www uncer ( Vehicle # 4 linear ( Venice $ 7 )


Fig . 27

Inhibition of Calcium Oxalate Formation - Test Solution 1 10

0 . 008 0 . 006 0 . 004 0 . 002 3 Absorbance ( 620 . 6 cum

- 0 . 002 - 0 . 004 . . . . . . . . . . . . . . . .

10 . 000 Hmeimin .

Test 1 Test 142 Test 1 * 3 Tast 1 4 & Test 175 Test 1 76

Fig . 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

0 . 003 = 0 . 0093 % 0 . 0017

* 0 , 2677 . . . . . .

0 . 002 . . . . . . . . V = - 7E - 05X * 0 . 0003

R2 - 00336 . . . . . -

. . . . . . . . . . . . . . . . . . . . . . .

0 . 0003 0 . 0003 R0 2445

@ . . . . . . . www . o . *

. . . . . . . . . X

. . . . . .

. . . . . . . rrrrrr . 00002X - 0 . 0009 * * * * 0107 engler

. . . . . . . . MAAK 0 . 002 X X X . XX IIIIIIIIIIIIIIIIIIIIIIIIII . . . open om man fristmagamamentumom . . . . . . . . . XX * %

y = 0 , 000SX - 0 . 0023 22 = 02435 .

- 0 . 003 . . . . . . . . . . . . . . . . * * * * * * . . . . . . . 0 . 0002 % - 0 . 003

22 - 0 . 1953 0004

• Test 11 Tact 162 & Test 1 # 3 * Test 1 * Test 1 45 O Testi 46 wwwwww . Linear ( Test 111 ) Unear ( Test 3721

near Test 1 75 ) annan Unsar ( Teci 184 ) . . . . . . . Linear ( Test 1 49 ) . . . . . Linear Test 1861


Fig . 29

inhibition of Caldum Oxalate Formation , Phase Ill Study Collective Data

- 8

- - - - - -

% inhibition ULTE Xinhibition 8 8 8 8 8 •

* Average bisition -

- - -

Test Solution identfication

Fig . 30

New Matrix 1 - - Test Solution 1 , Venice Runs

( 906 9079 ) 300egiosov 190323 Time min )

Venice Venice Vehicle 3 . 8 Vehicla *

atent 0ct . 17 , 2017 Sheet 16 of 78 US 9 , 789 , 152 B2

Fig . 31

? ?Y 1 • 1 * * 1 • 1 1 , ??? ?????? ?

8 { 17

} ~ . . . . . . . . .

? . - 2 . . . . . *

* * . . . } { 4 - - 2 ????? ?????? - ???

» 13 , ?? 5 . • ???? * ®® . . - ?? ???x -

= 33 1 ?? ? *

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k : . . . ?? 4 . . . . . .

?

-

- … . ! ?

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Fig . 32

{ ? ???? x 1 - ? ? ? } . . . .

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- . . . .

. . . . . . . . · · · · ·

.

11 . . … . . . . . .

- ? ????????????????? ????? ????? ????? ?? ? .

?? ?

:

?

- 11 -

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Fig . 33

Matrix 1 - Test Sol ' n 1 . . .

2 . 5 * * * * *

. . . . . .

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* * * * * * * 00 * * Du 9009 baasosay * * * * * * * * * * * * * * * * * * * * * * * * * *

- - - - - - - - y 3 - 0 . 0006 % - 0 . 0079

. . . . . . . . 0 . 0788 . N Y . . . . . . . . . . . . . . . . 44

4 6 . . . > - 0 . 01 * * * * * . . . . . . * * O v0 . 0004 00003 R = 0 . 0806

0 : 012 . . . . . . . . . .

Tiine linin

Tast son 151 . Test Solo 162 & • Waear Ten : sokn 1 $ 11 . . . . . Uricar Test Soru 823 . .

Test Son 183 lineer ( Test Soin 3631

Fig . 34

New Matrix 1 - Test Solution 2 - Vehicle Runs . . . . . 0 . 2

0 . 18

Absorbence 620 . 6 mm

0 . 06 0 . 04 0 . 02

Time ( min .

Vezicek7 Venice ia venice # 9


Fig . 35

New Matrix 1 - Test Solution 2 - Vehície Runs , Slope Test

O o o OOOOOOOOOO 1 0 2076700098 . . ir 0 . 14 0 . 17 . . . . . . . . . . .

09029 ouequosov TROLLERHEILLERIES

Y = 0 . 0189x10 . 0016 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . * * * * * * * * * * * * . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

y * 0 . 1098X 0 . 0034 * * 09903 . . . . . . . . SO .

* * * * * * * * * * erretere - 4222 - 44822241488224472ee444 - * * * * * * * * * * * * * * * * * * * * * *

0 . 5 1 . 5 S

Time ( mio . )

Venice ? * Vehicle 48 Venide 9 * : . . . . . Linear vehicle 87 ) . . . - Linear Vehicle 3 . . . . . . . Linear Vehicle

Fig . 36

New Matrix 1 . - Test Solution 2 0035

0 . 03 . . . . . .

- . - . - . - . - . - . - . - . - . - . - . - . . - . - . - . - . - . - . - . . - . - . - . - . - . . - . - . - . - . - . - . - . - . - . - . - . . - . . - . - . - . - . - . - . - . - . - . . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - .

Absorbanca 620 . 0 om

0 . 01 - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . . - . . - . . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - .

O

2 0 10 32 6

Time ( inin .

Test soin 261 Test Soin 2 $ Test Soin 273


Fig . 37

New Matrix 1 - Test Solution 2 , Slope Test V . 1 . 001 % % 0281 20 . 5737

* * * * * * vov796800000 " * * * * * * * * * * Absorbance 5206 mm .

Y - 0 . 003x * 0 . 0194 . . . . . . . . . . 06834

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

eeeeeeeeeeeeeeee TTTTTTTTT

0 . 5 1 . 5

Time ( min . )

Test Soln 27 Test Soin 2 # 2 Test Soin 263

Unear ( fest soln 2 $ 2 } vorsi Linear Test Scin 231 supernovo Linear Test soin 2 # 1 ) -

Fig . 38

New Matrix 1 - Test Solution 3 - Vehicle Runs

03

' Absorbance 620 . 6 mm

' ' ' ' ' ' ' ' ' ' ' ' ' ' ' '

- 0 . 05 Time min . )

Vehicle 21 Venice Venice Venice


Fig . 39

New Matrix 1 - Test Solution 3 - Vehicle Runs , Slope Test

Y * 9 . 1951x3 . 33298

. * . . . SES . . . . . . . W 9019 30uegosay . . . . . . . Y 119x 0 . 0041

R = 0 . 9606 . . . . . .

. . . . . . . . . . . . . . .

y 0 . 017ix - 0 . 003 * * 0 . 9937

0 . 0093 0 . 0025 . 2 = 0 : 2306 . .

2 : 5 * * * $ $ * 0 041068 * 80808 $ $ * * *

OS - OOS Time ( min . )

Venice 3 The vehicle 42 Venice Vehide # 4 svesnovo , Unear Velde # 1 ) - - - missi ' Uoga ( Venice # 2 ) - - soves . Unear ( Venice # 3 ) cssons . Uneor ( Venize ita

Fig . 40

New Matrix 1 - Test Soluton 3 0 . 025

0 . 02 .

LUU 2009 Buequosav

N

Time ( min . )

Test Son 3 # 1 Test Soin 362 Test solu 343

Venice 0 Vences Vehice 54

Time ( min . ) 5

. . . . . . . .

. ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' - ' . ' . ' . ' . inntinni . ' - ' . ' . ' . ' . ' . . iiiiiiiiiiiiiiii

Wu 90C9ouquosov New Matrix 1 - Test Solution 4 , Vehicle Runs

Fig . 42

roubam User ( Test Sol : 383 ) Test sans ta

ever . Unear Test Sol 363 . ) . . . . . . Unear ( Test Soln 33 ) Test Soin 3 # 2 1 Test soin

Time ( min S 2 , 5

0 . 0289 Y = 0 . 0094x * 0 . 0044

Y : * = 0 . 4167

W 90C9 2002gov N3000146 * 0 . 004 0 . 0

. . . . . . . . . . . . * * * *

0 , 6147 . . . Y + 0 . 0014 * * 0 . 0048

New Matrix 1 - Test Solution 3 , Slope Test

Fig . 41

US 9 , 789 , 152 B2 Sheet 21 of 78 Oct . 17 , 2017 U . S . Patent


Fig . 43

New Matrix 1 - Test Solution 4 - Vehicle Runs , Slope Test y : : 0 . 1103X * - 0 . 0297

02 - 0 . 9153 . W

. . . * * * Y = 0 . 0899x 00087 2 = 0 , 9533 . . . .

. . . . . . . . . . .

. 9 079 30MaquoSCY

* . . . .

sr . . * * * . * . . . . . . . . . . , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

, . . *

. + 1 . . * 0 . 0469x * 0 . 0043 0 . 9863

. . . Li4r . . .

1 . 5 1 . 5 25 Time inin ,

Venice 44 * venice # 5 Vehicle to svenssons unear ( Vehicle 44 . 3 " linear Vehicle is none Dosar Wende o

Fig . 44

New Matrix 1 - Test Solution 4 . .

0 . 08

Absorbance 620 . 6 . . oooooo Se 8 8 8 . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 2 10 12

Time ( min .

Test Son 443 Test soin 462 Test Son 443


Fig . 45

New Matrix 1 - Test Solution 4 , Slope Test 0 . 014 Y : 0 . 0031X3 . 005 .

2 . 0 3069 . 0 . 012 0 . 01 Erre * * * * * * *

- . - . - . - . - . - . - . - . - . - - - . - . - . - . - . - . - . - . - * * - 0 . 0009x10 . 0084 0 . 008 * . . . . . . .

* * * * * * * * * W9 029 aguedosay * * *

0 . 00 Y - 0 . 001 % + 0 . 0024

06506 Wix

0 . 007

* * * * * * * * * * * * * * * * * * * * * . . . . * *

$ 1 . 5 1 . 5 2 2 . 5 $ Tine coin ,

est soin 4x1 . Test Solna # 2 Test Sol

* * * * * * Linear Test Soin 40 . . com . Unear Test Soin 452 ) . . . . . . . Linear Test Soin 4899

Fig . 46

New Matrix 1 - Test Soln 5 - Vehicle Runs

Absorbance 620 . 6 mm

C . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ??????? ?????????????????????? - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

K 002 Time min

Vercel Vatica # 2 Venice # 3


Fig . 47

New Matrix 1 - Test Sol ' n 5 - Vehicle Runs , Slope Test

6 0 . 0402x - 0 . 0013 * 0 . 9865 0 . 08

. !

60 . 05 .

. . . .

wu9029 a .

. .

. . . .

. 40 . 04 . . .

0 . 0102 % 0 . 0006 $ 20 . 9195 posok # . 0

0 . 02 - 9 . 000x * 0 . 001

+ 0 . 9575 * *

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

002

vehide . Tine cinia . ) Vamicie ?

1 ) . . . . . . Linear Venice # 2 ) venice $ 3

. Linear Vehicle # 3 * * * * * burear ( Vehicle

Fig . 48

New Matrix 1 - Test Soto 5

Absorbance 620 . 6 nm . . . . . . . . .

. .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . mmmmmmmmmmmmmmmmmmmmmmmmmmmm mmmmmmmmm

N

Pris frain

Test Soin 5 $ 1 . Test Soin 6 # 2 Test son 5 * 3


Fig . 49 . .

New Matrix 1 - Test Soin 5 - Slope Test 0 . 07

? ? ? ? ? ? ? ? ? ? ? ? ? ? , , , , , V , V , V , V , V , V , V , * * * * 000198 00464 20 . 0564

. * * . * . . . .

Absorbance 6206 10 306006080

. . . 0 : 00000027 22 - 0 , 1179

00088808 Y 0 . 0001x0 0274 * * * 82 - 0 0813

0 . 5 1 . 5 . Ume ( min .

9 Test Som51 Test soin 542 . Avviso uincar Test Soin 581 ) . . ! gineer ( Test soin 5 # 2 :

Test Son 5 * 3 Ungar ( Test Son S3 )

Fig . 50 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

New Matrix 1 - Test Sol ' n 6 , Vehicle Runs

. ' . ' . ' . ' . ' . ' . '

. . . . . .

. ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . . . .

. . . . . . . . . . . . . . . . . . . . . .

r . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . ,

Absorbance 620 . 6 in . . . . .

. . . . . . .

. . . . . . . . . .

.

. ' . ' . ' . ' . ' . ' . ' .

o Won Time ( mio . )

vende te venice # 5 venice # 6


Fig . 51

New Matrix 1 - Test Soin 6 Vehide Runs , Slope Test

V + 0 . 123 . 3 % * 0 . 0706 . . . . . 8 0 . 8286 .

V = 0 . 11524 0 . 0699 R = 0 . 8411 w 9 ' 0792uegos y

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

1 .

TTTTT . OT 1 . 5 0

The min . )

Vehicle move * * * Unser Vehicle id )

Vehicle is ungar ( Vehicle 95 .

velide 6

unex Vanicie # 6 ) crescentescassossessionistes de todas as serescsesercicisssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss !

Fig . 52

New Matrix 1 - Test Sol ' n 6 0 . 09

0 . 08

PIPIE .

Absorbance 620 , 5 mm . . . . . . . . . . .

88 ©

* * . . . . . . . . . . . . . . . . * * * * * 0 0

Time ( min . )

Test Soin 5 Test Somo 652 Test Sol 63


Fig . 53

New Matrix 1 - Test Soin 6 - Slope Test 0 . 09 y : - 0 . 0027x + 0 . 0505

0 . 5701 008 : : : : : : :

Y = 0 . 0027x10 . 0936 . . . . . . . . . . . . . 30 . 0642 0 . 06 1 { { { { ' G?

1 . * * * .

Y ?? * - 0 . 00337 0 . 04

* : 0 . 8985 :

?? ? 0 . 09

0 . 02 :

:

0 . 01 :

0 1 . 5 0

Time ( min . .

Test Soin 61 * * * * * * * * Unear Test soin

Test Soto 6 42 & rett soin 673 se ungar Test Sala 623 . . . . . . . . . . Lire ( Test Soin 668 ) 23 .

Fig . 54

New Matrix 2 - Test So ' n 1 - Vehicle Runs 025

0 . 2

0 . is . . . . . . . . . .

Absorbance 620 . 6 am . . . . . . . . . . . . .

1 . .

- 0 . 05 . . . .

Time min . )

vatice h1 Vehicle # 2 Vehicle 33 Venice Venice os


Fig . 55

New Matrix 2 - Test Solo 1 Vehicle Runs , Slope Test

2093x : 0 . 0375 R2 : 0 . 8937

. . . . . . . . . . . .

. * . .

. . . . .

. . . . . . . . 30 . 0564x : 0 . 0063 . R2 * 0 . 9736 . . . . .

. . . . .

. . Wu 029 50ecoscy . . .

$ 90 . 0 . . 8888888888888 : 0 . 0105x - 0 . 0042

R ? - 09513 V03 . 0071 - 00049 20 . 9954

. .

.

15 22 - 0 . 9424 25 . . . . . . .

1905 Time ( mun .

Vehice 1 Venice 2 Vehce 3 Varice

* Vehicles voorvene rear ( Velice # 1 : . . . . . . . . Linear ( vehicle 82 . . . . . . . Ucar Vehicle 393 anovoroso Linear ( Venice * 43 . . . . . . . . , near Nehicles

Fig . 56

New Matrix 2 - Test Soln 1 0 . 02

. . . . . . . .

001

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Absorbance 620 . 6 mm 3000 Bu l

b anan 22

4 . 605 - 0 . 005 in : 0 . 01 L ' INTERESSE

Time ( min . ) NM Test So ' : * 2 ONM ? Test So ' n 1 1 NM 2 Test So ' n 183

. .


Fig . 57

New Matrix 2 - Test Solo 1 - Slope Test 002

0015 06 - 08 % 4 00048 22 0 . 0006

001

0 . 025 * * * . * 0 . 9029 ouequoscy

* *

. . . . . . . . . . . . . . . . . . . . . .

* * * *

0 . 00144 0 . 0011 . . . . . . . . . 0 . 3239

* * * * *

V = 0 . 00064 - 0 . 0035

. . . . . ' tiririririririririririririririririririririririririririt ' WwW . ' ' ' ' ' ' ' ' ' ' ' ' ' '

08998 3 . V N ,

W211217 - 0 . 008

- 0 . 01 Omeroin )

NM2 Test Soin 163 reservon Unear ( NM2 Test soin 11

NM2 Test Soin 142 NM 2 Test sol . 113 svars gineer ( MM2 Test soin 1 # 2 ) - Linear ( 2 Test Solin 163 )

Fig . 58

New Matrix 2 - Test Solution 2 Vehicle Runs 0 . 25

02

015

UD 9079 couequosqy

N

- . .

. . .

005 Ume frain ]

venice # 2 Vehicle 33 . veicieni Venice 44


Fig . 59

New Matrix 2 Test Solution 2 Vehicle Runs , Slope Test

Yz0972x + 0 . 0158 . . . . . . . R 09254 . . . . rrrrr .

. U 9 079 . . . . . . . . . .

. . . . .

. . . . ueqiosay PPPPPPPPPPP . ! . . .

. . . . * 0005ax 0 . 0032 . . . . . . = 0 . 9567

= 0 . 0037 % - 9 . 0012 20 . 9324 . . .

. . .

Y . . . . . . N09 25 - - - - 0 . 0072x - 0 . 0053

- 0 . 983 - 0 . 05 . . . . . . . .

Ime ( mio .

Verde # 1 0 Vendem vor . Unear Venica # 3 )

Vehics 62 mocanoves Linear ( Venice in corro , Gear ( Venide # 41

Vance 83 seisn . Unear Vehicle # 2 )

Fig . 60

New Matrix 2 - Test Solution 2 "

' . ' .

. . 0 . 03

. . . . . .

. .

-

. . 0 . 025 - -

. . . . . .

. .

. . . . . . . . 0 . 02 -

. .

.

. . . . .

Wu 9 079 20upoSCY - - - - - - - - - - -

. .

-

. . . . . . . .

. .

. . . .

. .

. .

. . . . . ????????????????????? . . .

* * * * * * * * " * * * * * * " rrrrrrrrrrrrrrrrrrrrrrr ! TITUTITITITITITI " " " " " " " " " .

*

. .

. .

. . Time ( min . ) . .

. .

. .

. .

Test Soin 241 Test So ' n 272 Test Soln 243 .


Fig . 61

New Matrix ? - Test Solution 2 - Slope Test 0 . 03

- -

0 . 025 y2 - 0 . 0013 10 . 02

3629 -

-

. . . . . . . . . . . - Absorbance 620 . 60m2 .

* * * " y = 0 . 0026 % + 0 0918 * * * 22 = 0 . 7347 11

. * * 0 . 00132 0 . 0109 = 0 . 6193

. . . . . . . . . . . . . . . .

2 . 5 G

Time ( min )

© Test son 2 # 1 " sessoes , Unear ( Pest So ' n 22 .

Test Sota 262 Test sai ' s 243 ineer ( Test Sol ' n 2 # 3 ) . neres . Unear ( Test Soin 2 : 3 ) .

Fig . 62

New Matrix 2 - Test Solution 3 - Venice Runs "

' . ' .

. .

. . . . . .

. .

. .

. . . . . .

. .

. . . . . . . .

. .

.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

WV 9 079 30vequosov

- - . - - . - - - - . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- . 202 - .

- .

- .

- . Time min . - .

- .

- .

- .

.

Verice is Venice to verde # 7 Vehície 68


Fig . 63

New Matrix 2 - Test Solution 3 - Vehice Runs , Slope Test

. . . * * * Y = 0 . 1025x + 0 , 1411 . . . . . 8 : 0 . 0 , 7006 .

. . . . .

* * * : . . . . . . t . . : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

* * * * 10 9 ' 079 osuequosos

" .

. . . . . . * * 0000043 20 . 9935

* * * 000980 : 0004 K290 . 9777

20 . 993 SOMO 99000039 . . 05 - 0 . 005

Tiina ( mains ,

venice 5 • * * • • * • . Unear ( Veticle # 5

Venice 76 Vehicle 47 Venice 48 . . . . . . Jen ( Venicia $ 61 . . . . . Unear ( Veticle 47 ; . . . sono en Venice no

Fig . 64

New Matrix 2 - Test Solution 3 0 . 045 004 0 . 03s 003

0 . 035 002

0 . 005

0 . 01

warrant 5

Test So ' n 3 * * Test Solri # 2 Test Soin 363


Fig . 65

New Matrix 2 - Test Solution 3 , Slope Test 0 . 016 - 0 . 005 % 0 . 0035

- 0 . 7925 0 . 014 .

0 . 012 * * : , ,

0 : 01 WO9 079 cuegiosa 0 . 008 68 - 066 - 0 . 0035 22 = 0 . 0039

0 . 006

0 . 004 . . . . . . . . . . . : . . . . .

. . . . . . . . . . . . . . . . . . * * *

$ * 888888888 * 8

0 . 0004x * 0 . 0018 = 0 . 2588

0 . 002 ?

0 . 5 1 . 5 2 , 5 0

mine inin )

Test soin 363 . asses ainear ( Test soin 361

Test So ' n 3 . 42 • Test solo * 3 . linearitet Sorn 32 . avons Unear { Test Soln 383 )

Fig . 66

New Matrix 2 - Test Solution 4 , Venica Runs 0 . 35

0 . 3

0 . 25

0 . 2 3

? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

2 0 . 05

Venice 49 Vercie 630 Vehicle 411 Venide 12 Venice # 15


Fig . 67

New Matrix 2 - Test Solution 4 - Vehicle Runs Slope Test . Y : 0 . 077101559

0 . 8394 LUX

. . . . . . .

. . . y = 0 : 33SAX * 0 . 0428 * * * 80 : 8631

H ivi . . . .

X II . . .

; , . . M 9 029 sovequosay

. , , .

. . , 1 + .

. .

. . . . . . . . . 3000578 3 . 0002 . AY - 0 . 9938

- 0 . 0037 * * 0 . 0974 .

00S . .

* * * 0 - 90 % 6 . 0059x00008 R = 0 . 9037 OS 15 215

- 0 . 05 Time min .

0 Vence # 9 Varicie # 13

Verside # 10 Vende Lingar Verkde * 9 ) . . . . . . . . . . Uncor Venice # 10 ; . . .

vehicle # 12 Linear ( Venice # 11 in

normscono Linear ( Vericia 12 . . . . . . Dnes ( Vanicie 713

Fig . 68

New Matrix 2 - Test Solution 4 0 . 025

0 . 02 WWW Wu gozo Buequoscy 20 . 015

8 0 . 01

0005

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - 4 ? ??? ? ??? ? - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

TV 10 11 Umé ( min .

Test So ' n 462 Test 5oi ' n 41 . Test Sola 4 * 3

U . S . Paten atent Oct . 17 , 2017 Sheet 35 of 78 US 9 , 789 , 152 B2

Fig . 69

New Matrix 2 . Test Solution 4 , Slope Test 0 . 005

0 . 0045 Y 001Sx * - 0 000

09344

0 . 004 $ 0 . 0035

* * *

0 . 00132 0 . 0003 08562

* * * ity 0 . 0011 * 0 . 0005

. . . . . . . . . . . . . . . . . . . . . . . . . . . 0 , 804

* * ;

. . . . . . . . . . .

Absorbance 620 . 6 mm . . . .

. s * *

* * *

0003

8 0 . 0025 0 . 002

8 0 . 0015 0 . 001

0 . 000 . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . .

. . . . . . . . Nr . 0 0 : 5 3 : 5 2 . 5

Time ( min . )

0 Test soin 421 Tesi Soln 4 * 2 . Test 1143

* * wwsuses Linear ( Test Soln 4 + 1 ) = nos . Onearest soin 4 # 2 ) . . . . . . . . Linear ( Test Soin 463 ,

Fig . 70

New Matrix 2 - Test Solution 5 , Vehicle Runs

. .

WU D ' OC9 aqueqxosqy

2 8 10 12 Time in

Velca # 1 Venice # 2 & Vehice is vehce 4 Venice 85


Fig . 71

New Matrix 2 - Test Solution 5 , Vehicle Runs - Slope Test

. . . . . . . . . . . . . . . . . . . . . .

y : 0 . 1157 * * 0 . 1103 07631 LINK

. . . . . . . . . . . . . . . : : : : : . . . . .

. . . wog ' 029 Bovequosgy .

. . . . . . .

" va OBBZ 0 . 0985 .

24 - 0 . 9563 . . . .

. . . . . . . . . V = 0 . 0350 000

0 . 9833 * 0 . 0126 % . . Q : 0065

0 . 01x 90068 22 0 . 8731 * * * * * * * * * * * *

0668959 $ $ $ $ o 1 . 5 0 . 5 25

me min . )

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Voice1 Velncie # 2 Vencia és verover linear Vehicle 21

- - - - - - - - - Linear ( Velide 141 . . . . . . . . Unear Vehicle 95

Vehicle 3 Verice 4 . . . . Unear ( Vehicle # 2 ) - 11 Unear Vehicle 83 )

Fig . 72

-

New Matrix 2 - Test Solution S -

0 . 06 -

-

0 . 05 -

-

-

- 2004 09029 -

-

2003 - bence - -

-

0002 -

-

- -

-

- -

-

- -

- -

- - 2 -

- Time ( min . st Son5 * 2 - - Test Sa ! ' 561 es Sa ! ' n 53

- - -


Fig . 73

New Matrix 2 - Test Solution 5 , Slope Test . . . . . .

0 . 0003x + 0 , 0484 201809

005 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

: * * * * 22 - 0 . 479

. . . . . . . . . . . . . . . . . .

Ya 08005x * 00396 22 : 0 . 4576

. . . . . . . . . .

ug ' 079 eurology

! . . . . . . . . . . . . . . . . . . . . . . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

05 2 . 5 Time ( mia ,

* Test soln $ # 1 * * * * * * * * * Unear { Test So ' n 5 # 2 ) . . . . . .

Test Soins * Test Solin 549 Jinear Tast soilo S62 ) . * * * Linear Test soln 573 )

Fig . 74

New Matrix 2 - Test Solution 6 , Venice Runs

Absorbance 620 . 6 am

Time min

vehicle in Venice Venice 48


Fig . 75

New Matrix 2 - Test Solution 6 , Vehicle Runs - Slope Test . . . . . . . . . . .

0 . 0940x 00106 * * 0 . 9897

? ! ! : ' ) SSSSSSSS 70 . 0162 % 0 . 0122 . . . . . . . . 09827

. . . . . . . . . . $ 4 , 3gSKY = 0 . 012x : 0 . 9196 2209776

. . . . .

0 . 5 1 . 5 2 . 5 Tiine ( min . )

Vehicle Vehicle # 7 varice 48

resme . ro Uinger ( Venice 15 ) . . . . . . . . . Unear ( Venice # ? } . . . . . . . . . Unear ( Venice 46

Fig . 76

New Matrix 2 - Test Solution 6

? ??st ( 47 : 3 ( 32£3 { ? ? ? ?

? .

Test Soin 6 + 1 Tesi son 572 Test So ' n 6 3


Fig . 77

New Matrix 2 - Test Soluton 6 - Slope Test

0 . 06 0 .

Y : 0 . 0019x40 . 0568 20 . 608

- 0 . 00098 0 . 0577 0 - 0 . 8066

Y = 0 . 002 + 0 . 0478

nowo 09 .

0 . 04 09 . 029 2008quos y

0 . 08

0 . 02

0 . 01

0 0 . 5 1 IS N

Time min .

Test soin 63 Test soin 6 . 1 . Test sa ' n 682 * * * * * * * * Wnear Test soln 5 11 . : : . . Unear Tedi soi ' n 6 $ 23 . Linear Test Soins # 81

Fig . 78


Absorbance 6206 mm ST Toe is ,

Vehície t1 Vehicie 42 Veticie 63 Vehicle 48


Fig . 79

New Matrix 3 - Test Solution 1 - Vehicle Runs , Slope Test 0 . 06

b = 0 . 023x10 . 0093 . 20 . 9721 0 . 05 * * + .

* * . * . .

0 . 03 - . . . .

. . .

005 0 . 00 0 . 0020 . ( OU 9029 ) Dovequosav

0 . 02 V = 0 . 0072 - 0 . 0005 - 0 . 9862

.

. . .

. .

. .

. . . . . .

y = 0 . 009iX : 0 . 001s R2 - 0 . 9623 "

' . ' . * * *

.

. . . . . . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ????? ? ? ? * *

. . OS . .

. . . . . .

. .

. . . . - 0 . 01

. . .

. .

Veride # 1 * Venide # 4 . . . . Unear ( Vehicle # )

Time ( inin Vehicle # ?

* * * * * * * * * Unear ( Venice # 3 ) . . co Wear ( Vehicle 29

& Vehicle # 3 - . . . . Crear Venice 82


Fig . 80

New Matrix 3 Test Solution 1 0 . 043 0 . 04 . . . . . . . . . . . . . . . . . . .

0035 OOS

$ 0 . 025 Absortance ( 620 . 6 m 0 . 02

0 . 015 0 . 01

0 . 005 10

Time min . )

NM3 Test Sai ' n 161 NM3 Test Solln 1 # 2 NMS TEST Soln 13 NM3 Teri 5019 1 # 4

Fig . 81

New Matrix 3 - Test Soin 1 - Slope Test * * * 00012 * 0 . 0035 . . . . . . . . . . . . . . 2 . & 397 . . . . 0 . 008

. . . .

0 . 007 iiiiiiiiiiiiiiiiiiiiiiii iiiiiiiiiiiiiiiiiiiiii

0 . 006 . . . . .

. . . . y = 0 . 0005x - 0 . 0042 . . . . . 8 0 . 5979 0 . 005 9

0 . 000 * * * y00013x + 0 . 0008 . : 0 : 3907 0 . 003 . . .

0 . 00 % . . . . . . . . = 0 . 005x : + 00002 . .

0 . 003 . . : : * * * . . . .

444444446 . 6 * * * 0 . 5 15 1 . 5 221

WM Test So ' 93 843 Test So01 ? M3 Test Soin 3

NM3 Test so scorsoo linca Me Test soin 1814 . . . . . Unear INKAS Test Sora 1 # res Linear ( NM3 Test Soin 1 g ) * * * * . Unear AMB Test soin 1849


fig . 82

{ ?x 3 - 1 1 ) - ??? ?

?

$

111 > $ $???????? ?

$ ?? ?? ?? ?

$ 11 12 ? . ??? .

????? ? ?? ??? ! ! $ $ e ???


Fig . 83

New Matrix 3 - Test Solution 2 - Venida Runs , Slope Test 0 . 07 . . . . . . . . . . . . .

Y - 0 . 0021X : 0 . 0508 * * 3 : 0797 Ü . 00

0 . 05 . . . .

: . . . . ( WO 9029 ) sougquosqe 8 . 00131X + 0 . 009

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

v = 0 0064x * 0 . 9934 . . . . = 0 . 9903 . . . .

0 . 01 0 . 406SX 0007 120 . 9943

one

1 . 5 2 . 5 N

Time çrrin .

Vehices venice # 6 Venice # 7 * Vetica Unicar ( Venice 85 ) . . . . . . . . . Linear Vehicle # 6 . . . . . . Wear ( Vahide # 7 ) co . . . Lines : ( Venice 48

Fig . 84


( ww goze ) . Su quosgy

899 * Time ( mun )

KMS Test Sobr283 NMS Test So ' n 242 MMB Test Solin 2 # 3 Nm 3 Test Soi ' n 2 # 4


Fig . 85 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


" : y = x - 313 2 : 0 . 9738

. . .

Absorbance ( 020 . 6 . no ) . . . 4 : 0 . 0007x : 0 . 0104 .

2 : 07148 0036 % + 0 . 0076 * . . .

* - 0 . 907

se pig . 9 . 0 $ . $ $ $ y = 0 . 0008 % + 0 . 0078 R : 0 . 877 . . "

.

-

" ' . ' ' . ' . ' .

0 0 . 5 29 2 . 9

Timis ini .

MMB Test son 2 * NV3 Test Soin ? $ 2 YMS Festso264 oncessbucar NN Test So ' n 2 # 0

. . . . . . . . Linea ( NMSes Sols243 ) con Pacar ( NM 3 Test Soin 24

2 M3 Test soin 2 43 . co Uncat ( Nm3 Test Soft2821

Fig . 86

New Matrix 3 - Test Solution 3 , Vehide Runs

. . . . . . . . . . . . ,

Absorbance ( 620 . 6 am

wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww

10 12 1 2

Tone ( min . )

varice 1 Velde 2 vehicie 13


Fig . 87

New Matrix 3 - Test Solution 3 - Vehice Runs , Slope Test , , , , , , , , , , , , , , , ,

0 . 045 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

0 . 04 v = 0 . 0078 * * 0 . 0255

- 0 . 9946 0035 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . sssssssssssssssssssssssssssssss 0 : 03

0 . 01094 + 0 . 0116 22 0 . 9977 Absorbence ( 620 . 6 mm ) ,

Y - 0 . 008 % + 0 . 0077 22 : 0 . 9839

. . . . . . . . . . . . . .

. . . * . . . . . . . . . . . sisisi assississississississssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss

0 . 01 0 . 005

: 2 2 . 5 Time ( min . )

Verice ? vetica 2 Vericia . . . * " near ( Venice 49 ) . . . . . . . . Linear Vehicle 80 ) . . . . . . . . . . Grea ! ( Veinicie 43 )

Fig . 88

New Matrix 3 - Test Solution 3 . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . '

'

( uso 9029 ) aouequosay . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . . . ' . ' , ' . ; . ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss . . . . . . . . . . .

- . , , , , , , , , , , , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : .

Time min .

NMKTS 541 NMTS 32 UNM # 1933


Fig . 89


Y = 0 . 0026x : 0 . 00x8 0 . 8471 0 . 014 ! . . : . : . : . : . : . : . : . : . : . : . : . : . . : . : . : . . : . : . : . : , ' , i , ' , i , ' , S , ' , t , ' , i , ' , , , , , , , , , , , , , , , , , , , , , , , , , , , ' . ' . ' . ' : . : . : . : . : . : . : : .

0012 120 . 00 * 1x 0 . 0054

. . . . . . . . . . R 3 , 9536 0 . 03 Absorbance ( 6208 . mm

0 . 008 . 0 . 0013 * * 0 , 70 * * * * 2706211

0 . 004

0 . 002 IIIIIIIIIIIIII

0 . 5 1 1 . 5 Time ( mini )

23 7S 36 NM3 . 15 342 M # TS33

vocnov Linear ( NMS 15 361 ) . . . . , Linea ( NM3 . 75 3 $ 2 } •s - vous uneer ( NM # 183 # 31

Fig . 90

New Matrix 3 . Test Solution 4 , Vehicle Runs 0 . 09

( 0 . 08 0 . 07

0 , 04 . . . . . . . . . . . .

9 oze ) anuequosay .

0 . 03 0 . 02

. . . . . . . . . . . .

N

Tirie mij

Venice Venice 65 venice 36


Fig . 91

New Matrix 3 - Test Solution 4 Vehicle Runs , Slope Test 007

Y = 09134X - 3 . 0244 BR0 . 9731 0 . 06 *

900 y $ 00153x + 0 . 0113

R = 0 . 9951 R .

Absorbance ( 620 , 6m

* * * . . . . . . . . . wa s 0 . 0093 % + 0 . 0022 i B = 0 . 9963

0 . 02 * * . . rsrsrsrsrsrsrsrsrsrsrsrsrsrsrs * . . . Kirsississississississississississississississississississsssssssssssssssssssssssssssssssssssssssss

2 . 01

0

3 1 . 5 2 . 5 N $

We min .

Venice 4 Vahde S & Vehicie 6 * * * * . . . Ungar ( Venice # % ) . . . Unear ( Venda # 5 ) . Unear ( Venice # 6

Fig . 92

New Matrix 3 - Test Solution 4 0 . 08 3 . 07 900 SOO Absorbance 620 . 6 . riin

0 . 03

0 . 02 0 . 01

. . .

10 Time min .

NM3 194 41 M315462 MM3 TS473


Fig . 93

New Matrix 3 - Test Solution 4 , Slope Test 0 . 05

0 . 045 1 . 08

y = 0 . 0058x - 0 . 0383 6802

0 . 035 * 0 . 007644 09258 = 0 . 986 . * * Absorbanca ( 620 . 5 20 R 0 . 03

0 . 025 0 . 02

0 0 . 015 . . . . . = 0 . 0926x : 00122

. .

20 . 00 0 . 005

. . . . . . . . . . . . . . . . 1 . 5 2 . 5

Time ( min . ) NM31941 NM3 15482 VM3 . 784 * 3

. . . lineer ( MMBT54 41 ) . . . . . . . Unear RM 18482 . ) . . . . . . . . . Unear V3 7543

Fig . 94 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


u 9079 ) aouequosay *

Tine in

o venice Venide 2 venice 13

& # 991 ENN 28SSI ZWN * * SSLEWNO

( 400 ) ew . 3 : 03

- 0 . 02 * * * * * * * * *

0 . 01 *

Absorbance ( 620 . 6 . mm

3 . 02

200


Fig . 96

roncson . Unear Venice 411 4 . 0 . . . Linear ( Venice 2 ) avrsends boear ( ehicle # 3 ) Venice Vanide # 2 Wenn

Time min . ) 200

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - 0 . 02

100 SK

61200X8810 ' 0

( WU 9029 ) coucquosay 0 . 02

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . . . . . . . . . . . . . . . - 305 985602 y = 0 . 0158x + 0 . 0328

0 . 04

. . . . . . , . , . , . , . , . , . , I . 2 . 05 21660 21900 + X18000

3 . 00

New Matrix 3 - Test Solution S , Vehicle Runs - Slope Test

Fig . 95

US 9 , 789 , 152 B2 Sheet 49 of 78 Oct . 17 , 2017 atent


Fig . 97


2008 = 0 . 0037 - 00222

R2 : 09308 - 0 . 00 . . . . . . . . . . .

Absorbance ( 620 . 6 mm - 0 , 015 y = 0 . 0045 - 0 . 025s

00524

Y = 0 . 00236 - 0 . 0271 13709169

0035

Time ( min . )

© NMISS NMISS 2 MTSS 73 cssroanne Linear ( NM3 T55 a - o s near ( NMS 755 821 - - vosowo Linear INM375583

Fig . 98

New Matrix 3 - Test Solution 6 , Vehicle Runs 0 . 07 0 . 00 005

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 09029 ) ouequosay - 0 . 01 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

. . . .

- 0 . 02 - 0 , 03

time ( min . ) Vendes Vehicle 46 vehicle # 4


Fig : 99

New Matrix 3 - Test Solution 6 , Vehicle Runs . Slope Test 0 : 04

003 - 0 . 0305x - 0 . 0282

R = 0 . 9342 y = 0 . 02248 - 0 . 0238

27 : : 0 . 9877 V = 0 , 0130 - 9 . 025

Rö : 0 . 9876

0 . 02 .

0 . 01 w www . g ' ozg ) asuegiosay

09 - 0 . 03 . * * * * * * * *

- 003 ires

- 0 . 04 Diner

Venica 15 Venice na Verica 6

sasovosa . Cinnar ( Venicie 4 ) . . . . . : Linear Vehicle $ 5 ) Mina Unear ( vehidle } HM M M MMMMMMMMMMM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . mmmmmmmmmm !

Fig . 100


0 . 05 0 . 04 2 . 0

29 Absorbance ( 620 . 6 mm

. . . .

- 0 . 02 - 0 . 03 - 0 . 04 . . . . . . . . . . . .

me min . NM TS6 * 2 N3 TS643 OMV TSG 1


Fig . 101

New Matrix 3 - Test Solution 6 - Slope Test 0 , 02

. . - 0 . 0225x - 0029

R 9 . 9893 . . . * * * . . .

* . . .

*

. : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : . : : : LLLLLLLLLLLS LLLLLL Absorbance ( 6206 m *

y = 0 . 0094K - 0 . 027 0 . 3905

0 . 0087X - 0 . 0301 *

32 *

- 0 . 0 % . . .

Time ( min .

WM3 756 * 1 NMS 7S5 * 2 . AM3 563

- - * * * * Linear M3756 11 . . . Linear RM3 TS682 ) . soon . Linear ( NM3 136631

Fig . 102

0 . 12 New Matrix 4 Test Solution 1 Vehicle Runs . 0 .

0 . 08 PS Y . . , . , - , - - - - , - - , , - , . . . . . . . . . . . . . . . . . . . . - - - - - - - - - - - - . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

06 Absorbande ( 620 . 6 mm

20 . 02

%

. .

- 12 . 02 Time main

Venice Vahdeki Venice # 3


Fig . 103

.

0 . 96 . . . . . . . . . . . . . . . . .

400 - 00179400197 . . . 6 . 9807 005

0 . 04

20 . 037 % - 0 . 0003 R0 . 9827

0 . 39

0 . 11 . 11 : IIIII Absorbence ( 5206 am 0 . 01 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Y - 0 . 0073 % - 0 . 0113 outs2 - 07635 . .

1 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , . - . - . - . - . - . - . - . - . - . - . - . - , , , , - , , - , , , , - , * . * . * . * . * .

* * * * * *

: 08088098069 . . . . .

0 . 02

Veikcle 3 » Venicles

H . - Unear Venice # 2

In : ( min . ) * Verde # 2

rosecome linear ( Vehicle 621 conssen Linear ( Vehicle 43

Fig . 104

New Metrix 4 - Test Solution 1 . . . . . . .

. . . . . . . . . . . . . . . . . .

.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Absorbance ( 620 . 60m

. . . . . . . . . . . .

. .

. .

. . 10 . .

. .

. . Time ( min . . .

. .

. .

ONM4751 # 1 NM4 T5162 MMTS19 NM4 IS1 4


Fig . 105

New Matrix 4 . Test Solution 1 , Slope Test 0 . 025

ya 0 . 0008 * * 0 . 021 . . . . . . . . 255 . . . .

0 . 015 . . . " y = - 0 . 0012K + 0 . 0199

: 0 . 5355 . . . . . . . . . . . .

9 . 01

Wu9029 ) au oscy * * * * * * * * * * * * * * 000 80808 09 0 : 03 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . .

: : - 2002SX00148 20 . 7397

0 . 005 y = - 0 . 001x * 0 . 0079 305645

- - - - ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

15 1 , 5 0 . 5 1

Time ( min . )

0 NM4 TSI 1 VW 181 * 3 NM4 793 . 63 MM 151 84

autoremon Linear NM415141 , son . Unear NM4 751 # 2 ) corredore Enear INMATS163 ) . . . . . . . einer NM & T81 # 8

Fig . 106

New Matrix 4 - Test Solution 2 - Vehicle Runs

. ' . ' . ' . ' . ' . ' . ' .

WW9029 ) Juegosav : : : : : : : : : : : : : :

. . . . . . . .

- - - . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . .

Time ( min . )

Veixcie 610 vende $ 11 Vehicle # 12


Fig . 107

New Matrix 4 . Test Solution 2 - Vehicle Runs , Slope Test 0 . 09

0 . 08 y = 0 . 03257 0 . 0377

* * * 09901

002 : ) : ) : ) : ) : : : ) : ) : : ) : ) : : ) : : ) : ) : ) : ) : ) : ) : ) : ) : ) : ) : : ) : : ) : ) : ) : ) : * * * SIENYNNYTYSSN

0 . 0246x00205 . . . 0 . 0 . 9012

wiu 9079 ) Dougos * V = 0002400174 - 9 . 9909

0 . 02

0 . 01

4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . . . 4 . 4 . 4 . 4 . 4 . . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4

2 . 5 Tirne min .

Venice # 10 Vehicle 80 venice 132 near ( Vaircie 10 ) . . . . . . . Linear Vehicle # 233 . . . . . . . . Dez ( Venice * * * * 2

Fig . 108

New Matrix 4 - Test Solution 2 0 . 045 0 . 04

$ 0 . 035 0 . 03

0 . 025 8 0 . 02 8 0 . 015 30 . 01 wu90791 2ouequera

0005

Time min . )

NM 1924 RV41532 NM4 19243 .


Fig . 109


0 . 04 * *

* * * * - 0 . 003 0 . 0303 . . . . . . 02304 . 0 . 0 . 3 : : : : : : : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ' i ' " " " 000287 0 . 0297 20 . 6558 0 . 625 Absorbance ( 620 . 6 mm

0 . 02 . . . . . . . . . . . 0 . 0024X : 0 . 0282 . R ? = 0 . 7713

0035 . . . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' .

0 . 01 - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . , , , , , , , , , , , , , , , , , , , , . - . . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - .

0 . 005

1

Time min )

NRGA IS2 # 1 WMA TS2 # 2 • NM4 752 63 rooms . Unear INMATS # 1 ) . . . . . . . . . . singer M T6282 ) . . . . . . . . inga ( NM4 75231

Fig . 110

New Matrix 4 - Test Solution 3 - Vehice Runs

Absorbance ( 620 . 6 mj

3923 " Tone ( min .

Vericia # Vemide # 5 & Vehicle


Fig . 111

New Matrix 4 . . Test Solution 3 - Vehicle Runs , Slope Test 0 . 06

001736 * 00169 - 0 . 9838

3 . 04 V 0 . 0073x10 . 0714 22 - 0 . 9438

. . .

Absorbance ( 620 . 6 mm 0 . 08 "

- 0 . 00523 - 0 . 0186 0 . 8981

0 , 01

0 . 5 2 , 5 Time min )

Venice Vehicles Veide 6 ? . . Unear ( Vehicle 84 ; - . . . Lireos Venice 651 . . . 0 . . . linear ( Venice 6 )

Fig . 112


Absorbance 620 . 6 mm

IIIIIIIIIIIIIIIII

. : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . :

10 32

Time ( irin . )

NV4 TS341 NM4 TS367 NM4 TS33


Fig . 113


. . .

. .

. . Y 0 . 0002 * 0 . 0238 0 . 0308

. .

. .

. . 0 . 025

0 . 02 . . . ini YE - 16 - OSX 0 . 02

* * 5605 * * * * * * * * * * * * ovo 300 . 000 . 00 Absorbance ( 620 . 6mm

0 . 002 % 100205 P = 0 . 3079

001 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

BILL . 0 . 005

2 Time ( muin .

6 NMG 153 81 WM4 153 82

masoveso unear ( NMAT53 81 ) . . . ? " . Lingar ( NMT53 . 821 Moves . Unger ( NMTS3 # 31

Fig . 114

New Matrix - Test Solution 4 - Vehicle Runs a 0 . 1 ?

01

0 . 08

w99 079 ) DucoSOV 0 . 06

0 . 02

*

ime ( nin . Voice Venice Venice 89


Fig . 115

New Matrix 4 - Test Solution 4 - Vehicle Runs , Slope Test 0 . 0206 % + 0 . 0196 22 : 09689

: 0 . 022842 . 00152 09942 . . .

y = - 0 0141 + 0 . 024 . . . in 0 . 9851 Absorbance ( 620 . 6 am

SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS

0 . 5 2 . 5

Vehicle 7 Vehice ng

* * * * th . Liriear Vehicle $ 81 .

15 2 . 5 og min ,

u Verdes cocoa Unear ( Vehirde 7 On Linnar ( Vatica + 91

Fig . 116


. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Absorbance ( 620 . 6 mm . . . . .

. . . . . . . .

. .

. . . . . .

. .

. .

. . . . . .

2 ir CK 10 10 2 .

.

. Time ( min . ) .

ONMA 154 1 M4 1943 PM479 * 39


Fig . 117 1

New Matrix - Test Solution 4 , Slope Test 0 . 035 = 0 . 0025 % 4 0 . 0253

0 . 03 - 0 . 001 $ X + 0 . 02SS

0 . 025 - 0 . 00378 0 . 0399

R = 0 . 9702

goz9 ) Suggioso 0 . 005 Prinsesse

0 . 01

3 . 005

. . . . . . . . . . . . . . . . . . . . . . . . . . 00 Ve 1 . 5 ? Tinie mia

NM415462 VMS4 ? WV4 TS3

moci . . . Unear NM4 18 491 . . . . Une NM 1942 ) . . . . . . . . . . Unica ( NM4 TSA # 3

Fig . 118 .

New Matrix 4 - Test Solution 5 , Vehicle Runs . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

(

. . . . . . . .

. .

. . . . . . . . . . . . . . . . . iii . . . . . . . . . . . . . . . . . . . . . . 9 029 ) ouenosov . . . . . . . .

. . . . . . .

. . . . . . . . . . . . . . . . . .

W9 . . Erit . . . . . . . .

. . . . . . . . . .

venice # venice # 2 Varice3 . . . . . .


Fig . 119

New Matrix 4 - Test Solution 5 - Vehicle Runs ; Slope Test 0 . 02 . . . . . . . . . . . - . - . - . - . - . - . - . - . . . . . . . . . . .

Y = 0 . 0052K * 0 . 003 0 . 7975

0 . 035

is . . . . wy : 0 . 0083x - 0 . 0017 0 . 9694

. wu9029 ) Buequosov . * . y = 0 . 0067 % - 0 . 0036 0 . 954 . *

.

0 . 005 * * * . . r .

* * * * * * - - - - - -

. . . .

. . . . . *

. SV . - ini *

* * * * - - -

. . . .

- 0 . 005 Time min )

Venica 2 Vehicle 42 Vehide 3 soessores near ( Venice # 1 ) . . . . . . linear Venice # 2 - * * * ? " . Drea : ( Venice # 3 )

Fig . 120


Absorbance ( 620 . 6 mm )

.

Ime min . )

ONMA 155 61 NMISS # 2 NM4 TS583


Fig . 121

New Matrix 4 - Test Solution 5 , Slope Test 008

6025 0 . 0034 * 0 : 0253 0 . 6526

* * * *

002 . . . * * * & y = - 0 , 0025 % 0 . 0207

0 . 015 * . . . . . . . . . . . . . . . . . . . . . . . . . . . . . w 9009 ) FOUEQUOSOV . 0 . 01 * * * * * * * * * * * * * * . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

y = - 0 . 002 % + 0014 ? - 0 . 7753

0 . 5 Time in .

NMA 195 $ 1 . * NM4 TS562 . NVA 185 43

. * * . Whem ( NKAATSS AL . . . . . . . . Linear ( NM4 785 82 ) . . . . . . . . . Dnear MMA TSS 35

Fig . 122

New Matrix 4 - Test Solution 6 , Venice Runs K 0 . 1 ; : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : :

0 . 08 0 . 06 Absorbance ( 620 . 6670 0 . 04

0 . 02 . . . . .

- 0 . 02 . Time min .

Veidem Vahice Venice * 6 Vehicle 47


Fig . 123

New Matrix 4 * - Test Solution 6 - Vehicle Runs , Sloge Test 0 . 045 Y - 0 . 0221 % - 0 . 0066

0 : 08 : 19 004 . . . . .

0 . 085 0 . 03 y = 0 . 0071x * 0 . 03 . 33

- 0 . 9873 0 . 025 - . - . - . - . - . . " , " . . . . : : : : : : : : : : :

0 . 02 Absorbance ( 6206 nmi = 0 . 0099x 0 . 0059 * * P = 0 . 9903

0015 0 . 0089x : 00018

. 6 . 9886 0 . 01

0 . 005 EEEEEEEEEEEEEEEEEEEEE

- 0 . 006 " . . . . . . . .

- 0 . 01 Time ( min . )

venice # 4 vehicle is Vanice na e » Ungar ( Venice # 41 . . . . . . . . Dnear ( Vehicle 35 ) . . . . . . . . . Urear ( Versicle 46 ) . . . .

venice # 7 Unear ( Vehicle 47 ) . .

Fig . 124


. . . . .

0 . 045 0 . 04

€ 0 . 036 . . .

. . . .

0 0 . 023 . Absorbance ( 620 . 6 m 0 . 02 0015 0 . 01

0 . 005 . . . . . . . . . . . . . .

? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ??? ? ? ?

Tirne rain .

ONM4 186 1 NM4 TS6 * 2 1478643


Fig . 125

New Matrix 4 . - Test Solution 6 , Siope Test . 0 . 045

0 . 04 . V . 2008D0979 . .

09 . 00 * * * I I . 1 . 1 . * W 8088888888888

* * 0006980 wao . . . . .

. . . 0 . 025

* * * * * * * * 00041 00339 888888888 R2 = 0 . 7400 08 . 08 . 2007

* * * * * * y - 00039400296

. . . . . . . . . . . . . . Absortance ( 620 , 5 cm 0 . 02

0 . 015

0 . 91

0 . 005

???

Time min ,

© NM4 TS & # 1 TSE 51 M4 756 82 M4 TSG 212 Oreces lineas ( NMA T96 411 . . . . . . . Ungar ( M4 TS6 # 2 )

NM4 TS883 Unear ( AM4 7663 )


Fig . 126

New Matrix 5 - Test Solution 1 , Vehice Runs

399 Absorbance ( 620 . 6 m

10 22 0 . 02

- 0 . 04 Time min .

ovehide vehicle 2 Venice Venice

Fig . 127

New Matrix 5 - Test Solution 1 , Vehicle Runs - Slope Test 0 . 05 Y = 0 . 0306x - 0 . 0238

09835 0 . 04

Y = 20226x - 0 . 0361 22 - 09853 Absorábance ( 620 , 6 nm )

Y 0 . 0105X - 0 . 0319 R = 0 . 924 25

* * * * * * * * * * . . . . . 00s9x . . . ) . 0285 . . . . . .

0 . 9008 * * * *

Tre mi ,

Venide vi Venide 2 Vehicie 13 Venice 4 near ( Vahide # 1 ) . . . . . ons near ( Venice 82 . sv . . Unear Merida 89 ) . . . . . . . Gear Venice # 4 socce


Fig 128

New Matrix 5 - Test Solution 1 . . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : .

- 0 . 005

0 . 01

- 0 , 015 Absorbance ( 620 . 6 mm )

- 0 . 02

0 . 025

0 . 09

0 . 035 me min .

ONMS TSI 81 NMS T81 # 2 ONKSTS : * *

Fig 129

New Matrix 5 - Test Solution 1 . Slope Test

- 0 . 005

- 0 . 01

- 0015 - 0 . 0018x - 00255 $ 0 . 9197

Absorbance ( 620 . 6 am )

- 0 . 02 Y 0001x = 00263 03352

- 0025

V 0 : 0010x 0 , 03

- 0 . 035 . . . . .

Time min . .

WM5751 1 arocoso Linear NMS TSI WII

M $ 75142 - NMS TSI 3 : Unear ( NMS T81 # 2 ) - - Crear NMS 15163 )


Fig 130


Absorbance ( 620 . 6 am

.

. . . . G . . .

. . . . .

Time ( min . )

ovenidess Venice 86 Venide # 7 $ venide 8

Fig 131

New Matrix 5 - Test Solution 2 ; Vehicle Runs , Slope Test . . ' . ' . ' . ' . ' .

. * . vii . * .

* 8 * 0 . 097 % - 0 . 0007 * R ? = 0 . 916

. . . .

. . . . - . - . . . - . - . - . - . - . - . - . - . - . - . - . - . - . .

. .

. . . . . sil .

Absorávance ( 620 . 6 mm ) .

. . . - 0 . 04486 % - 0 . 0808

92 . 0 . 9685 # . . 0000 . . . . . .

IR . .

. . . . . . . .

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US 9 , 789 , 152 B2 COMPOSITIONS AND METHODS TO stones . Once of a certain size , stones often fragment or a INHIBIT KIDNEY STONE GROWTH break off from the Randall plaque region and can either pass

out of the body or get stuck along the urinary tract , resulting CROSS - REFERENCE TO RELATED in clinical symptoms such as reduced urine flow , pain or

APPLICATIONS 5 bleeding . Prevalence of kidney stones in the United States has been This application is a continuation of U . S . application Ser . estimated at 8 . 8 % ( roughly 1 in 11 people ) . Among men , the No . 15 / 266 , 464 , filed Sep . 15 , 2016 , which is a divisional of prevalence of stones was 10 . 6 % , compared with 7 . 1 % U . S . application Ser . No . 15 / 059 , 644 , filed Mar . 3 , 2016 now

issued as U . S . Pat . No . 9 , 492 , 491 , which is a continuation - 10 10 among women . Kidney stones were more common among in - part of U . S . application Ser . No . 14 / 960 , 692 , filed Dec . 7 , obese than normal - weight individuals . ( Eur Urol . 2012 July ; 2015 , which is a continuation application of U . S . application 62 ( 1 ) : 160 - 5 . ) Ser . No . 14 / 845 , 612 , filed Sep . 4 , 2015 , now issued as U . S . Reoccurrence of stones in patients has been estimated to Pat . No . 9 , 233 , 135 , each of which is incorporated herein by be as high as 50 percent within 5 years of the initial event . reference in its entirety . 15 Rates of emergency department visits for kidney stone

disease have increased 20 percent between 2005 and 2009 . FIELD OF INVENTION In 2014 , one study suggested that kidney stone interven

The disclosure relates to novel compositions comprised of u tions cost an estimated $ 10 billion annually in the United active agents including vitamins , minerals , and food addi - 20 States and patients who have an unplanned hospital visit for tives ingredients to prevent and treat kidney stone formation kidney stones incur average costs of nearly $ 30 , 000 , and promote overall improved kidney health for patients that depending on the type of procedure and the subsequent care . may be susceptible to forming stones in the kidney , renal ( Duke University Medical Center . “ Complications from pelvis , ureter , bladder , or all other renal genitourinary areas . kidney stone treatments are common , costly ” ScienceDaily .

25 28 Apr . 2014 ) BACKGROUND Medical treatment options depend on severity of pain ,

Kidney stones , also called renal calculi , are solid crystal size of stone , and location of stone . Smaller stones will often aggregations of dissolved minerals in urine . Depending on pass on their own . For larger stones , some form of inter their location in the urinary tract these calculi are called by 30 vention is usually required and include : ureteroscopy and various names , e . g . , kidney stones , ureteric stones , bladder laser stone lithotripsy ( the stone is located with a small stones , or urethral stones . Most kidney stones are caused by camera inserted into the urethra and removed with a small the precipitation of calcium in the form of calcium oxalate . basket or broken up with a laser ) ; extracorporeal shockwave A minority of stones may also be caused by or include lithotripsy ( ESWL ; breaks up stone from the outside of the precipitated calcium hydroxyl phosphate ( apatite ) , magne - 35

body with shockwaves that travel through a gel - like sium ammonium phosphate ( struvite ) , uric acid , or cysteine . In addition to excruciating pain , symptoms of kidney stones medium ) ; Percutaneous Nephrolithotomy ( PCNL ; inpatient may also include blood in the urine due to minor damage to procedure for very large stones , which typically requires an inside lining of kidney , ureter , and urethra ; reduced urine overnight hospital stay ) . If patient has more than one kidney volume caused by obstruction of the bladder or urethra by 40 stone or stone occurrence , physician often recommends the stones ; kidney infection as a result of stone blockage ; getting a special urine study done . A 24 - hour urine study will abdominal distention ; nausea or vomiting ; and fever and show the composition of urine in relation to kidney stone chills . Kidney stone disease is an ailment afflicting human kind formation . Diet can be altered or improved based on these

for many centuries . It can affect up to a quarter of the 45 results to help in preventing reoccurrence of a stone . Rarely population in certain geographic areas and hence poses a patients are placed on a prescription medication as the significant health problem . Approximately 85 % of the stones options are very limited and can have serious side effects or in human are calcium stones comprising oxalate and phos risks for the patient . Sometimes pain medications are uti phate , either alone or combined . The pathogenesis of cal lized as the stone is passing through the person ' s system . cium oxalate stone formation is a multi - step process and in 50 One goal in diet alteration is to try to prevent crystal essence includes / nucleation , crystal growth , crystal aggre gation , and crystal retention . Various substances in the body formation . Common recommendations include : drink more have an effect on one or more of the above stone forming water , often at least 6 - 8 glasses per day ; decrease caffeine processes , thereby influencing a person ' s ability to promote intake ; eliminate colas due to phosphoric acid content ; drink or prevent stone formation . Low urine volume , low urine 55 lemon water ; decrease sodium , sugar , and red meat and pH , calcium , sodium , oxalate , and urate are known to oxalate - rich foods ( e . g . , Spinach , strawberries , nuts , tea ) ; promote stone formation . Many inorganic ( e . g . , magnesium ) and increase fiber intake . and organic ( e . g . , urinary prothrombin fragment 1 , gly

Various active agents are known to have an effect on cosaminoglycans , osteopontin , citrate ) substances are known to inhibit stone formation . 60 kidney stones , including citric acid , magnesium citrate ,

The initiation of growth of a calcium oxalate stone is phytin , pyridoxine , and musa , however , these active agents thought to occur at sites of inflammation or damage within have not been combined in one composition , nor have they the kidney . The stones form by an initial deposition of been combined in amounts that maximize the percent inhi calcium crystals at the sites of inflammation or damage and bition of crystal formation . are known in the literature as Randall ' s plaques . These 65 Thus , there remains a need for a simple and effective Randall ' s plaques then serve as nuclei for formation of method and composition for preventing and treating kidney calcium oxalate on top of the calcium hydroxyapatite mini - stones that optimizes the inhibition of crystal formation .

US 9 , 789 , 152 B2

SUMMARY BRIEF DESCRIPTION OF THE DRAWINGS

Disclosed is a novel oral dosage form or a plurality of oral The following is a brief description of the drawings which dosage forms . are presented for the purposes of illustrating the exemplary

In an embodiment , the oral dosage form or plurality of 5 embodiments disclosed herein and not for the purposes of oral dosage forms comprises as active ingredients citric acid , limiting the same . magnesium citrate , phytin , pyridoxine , and musa . FIG . 1 is a graph showing absorbance at 620 . 6 nm as a

In an embodiment , the oral dosage form or plurality of function of time for Control Vehicle Runs Associated with oral dosage forms comprises as active ingredients citric acid , Test Solution 1 . magnesium citrate , phytin , and pyridoxine . FIG . 2 is a graph showing absorbance at 620 . 6 nm as a

In an embodiment , the oral dosage form or plurality of function of time to determine the Slope for Control Vehicle oral dosage forms comprises as active ingredients citric acid , Runs Associated with Test Solution 1 . magnesium citrate , phytin , and musa . FIG . 3 is a graph showing absorbance at 620 . 6 nm as a

In an embodiment , the oral dosage form or plurality of function of time for Test Solution 1 . oral dosage forms comprises as active ingredients citric acid , FIG . 4 is a graph showing absorbance at 620 . 6 nm as a magnesium citrate , pyridoxine , and musa . function of time to determine the Slope for Test Solution 1 .

In an embodiment , the oral dosage form or plurality of FIG . 5 is a graph showing absorbance at 620 . 6 nm as a oral dosage forms comprises as active ingredients citric acid , function of time for Control Vehicle Runs Associated with phytin , pyridoxine , and musa . 20 Test Solution 2 .

In an embodiment , the oral dosage form or plurality of FIG . 6 is a graph showing absorbance at 620 . 6 nm as a oral dosage forms comprises as active ingredients magne - function of time to determine the Slope for Control Vehicle sium citrate , phytin , pyridoxine , and musa Runs Associated with Test Solution 2 .

Also disclosed is a method of treating and / or inhibiting FIG . 7 is a graph showing absorbance at 620 . 6 nm as a growth of kidney stones . 25 function of time for Test Solution 2 .

In an embodiment , the method comprises administering to FIG . 8 is a graph showing absorbance at 620 . 6 nm as a a patient in need thereof the oral dosage form or plurality of function of time to determine the Slope for Test Solution 2 . dosage forms disclosed herein . FIG . 9 is a graph showing absorbance at 620 . 6 nm as a

In an embodiment , the method comprises administering to function of time for Control Vehicle Runs Associated with 30 Test Solution 3 . a patient in need thereof about 101 mg to about 700 mg citric FIG . 10 is a graph showing absorbance at 620 . 6 nm as a acid ; about 76 mg to about 226 mg magnesium citrate ; about function of time to determine the Slope for Control Vehicle 3 mg to about 600 mg phytin ; about 0 . 1 mg to about 15 mg Runs Associated with Test Solution 3 . pyridoxine ; and about 1 mg to about 251 mg musa . FIG . 11 is a graph showing absorbance at 620 . 6 nm as a

Also disclosed is a method of inhibiting growth of cal - 35 function of time for Test Solution 3 cium oxalate crystals . FIG . 12 is a graph showing absorbance at 620 . 6 nm as a

In an embodiment , the method comprises contacting an function of time to determine the Slope for Test Solution 3 . aqueous solution comprising calcium oxalate with the oral FIG . 13 is a graph showing absorbance at 620 . 6 nm as a dosage form or plurality of dosage forms disclosed herein . function of time for Control Vehicle Runs Associated with

In an embodiment , the method comprises contacting an 40 Test Solution 4 . aqueous solution comprising calcium oxalate with a com - FIG . 14 is a graph showing absorbance at 620 . 6 nm as a position comprising as active ingredients citric acid , mag - function of time to determine the Slope for Control Vehicle nesium citrate , phytin , pyridoxine , and musa . Runs Associated with Test Solution 4 .

In an embodiment , the method comprises contacting an FIG . 15 is a graph showing absorbance at 620 . 6 nm as a aqueous solution comprising calcium oxalate with a com - 45 function of time for Test Solution 4 . position comprising as active ingredients citric acid , mag - FIG . 16 is a graph showing absorbance at 620 . 6 nm as a nesium citrate , phytin , and pyridoxine . function of time to determine the Slope for Test Solution 4 .

In an embodiment , the method comprises contacting an FIG . 17 is a graph showing absorbance at 620 . 6 nm as a aqueous solution comprising calcium oxalate with a com function of times for Control Vehicle Runs Associated with position comprising as active ingredients citric acid , mag 50 Test Solution 5 .

FIG . 18 is a graph showing absorbance at 620 . 6 nm as a nesium citrate , phytin , and musa . In an embodiment , the method comprises contacting an function of time to determine the Slope for Vehicle Runs

Associated with Test Solution 5 . aqueous solution comprising calcium oxalate with a com FIG . 19 is a graph showing absorbance at 620 . 6 nm as a position comprising as active ingredients citric acid , mag - se ay 55 function of time for Test Solution 5 . nesium citrate , pyridoxine , and musa . FIG . 20 is a graph showing absorbance at 620 . 6 nm as a In an embodiment , the method comprises contacting an In an embodiment , the method comprises contacting an function of time to determine the Slope for Test Solution 5 . function of time

aqueous solution comprising calcium oxalate with a com FIG . 21 is a graph showing absorbance at 620 . 6 nm as a position comprising as active ingredients citric acid , phytin , function of time for Control Vehicle Runs Associated with pyridoxine , and musa . 60 Test Solution 6 .

In an embodiment , the method comprises contacting an FIG . 22 is a graph showing absorbance at 620 . 6 nm as a aqueous solution comprising calcium oxalate with a com - function of time to determine the Slope for Control Vehicle position comprising as active ingredients magnesium citrate , Runs Associated with Test Solution 6 . phytin , pyridoxine , and musa . FIG . 23 is a graph showing absorbance at 620 . 6 nm as a

These and other advantages , as well as additional 65 function of time for Test Solution 6 . inventive features , will be apparent from the following FIG . 24 is a graph showing absorbance at 620 . 6 nm as a Drawings , Detailed Description , Examples , and Claims . function of time to determine the Slope for Test Solution 6 .

US 9 , 789 , 152 B2 5

FIG . 25 is a graph showing absorbance at 620 . 6 nm as a FIG . 48 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with function of time for Matrix 1 for Test Solution 5 . Test Solution 7 ( Repeat of Test Solution 1 ) . FIG . 49 is a graph showing absorbance at 620 . 6 nm as a

FIG . 26 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 1 for Test function of time to determine the Slope for Control Vehicle 5 Solution 5 . Runs Associated with Test Solution 7 ( Repeat of Test FIG . 50 is a graph showing absorbance at 620 . 6 nm as a Solution 1 ) . function of time for Control Vehicle Runs Associated with

FIG . 27 is a graph showing absorbance at 620 . 6 nm as a Matrix 1 for Test Solution 6 . function of time for Test Solution 7 ( Repeat of Test Solution FIG . 51 is a graph showing absorbance at 620 . 6 nm as a 1 ) . u function of time to determine the Slope for Control Vehicle

FIG . 28 is a graph showing absorbance at 620 . 6 nm as a Runs Associated with Matrix 1 for Test Solution 6 . function of time to determine the Slope for Test Solution 7 FIG . 52 is a graph showing absorbance at 620 . 6 nm as a ( Repeat of Test Solution 1 ) . function of time for Matrix 1 for Test Solution 6 .

FIG . 29 is a histogram showing median and mean inhi - 15 FIG . 53 is a graph showing absorbance at 620 . 6 nm as a bition of calcium oxalate crystal formation by Test Solutions f unction of time to determine the Slope for Matrix 1 for Test 1 - 6 . Solution 6 .

FIG . 30 is a graph showing absorbance at 620 . 6 nm as a FIG . 54 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with function of time for Control Vehicle Runs Associated with Matrix 1 for Test Solution 1 . 20 Matrix 2 for Test Solution 1 .

FIG . 31 is a graph showing absorbance at 620 . 6 nm as a FIG . 55 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Control Vehicle function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 1 for Test Solution 1 . Runs Associated with Matrix 2 for Test Solution 1 .

FIG . 32 is a graph showing absorbance at 620 . 6 nm as a FIG . 56 is a graph showing absorbance at 620 . 6 nm as a function of time for Matrix 1 for Test Solution 1 . 25 function of time for Matrix 2 for Test Solution 1 .

FIG . 33 is a graph showing absorbance at 620 . 6 nm as a FIG . 57 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 1 for Test function of time to determine the Slope for Matrix 2 for Test Solution 1 . Solution 1 .

FIG . 34 is a graph showing absorbance at 620 . 6 nm as a FIG . 58 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with 30 function of time for Control Vehicle Runs Associated with Matrix 1 for Test Solution 2 . Matrix 2 for Test Solution 2 .

FIG . 35 is a graph showing absorbance at 620 . 6 nm as a FIG . 59 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Control Vehicle function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 1 for Test Solution 2 . Runs Associated with Matrix 2 for Test Solution 2 .

FIG . 36 is a graph showing absorbance at 620 . 6 nm as a 35 FIG . 60 is a graph showing absorbance at 620 . 6 nm as a function of time for Matrix 1 for Test Solution 2 . function of time for Matrix 2 for Test Solution 2 .

FIG . 37 is a graph showing absorbance at 620 . 6 nm as a FIG . 61 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 1 for Test function of time to determine the Slope for Matrix 2 for Test Solution 2 . Solution 2 .

FIG . 38 is a graph showing absorbance at 620 . 6 nm as a 40 FIG . 62 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with function of time for Control Vehicle Runs Associated with Matrix 1 for Test Solution 3 . Matrix 2 for Test Solution 3 .

FIG . 39 is a graph showing absorbance at 620 . 6 nm as a FIG . 63 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Control Vehicle function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 1 for Test Solution 3 . 45 Runs Associated with Matrix 2 for Test Solution 3 .

FIG . 40 is a graph showing absorbance at 620 . 6 nm as a FIG . 64 is a graph showing absorbance at 620 . 6 nm as a function of time for Matrix 1 for Test Solution 3 . function of time for Matrix 2 for Test Solution 3 .

FIG . 41 is a graph showing absorbance at 620 . 6 nm as a FIG . 65 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 1 for Test function of time to determine the Slope for Matrix 2 for Test Solution 3 . 50 Solution 3 .

FIG . 42 is a graph showing absorbance at 620 . 6 nm as a FIG . 66 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with function of time for Control Vehicle Runs Associated with Matrix 1 for Test Solution 4 . Matrix 2 for Test Solution 4 .

FIG . 43 is a graph showing absorbance at 620 . 6 nm as a FIG . 67 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Control Vehicle 55 function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 1 for Test Solution 4 . Runs Associated with Matrix 2 for Test Solution 4 .


FIG . 45 is a graph showing absorbance at 620 . 6 nm as a FIG . 69 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 1 for Test 60 function of time to determine the Slope for Matrix 2 for Test Solution 4 . Solution 4 .

FIG . 46 is a graph showing absorbance at 620 . 6 nm as a FIG . 70 is a graph showing absorbance at 620 . 6 nm as a function of times for Control Vehicle Runs Associated with function of times for Control Vehicle Runs Associated with Matrix 1 for Test Solution 5 . Matrix 2 for Test Solution 5 .

FIG . 47 is a graph showing absorbance at 620 . 6 nm as a 65 FIG . 71 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Vehicle Runs function of time to determine the Slope for Vehicle Runs Associated with Matrix 1 for Test Solution 5 . Associated with Matrix 2 for Test Solution 5 .

US 9 , 789 , 152 B2





FIG . 76 is a graph showing absorbance at 620 . 6 nm as a FIG . 100 is a graph showing absorbance at 620 . 6 nm as function of time for Matrix 2 for Test Solution 6 . a function of time for Matrix 3 for Test Solution 6 .

FIG . 77 is a graph showing absorbance at 620 . 6 nm as a 10 FIG . 101 is a graph showing absorbance at 620 . 6 nm as function of time to determine the Slope for Matrix 2 for Testa function of time to determine the Slope for Matrix 3 for Solution 6 . Test Solution 6 .

FIG . 78 is a graph showing absorbance at 620 . 6 nm as a FIG . 102 is a graph showing absorbance at 620 . 6 nm as function of time for Control Vehicle Runs Associated with a function of time for Control Vehicle Runs Associated with Matrix 3 for Test Solution 1 . 20 Matrix 4 for Test Solution 1 .

FIG . 79 is a graph showing absorbance at 620 . 6 nm as a FIG . 103 is a graph showing absorbance at 620 . 6 nm as function of time to determine the Slope for Control Vehicle a function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 3 for Test Solution 1 . Runs Associated with Matrix 4 for Test Solution 1 .

FIG . 80 is a graph showing absorbance at 620 . 6 nm as a FIG . 104 is a graph showing absorbance at 620 . 6 nm as function of time for Matrix 3 for Test Solution 1 . 25 a function of time for Matrix 4 for Test Solution 1 .

FIG . 81 is a graph showing absorbance at 620 . 6 nm as a FIG . 105 is a graph showing absorbance at 620 . 6 nm as function of time to determine the Slope for Matrix 3 for Test a function of time to determine the Slope for Matrix 4 for Solution 1 . Test Solution 1 .

FIG . 82 is a graph showing absorbance at 620 . 6 nm as a FIG . 106 is a graph showing absorbance at 620 . 6 nm as function of time for Control Vehicle Runs Associated with 30 a function of time for Control Vehicle Runs Associated with Matrix 3 for Test Solution 2 . Matrix 4 for Test Solution 2 .

FIG . 83 is a graph showing absorbance at 620 . 6 nm as a FIG . 107 is a graph showing absorbance at 620 . 6 nm as function of time to determine the Slope for Control Vehicle a function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 3 for Test Solution 2 . Runs Associated with Matrix 4 for Test Solution 2 .

FIG . 84 is a graph showing absorbance at 620 . 6 nm as a 35 FIG . 108 is a graph showing absorbance at 620 . 6 nm as function of time for Matrix 3 for Test Solution 2 . a function of time for Matrix 4 for Test Solution 2 .

FIG . 85 is a graph showing absorbance at 620 . 6 nm as a FIG . 109 is a graph showing absorbance at 620 . 6 nm as function of time to determine the Slope for Matrix 3 for Testa function of time to determine the Slope for Matrix 4 for Solution 2 . Test Solution 2 .

FIG . 86 is a graph showing absorbance at 620 . 6 nm as a 40 FIG . 110 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with function of time for Control Vehicle Runs Associated with Matrix 3 for Test Solution 3 . Matrix 4 for Test Solution 3 .

FIG . 87 is a graph showing absorbance at 620 . 6 nm as a FIG . 111 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Control Vehicle function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 3 for Test Solution 3 . 45 Runs Associated with Matrix 4 for Test Solution 3 .






FIG . 93 is a graph showing absorbance at 620 . 6 nm as a FIG . 117 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 3 for Test 60 function of time to determine the Slope for Matrix 4 for Test Solution 4 . Solution 4 .

FIG . 94 is a graph showing absorbance at 620 . 6 nm as a FIG . 118 is a graph showing absorbance at 620 . 6 nm as a function of times for Control Vehicle Runs Associated with function of times for Control Vehicle Runs Associated with Matrix 3 for Test Solution 5 . Matrix 4 for Test Solution 5 .

FIG . 95 is a graph showing absorbance at 620 . 6 nm as a 65 FIG . 119 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Vehicle Runs function of time to determine the Slope for Vehicle Runs Associated with Matrix 3 for Test Solution 5 . Associated with Matrix 4 for Test Solution 5 .

US 9 , 789 , 152 B2 10

FIG . 120 is a graph showing absorbance at 620 . 6 nm as FIG . 144 is a graph showing absorbance at 620 . 6 nm as a function of time for Matrix 4 for Test Solution 5 . a function of time for Matrix 5 for Test Solution 5 .

FIG . 121 is a graph showing absorbance at 620 . 6 nm as FIG . 145 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 4 for a function of time to determine the Slope for Matrix 5 for Test Solution 5 . 5 Test Solution 5 .

FIG . 122 is a graph showing absorbance at 620 . 6 nm as FIG . 146 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with a function of time for Control Vehicle Runs Associated with Matrix 4 for Test Solution 6 . Matrix 5 for Test Solution 6 .

FIG . 123 is a graph showing absorbance at 620 . 6 nm as FIG . 147 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Control Vehicle 10 a function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 4 for Test Solution 6 . Runs Associated with Matrix 5 for Test Solution 6 .

FIG . 124 is a graph showing absorbance at 620 . 6 nm as FIG . 148 is a graph showing absorbance at 620 . 6 nm as a function of time for Matrix 4 for Test Solution 6 . a function of time for Matrix 5 for Test Solution 6 .

FIG . 125 is a graph showing absorbance at 620 . 6 nm as 15 FIG . 149 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 4 for a function of time to determine the Slope for Matrix 5 for Test Solution 6 . Test Solution 6 .

FIG . 126 is a graph showing absorbance at 620 . 6 nm as FIG . 150 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with a function of time for Control Vehicle Runs Associated with Matrix 5 for Test Solution 1 . 20 Matrix 5 for Test Solution 7 .

FIG . 127 is a graph showing absorbance at 620 . 6 nm as FIG . 151 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Control Vehicle a function of time to determine the Slope for Control Vehicle Runs Associated with Matrix 5 for Test Solution 1 . Runs Associated with Matrix 5 for Test Solution 7 .

FIG . 128 is a graph showing absorbance at 620 . 6 nm as FIG . 152 is a graph showing absorbance at 620 . 6 nm as a function of time for Matrix 5 for Test Solution 1 . 25 a function of time for Matrix 5 for Test Solution 7 .

FIG . 129 is a graph showing absorbance at 620 . 6 nm as FIG . 153 is a graph showing absorbance at 620 . 6 nm as a function of time to determine the Slope for Matrix 5 for a function of time to determine the Slope for Matrix 5 for Test Solution 1 . Test Solution 7 .

FIG . 130 is a graph showing absorbance at 620 . 6 nm as a function of time for Control Vehicle Runs Associated with 30 DETAILED DESCRIPTION Matrix 5 for Test Solution 2 .

FIG . 131 is a graph showing absorbance at 620 . 6 nm as A novel oral dosage form or a plurality of oral dosage a function of time to determine the Slope for Control Vehicle forms comprising the ingredients citric acid , magnesium Runs Associated with Matrix 5 for Test Solution 2 . citrate , phytin , pyridoxine , and musa is disclosed herein . The

FIG . 132 is a graph showing absorbance at 620 . 6 nm as 35 disclosed oral dosage form or plurality of dosage forms is a function of time for Matrix 5 for Test Solution 2 . useful for treating and / or inhibiting growth of kidney stones .

FIG . 133 is a graph showing absorbance at 620 . 6 nm as Methods of using the oral dosage form or plurality of dosage a function of time to determine the Slope for Matrix 5 for forms to treat or inhibit growth of kidney stones are also Test Solution 2 . disclosed .

FIG . 134 is a graph showing absorbance at 620 . 6 nm as 40 Although there is some clinical evidence that each of a function of time for Control Vehicle Runs Associated with these ingredients individually plays a role in preventing or Matrix 5 for Test Solution 3 . treating kidney stones , all five ingredients have never pre

FIG . 135 is a graph showing absorbance at 620 . 6 nm as viously been combined in one formulation or dosing regi a function of time to determine the Slope for Control Vehicle men for treating or inhibiting formation of kidney stones . In Runs Associated with Matrix 5 for Test Solution 3 . 45 addition , combinations containing four of these ingredients

FIG . 136 is a graph showing absorbance at 620 . 6 nm as have never been combined in one formulation or dosing a function of time for Matrix 5 for Test Solution 3 . regimen for treating or inhibiting formation of kidney

FIG . 137 is a graph showing absorbance at 620 . 6 nm as stones a function of time to determine the Slope for Matrix 5 for Surprisingly , not all concentration ranges of the active Test Solution 3 . 50 ingredients in the combination provide effective inhibition

FIG . 138 is a graph showing absorbance at 620 . 6 nm as of kidney stones or calcium oxalate growth . In particular , we a function of time for Control Vehicle Runs Associated with have discovered preferred ranges in the combination of the Matrix 5 for Test Solution 4 . five active ingredients that maximize the percent inhibition

FIG . 139 is a graph showing absorbance at 620 . 6 nm as of kidney stones and more particularly calcium oxalate a function of time to determine the Slope for Control Vehicle 55 crystal growth , resulting in mean percent inhibition of the Runs Associated with Matrix 5 for Test Solution 4 . calcium oxalate crystal growth of at least about 92 % .

FIG . 140 is a graph showing absorbance at 620 . 6 nm as Compositions of the five active ingredients having concen a function of time for Matrix 5 for Test Solution 4 . trations outside the preferred ranges are unexpectedly much

FIG . 141 is a graph showing absorbance at 620 . 6 nm as less effective in inhibiting calcium oxalate crystal growth . In a function of time to determine the Slope for Matrix 5 for 60 addition , we have discovered preferred ranges in combina Test Solution 4 . tions containing four of the five active ingredients that

FIG . 142 is a graph showing absorbance at 620 . 6 nm as maximize the percent inhibition of kidney stones and more a function of times for Control Vehicle Runs Associated with particularly calcium oxalate crystal growth . Compositions Matrix 5 for Test Solution 5 . containing four of the five active ingredients having con

FIG . 143 is a graph showing absorbance at 620 . 6 nm as 65 centrations outside the preferred ranges are unexpectedly a function of time to determine the Slope for Vehicle Runs much less effective in inhibiting calcium oxalate crystal Associated with Matrix 5 for Test Solution 5 . growth .

US 9 , 789 , 152 B2

For a dosage form or plurality of dosage forms containing magnesium citrate is about 2 . 32 mg to about 201 mg , phytin all five ingredients , a preferred range for citric acid is about is about 100 mg to about 600 mg , and musa is about 1 . 51 mg 101 mg to about 700 mg ; and more preferably about 101 mg to about 251 mg . to about 352 mg , about 101 mg to about 176 mg , about 176 More preferably for a dosage form or plurality of dosage mg to about 700 mg , or about 352 mg to about 700 mg . A 5 forms containing citric acid , magnesium citrate , phytin , and preferred range for magnesium citrate is about 76 mg to musa , citric acid is present in an amount selected from : about 226 mg ; and more preferably about 76 mg to about about 102 mg to about 700 mg , about 102 mg to about 352 201 mg , about 76 mg to about 150 mg , about 150 to about mg , about 102 mg to about 177 mg , about 177 mg to about 226 mg , or about 201 mg to about 226 mg . A preferred range 1052 mg , about 177 mg to about 700 mg , about 177 mg to for phytin is about 3 mg to about 600 mg ; more preferably about 352 mg , about 351 mg to about 1052 mg , about 351 about 3 mg to about 400 mg , about 3 mg to about 202 mg , mg to about 700 mg , and about 700 mg to about 1052 mg ; about 3 mg to about 100 mg , about 100 mg to about 600 mg , magnesium citrate is present in an amount selected from : about 201 mg to about 600 mg , or about 400 mg to about 600 about 2 . 32 mg to about 201 mg , about 2 . 32 mg to about 151 mg . A preferred range for pyridoxine is about 0 . 2 mg to 15 mg , about 2 . 32 to about 77 mg , about 77 to about 201 mg , about 15 mg ; more preferably about 0 . 2 mg to about 10 . 1 about 77 to about 151 mg , and about 150 mg to about 201 mg , about 0 . 2 mg to about 6 mg , about 0 . 2 mg to about 2 . 7 mg ; phytin is present in an amount selected from : about 100 mg , about 2 . 7 mg to about 15 mg , about 6 . 0 mg to about 15 mg to about 401 mg , about 100 mg to about 202 mg , about mg , or about 10 mg to about 15 mg . A preferred range for 201 mg to about 600 mg , about 201 mg to about 401 mg , and musa is about 1 mg to about 251 mg ; more preferably about 20 about 401 mg to about 600 mg ; and musa is present in an 1 mg to about 167 mg , about 1 mg to about 85 mg , about 1 amount selected from : about 1 . 51 mg to about 167 mg , about mg to about 41 mg , about 41 mg to about 251 mg , about 85 1 . 51 mg to about 86 mg , about 1 . 51 mg to about 41 mg , mg to about 251 mg , or about 167 mg to about 251 mg . about 41 mg to about 251 mg , about 41 mg to about 167 mg ,

Most preferred is an oral dosage form or a plurality of about 41 mg to about 86 mg , about 86 mg to about 251 mg , dosage forms comprising citric acid , magnesium citrate , 25 about 86 mg to about 167 , and about 167 mg to about 251 phytin , pyridoxine , and musa where citric acid is present in mg . an amount of about 350 mg , magnesium citrate is present in Most preferred is an oral dosage form or a plurality of an amount of about 150 mg , phytin is present in an amount dosage forms containing citric acid , magnesium citrate , of about 200 mg , pyridoxine is present in an amount of about phytin , and musa where citric acid is present in an amount 5 mg , and musa is present in amount of about 250 mg . 30 of about 350 mg , magnesium citrate is present in an amount

For a dosage form or plurality of dosage forms containing of about 150 mg , phytin is present in an amount of about 200 citric acid , magnesium citrate , phytin , and pyridoxine , a mg , and musa is present in amount of about 250 mg . preferred range for citric acid is about 101 mg to about 699 For a dosage form or plurality of dosage forms containing mg , magnesium citrate is about 77 mg to about 227 mg , citric acid , magnesium citrate , pyridoxine , and musa , a phytin is about 3 . 06 mg to about 600 mg , and pyridoxine 35 preferred range for citric acid is about 101 mg to about 1051 about 0 . 23 mg to about 15 . 13 . mg , magnesium citrate is 2 . 14 mg to about 226 mg , pyri More preferably for a dosage form or plurality of dosage doxine is 0 . 25 mg to about 10 . 23 mg , and musa is about

forms containing citric acid , magnesium citrate , phytin , and 41 . 02 mg to about 252 mg . pyridoxine , citric acid is present in an amount selected from : More preferably for a dosage form or plurality of dosage about 101 mg to about 354 mg , about 101 mg to about 178 40 forms containing citric acid , magnesium citrate , pyridoxine , mg , about 178 mg to about 699 mg , about 178 mg to about and musa , citric acid is present in an amount selected from : 354 mg , and about 352 mg to about 699 mg ; magnesium about 101 mg to about 700 mg , about 101 mg to about 353 citrate is present in an amount selected from : about 77 mg mg , about 101 mg to about 176 mg , about 176 mg to about to about 202 mg , about 77 mg to about 151 mg , about 151 1051 mg , about 176 mg to about 700 mg , about 176 mg to to about 227 mg , about 151 to about 202 mg , and about 202 45 about 353 mg , about 352 mg to about 1051 mg , about 352 mg to about 227 mg ; phytin is present in an amount selected mg to about 700 mg , and about 700 mg to about 1051 mg ; from : about 3 . 06 mg to about 400 mg , about 3 . 06 mg to magnesium citrate is present in an amount selected from : about 201 mg , about 3 . 06 mg to about 100 mg , about 100 mg about 2 . 14 mg to about 202 mg , about 2 . 14 mg to about 153 to about 600 mg , about 100 mg to about 400 mg , about 100 mg , about 2 . 14 mg to about 77 mg , about 77 to about 226 mg to about 201 mg , about 201 mg to about 600 mg , about 50 mg , about 77 to about 202 mg , about 77 to about 153 mg , 201 mg to about 400 mg , and about 400 mg to about 600 mg ; about 151 mg to about 226 mg , about 151 mg to about 202 and pyridoxine is present in an amount selected from : about mg , and about 202 mg to about 226 mg ; pyridoxine is 0 . 23 mg to about 10 . 67 mg , about 0 . 23 mg to about 5 . 95 mg , present in an amount selected from : about 0 . 25 mg to about about 0 . 23 mg to about 2 . 68 mg , about 2 . 68 mg to about 5 . 95 mg , about 0 . 25 mg to about 2 . 63 mg , about 2 . 63 mg to 15 . 13 mg , about 2 . 68 mg to about 10 . 67 mg , about 2 . 68 mg 55 about 10 . 23 mg , about 2 . 63 mg to about 5 . 95 mg , and about to about 5 . 95 mg , about 5 . 45 mg to about 15 . 13 mg , about 5 . 41 mg to about 10 . 23 mg ; and musa is present in an 5 . 45 mg to about 10 . 67 mg , and about 10 . 67 mg to about amount selected from : about 41 . 02 mg to about 167 mg , 15 . 13 mg . about 41 . 02 mg to about 85 mg , about 85 mg to about 252 Most preferred for a dosage form or plurality of dosage mg , about 85 mg to about 167 mg , and about 167 mg to

forms containing citric acid , magnesium citrate , phytin , and 60 about 252 mg . pyridoxine is one in which citric acid is present in an amount Most preferred is an oral dosage form or a plurality of of about 350 mg , magnesium citrate is present in an amount dosage forms comprising citric acid , magnesium citrate , of about 150 mg , phytin is present in an amount of about 200 pyridoxine , and musa where citric acid is present in an mg , and pyridoxine is present in an amount of about 5 mg . amount of about 350 mg , magnesium citrate is present in an

For a dosage form or plurality of dosage forms containing 65 amount of about 150 mg , pyridoxine is present in an amount citric acid , magnesium citrate , phytin , and musa , a preferred of about 5 mg , and musa is present in an amount of about range for citric acid is about 102 mg to about 1052 mg , 250 mg .

doo

US 9 , 789 , 152 B2 13 14

For a dosage form or plurality of dosage forms containing about 200 mg , pyridoxine is present in an amount of about citric acid , phytin , pyridoxine , and musa a preferred range 5 mg , and musa is present in amount of about 250 mg . for citric acid is about 101 mg to less than about 700 mg , Also disclosed is an oral dosage form or plurality of phytin is about 101 mg to about 600 mg , pyridoxine is about dosage forms comprising as active ingredients citric acid , 0 . 23 mg to about 15 . 12 mg , and musa is about 1 . 46 mg to 5 magnesium citrate , phytin , pyridoxine , and musa wherein about 252 mg . the percent inhibition of the formation of calcium oxalate More preferably for a dosage form or plurality of dosage crystals caused by this combination of active ingredients is

forms containing citric acid , phytin , pyridoxine , and musa , greater than about 92 % , more preferably greater than about citric acid is present in an amount selected from : about 101 96 % , and most preferably greater than about 99 % . mg to about 353 mg , about 101 mg to about 177 mg , about 10 Also disclosed is an oral dosage form or plurality of 177 mg to less than about 700 mg , about 177 mg to about dosage forms comprising as active ingredients citric acid ,

magnesium citrate , phytin , and pyridoxine wherein the per 353 mg , and about 352 mg to less than about 700 mg ; phytin cent inhibition of the formation of calcium oxalate crystals is present in an amount selected from : about 101 mg to about caused by this combination of active ingredients is greater 400 mg , about 101 mg to about 203 mg , about 202 mg to 15 than about 89 % more preferably greater than about 94 % . about 600 mg , about 202 to about 400 mg , and about 400 to and most preferably greater than about 98 % . about 600 mg ; pyridoxine is present in an amount selected Also disclosed is an oral dosage form or plurality of from : about 0 . 23 mg to about 10 . 20 mg , about 0 . 23 mg to dosage forms comprising as active ingredients citric acid , about 6 . 00 mg , about 0 . 23 mg to about 2 . 69 mg , about 2 . 69 magnesium citrate , phytin , and musa wherein the percent mg to about 15 . 12 mg , about 2 . 69 mg to about 10 . 20 mg , 20 inhibition of the formation of calcium oxalate crystals about 2 . 69 mg to about 6 . 00 mg , about 5 . 45 mg to about caused by this combination of active ingredients is greater 15 . 12 mg , about 5 . 45 mg to about 10 . 20 mg , and about 10 . 20 than about 92 % , more preferably greater than about 96 % , mg to about 15 . 12 mg ; and musa is present in an amount and most preferably greater than about 100 % . selected from : about 1 . 46 mg to about 167 mg , about 1 . 46 Also disclosed is an oral dosage form or plurality of mg to about 86 mg , about 1 . 46 mg to about 41 mg , about 41 25 dosage forms comprising as active ingredients citric acid , mg to about 252 mg , about 41 mg to about 167 mg , about magnesium citrate , pyridoxine , and musa wherein the per 41 mg to about 86 mg , about 86 mg to about 252 mg , about cent inhibition of the formation of calcium oxalate crystals 86 mg to about 167 mg , and about 167 mg to about 252 mg . caused by this combination of active ingredients is greater Most preferred is an oral dosage form or a plurality of than about 59 % , more preferably greater than about 62 % ,

dosage forms containing citric acid , phytin , pyridoxine , and 30 and most preferably greater than about 66 % . musa where citric acid is present in an amount of about 350 Also disclosed is an oral dosage form or plurality of mg , phytin is present in an amount of about 200 mg dosage forms comprising as active ingredients citric acid , pyridoxine is present in an amount of about 5 mg , and musa phytin , pyridoxine , and musa wherein the percent inhibition is present in amount of about 250 mg . of the formation of calcium oxalate crystals caused by this

For a dosage form or plurality of dosage forms containing 35 combination of active ingredients is greater than about 88 % , magnesium citrate , phytin , pyridoxine , and musa a preferred more preferably greater than about 100 % , and most prefer range for magnesium citrate is about 2 . 03 mg to about 203 ably greater than about 108 % . mg , phytin is about 100 mg to about 600 mg , pyridoxine is Also disclosed is an oral dosage form or plurality of about 0 . 22 mg to about 15 . 1 mg , and musa is about 1 . 46 mg dosage forms comprising as active ingredients magnesium to about 252 mg . 40 citrate , phytin , pyridoxine , and musa wherein the percent More preferably for a dosage form or plurality of dosage inhibition of the formation of calcium oxalate crystals

forms containing magnesium citrate , phytin , pyridoxine , and caused by this combination of active ingredients is greater musa , magnesium citrate is present in an amount selected than about 99 % , more preferably greater than about 104 % , from : about 2 . 03 mg to about 77 mg , about 2 . 03 mg to about and most preferably greater than about 106 % . 151 mg , about 77 mg to about 151 mg , about 77 mg to about 45 Also disclosed herein are methods for treating and / or 203 mg , and about 151 mg to about 203 mg ; phytin is inhibiting formation of kidney stones . present in an amount selected from : 100 mg to about 475 In an embodiment , the method comprises administering mg , 100 mg to about 400 mg , about 100 mg to about 202 mg , an oral dosage form or a plurality of dosage forms disclosed about 201 mg to about 600 mg , about 201 mg to about 475 herein to a patient in need thereof . The dosage form ( s ) can mg , about 201 to about 400 mg , about 400 mg to about 600 50 be administered to the patient one time or multiple times per mg , about 400 to about 475 mg , and about 475 mg to about day , preferably one to four times per day and more prefer 600 mg ; pyridoxine is present in an amount selected from : ably twice per day . Multiple oral dosage forms can be taken about 0 . 22 mg to about 10 . 11 mg , about 0 . 22 mg to about per dosing , preferably one to four dosage forms , preferably 6 . 01 mg , about 0 . 22 mg to about 2 . 69 mg , about 2 . 69 mg to one to two dosage forms , and more preferably 1 dosage about 15 . 1 mg , about 2 . 69 mg to about 10 . 11 mg , about 2 . 69 55 form . mg to about 6 . 01 mg , about 5 . 4 mg to about 15 . 1 mg , about In an embodiment , the method comprises administering to 5 . 4 mg to about 10 . 1120 mg , and about 10 . 11 mg to about a patient in need thereof about 101 mg to about 700 mg citric 15 . 1 mg ; and musa is present in an amount selected from : acid ; about 76 mg to about 226 mg magnesium citrate ; about about 1 . 46 mg to about 168 mg , about 1 . 46 mg to about 85 3 mg to about 600 mg phytin ; about 0 . 1 mg to about 15 mg mg , about 1 . 46 mg to about 42 mg , about 41 mg to about 252 60 pyridoxine ; and about 1 mg to about 251 mg musa . In an mg , about 41 mg to about 168 mg , about 41 mg to about 85 embodiment , the method comprises administering to the mg , about 85 mg to about 252 mg , about 85 mg to about 168 patient about 350 mg citric acid , about 150 magnesium mg , and about 168 mg to about 252 mg . citrate , about 200 mg phytin , about 5 mg pyridoxine , and Most preferred is an oral dosage form or a plurality of about 250 mg musa . The administering can occur one time

dosage forms containing magnesium citrate , phytin , pyri - 65 or multiple times per day , preferably 1 to 4 times per day , doxine , and musa where magnesium citrate is present in an and more preferably twice per day . The combination of the amount of about 150 mg , phytin is present in an amount of citric acid , magnesium citrate , phytin , pyridoxine , and musa

US 9 , 789 , 152 B2 16

1181

can be administered to the patient in form of an oral dosage Also disclosed is a method of inhibiting growth of cal form , e . g . a tablet or a capsule , preferably a capsule . cium oxalate crystals .

In an embodiment , the method comprises administering to In an embodiment , the method comprises contacting an a patient in need thereof any of the preferred amounts of aqueous solution comprising calcium oxalate with an oral active ingredients disclosed in the various embodiments 5 dosage form or a plurality of dosage forms disclosed herein . herein . In an embodiment , the method comprises contacting an

In an embodiment , the method comprises administering to aqueous solution comprising calcium oxalate with a com a patient in need thereof about 101 mg to about 699 mg citric position comprising as active ingredients citric acid , mag acid , about 77 mg to about 227 mg magnesium citrate , about nesium citrate , phytin , pyridoxine , and musa . A preferred 3 . 06 mg to about 600 mg phytin , and about 0 . 23 mg to about range for citric acid is about 101 mg to about 700 mg ; and 15 . 13 pyridoxine . In an embodiment , the method comprises more preferably about 101 mg to about 352 mg , about 101 administering to the patient about 350 mg citric acid , about mg to about 176 mg , about 176 mg to about 700 mg , or about 150 magnesium citrate , about 200 mg phytin , and about 5 352 mg to about 700 mg . A preferred range for magnesium mg pyridoxine . The combination of the citric acid , magne - 15 citrate is about 76 mg to about 226 mg ; and more preferably sium citrate , phytin , and pyridoxine , can be administered to about 76 mg to about 201 mg , about 76 mg to about 150 mg , the patient in form of an oral dosage form , e . g . a tablet or a about 150 to about 226 mg , or about 201 mg to about 226 capsule , preferably a capsule . mg . A preferred range for phytin is about 3 mg to about 600

In an embodiment , the method comprises administering to mg ; more preferably about 3 mg to about 400 mg , about 3 a patient in need thereof about 102 mg to about 1052 mg 20 mg to about 202 mg , about 3 mg to about 100 mg , about 100 citric acid , about 2 . 32 mg to about 201 mg magnesium mg to about 600 mg , about 201 mg to about 600 mg , or about citrate , about 100 mg to about 600 mg phytin , and about 1 . 51 400 mg to about 600 mg . A preferred range for pyridoxine mg to about 251 mg musa . In an embodiment , the method is about 0 . 2 mg to about 15 mg ; more preferably about 0 . 2 comprises administering to the patient about 350 mg citric mg to about 10 . 1 mg , about 0 . 2 mg to about 6 mg , about 0 . 2 acid , about 150 magnesium citrate , about 200 mg phytin , 25 mg to about 2 . 7 mg , about 2 . 7 mg to about 15 mg , about 6 . 0 and about 250 mg musa . The combination of the citric acid , mg to about 15 mg , or about 10 mg to about 15 mg . A magnesium citrate , phytin , and musa can be administered to preferred range for musa is about 1 mg to about 251 mg ; the patient in form of an oral dosage form , e . g . a tablet or a more preferably about 1 mg to about 167 mg , about 1 mg to capsule , preferably a capsule . about 85 mg , about 1 mg to about 41 mg , about 41 mg to

In an embodiment , the method comprises administering to 30 about 251 mg , about 85 mg to about 251 mg , or about 167 a patient in need thereof about 101 mg to about 1051 mg mg to about 251 mg . In an embodiment , the composition citric acid ; about 2 . 14 mg to about 226 mg magnesium comprises about 101 mg to about 700 mg citric acid ; about citrate ; about 0 . 25 mg to about 10 . 23 mg pyridoxine ; and 76 mg to about 226 mg magnesium citrate ; about 3 mg to about 41 . 02 mg to about 252 mg musa . In an embodiment , about 600 mg phytin ; about 0 . 1 mg to about 15 mg pyri the method comprises administering to the patient about 350 35 doxine ; and about 1 mg to about 251 mg musa ; specifically , mg citric acid , about 150 magnesium citrate , about 5 mg the composition comprises citric acid in an amount of about pyridoxine , and about 250 mg musa . The combination of the 350 mg , magnesium citrate in an amount of about 150 mg , citric acid , magnesium citrate , pyridoxine , and musa can be phytin in an amount of about 200 mg , pyridoxine in an administered to the patient in form of an oral dosage form , amount of about 5 mg , and musa in amount of about 250 mg . e . g . a tablet or a capsule , preferably a capsule . 40 In an embodiment , the method comprises contacting an

In an embodiment , the method comprises administering to aqueous solution comprising calcium oxalate with a com a patient in need thereof about 101 mg to less than about 700 position comprising as active ingredients any four of citric mg citric acid ; about 101 mg to about 600 mg phytin ; about acid , magnesium citrate , phytin , pyridoxine , and musa . In an 0 . 23 mg to about 15 . 12 mg pyridoxine ; and about 1 . 46 mg embodiment , the amount of each active ingredient is any of to about 252 mg musa . In an embodiment , the method 45 the amounts for that active ingredient disclosed herein . In an comprises administering to the patient about 350 mg citric embodiment , the method comprises contacting an aqueous acid , about 200 mg phytin , about 5 mg pyridoxine , and about solution comprising calcium oxalate with any of the pre 250 mg musa . The combination of the citric acid , phytin , ferred amounts of active ingredients disclosed in the various pyridoxine , and musa can be administered to the patient in embodiments herein . form of an oral dosage form , e . g . a tablet or a capsule , 50 Definitions preferably a capsule . Unless defined otherwise , all technical and scientific

In an embodiment , the method comprises administering to terms used herein have the same meaning as is commonly the patient about 150 mg magnesium citrate , about 200 mg understood by one of ordinary skill in the art to which this phytin , about 5 mg pyridoxine , and about 250 mg musa . The invention belongs . In the event that there is a plurality of combination of the magnesium citrate , phytin , pyridoxine , 55 definitions for a term used herein , those definitions in this and musa can be administered to the patient in form of an section shall prevail . oral dosage form , e . g . a tablet or a capsule , preferably a The terms " a " and " an " do not denote a limitation of capsule . In an embodiment , the method comprises admin - quantity , but rather denote the presence of at least one of the istering to a patient in need thereof about 2 . 03 mg to about referenced item . 203 mg magnesium citrate ; about 100 mg to about 600 mg 60 The term “ about ” as used herein is inclusive of the stated phytin ; about 0 . 22 mg to about 15 . 1 mg pyridoxine ; and value and means within the routine experimental error about 1 . 46 mg to about 252 mg musa . associated with measurement of the particular quantity ( i . e . ,

In any of the embodiments of the method for treating the limitations of the measurement system ) or in the case of and / or inhibiting formation of kidney stones disclosed a weight , within + 10 % of the stated value . herein , the administering can occur one time or multiple 65 The term “ active agent ” or “ active ingredient ” as used times per day , preferably 1 to 4 times per day , and more herein includes all pharmaceutically acceptable molecules , preferably twice per day . plant extracts , vitamins , salt forms , crystalline forms , amor

US 9 , 789 , 152 B2 17 18

phous form , polymorphic forms , solvates , and hydrates that kidney stones . Citrate inhibits stone formation by complex are useful for treating a medical condition . ing with calcium in the urine , inhibiting spontaneous nucle

“ Administering an oral dosage form or plurality of dosage ation , and preventing growth and agglomeration of crystals . forms comprising as active ingredients citric acid , magne Citric acid has been shown to inhibit the initial crystalliza sium citrate , phytin , pyridoxine , and musa ” or “ co - admin - 5 tion of calcium hydroxyapatite at Randall ' s plaques as well istering a plurality of dosage forms comprising as active as the aggregation of calcium oxalate crystals and their ingredients citric acid , magnesium citrate , phytin , pyridox - attachment to urinary epithelium . For citric acid , this term is ine , and musa ” means that each active ingredient is admin - defined to include other compounds that provide the equiva istered simultaneously in a single dosage form , administered lent amount of citrate ion in solution as the amount available concomitantly in separate dosage forms , or administered in 10 from citric acid used in the invention . separate dosage forms separated by some amount of time Ingestion of alkali salts ( i . e . potassium and magnesium that is within the time in which all of the active ingredients salts ) reduces urine calcium excretion and increases the are within the blood stream of a patient . reabsorption of calcium in the proximal tubule reabsorption .

The terms " comprising ” , “ having ” , “ including ” , and Oral administration of potassium citrate is known to prevent " containing ” are to be construed as open - ended terms ( i . e . , 15 the recurrence of kidney stones . Potassium citrate attaches to meaning “ including , but not limited to ” ) . calcium in the urine , preventing the formation of mineral

A " dosage form ” means a unit of administration of an crystals that can develop into kidney stones . Potassium active agent . An " oral dosage form ” means a unit dosage citrate also prevents the urine from becoming too acidic . form for oral administration . This helps prevent uric acid or cysteine kidney stones from As used herein " food ” means a solid food with sufficient 20 forming . Magnesium inhibits calcium oxalate crystallization

bulk and fat content that it is not rapidly dissolved and in human urine and model systems by forming a soluble absorbed in the stomach . More specifically , the food is a chelate with oxalate in the urine allowing for excretion . meal , such as breakfast , lunch , or dinner . An oral dosage Magnesium also inhibits absorption of dietary oxalate from form administered to a patient " with food ” is administered the gut lumen . Magnesium has been shown to inhibit crystal to the patient between about 30 minutes prior to eating a 25 formation thus reducing the risk for forming kidney stones . meal to about 2 hours after eating a meal ; more specifically , Various forms of alkali salt can be used in the compositions the dosage is administered within 15 minutes of eating a of this invention . For magnesium citrate , this term is defined meal . The term “ without food ” is defined to mean the to include other magnesium compounds that provide the condition of the patient not having consumed solid food for equivalent amount of free magnesium ion in solution as the about one hour prior to administration of the oral dosage 30 amount of magnesium citrate used in the invention . form until about 2 hours after administration of the oral Phytin is a calcium - magnesium salt of phytic acid that dosage form . occurs in plants . Phytic acid ( known as inositol hexakispho

The term " kidney stone ” includes a stone , crystal , calcu - sphate ( IP6 ) , inositol polyphosphate , or phytate when in salt lus , or nephrolith that is formed and affects any part of the form ) has a strong binding affinity for calcium . Phytin acts urinary tract including the kidney , bladder , and ureter . 35 by preventing crystallization of calcium salts . For phytin ,

The term “ medical condition ” includes disease , illness , this term is defined to include other compounds that provide ailment , syndrome , and / or disorder . the equivalent amount of phytate ion in solution as the

The term " patient ” means a human or non - human animal amount available from phytin used in the invention . in need of medical treatment . Pyridoxine ( 4 , 5 - Bis ( hydroxymethyl ) - 2 - methylpyridin - 3

The terms " treating ” and “ treatment ” mean implementa - 40 ol , or vitamin B6 ) reduces oxalate levels . It is believed that tion of therapy with the intention of reducing in severity or pyridoxine enhances the activity of an enzyme ( alanine : frequency symptoms , elimination of symptoms or underly - glyoxylate aminotransferase ) which diverts metabolites to ing cause , prevention of the occurrence of symptoms or their other uses in the body rather than having them form oxalate . underlying cause , and improvement or remediation of dam - For pyridoxine , this term is defined to include vitamers of age . 45 vitamin B6 , including pyridoxine ( PN ) , pyridoxine 5 ' - phos

By an " effective amount ” or a “ therapeutically effective phate ( PNP ) , pyridoxal ( PL ) , pyridoxal 5 ' - phosphate ( PLP amount " of an active agent is meant a sufficient amount of also known as P - 5 - P vitamin supplement ) , pyridoxamine the active agent to produce a therapeutic effect in the patient . ( PM ) , pyridoxamine 5 ' - phosphate ( PMP ) and 4 - Pyridoxic The amount that is " effective ” will vary from subject to acid ( PA ) . subject , depending on the age and general condition of the 50 Musa ( extracts from the banana plant or stem ) been used individual , the particular active agent , and the like . Thus , it in traditional medicine to prevent stone growth and to aid is not always possible to specify an exact " effective stone passage . From a mechanistic standpoint , extracts from amount . ” However , an appropriate " effective ” amount in Musa normalize multiple abnormal urinary parameters any individual case may be determined by one of ordinary which are known to induce stone growth , including calcium , skill in the art using routine experimentation . 55 phosphate , and oxalate . In this manner , high levels of the

The suffix “ ( s ) ” as used herein is intended to include both precipitating species that initiate stone growth are no longer the singular and the plural of the term that it modifies , excreted into the urine at high levels . Furthermore , Musa thereby including one or more of that term ( e . g . , the dosage decreases the expression of liver glycolate oxidase and form ( s ) includes one or more dosage forms ) . lactate dehydrogenase , enzymes associated with the produc Ingredients 60 tion of oxalate in the body . In addition to these activities ,

Citric acid is a GRAS food additive that is well absorbed Musa extracts have significant diuretic effect that aids the and is excreted into the renal tubule where it forms soluble passage of any stones as they are generated ( Devi , V . K . et complexes with calcium , reducing the concentration of free al . , Ancient Science of Life , 1993 , 12 ( 3 & 4 ) : 451 - 461 ; Pillai , calcium in the urine . Citric acid can be in the form of citric R . G . Ancient Science of Life , 1995 , 15 ( 1 ) : 2 - 6 ; Patankar , S . acid or a citrate salt such as magnesium citrate , calcium 65 et al . , 2008 , The Journal of Alternative and Complementary citrate or other physiologically acceptable salts . Low urinary Medicine 14 ( 10 ) : 1287 - 90 ; Prasobh , G . R . , International citrate excretion is a risk factor for the development of Journal of Research in Pharmaceutical and Biomedical

US 9 , 789 , 152 B2 19 20

Sciences , 2012 , 3 ( 4 ) : 1251 - 1255 ) . For musa , this term is sulfate , magnesium lauryl sulfate , sodium stearyl fumarate , defined to include all musa varieties listed in World Check - stearic acid , zinc stearate , or a combination thereof . list of Selected Plant Families . Royal Botanic Gardens , Kew . Exemplary glidants include colloidal silica , amorphous Formulation silica , precipitated silica , talc , calcium phosphate tribasic ,

Active agents used in this invention can be formulated 5 calcium silicate , magnesium silicate , magnesium trisilicate , into any oral dosage form including , solid , semi - solid , or a combination thereof , and the like . liquid , powder , sachet , and the like . Solid oral dosage forms Active agents can be formulated into dosage forms using can include , for example , a tablet , a capsule ( hard or soft ) , known techniques in the pharmaceutical art including dry or subunits , and the like . “ Subunit ” includes a minitablet , a blending and compression , wet granulation , encapsulation , bead , a spheroid , a microsphere , a seed , a pellet , a caplet , a 10 dry granulation or wet granulation followed by compression microcapsule , a granule , a particle , and the like that can or compaction , melt extrusion and spheronization , layering provide an oral dosage form alone or when combined with ( e . g . , spray layering suspension or solution ) , and the like . other subunits . Exemplary semi - solid or liquid dosage forms include a suspension , a solution , an emulsion , and the like . Examples of such techniques include direct compression ,

The oral dosage form can be formulated for a specific type 15 using appropriate punches and dies , the punches and dies are of release including immediate - release , controlled - release , fitted to a suitable rotary tableting press ; injection or com sustained - release , or extended - release pression molding using suitable molds fitted to a compres

Exemplary solid oral dosage forms can be prepared by sion unit , granulation followed by compression , and extru combining active agents with one or more pharmaceutically sion in the form of a paste , into a mold or to an extrudate to acceptable excipients and then forming into the dosage 20 be cut into lengths . form . As used herein , “ pharmaceutically acceptable excipi - Tablets can be prepared by compression into a com ent ” means any other component added to the pharmaceu pressed form using conventional tableting equipment using tical formulation other than the active agent . Excipients may standard techniques . Techniques and compositions for mak be added to facilitate manufacture , enhance stability , ing tablets ( compressed and molded ) are described in Rem enhance product characteristics , enhance bioavailability , 25 ington ' s Pharmaceutical Sciences , ( Aurther Osol . , editor ) , enhance patient acceptability , etc . Pharmaceutical excipients pp . 1553 - 1593 ( 1980 ) . include carriers , fillers , binders , disintegrants , lubricants , Layering techniques suitable to prepare subunits include glidants , granulating agent , compression aids , colors , sweet coating inert cores with a layering solution or dispersion of eners , preservatives , suspending agents , dispersing agents , the active agent and a pharmaceutically acceptable excipi film formers , flavors , printing inks , buffer agents , pH adjust - 30 ent . Repeated layering can be used to build the subunit size ers , preservatives etc . In some instances , a single material and increase active agent amount . will meet two or more of the foregoing general classifica . The controlled - release dosage form can be prepared using tions . controlled - release matrix materials , controlled - release coat

Exemplary pharmaceutically acceptable excipients ing materials , or a combination thereof . include fillers , such as water - insoluble filler , water soluble 35 The dosage forms may include functional or nonfunc filler , or a combination thereof . The filler may be a water - tional coatings . By “ functional coating ” is meant to include insoluble filler , such as carnauba wax , stearic acid , silicon a coating that modifies the release properties of the total dioxide , titanium dioxide , talc , alumina , starch , kaolin , composition , for example , a controlled - release coating polacrilin potassium , powdered cellulose , microcrystalline including a sustained - release or delayed - release coating . By cellulose , sodium citrate , dicalcium phosphate , or a combi - 40 “ non - functional coating ” is meant to include a coating that nation thereof . Exemplary water - soluble fillers include is not a functional coating , for example , a cosmetic coating . water soluble sugars and sugar alcohols , specifically lactose , non - functional coating can have some impact on the glucose , fructose , sucrose , mannose , dextrose , galactose , the release of the active agent due to the initial dissolution , corresponding sugar alcohols and other sugar alcohols , such hydration , perforation of the coating , etc . , but would not be as mannitol , sorbitol , Xylitol , or a combination thereof . 45 considered to be a significant deviation from the non - coated

Exemplary binders include alginic acid , a carbomer , car - composition . boxymethylcellulose calcium , carboxymethylcellulose Exemplary non - functional coatings include film forming sodium , carrageenan , cellulose acetate phthalate , chitosan , polymers such as a water soluble hydroxyl cellulose ( e . g . ethyl cellulose , guar gum , hydroxyethyl cellulose , hydroxy - hydroxylpropyl methylcellulose , etc . ) , polyvinyl alcohol , ethylmethyl cellulose , hydroxypropyl cellulose , hydroxy - 50 and the like ; optionally further including an additional propyl methyl cellulose , methyl cellulose , microcrystalline pharmaceutically acceptable coating excipient such as a cellulose , poloxamer , polyethylene oxide , polymethacry - plasticizer , a stabilizer , an anti - tacking agent ( e . g . , talc ) , a lates , povidone , a saccharide , starch , partially pregelatinized surfactant , and the like , or a combination thereof . starch , and the like , or a combination thereof . Exemplary functional coatings include polymers such as

Exemplary disintegrants include alginic acid , carboxym - 55 cellulose esters ( e . g . ethylcellulose ) ; a polymethacrylate ethylcellulose calcium , carboxymethylcellulose sodium , ( e . g . copolymers of acrylic and methacrylic acid esters ) , and cross - linked sodium carboxymethylcellulose ( sodium cros - the like ; optionally further including an additional pharma carmellose ) , powdered cellulose , chitosan , croscarmellose ceutically acceptable coating excipient such as a plasticizer , sodium , crospovidone , guar gum , low substituted hydroxy - a stabilizer , a water - soluble component ( e . g . pore formers ) , propyl cellulose , methyl cellulose , microcrystalline cellu - 60 an anti - tacking agent ( e . g . , talc ) , a surfactant , and the like , or lose , sodium alginate , sodium starch glycolate , partially a combination thereof . pregelatinized starch , pregelatinized starch , starch , sodium Suitable methods known in the pharmaceutical art can be carboxymethyl starch , and the like , or a combination used to apply the coating material . Processes such as simple thereof . or complex coacervation , interfacial polymerization , liquid

Exemplary lubricants include calcium stearate , magne - 65 drying , thermal and ionic gelation , spray drying , spray sium stearate , glyceryl behenate , glyceryl palmitostearate , chilling , fluidized bed coating , pan coating , or electrostatic hydrogenated castor oil , light mineral oil , sodium lauryl deposition may be used .

US 9 , 789 , 152 B2 21 22

Dosing and Administration using a spectrophotometer . A Vernier SpectroVis spectro Oral dosage forms containing active agents can be admin - photometer was used . Measurements were made in the

istered to prevent or treat formation of kidney stones any Absorbance versus Time mode , using ten ( 10 ) minutes for a where from once to multiple times per day , preferably one full run with an acquisition of 10 samples per minute . Other to four times per day and most preferabiv twice per day to four times per day and most preferably twice per day . 5 spectrophotometers , wavelengths , and methods 5 spectrophotometers , wavelengths , and methods may also be Multiple dosage forms can be taken per dosing preferably Multiple dosage forms can be taken per dosing , preferably used to determine calcium oxalate crystal formation over

time . one to four dosage forms and most preferably one to two dosage forms and ideally , 1 dosage form . The dosage form The inhibition of the kinetics of calcium oxalate crystal

formation by the various Test Solutions set forth below was can be taken with or without regard to food . determined using the method described above with the 10

EXAMPLES following change . Before the sodium oxalate solution was added , 200 uL of the Test Solution is added to the cuvette . The remainder of the procedure was the same as described Example 1 above . The inhibition of crystal growth was determined by comparison of the effect of the Test Solution on the slope of

A series of tests was run to evaluate the impact that 15 the initial velocity ( compared to vehicle control , during the various formulations of ingredients had on the rate of first two minutes ) , as described by Hess ( Hess , 2000 ) . calcium oxalate crystal growth . Formulations were evalu - Individual replicates identified as outliers by the Grubb ' s ated for their ability to achieve 100 % inhibition of the in test were not included in the calculation ( Grubbs , Frank E . , vitro growth rate of calcium oxalate crystals . Initially , the 1950 , Sample criteria for testing outlying observations , The growth of calcium oxalate crystals in aqueous solution was 3 Annals of Mathematical Statistics 21 ( 1 ) , p . 27 - 58 . ) . Other determined by UV - Visible spectroscopy and is referred to as methods of determining percent inhibition of calcium a “ Control Vehicle ” . Then , various formulations were evalu oxalate crystal formation , such as by individual runs or other ated for their ability to inhibit the growth rate of calcium statistical methods are also possible . oxalate crystals compared to the Control Vehicle . The Test Solutions were prepared by adding the following

All reagents were chemical grade or plant extracts as ingredients in the amounts given in Tables 1 and 11 - 15 in the listed in the Reagent Table below . Other grades and sources 25 order listed ( for an ingredient not used in Matrix 1 through of reagents may be used . 5 , the order remained the same but that ingredient was

omitted ) to a 100 mL volumetric flask : Citric acid — added as a dry powder to a 100 mL volu

Reagent Table metric flask ; 30 Magnesium citrate _ added as a dry powder to above

Chemical volumetric flask and 50 mL distilled H2O added and Reagent Grade Commercial Source Lot # vortexed until clear

Phytin - added to above volumetric flask and vortexed Calcium ACS analytical Mallinkrodt G23H14 chloride , until clear grade dihydrate Pyridoxine added to above volumetric flask and vor Sodium oxalate ACS Reagent Sigma - Aldrich MKBP6508V texed until clear

> 99 . 5 % Musa — 50 mL of the prepared solution ( see below ) added Sodium acetate AR analytical Fisher Scientific 7372KVND to the above volumetric flask and made up to final reagent volume of 100 mL with water . Sodium USP food Mallinkrodt 7532KVPG Chloride The Musa samples were prepared by placing the indicated Banana stem Acetar Biotech TY140603 40 amount of Musa , as a dry powder , ( see Table 1 ) in a 100 mL extract - Musa volumetric flask and making up to volume with water . The Phytin TCI America FFEKL - FA flask was vortexed intermittently for 5 minutes . At this time Magnesium BulkSupplements . com 20141019 the sample was transferred to a centrifuge tube and centri citrate fuged at 3000 rpm for 30 minutes . 50 mL of the supernatant Pyridoxine HCl 98 % HPLC Sigma Aldrich SLBK1634V Citric acid TCI America SVIKMIT 46 was carefully transferred to a 50 mL volumetric flask and

vortexed to assure complete solubility . This 50 mL homo geneous solution was transferred to the original 100 mL

Experimental Spectrophotometric Method : volumetric flask and vortexed to assure complete solubility . The spectrophotometric method employed was based on For Matrix 5 test solutions , which did not include any

the work of Chow ( Chow , 2004b , Citrate inhibits growth of citric acid , the entire procedure was the same except mag residual fragments in an in vitro model of calcium oxalate 50 nesium citrate was added as a dry powder to a 100 mL renal stones . Kidney International , 665 : 1724 - 1730 ) and is volumetric flask to which 40 mL distilled H , was added briefly described below . The study was conducted using a and then sufficient 1 N HCl to impart a pH of between 1 and sodium acetate / sodium chloride buffer at pH 5 . 7 as recom 2 to the final solution . The flask was vortexed until complete mended by Khan ( Khan 2012 , Antiurolithic activity of dissolution . The total volume of the magnesium citrate Origanum vulgare is mediated through multiple pathways 55 solution was < 50 mL . Phytin , pyridoxine , and musa were BMC Complementary and Alternative Medicine 11 : added to complete the 100 mL Matrix 5 test solutions as 96 - 112 . ) . described above . For Matrix 5 Test solution 7 , magnesium

The kinetics of calcium oxalate crystal formation in a citrate ( 203 mg ) was added to a 100 mL volumetric flask to control vehicle were characterized by the slope method of which 35 mL distilled water added and then 2 . 5 mL 1 N HC1 Hess ( Hess , B . et al . , Nephrol . Dial . Transplant , 2000 , 15 ( 3 ) : was added , yielding a pH of between 1 and 2 . The flask was 366 - 374 ) . Briefly , 1 . 6 milliliters of an 8 . 5 mM solution of " vortexed until clear . To this volumetric flask was added 600 calcium chloride was added to a plastic cuvette and 1 . 6 mg phytin and then 10 mL distilled water . The solution was milliliters of a 1 . 5 mM sodium oxalate solution was then vortexed , and then permitted to stand for approximately 3 added . Both of the solutions were prepared in a buffer minutes until the top of the liquid was clear . The pH was pH composed of 50 mM sodium acetate and 100 mM sodium 6 . An additional 2 . 5 mL 1 N HCl was added to yield a pH chloride at pH 5 . 7 . Immediately upon combining the solu - 65 between 1 and 2 . The flask was vortexed until clear . Pyri tions , the cuvette was mixed by inversion and the kinetics of doxine and musa were then added to complete the 100 mL calcium oxalate crystal formation were monitored at 620 nm Matrix 5 Test Solution , as described above .

35

grade

US 9 , 789 , 152 B2 23 24

TABLE 1 Amounts of Active Ingredients in Five Ingredient Test Solutions .

Active Ingredient

Test Test Test Test Test Solution 1 Solution 2 Solution 3 Solution 4 Solution 5

Test Solution 6

Test Solution 7

Citric Acid Mg Citrate Phytin Pyridoxine Musa

352 mg 151 mg 202 mg 5 . 4 mg 251 mg

101 mg 1050 mg 76 mg 2 . 02 mg 201 mg 100 mg 10 . 1 mg 5 . 99 mg 251 mg 167 mg

700 mg 226 mg

3 . 03 2 . 67 85 mg

352 mg 201 mg 600 mg 0 . 2 mg 41 mg

176 mg 150 mg 400 mg 15 . 1 mg 1 . 4 mg

351 mg 152 mg 200 mg 5 . 3 mg 251 mg

FIG . 1 shows the absorbance as function of time for the Solution 2 . From the figure it can be seen that calcium first 10 minutes and measures the formation of calcium oxalate crystals are indeed forming during the ten minutes of oxalate over time for the Control Vehicle runs used for Test 15 the run . FIG . 6 shows the slopes of the curves for the initial Solution 1 . From the figure it can be seen that calcium two minutes of the runs for the Control Vehicle used for Test oxalate crystals are indeed forming during the ten minutes of Solution 2 . Since the data was linear ( R - > 0 . 95 ) for the first

two ( 2 ) minutes , this data was plotted for slope determina the run . FIG . 2 shows the slopes of the curves for the initial tion by linear regression analysis . FIG . 7 shows the absor two minutes of the runs for the Control Vehicle used for Test 20 bance as function of time for the first 10 minutes and Solution 1 . Since the data was linear ( R2 > 0 . 95 ) for the first measures the formation of calcium oxalate over time for the two ( 2 ) minutes , this data was plotted for slope determina Control Vehicle runs used for Test Solution 1 . FIG . 8 shows tion by linear regression analysis . FIG . 3 shows the absor the slopes of the curves for the initial two minutes of the runs bance as function of time for the first 10 minutes and for Test Solution 2 . Since the data was linear ( R2 > 0 . 95 ) for measures the formation of calcium oxalate over time for the 25 the first two ( 2 ) minutes , this data was plotted for slope Control Vehicle runs used for Test Solution 1 . FIG . 4 shows determination by linear regression analysis . Table 3 shows the slopes of the curves for the initial two minutes of the runs the analysis of the slopes FIGS . 6 and 8 . Each run is for Test Solution 1 . Since the data was linear ( R2 > 0 . 95 ) for designated as a Replicate .

TABLE 3 Data Analysis for Slope Test , Control Vehicle & Test Solution 2

Replicate Replicate # 2

Replicate # 3

Replicate # 4

Replicate # 5

Replicate # 6

Median % Inhibition # 1 Median

0 . 0334 Control Vehicle Test Solution 2

- 0 . 028 - 0 . 0007

0 . 0666 - 0 . 0008

0 . 0634 - 0 . 0012

0 . 0855 - 0 . 0012

0 . 0406 -

0 . 0634 - 0 . 001 101 . 5773

the first two ( 2 ) minutes , this data was plotted for slope FIG . 9 shows the absorbance as function of time for the determination by linear regression analysis . 40 first 10 minutes and measures the formation of calcium

Table 2 shows the analysis of the slopes FIGS . 2 and 4 . oxalate over time for the Control Vehicle runs used for Test Each run is designated as a Replicate . Outlier data identified Solution 3 . From the figure it can be seen that calcium using the Grubbs ' Test ( Grubbs , 1950 ) were not included in oxalate crystals are indeed forming during the ten minutes of % inhibition calculations . The median % Inhibition was the run . FIG . 10 shows the slopes of the curves for the initial calculated according to the method of Hess ( Hess , 2000 ) 45 two minutes of the runs for the Control Vehicle used for Test using the following equation : Solution 3 . Since the data was linear ( R2 > 0 . 95 ) for the first

two ( 2 ) minutes , this data was plotted for slope determina % Inhibition = 100 % * ( 1 - ( Slope of Test Solution / tion by linear regression analysis . FIG . 11 shows the absor Slope of Control Vehicle ) ) . bance as function of time for the first 10 minutes and The mean ( average ) percent inhibition can also be calculated so measures the formation of calcium oxalate over time for the from the data . Median and mean percent inhibitions are Control Vehicle runs used for Test Solution 3 . FIG . 12 shows presented in Tables 9 , 11 - 15 . In some embodiments , the the slopes of the curves for the initial two minutes of the runs median percent inhibition is the preferred measure of per for Test Solution 3 . Since the data was linear ( R2 > 0 . 95 ) for cent inhibition . the first two ( 2 ) minutes , this data was plotted for slope

TABLE 2

Data Analysis for Slope Test , Control Vehicle & Test Solution 1 Replicate

# 1 Replicate

# 2 Replicate

# 3 Replicate

# 4 Replicate

# 5 Replicate

# 6 Median Median % Inhibition

Control Vehicle Test Solution 1

0 . 0047 - 0 . 0002

0 . 0172 0 . 0002

0 . 0022 0 . 00003

0 . 0042 0 . 00007

0 . 0057 - 0 . 0003

0 . 0036 0 . 001

0 . 00445 0 . 00005 98 . 8764

FIG . 5 shows the absorbance as function of time for the 65 determination by linear regression analysis . Table 4 shows first 10 minutes and measures the formation of calcium the analysis of the slopes FIGS . 10 and 12 . Each run is oxalate over time for the Control Vehicle runs used for Test designated as a Replicate .

US 9 , 789 , 152 B2 25 26

TABLE 4 Data Analysis for Slope Test , Control Vehicle & Test Solution 3

Replicate # 1 Replicate # 2 Replicate # 3 Replicate # 4 Median Median % Inhibition


0 . 0073 0 . 0014

0 . 0123 0 . 0077

0 . 0129 0 . 0039

0 . 0115 0 . 0035

0 . 0119 0 . 0035 70 . 5882

10

# 1 # 2 # 3

FIG . 13 shows the absorbance as function of time for the for Test Solution 5 . Since the data was linear ( R2 > 0 . 95 ) for first 10 minutes and measures the formation of calcium the first two ( 2 ) minutes , this data was plotted for slope oxalate over time for the Control Vehicle runs used for Test determination by linear regression analysis . Table 6 shows Solution 4 . From the figure it can be seen that calcium the analysis of the slopes FIGS . 18 and 20 . Each run is oxalate crystals are indeed forming during the ten minutes of 15 designated as a Replicate . the run . FIG . 14 shows the slopes of the curves for the initial two minutes of the runs for the Control Vehicle used for Test TABLE 6 Solution 4 . Since the data was linear ( R2 > 0 . 95 ) for the first two ( 2 ) minutes , this data was plotted for slope determina Data Analysis for Slope Test , Control Vehicle & Test Solution 5 tion by linear regression analysis . FIG . 15 shows the absor - 20 bance as function of time for the first 10 minutes and Replicate Replicate Replicate Median % measures the formation of calcium oxalate over time for the Median Inhibition

Control Vehicle runs used for Test Solution 4 . FIG . 16 shows the slopes of the curves for the initial two minutes of the runs 25 Control 0 . 0851 0 . 0508 0 . 0467 0 . 0588 for Test Solution 4 . Since the data was linear ( R2 > 0 . 95 ) for Vehicle the first two ( 2 ) minutes , this data was plotted for slope Test Solution 5 0 . 0007 0 . 0003 0 . 0004 0 . 0004 99 . 3197 determination by linear regression analysis . Table 5 shows the analysis of the slopes FIGS . 14 and 16 . Each run is designated as a Replicate . 30 FIG . 21 shows the absorbance as function of time for the

first 10 minutes and measures the formation of calcium TABLE 5 oxalate over time for the Control Vehicle runs used for Test

Solution 6 . From the figure it can be seen that calcium Data Analysis for Slope Test , Control Vehicle & Test Solution 4 35 oxalate crystals are indeed forming during the ten minutes of

Replicate Replicate Replicate Median % the run . FIG . 22 shows the slopes of the curves for the initial Median Inhibition two minutes of the runs for the Control Vehicle used for Test

Control 0 . 0772 0 . 107 0 . 081 0 . 081 Solution 6 . Since the data was linear ( R2 > 0 . 95 ) for the first Vehicle Test Solution 4 0 . 0026 0 . 0007 0 . 0006 0 . 0004 99 . 5679 two ( 2 ) minutes , this data was plotted for slope determina

tion by linear regression analysis . FIG . 23 shows the absor FIG . 17 shows the absorbance as function of time for the bance as function of time for the first 10 minutes and

first 10 minutes and measures the formation of calcium measures the formation of calcium oxalate over time for the oxalate over time for the Control Vehicle runs used for Test Control Vehicle runs used for Test Solution 6 . FIG . 24 shows Solution 5 . From the figure it can be seen that calcium 45 the slopes of the curves for the initial two minutes of the runs oxalate crystals are indeed forming during the ten minutes of for Test Solution 6 . Since the data was linear ( R2 > 0 . 95 ) for the run . FIG . 18 shows the slopes of the curves for the initial two minutes of the runs for the Control Vehicle used for Test the first two ( 2 ) minutes , this data was plotted for slope Solution 5 . Since the data was linear ( R2 > 0 . 95 ) for the first determination by linear regression analysis . Table 7 shows two ( 2 ) minutes , this data was plotted for slope determina - 50 the analysis of the slopes FIGS . 22 and 24 . Each run is tion by linear regression analysis . FIG . 19 shows the absor - designated as a Replicate .

TABLE 7

# 1 # 2 # 3

Data Analysis for Slope Test , Control Vehicle & Test Solution 6

Replicate # 1

Replicate # 2

Replicate # 3

Replicate # 4

Replicate # 5 Median

Median % Inhibition


0 . 0068 - 0 . 0033

0 . 0717 - 0 . 0035

0 . 038 - 0 . 0028

0 . 0594 - 0 . 0045

0 . 0037 - 0 . 0012

0 . 0224 - 0 . 0031 113 . 6161

bance as function of time for the first 10 minutes and Table 8 shows the analysis of the slopes of solution 7 , a measures the formation of calcium oxalate over time for the 65 duplicate of test solution 1 , which was calculated similarly Control Vehicle runs used for Test Solution 5 . FIG . 20 shows to Test Solution 1 . Each run is designated as a Replicate . The the slopes of the curves for the initial two minutes of the runs data from these experiments are shown FIGS . 25 - 28 .

US 9 , 789 , 152 B2 27

TABLE 8

Data Analysis for Slope Test , Control Vehicle & Test Solution 7

% Replicate # 1

Replicate # 2

Replicate # 3

Replicate # 4

Replicate # 5

Replicate # 6 # 1 # 2 # 3 # 4 # 5 # 6 Median Median Inhibition Inhibition

Vehicle Test Solution 1

0 . 0084 - 0 . 0000005

0 . 0204 - 0 . 0003

0 . 0282 - 0 . 0002

0 . 0054 0 . 0005

0 . 0193 - 0 . 0003

0 . 0306 - 0 . 0002

0 . 01985 - 0 . 0002 101 . 0076

Table 9 shows the percent inhibition results ( calculated as median and average ) and the ingredient weights for Test 15 Solutions 1 through Test Solution 7 .

TABLE 9

Median and Mean Inhibition of Calcium Oxalate Crystal Growth by 5 ingredient Test Solutions

Test Test Test Test Test Test Test Test Test Test Test Test Test Test Solution 1 Solution 2 Solution 3 Solution 4 Solution 5 Solution 6 Solution 7

Median % 98 . 88 101 . 58 70 . 59 99 . 57 99 . 32 113 . 62 101 . 00 Inhibition

96 . 26 103 . 11 64 . 39 99 . 48 99 . 27 92 . 44 99 . 19 Average % Inhibition

Citric Acid Mg Citrate Phytin

352 mg 151 mg 202 mg 5 . 4 mg 251 mg

101 mg 1050 mg 700 mg 75 mg 2 . 02 mg 226 mg 201 mg 100 mg 3 . 03 mg 10 . 2 mg 5 . 99 mg 2 . 67 mg 251 mg 167 mg 85 mg

352 mg 201 mg 600 mg 0 . 2 mg 41 mg

176 mg 150 mg 400 mg 15 . 1 mg 1 . 4 mg

351 mg 152 mg 200 mg 5 . 3 mg 251 mg

Pyridoxine Musa

The results in Table 9 show that compositions having FIGS . 30 to 53 are graphs showing absorbance as function about 101 mg to about 700 mg citric acid ; about 76 mg to 40 of time and slope determinations for the Control Vehicle and about 226 mg magnesium citrate ; about 3 mg to about 600 Test Solution replicates for the six Matrix 1 Test Solutions . mg phytin ; about 0 . 1 mg to about 15 mg pyridoxine ; and FIGS . 54 to 77 are graphs showing absorbance as a about 1 mg to about 251 mg musa . result in a mean percent inhibition of calcium oxalate crystal growth of at least about function of time and slope determinations for the Control 92 % , while compositions having citric acid , magnesium 45 Vehicle and Test Solution replicates for the six Matrix 2 Test citrate , phytin , pyridoxine , and musa concentrations outside Solutions . these ranges are unexpectedly much less effective , resulting FIGS . 78 to 101 are graphs showing absorbance as a in mean percent inhibition of calcium oxalate crystal growth function of time and slope determinations for the Control of only about 64 % . Vehicle and Test Solution replicates for the six Matrix 3 Test Inhibition of the kinetics of calcium oxalate crystal for - 50 Solutir of 50 Solutions . mation was also determined , using the method described above , for the four combinations of four out of the five FIGS . 102 to 125 are graphs showing absorbance as a

function of time and slope determinations for the Control ingredients in Table 1 each including citric acid . Herein , each of these four - ingredient combinations is referred to as Vehicle and Test Solution replicates for the six Matrix 4 Test

Solutions . a " Matrix ” . “ Matrix 1 ” refers to a combination of citric acid , 55 magnesium citrate , phytin , and pyridoxine . “ Matrix 2 ” refers FIGS . 126 to 153 are graphs showing absorbance as a to a combination of citric acid , magnesium citrate , phytin , function of time and slope determinations for the Control

Vehicle and Test Solutions replicates for the seven Matrix 5 and musa . “ Matrix 3 ” refers to a combination of citric acid , Test Solutions . magnesium citrate , pyridoxine , and musa . “ Matrix 4 ” refers to a combination of citric acid , phytin , pyridoxine , and ou 60 Since the data was linear ( R2 > 0 . 95 ) for the first two ( 2 ) musa . Matrix 5 refers to a combination of magnesium minutes of the runs , that data was plotted for slope deter

mination by linear regression analysis . The slopes deter citrate , phytin , pyridoxine , and musa . The amounts of the mined for the Control Vehicle and Test Solutions 1 - 6 runs for ingredients in the Test Solutions for each of the five Matrices each of Matrix 1 . 2 . 3 . 4 and 5 are tabulated in Table 10 . are set forth below in Tables 11 - 15 , respectively , along with 65 Table 10 further shows the results of analysis of the slopes median and mean percent inhibition values determined for to provide the median percent inhibition by each Test each Test Solution . Solution . Each run is designated as a Replicate .

US 9 , 789 , 152 B2 29 30

TABLE 10

Data Analysis for Slope Test for Control Vehicles and Test Solutions for Matrix 1 , Matrix 2 , Matrix 3 , Matrix 4 and Matrix 5

Matrix 1 through 5 - Four Ingredient Data Analysis for Slope Tests , Control Vehicles & Test Solutions

Replicate 1 Replicate 2 Replicate 3 Median % Inhibition Median Matrix 1 - Citric Acid , Mg Citrate , Phytin , Pyridoxine

Matrix 1

104 . 5 %

106 . 5 %

88 . 2 %

Control Vehicle Test Solution 1 Control Vehicle Test Solution 2 Control Vehicle Test Solution 3 Control Vehicle Test Solution 4 Control Vehicle Test Solution 5 Control Vehicle Test Solution 6

0 . 0081 0 . 0088 0 . 0145 0 . 0088 0 . 0004 - 0 . 0004 - 0 . 0006 - 0 . 0004 0 . 0098 0 . 0199 0 . 0767 0 . 0199

- 0 . 0013 - 0 . 001 - 0 . 0017 - 0 . 0013 0 . 0119 0 . 0093 0 . 0171 0 . 0119 0 . 0014 0 . 0014 0 . 0004 0 . 0014 0 . 0469 0 . 0899 0 . 1103 0 . 0899 0 . 0031 0 . 0009 0 . 001 0 . 001 0 . 0103 0 . 008 0 . 0482 0 . 0103 0 . 0006 0 . 0019 0 . 0001 0 . 0006 0 . 1182 0 . 1233 0 . 1278 0 . 1233

- 0 . 0027 - 0 . 0022 - 0 . 0027 - 0 . 0027 Matrix 2 - Citric Acid , Mg Citrate , Phytin , Musa

98 . 9 %

94 . 2 %

102 . 2 %

Matrix 2

100 . 9 %

119 . 1 %

96 . 7 %


0 . 0056 0 . 0071 0 . 0105 0 . 0105 - 0 . 00009 - 0 . 0006 0 . 0014 - 0 . 00009 0 . 0078 0 . 0037 0 . 0058 0 . 0068

- 0 . 0026 - 0 . 0011 - 0 . 0013 - 0 . 0013 0 . 007 0 . 0141 0 . 0098 0 . 01195 0 . 005 0 . 00006 0 . 0004 0 . 0004 0 . 0157 0 . 0059 0 . 0117 0 . 0157 0 . 0013 0 . 0011 0 . 0013 0 . 0013 0 . 01 0 . 0359 0 . 0332 0 . 0332 0 . 0004 - 0 . 0005 - 0 . 0003 - 0 . 0003 0 . 0162 0 . 0349 0 . 013 0 . 0162

- 0 . 0019 - 0 . 0029 - 0 . 002 - 0 . 002 Matrix 3 - Citric Acid , Mg Citrate , Pyridoxine , Musa

91 . 7 %

100 . 9 %

112 . 3 %

Matrix 3

87 . 1 %

66 . 2 %

67 . 5 %


0 . 0072 0 . 0051 0 . 006 0 . 006 0 . 0005 0 . 0013 0 . 0012 0 . 00085 0 . 0064 0 . 0065 0 . 0131 0 . 0065 0 . 0036 0 . 0007 0 . 0008 0 . 0022 0 . 0109 0 . 008 0 . 0078 0 . 008 0 . 0013 0 . 0041 0 . 0026 0 . 0026 0 . 0093 0 . 0153 0 . 0184 0 . 0153 0 . 0076 0 . 0058 0 . 0026 0 . 0058 0 . 0168 0 . 0081 0 . 0135 0 . 0135 0 . 0023 0 . 0037 0 . 0045 0 . 0037 0 . 0224 0 . 0305 0 . 0186 0 . 0224 0 . 0057 0 . 0094 0 . 0225 0 . 0094 Matrix 4 - Citric Acid , Phytin , Pyridoxine , Musa

62 . 1 %

72 . 6 %

58 . 0 %

Matrix 4

108 . 8 %

109 . 8 %


100 . 1 %

0 . 0073 - 0 . 0018 0 . 0246

- 0 . 003 0 . 0072

- 0 . 0021 0 . 0206 0 . 0013 0 . 0052

- 0 . 0024 0 . 0089

- 0 . 0039

0 . 017 - 0 . 001 0 . 0325

- 0 . 0023 0 . 0052

- 0 . 00001 0 . 0228 0 . 0025 0 . 0083

- 0 . 002 0 . 0099

0 . 0179 - 0 . 0025

0 . 0124 - 0 . 0024 0 . 0173 0 . 0002 0 . 0141 0 . 0037 0 . 0067

- 0 . 0025 0 . 0071

- 0 . 0041

0 . 017 - 0 . 0015 0 . 0246

- 0 . 0024 0 . 0072

- 0 . 00001 0 . 0206 0 . 0025 0 . 0067

- 0 . 0024

0 . 0094 - 0 . 004

87 . 9 %

135 . 8 % SI - 0 . 004 142 . 6 %

US 9 , 789 , 152 B2 31 TABLE 10 - continued

Data Analysis for Slope Test for Control Vehicles and Test Solutions for Matrix 1 , Matrix 2 , Matrix 3 , Matrix 4 and Matrix 5

Matrix 1 through 5 - Four Ingredient Data Analysis for Slope Tests , Control Vehicles & Test Solutions

Replicate 1 Replicate 2 Replicate 3 Median % Inhibition Median Matrix 5 - Mg Citrate , Phytin , Pyridoxine and Musa

Matrix 5

109 . 7 %

106 . 6 %

109 . 0 %

Control Vehicle Test Solution 1 Control Vehicle Test Solution 2 Control Vehicle Test Solution 3 Control Vehicle Test Solution 4 Control Vehicle Test Solution 5 Control Vehicle Test Solution 6 Control Vehicle Test Solution 7

0 . 0306 - 0 . 0018 0 . 0486

- 0 . 0019 0 . 0062

- 0 . 001 0 . 0091

- 0 . 0004 0 . 0244

- 0 . 0028 0 . 0185

- 0 . 0068 0 . 0217

- 0 . 0009

0 . 0226 - 0 . 0016

0 . 009 - 0 . 0023 0 . 0115

- 0 . 0012 0 . 0518 0 . 0018 0 . 0089

- 0 . 0054 0 . 0348

- 0 . 0056 0 . 0133

- 0 . 0025

0 . 0105 - 0 . 001 0 . 0082

- 0 . 0016 0 . 0111

- 0 . 001 0 . 0139 0 . 0002 0 . 0082

- 0 . 0062 0 . 012

- 0 . 0078 0 . 0214 0 . 0003

0 . 01655 - 0 . 0016 0 . 0288

- 0 . 0019 0 . 0111

- 0 . 001 0 . 0139 0 . 0002 0 . 0089

- 0 . 0054 0 . 0185

- 0 . 0068 0 . 0214

- 0 . 0009

98 . 6 %

160 . 7 %

136 . 8 %

104 . 2 %

Table 11 shows the percent inhibition results ( calculated 25 as median and average ) and the ingredient weights for Matrix 1 ( citric acid , magnesium citrate , phytin , and pyri doxine ) Test Solutions 1 through Test Solution 6 .

TABLE 11 Matrix 1 Test Solution Ingredient Amounts and Median and Mean Percent

Inhibition of Calcium Oxalate Crystal Growth

Matrix 1

Test Test Test Test Test Test Solution 1 Solution 2 Solution 3 Solution 4 Solution 5 Solution 6 mg mg mg mg mg mg Ingredient

178 Citric Acid Mg Citrate Phytin Pyridoxine Median % inhibition Average % inhibition

354 151 201

5 . 45 104 . 55 101 . 25

101 77 201 10 . 67

106 . 53 106 . 84

1051 2 . 31

100 5 . 95

88 . 24 90 . 28

699 227

3 . 06 2 . 68

98 . 89 97 . 16

352 202 600

0 . 23 94 . 17 90 . 07

151 400 15 . 13

102 . 19 102 . 06

45 The results in Table 11 show that compositions where

citric acid is present in an amount of about 101 mg to about 699 mg , magnesium citrate is present in an amount of about 77 mg to about 227 mg , phytin is present in an amount of about 3 . 06 mg to about 600 mg , and pyridoxine is present in 50 an amount of about 0 . 23 mg to about 15 . 13 mg result in a median percent inhibition of calcium oxalate crystal growth of at least about 94 % , while compositions having citric acid ,

magnesium citrate , phytin , and pyridoxine concentrations outside these ranges are unexpectedly much less effective , resulting in median percent inhibition of calcium oxalate crystal growth of only about 88 % .

Table 12 shows the percent inhibition results ( calculated as median and average ) and the ingredient weights for Matrix 2 ( citric acid , magnesium citrate , phytin , and musa ) Test Solutions 1 through Test Solution 6 .



Matrix 2

Test Test Test Test Test Test Solution 1 Solution 2 Solution 3 Solution 4 Solution 5 Solution 6 mg mg mg mg mg mg Ingredient mg mg mo

102 Citric Acid Mg Citrate Phytin

352 151 202

77 1052

2 . 32 100

700

226 3 . 28

351 201 600

177 150 401 201

US 9 , 789 , 152 B2 33 TABLE 12 - continued

34

Matrix 2 Test Solution Ingredient Amounts and Median and Mean Percent Inhibition of Calcium Oxalate Crystal Growth

Matrix 2

Solution 1 Solution Test Test

Solution 1 Solution 2 mg mg mg

Test Solution 3 mg mg

Test Solution 4 mg Sn 4 solution s solution 6

Test Solution 5 mg mg

Test Solution 6 mg mg Ingredient mg

Musa Median % inhibition Average % inhibition

251 100 . 86 98 . 91

251 119 . 12 128 . 49

167 96 . 65 74 . 69

86 91 . 72 87 . 32

41 41 100 . 90 99 . 43

1 . 51 112 . 35 111 . 81

The results in Table 12 show that compositions where 15 1051 mg , magnesium citrate is present in an amount of about citric acid is present in an amount of about 102 mg to about 2 . 14 mg to about 226 mg , pyridoxine is present in an amount 1052 mg , magnesium citrate is present in an amount of about 2 . 32 mg to about 201 mg , phytin is present in an amount of of about 0 . 25 mg to about 10 . 23 mg , and musa is present in about 100 mg to about 600 mg , and musa is present in an an amount of about 41 . 02 mg to about 252 mg result in a amount of about 1 . 51 mg to about 251 mg result in a median 20 me am 20 median percent inhibition of calcium oxalate crystal growth percent inhibition of calcium oxalate crystal growth of at least about 96 % , while compositions citric acid , magnesium of at least about 62 % , while compositions citric acid , citrate , phytin , and musa concentrations outside these ranges magnesium citrate , pyridoxine , and musa concentrations are unexpectedly much less effective , resulting in median outside these ranges are unexpectedly much less effective , percent inhibition of calcium oxalate crystal growth of only 25 about 92 % . resulting in median percent inhibition of calcium oxalate

Table 13 shows the percent inhibition results ( calculated crystal growth of only about 58 % . as median and average ) and the ingredient weights for Matrix 3 ( citric acid , magnesium citrate , pyridoxine , and Table 14 shows the percent inhibition results ( calculated musa ) Test Solutions 1 through Test Solution 6 . as median and average ) and the ingredient weights for



Matrix 3

Test Test Test Test Test Test Solution 1 Solution 2 Solution 3 Solution 4 Solution 5 Solution 6 mg mg mg mg mg mg Ingredient

101 77

Citric Acid Mg Citrate Pyridoxine Musa Median % inhibition Average % inhibition

352 153

5 . 41 251 87 . 12 82 . 52

10 . 23 252 66 . 15 75 . 62

1051 2 . 14 5 . 95

167 67 . 50 67 . 83

700 226

2 . 63 85 62 . 09 55 . 41

353 202

0 . 25 41 . 02 72 . 59 69 . 10

176 151 15 . 14

1 . 41 58 . 04 40 . 92

The results in Table 13 show that compositions where citric acid is present in an amount of about 101 mg to about

Matrix 4 ( citric acid , phytin , pyridoxine , and musa ) Test Solutions 1 through Test Solution 6 .

TABLE 14

Matrix 4 Test Solution Ingredient Amounts and Median and Mean Percent Inhibition of Calcium Oxalate Crystal Growth

Matrix 4

Test Test Test Test Test Test Solution 1 Solution 2 Solution 3 Solution 4 Solution 5 Solution 6 mgmgmgmgmgmg Ingredient

Citric Acid Phytin Pyridoxine Musa Median % inhibition Average % inhibition

353 353 203

5 . 45 252 252 108 . 82 114 . 84

101 1011050700352177 1050 700 352 177 202 101 3 . 01 600 400 10 . 20 6 2 . 69 0 . 23 15 . 12

252 252 167 167 86 86 41 41 1 . 46 1 . 46 109 . 76 100 . 14 87 . 86 135 . 82 142 . 55 112 . 88 109 . 40 85 . 49 135 . 85 147 . 32

US 9 , 789 , 152 B2 35 36

are blended in the indicated amounts and deposited into a hard shell capsule , e . g . , a hydroxypropyl methylcellulose ( HPMC ) capsule , such as a DRcapTM ( Capsugel® , Morris town , N . J . ) .

TABLE 17

Matrix 1 Oral Capsule

The results in Table 14 show that compositions wherein citric acid is present in an amount of about 101 mg to less than about 700 mg , phytin is present in an amount of about 101 mg to about 600 mg , pyridoxine is present in an amount of about 0 . 23 mg to about 15 . 12 mg , and musa is present in 5 an amount of about 1 . 46 mg to about 252 mg result in a median percent inhibition of calcium oxalate crystal growth of at least about 100 % , while compositions citric acid , phytin , pyridoxine , and musa concentrations outside these ranges are unexpectedly much less effective , resulting in 10 median percent inhibition of calcium oxalate crystal growth of only about 88 % .

Table 15 shows the percent inhibition results ( calculated as median and average ) and the ingredient weights for Matrix 5 ( magnesium citrate , phytin , pyridoxine and musa ) 15 Test Solutions 1 through Test Solution 6 .

Ingredient Amount

Citric Acid Mg Citrate Phytin Pyridoxine

about 101 mg to about 699 mg about 77 mg to about 227 mg about 3 . 06 mg to about 600 mg about 0 . 23 mg to about 15 . 13 mg



Matrix 5

Test Test Test Test Test Test Test Solution 1 Solution 2 Solution 3 Solution 4 Solution 5 Solution 6 Solution 7 mg mgmgmgmgmg mg mg mg mg mg mg Ingredient mg mg

151 77 201

203 600

0 . 22

Magnesium Citrate Phytin Pyridoxine Musa Median % Inhibition Average % Inhibition

202 5 . 4

252 109 . 67 107 . 50

2 . 03 2 . 03 100

6 . 01 168 109 . 01 111 . 86

10 . 11 252 106 . 60 116 . 33

226 226 3 . 02 2 . 69

85 98 . 56 99 . 83

201 201 475

0 . 25 42 160 . 67 149 . 25

151 400 15 . 1

1 . 46 136 . 76 139 . 28

41 104 . 21 107 . 18

TABLE 18

Matrix 2 Oral Capsule

Ingredient Amount

The results in Table 15 show that compositions wherein magnesium citrate is present in an amount of about 2 . 03 mg 35 to 203 mg , phytin is present in an amount of about 100 mg to about 600 mg , pyridoxine is present in an amount of about 0 . 22 mg to about 15 . 1 mg , and musa is present in an amount of about 1 . 46 mg to about 252 mg result in a median percent inhibition of calcium oxalate crystal growth of at least about 40 104 % , while compositions magnesium citrate , phytin , pyri doxine , and musa concentrations outside these ranges are unexpectedly much less effective , resulting in median per cent inhibition of calcium oxalate crystal growth of only about 98 % . 45 -

Citric Acid Mg Citrate Phytin

about 102 mg to about 1052 mg about 2 . 32 mg to about 201 mg about 100 mg to about 600 mg about 1 . 51 mg to about 251 mg Musa

45

Example 2 TABLE 19

Oral Dosage Forms Matrix 3 Oral Capsule 50

Ingredient Amount TABLE 16

Five Ingredient Oral Capsule Citric Acid Mg Citrate Pyridoxine Musa

about 101 mg to about 1051 mg about 2 . 14 mg to about 226 mg about 0 . 25 mg to about 10 . 23 mg about 41 . 02 mg to about 252 mg Ingredient Amount

Citric Acid Mg Citrate Phytin Pyridoxine Musa

about 101 mg to about 700 mg about 76 mg to about 226 mg about 3 mg to about 600 mg about 0 . 1 mg to about 15 mg about 1 mg to about 251 mg

TABLE 20

Matrix 4 Oral Capsule 60

Ingredient Amount The five active ingredients are blended in the above amounts and deposited into a hard shell capsule , e . g . , a hydroxypropyl methylcellulose ( HPMC ) capsule , such as a DRcapTM ( Capsugel® , Morristown , N . J . ) . 65

Tables 17 - 21 below provide additional oral capsule for mulations . In each formulation , the four active ingredients

Citric Acid Phytin Pyridoxine Musa

about 101 mg to less than about 700 about 101 mg to about 600 mg about 0 . 23 mg to about 15 . 12 mg about 1 . 46 mg to about 252 mg

US 9 , 789 , 152 B2 38

TABLE 21 Embodiment 9 Matrix 5 Oral Capsule

Ingredient Amount

Magnesium Citrate Phytin Pyridoxine Musa

about 2 . 03 mg to 203 mg about 100 mg to about 600 mg about 0 . 22 mg to about 15 . 1 mg about 1 . 46 mg to about 252 mg

The oral dosage form or plurality of dosage forms accord ing to embodiment 8 wherein pyridoxine is present in an amount selected from : about 0 . 2 mg to about 10 mg , about 0 . 2 mg to about 6 mg , about 0 . 2 mg to about 2 . 7 mg , about 2 . 7 mg to about 15 mg , about 6 . 0 mg to about 15 mg , and about 10 mg to about 15 mg .

Embodiment 10 Set forth below are some embodiments of the oral dosage forms and methods for disclosed herein .

Sage 10

Embodiment 1 The oral dosage form or plurality of dosage forms of

embodiment 1 , wherein musa is present in amount of about 1 mg to about 251 mg . 15

Embodiment 11 An oral dosage form or a plurality of dosage forms comprising as active ingredients citric acid , magnesium citrate , phytin , pyridoxine , and musa .

Embodiment 2 The oral dosage form or plurality of dosage forms accord

ing to embodiment 10 wherein musa is present in an amount selected from : about 1 mg to about 167 mg , about 1 mg to about 85 mg , about 1 mg to about 41 mg , about 41 mg to about 251 mg , about 85 mg to about 251 mg , and about 167 mg to about 251 mg .

The oral dosage form or plurality of dosage forms of embodiment 1 , wherein citric acid is present in an amount of about 101 mg to about 700 mg .

25

Embodiment 3 Embodiment 12

The oral dosage form or plurality of dosage forms accord - The oral dosage form or plurality of dosage forms of ing to embodiment 2 wherein citric acid is present in an embodiment 1 wherein citric acid is present in an amount of amount selected from : about 101 mg to about 352 mg , about 30 about 101 mg to about 700 mg ; magnesium citrate is present 101 mg to about 176 mg , about 176 mg to about 700 mg , and in an amount of about 76 mg to about 226 mg ; phytin is about 352 mg to about 700 mg . present in an amount of about 3 mg to about 600 mg ;

pyridoxine is present in an amount of about 0 . 1 mg to about Embodiment 4 15 mg ; and musa is present in amount of about 1 mg to about

35 251 mg . The oral dosage form or plurality of dosage forms of

embodiment 1 , wherein magnesium citrate is present in an Embodiment 13 amount of about 76 mg to about 226 mg . The oral dosage form or plurality of dosage forms accord

Embodiment 5 40 ing to embodiment 12 wherein citric acid is present in an amount selected from : about 51 mg to about 352 mg , about

The oral dosage form or plurality of dosage forms accord - 101 mg to about 176 mg , about 176 mg to about 700 mg , and ing to embodiment 4 wherein magnesium citrate is present about 352 mg to about 700 mg ; magnesium citrate is present in an amount selected from : about 76 mg to about 201 mg , in an amount selected from : about 76 mg to about 201 mg , about 76 mg to about 150 mg , about 150 to about 226 mg . 45 about 76 mg to about 150 mg , about 150 to about 226 mg , and about 201 mg to about 225 mg . and about 201 mg to about 225 mg ; phytin is present in an

amount selected from : about 3 mg to about 400 mg , about Embodiment 6 3 mg to about 202 mg , about 3 mg to about 100 mg , about

100 mg to about 600 mg , about 200 mg to about 600 mg , and The oral dosage form or plurality of dosage forms of 50 about 400 mg to about 600 mg ; pyridoxine is present in an

embodiment 1 , wherein phytin is present in an amount of amount selected from : about 0 . 2 mg to about 10 mg , about about 3 mg to about 600 mg . 0 . 2 mg to about 6 mg , about 0 . 2 mg to about 2 . 7 mg , about

2 . 7 mg to about 15 mg , about 6 . 0 mg to about 15 mg , and Embodiment 7 about 10 mg to about 15 mg ; and musa is present in an

55 amount selected from : about 1 mg to about 167 mg , about The oral dosage form or plurality of dosage forms accord - 1 mg to about 85 mg , about 1 mg to about 41 mg , about 41

ing to embodiment 6 wherein phytin is present in an amount mg to about 251 mg , about 85 mg to about 251 mg , and selected from : about 3 mg to about 400 mg , about 3 mg to about 167 mg to about 251 mg . about 202 mg , about 3 mg to about 100 mg , about 100 mg to about 600 mg , about 200 mg to about 600 mg , and about 60 Embodiment 14 400 mg to about 600 mg .

The oral dosage form or plurality of dosage forms of Embodiment 8 embodiment 1 , wherein the amount of one of the active

ingredients is selected from : citric acid is present in an The oral dosage form or plurality of dosage forms of 65 amount of about 101 mg to about 700 mg ; magnesium citrate

embodiment 1 , wherein pyridoxine is present in an amount is present in an amount of about 76 mg to about 226 mg ; of about 0 . 2 mg to about 15 mg . phytin is present in an amount of about 3 mg to about 600

hayer et al . ( 45 ) date of patent : * oct . 17 , 2017 · u . s . c . 154 ( b ) by 0 days . this...

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