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Solid self-emulsifying drug delivery systems/Asian Journal of Pharmaceutical Sciences 2009, 4 (4): 240-253 240 1 Approaches for the development of solid self-emulsifying drug delivery systems and dosage forms Suman Katteboina a, * , V S R Chandrasekhar. P b , Balaji. S c a Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur Dist, Andhra Pradesh, India–522101 b Department of Pharmaceutics, Hindu College of Pharmacy, Amaravathi road, Guntur, Andhra Pradesh, India–522002 c Department of Pharmaceutics, University College of Pharmaceutical Sciences, Andhra University, India–530003 Received 2 March 2009; Revised 15 June 2009; Accepted 12 July 2009 _____________________________________________________________________________________________________________ Abstract As a consequence of modern drug discovery techniques, there has been a steady increase in the number of new pharmacologically active lipophilic compounds that are poorly water-soluble. It is a great challenge for pharmaceutical scientists to convert those molecules into orally administered formulations with sufficient bioavailability. Among the approaches to improve the oral bioavailability of these molecules, the use of self-emulsified drug delivery systems (SEDDS) has been shown to be reasonably successful in improving the oral bioavailability of poorly water-soluble and lipophilic drugs. The present review examines the recent advances in Solid SEDDS (S-SEDDS) with regard to the selection of lipid systems for current formulations, solidification techniques and the development of solid SE (self-emulsifying) dosage forms and their related problems and possible future research directions. Keywords: Lipid-based formulation; Self-emulsifying drug delivery system; Lipid formulation classification system; Excipient; Surfactant; Self-dispersion _____________________________________________________________________________________________________________ 1. Introduction The oral route has been the major route of drug deli- very for the chronic treatment of many diseases. Nearly 40% of new drug candidates exhibit low solubility in water, which leads to poor oral bioavailability (BA), high intra-and inter-subject variability, and lack of dose proportionality. Thus, for those drugs, the absorption rate from the lumen of the gastrointestinal tract (GI) is controlled by dissolution [1-2]. Hence, producing suitable formulations is essential to improve the solu- bility and bioavailability of such drugs. One of the most popular and commercially viable formulation approaches for solving these problems is self-emulsifying drug deli- very systems (SEDDS) which have attracted considerable attention from pharmaceutical scientists who want to increase the oral bioavailability of such poorly water- soluble drugs. So, we have prepared this review to describe a number of aspects of self-emulsifying drug delivery systems. Self-emulsifying drug delivery systems (SEDDS) or self-emulsifying oil formulations (SEOF) are defined as isotropic mixtures of natural or synthetic oils, solid or liquid surfactants or, alternatively, one or more hydrophilic solvents, and co-solvents/surfactants [3-8]. These systems have a unique property: they are able to self-emulsify rapidly in gastro-intestinal fluids and, under the gentle agitation provided by the motion of the gastro-intestinal tract, they form fine O/W emulsions. These fine O/W emulsions produce small droplets of oil dispersed in the gastro-intestinal fluids that provide a large interfacial area increasing the activity of pan- creatic lipase to hydrolyze triglycerides and, thereby, promote a faster release of the drug and/or formation of mixed micelles of the bile salts containing the drug. Furthermore, in most cases the surfactant used for such formulations increases the bioavailability of the drug by activation of different mechanisms, maintaining the drug in solution and, thus, avoiding the dissolution step from the crystalline state and enhancing intestinal epithelial permeability at the same time. Moreover, the __________ *Corresponding author. Address: Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur Dist, Andhra Pradesh, India–522101. Tel.: +91-9177986966; Fax: +91-9490263657 E-mail: [email protected]

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Approaches for the development of solid self-emulsifying drug delivery systems and dosage forms

Suman Katteboinaa, *, V S R Chandrasekhar. Pb, Balaji. Sc

aDepartment of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur Dist, Andhra Pradesh, India–522101bDepartment of Pharmaceutics, Hindu College of Pharmacy, Amaravathi road, Guntur, Andhra Pradesh, India–522002

cDepartment of Pharmaceutics, University College of Pharmaceutical Sciences, Andhra University, India–530003Received 2 March 2009; Revised 15 June 2009; Accepted 12 July 2009

_____________________________________________________________________________________________________________

Abstract

As a consequence of modern drug discovery techniques, there has been a steady increase in the number of new pharmacologically active lipophilic compounds that are poorly water-soluble. It is a great challenge for pharmaceutical scientists to convert those molecules into orally administered formulations with sufficient bioavailability. Among the approaches to improve the oral bioavailability of these molecules, the use of self-emulsified drug delivery systems (SEDDS) has been shown to be reasonably successful in improving the oral bioavailability of poorly water-soluble and lipophilic drugs. The present review examines the recent advances in Solid SEDDS (S-SEDDS) with regard to the selection of lipid systems for current formulations, solidification techniques and the development of solid SE (self-emulsifying) dosage forms and their related problems and possible future research directions.

Keywords: Lipid-based formulation; Self-emulsifying drug delivery system; Lipid formulation classification system; Excipient; Surfactant; Self-dispersion_____________________________________________________________________________________________________________

1. Introduction

The oral route has been the major route of drug deli-very for the chronic treatment of many diseases. Nearly 40% of new drug candidates exhibit low solubility in water, which leads to poor oral bioavailability (BA), high intra-and inter-subject variability, and lack of dose proportionality. Thus, for those drugs, the absorption rate from the lumen of the gastrointestinal tract (GI)is controlled by dissolution [1-2]. Hence, producing suitable formulations is essential to improve the solu-bility and bioavailability of such drugs. One of the mostpopular and commercially viable formulation approachesfor solving these problems is self-emulsifying drug deli-very systems (SEDDS) which have attracted considerableattention from pharmaceutical scientists who want to increase the oral bioavailability of such poorly water-soluble drugs. So, we have prepared this review to

describe a number of aspects of self-emulsifying drug delivery systems.

Self-emulsifying drug delivery systems (SEDDS) or self-emulsifying oil formulations (SEOF) are defined as isotropic mixtures of natural or synthetic oils, solid or liquid surfactants or, alternatively, one or more hydrophilic solvents, and co-solvents/surfactants [3-8].

These systems have a unique property: they are able to self-emulsify rapidly in gastro-intestinal fluids and, under the gentle agitation provided by the motion of the gastro-intestinal tract, they form fine O/W emulsions. These fine O/W emulsions produce small droplets of oil dispersed in the gastro-intestinal fluids that providea large interfacial area increasing the activity of pan-creatic lipase to hydrolyze triglycerides and, thereby, promote a faster release of the drug and/or formation of mixed micelles of the bile salts containing the drug. Furthermore, in most cases the surfactant used for such formulations increases the bioavailability of the drug by activation of different mechanisms, maintaining the drug in solution and, thus, avoiding the dissolution step from the crystalline state and enhancing intestinal epithelial permeability at the same time. Moreover, the

__________*Corresponding author. Address: Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur Dist, Andhra Pradesh, India–522101. Tel.: +91-9177986966; Fax: +91-9490263657 E-mail: [email protected]

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oil droplets lead to a faster and more uniform distribu-tion of the drug in the gastrointestinal tract, minimizing the irritation due to contact between the drug and the gutwall [3-6]. In addition, lipids affect the oral bioavaila-bility of drugs by exerting their effect through several mechanisms, including protection of the drug from enzymatic or chemical degradation in the oil droplets and activation of lipoproteins promoting the lymphatic transport of lipophilic drugs [9].

These systems may then be incorporated into capsules directly, or transformed into granules, pellets, and powders for dry filled capsules as well as tablet preparations. The latter option is possible by innovative adaptations of conventional equipment with relative ease and process simplicity, using methods like melt granulation, adsorption on a solid support, spray drying, spray cooling, melt-extrusion/spheronization, and super-critical fluid based methods. SEDDS typically produce emulsions with a droplet size between 100 and 300 nm,

while SMEDDS (self-micro-emulsifying drug delivery systems) form transparent micro emulsions with a droplet size of less than 50 nm. When compared with emulsions, which are sensitive and metastable dispersed forms, SEDDS are physically stable formulations that are easy to manufacture. Thus, for lipophilic drugs that exhibit dissolution rate-limited absorption, these systems offer an improved rate and extent of absorption, resulting in more reproducible blood-time profiles.

2. Lipid formulation classification system (LFCS)

LFCS was established by Pouton in 2000 and recently updated in 2006 to help stratify formulations into those with similar component parts [10]. The LFCS briefly classifies lipid-based formulations into four types according to their composition and the possible effect of dilution and digestion on their ability to prevent drug precipitation and they are shown in Table 1.

Increasing Hydrophilic Content →

Typical composition (%) Type I Type II Type IIIA Type IIIB Type IV

Triglycerides or mixed glycerides 100 40–80 40–80 < 20 —

Water-insoluble surfactants (HLB < 12) — 20–60 — — 0–20

Water-soluble surfactants (HLB > 12) — — 20–40 20–50 30–80

Hydrophilic cosolvents — — 0–40 20–50 0–50

Particle size of dispersion 100–250 (nm) Coarse 100–250 100–250 50– 100 < 50

Significance of aqueous dilution Limited Importance Solvent capacity

unaffected Some loss of

solvent capacity

Significant phase changes and

potential loss of solvent capacity

Significant phase changes and potential

loss of solvent capacity

Significance of digestibility Crucial Requiremet Not crucial but

likely to occurNot crucial but

may be inhibited Not required Not required

AdvantagesGRAS status; simple;

excellent capsule compatibility

Unlikely to lose solvent capacity

on dispersion

Clear or almost clear dispersion; drug

absorption without digestion

Clear dispersion; drug absorption

without digestion

Formulation has good solvent capacity for

many drugs

DisadvantagesFormulation haspoor

solvent capacity unless drug is highly lipophilic

Turbid o/w dispersion (particle

size 0.25–2 μm)

Possible loss of solvent capacity on dispersion;

less easily digested

likely loss of solvent capacity on

dispersion

Likely loss of solvent capacity on dispersion; may not be digestible

Table 1Lipid formulation classification system (LFCS) as described by Pouton showing typical compositions and properties of lipid-based formulations [9, 14].

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2.1. Type I - Non-dispersing systems

Type I systems consist of formulations where the drugis in a solution of triglycerides and/or mixed glyceridesor in an oil-in-water emulsion stabilised by low concen-trations of emulsifiers such as 1% w/v polysorbate 60 [11] and 1.2% w/v lecithin [12]. These systems exhibit poor initial aqueous dispersion and require digestion by pancreatic lipase/co-lipase in the GIT to generate more amphiphilic lipid digestion products and promote drug transfer into the colloidal aqueous phase. Type I lipid formulations represent a relatively simple formulation option for potent drugs or highly lipophilic compounds where drug solubility in oil is sufficient to allow incor-poration of the required “payload” dose.

2.2. Type II-SEDDS: non-water soluble component systems

Type II lipid formulations, referred as a self-emulsify-

ing drug delivery systems, (SEDDS) are isotropic mix-tures of lipids and lipophilic surfactants with HLB < 12 that self-emulsify to form fine oil-in-water emulsions in aqueous media [13-14]. Self-emulsification is generally obtained at a surfactant content above 25% w/w. However, at a surfactant content of 50-60% w/w, the emulsification process may be compromised by the formation of viscous liquid crystalline gels at the oil/water interface [14-15]. Poorly water-soluble drugs (PWSD) can be dissolved in SEDDS and encapsulated in hard or soft gelatin capsules to produce convenient single unit dosage forms. Type II lipid-based formula-tions offer the advantage of overcoming the slow dissolution step typically observed with solid dosage forms and, as described above, and they are able to generate large interfacial areas which in turn allow effi-cient partitioning of drug between the oil droplets and the aqueous phase from which absorption occurs [16].

2.3. Type III-SEDDS: water soluble component systems

Type III lipid-based formulations, commonly referredto as self-microemulsifying drug delivery systems

(SMEDDS), are defined by the inclusion of hydrophilic surfactants with HLB > 12 and co-solvents such as ethanol, propylene glycol and polyethylene glycol. Type III formulations can be further divided into Type IIIA and Type IIIB formulations in order to identify more hydrophilic systems. In Type IIIB, the content of hydro-philic surfactants and co solvents is increased and thelipid content is reduced. Type IIIB formulations typicallyachieve greater dispersion rates when compared with Type IIIA although the risk of drug precipitation on dispersion of the formulation is higher owing to the lower lipid content. The distinction between SEDDS (Type II) and SMEDDS (Type III) formulations is alsocommonly made based on the particle size and optical clarity of the resultant dispersion. Thus, SEDDS formu-lations typically provide opaque dispersions with particlesizes > 100 nm whereas SMEDDS formulations (which contain higher concentrations of hydrophilic surfactants and co-solvents) disperse to give smaller droplets with particle sizes < 100 nm, and provide optically clear or slightly opalascent dispersions, more consistent with the presence of a microemulsion. However, rigorous evaluation of the presence of a true microemulsion rather than an emulsion with very small particle size is rarely attempted.

SEDDS and SMEDDS formulations have contributed to the improvement of the oral bioavailability of several PWSD and some of examples summarised in Table 2. Perhaps the best known example of a successfully marketed SMEDDS formulation is the Neoral cyclo-sporine formulation that consists of corn oil-derived MG, DG and TG as a lipid phase, Cremophor RH40 (polyoxyl 40 hydrogenated castor oil) as a surfactant, propylene glycol and ethanol as co solvents and DL-α-tocopherol as an antioxidant. In contrast to the earlier Sandimmun cyclosporin formulation consisting of cornoil, polyoxyethylated glycerides (labrafil M-2125-CS and ethanol [29] which form a coarse emulsion on dispersion in water, Neoral spontaneously forms a transparent and thermodynamically stable dispersion with a droplet size below 100 nm when introduced into an aqueous medium [31, 23]. The improved dispersion characteristics of Neoral have been suggested to be

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responsible for the increased absorption and reduction in inter- and intra-patient variability in bioavailability obtained following oral administration of Neoral to healthy volunteers, when compared with Sandimmun [32, 34, 24 25].

However, recent suggestions of a possible inhibitory effect of some lipid excipients, like polyoxyethylene sorbitan fatty acid esters, polyoxyethoxylated castor oil and D-α-tocopheryl polyethylene glycol 1000 succinate, on CYP3A and P-gp functionality involve the increase in bioavailability observed after oral administration of Neoral and many other SMEDS formulations.

2.4. Type IV-dispersion systems: non-oil micellar Systems

The type IV category was recently added to the LipidFormulation Classification System [30]. Type IV formu-lations do not contain natural lipids and represent the most hydrophilic formulations. These formulations commonly offer increased drug payloads due to higher drug solubility in the surfactants and co-solvents. Whencompared with formulations containing simple glyceridelipids they also produce very fine dispersions when intro-duced in aqueous media. It has been suggested that they

Compound Formulation (s) Study design Observations Ref.

Win 54954 SEDDS (35% drug, 40% Neobee M5 (MCT) and 25% Tagat TO) or PEG 600 solution

Relative BA in dogs

No difference in BA but Improved reproducibility, increased Cmax

[16]

Cyclosporine

Sandimmum (SEDDS: corn oil and ethanol) or neoral (SMEDDS: Corn oil glycerides, Cremoph or RH40, PG,

DL-a-toco pherol and ethanol)

Relative BA in humans

Increased BA and Cmax and reduced tmax from SMEDDS [17]

Sandimmum (SEDDS) or neoral (SMEDDS) Relative BA in humans

Increased Cmax, AUC and dose linearity reduced food effect from

SMEDDS [18]

Sandimmum (SEDDS) or neoral (SMEDDS) Relative BA in humans

Reduced intra and inter subject variability from SMEDDS [19]

OntazolastSoybean oil emuls ion drug solution in peceol drug suspension or two semi-solid SEDDS consisting of

gelucrie 44/14 and peceol in the ratios 50: 50 and 80: 20

Absolute BA in rats

BA increases of at least 10-fold from all lipid based formulations [20]

Vitamin E SEDDS (Tween 80: Span 80: palm oil (LCT ) in a 4:2:4 ratio) or soybean oil (LCT) solution

Relative BA in humans BA 3-fold higher from SEDDS [21]

Coenzyme Q10 SMEDDS (40% Myvacet 9-45, 50% labrasol and 10% lauro glycol) or powder formulation

Relative BAin dogs BA 2-fold higher from SEDDS [22]

Simvastatin SMEDDS (37% Cap ryol90 28% cremophor EL, 28% Carb itol) or tablet

Relative BA in dogs BA 1.5-fold higher from SEDDS [23]

Carvedilol SEDDS (labrafil M1944CS, Tween 80 and Transcutol) and tablets

Relative BA in dogs BA 4-fold higher from SEDDS [24]

Tocotrienols Two SEDDS (Tween 80 and labrasol) or LCT solution Relative BA in humans

BA 2 to 3 fold higher from SEDDS [25]

Biphenyl dimethyl dicarboxylate

SEDDS (43% Tween 80, 35% triacetin and 22% Neobee M-5 (MCT)) or powder formulation

Relative BA in rats BA 5-fold higher from SEDDS [26]

Indomethacin SEDDS (70% ethyl oleate and 30% Tween 85 ) or powder formulation

Relative BA in rats

BA significantly increased from SEDDS [27]

Table 2Examples of studies describing the bioavailability enhancement of PWSD after administration of SEDDS and SMEDDS formulations.

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produce rapid drug release and increased drug absorp-tion. However, little is known about the solubilisation capacity of these systems in vivo and, in particular, whether they are equally capable of maintaining PWSDin solution during passage along the GIT when comparedwith formulations consisting of natural oils (Type II and Type III). An example of a Type IV formulation is the current capsule formulation of the HIV protease inhibitor amprenavir (Agenerase) which contains TPGS as a surfactant and PEG 400 and propylene glycol as co-solvents.

3. Solid self-emulsifying drug delivery system (S-SEDDS)

3.1. Definition

SEDDS can exist in either liquid or solid states. However, SEDDS are usually limited to liquid dosage forms because many excipients used in SEDDS are not solids at room temperature. Given the advantages of solid dosage forms, S-SEDDS have been extensively exploited in recent years as they are frequently more effective alternatives to conventional liquid SEDDS. In the 1990s, S-SEDDS were usually in the form of SE (self emulsifying) capsules, SE solid dispersions and dry emulsions, but other solid SE dosage forms have emerged in recent years, such as SE pellets/tablets, SE beads, microspheres/nanoparticles and SE suppositories/implants.

3.2. Solidification techniques

The main techniques for transforming liquid and semi-solid formulations into solid lipid-based particles or granules are spray-cooling, spray drying, adsorption onto solid carriers, melt granulation, melt extrusion,super-critical fluid based methods and high pressure homogenization (to produce solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC)). Each of these techniques is described here along with a discussion of current practices pertaining to bioavailability enhance-ment with lipids. Whereever possible, the advantages

and limitations of the technique are also presented. Thesetechniques are listed in Table 3 according to the physicalnature of the excipients used, the lipid exposure capacity, and the maximum drug loading.

3.2.1. Spray cooling

Spray cooling, also referred to as spray congealing, is a process whereby the molten formula is sprayed into a cooling chamber and, upon contact with the cooling air, the molten droplets congeal and re-crystallize intospherical solid particles that fall to the bottom of the chamber and can subsequently be collected as fine powder. The fine powder may then be used for develop-ment of solid dosage forms such as tablets or capsules.

Equipment like rotary, pressure, two-fluid or ultra-sonic atomizers are available to atomize the liquid mixture and to generate droplets [31]. Most of the recentresearch conducted on spray cooling with lipid-basedexcipients used ultrasonic atomizers. The main classs ofexcipient used with this technique are polyoxylglycerides and, more specifically, stearoyl polyoxylglycerides Gelucire® 50/13 facilitating the production of micro-particles with a narrow size distribution that exhibit signi-nificantly enhanced drug release profiles for poorlysoluble drugs such as diclofenac or praziquantel [32-33].

3.2.2. Spray drying

Essentially, this technique involves the preparation of a formulation by mixing lipids, surfactants, drug, solidcarriers, and solubilisation of the mixture before spraydrying. The solubilized liquid formulation is then ato-mized into a spray of droplets which are introduced into a drying chamber; the volatile phase (water contained in an emulsion) evaporates, forming dry particles under controlled temperature and airflow conditions. Such particles can be further processed into tablets or capsules. The atomizer, the temperature, the most suitable airflow pattern and the drying chamber design are selected according to the drying characteristics of the product and powder specifications. Spray drying has been employed to prepare dry emulsions by removing water

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from an ordinary emulsion containing a water-soluble solid carrier. The solid SMEDDS was prepared by spray-drying the liquid SMEDDS in a laboratory spray dryer, using dextran as a solid carrier for nimodipine [34].

3.2.3. Adsorption to solid carriers

Free flowing powders may be obtained from liquid SE formulations (LSEF) by adsorption to solid carriers. The adsorption process is simple and involves only addition of the liquid formulation to carriers by mixing in a blender. The resulting powder may then be filled directly into capsules or, alternatively, mixed with suitable excipients before compression into tablets. A significant benefit of the adsorption technique is good content uniformity. SEDDS can be adsorbed at high levels up to 70% w/w onto suitable carriers [35]. Solid carriers can be microporous inorganic substances, high surface-area colloidal inorganic adsorbent substances, cross-linked polymers or nanoparticle adsorbents. For example, silica, silicates, magnesium trisilicate, magne-sium hydroxide, talcum, crospovidone, cross-linked sodium carboxymethyl cellulose and crosslinked poly-methyl methacrylate are typical solid carriers [36]. Cross-linked polymers create a favourable environment to sustain drug dissolution and also assist in slowing down

drug reprecipitation [37]. Nanoparticle adsorbents include porous silicon dioxide (Sylysia 550), carbon nanotubes, carbon nanohorns, fullerene, charcoal and bamboo charcoal [38]. The adsorption technique has been successfully applied to gentamicin and erythropoietin with caprylocaproyl polyoxylglycerides (Labrasol®) formulations that maintain their bioavailability-enhanc-ing effect after adsorption on carriers.

At present, colloidal silicon dioxide is widely used as a adsorbing agent for various drugs like ketoprofen, ezetimibe, and Siramesine hydrochloride. It has been reported that porous polystyrene beads can be used as carriers for a self-emulsifying system containing lorata-dine. Silicone dioxide has been used as an adsorption carrier for ketoprofen. It is also currently used in formu-lations of drugs like ketoprofen, ezetimibe, siramesine hydrochloride, and gentamicin.

3.2.4. Melt granulation

Melt granulation is a process in which powder agglo-meration is obtained through the addition of a binder that melts or softens at relatively low temperatures. As a ‘one-step’ operation, melt granulation offers severaladvantages compared with conventional wet granulation, since liquid addition and the subsequent drying phase

Formulation techniques for solid and semi-solid formulations

Physical property of the lipid excipients applied Formulations advantages and limits

Liquid tosolid Semi-solid

Maximum lipid Maximum drug

Lip exposure* (%, w/w) Loading (%, w/w)

Capsule filling X X 99 50

Spray-cooling X 99 30

Spray drying X X 60 50

Adsorption on solid carrier X 80 10

Melt granulation X 50 80

Melt extrusion X 50 60

Super critical fluid based methods X 99 20

Solid lipid nanoparticles X X 99 50

Table 3Considerations in selection of formulation techniques for bioavailability enhancement with lipid-based excipients.

*Percentage calculated after evaporation of solvent where applicable.

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are omitted. Moreover, it is also a good alternative to the use of solvent. The melt granulation technique, also described as “thermoplastic pelletization”, is easily adapt-able to lipid-based excipients that exhibit thermoplastic properties. A wide range of solid and semi-solid lipids can be used as a meltable binder for solid dispersions. Generally, lipids with a low HLB and high melting point are suitable for sustained release applications. Semi-solidexcipients with high HLB, on the other hand, may be used for immediate release and bioavailability enhancement.

Of these, Gelucire1, a family of vehicles derived frommixtures of mono-/di-/tri-glycerides and polyethylene glycols (PEG) esters of fatty acids, is able to further increase the dissolution rate compared with PEG. This is probably because of its SE ability [39]. Other lipid-based excipients evaluated for melt granulation to create solid SES include lecithin, partial glycerides, or polysorbates. The melt granulation process is usually used for adsorbing SES onto solid neutral carriers like silica and magnesium alumino meta-silicate [40-41].The main parameters that control the granulation processare the impeller speed, mixing time, binder particle size, and the viscosity of the binder.

3.2.5. Melt extrusion/extrusion spheronization

Melt extrusion is a solvent-free process that allows high drug loading up to 60% [42], as well as content uniformity. Extrusion is a procedure in which a raw material with plastic properties is converted into a product of uniform shape and density, by forcing it through a die under controlled temperature, product flow, and pressure conditions [43]. The size of the extruder aperture determines the approximate size of the result-ing spheroids. The extrusion-spheronization process is commonly used in the pharmaceutical industry to make uniformly sized spheroids (pellets).

Ubiquinone has been formulated as eutectic-based solid self-nanoemulsifying drug delivery systems (SNEDDS) and then tablets can be prepared by extrusionspheronization using MCC malt dextrin and copolyvi-done [44]. The bioavailability of propranolol was

improved by preparing a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extrudedethylcellulose pipe surrounding a drug-containing HPMC-Gelucire® 44/14 core [45]. This approach has been successfully applied to 17β-estradiol and two modeldrugs (methyl and propyl parabens) with surfactants suchas sucrose monopalmitate (Surfhope® D-1616), lauroylpolyoxylglycerides (Gelucire®™ 44/14) and polysorbate80 (Tween® 80) [46]. Applying extrusion-spheroniza-tion, SE pellets of diazepam and bi-layered cohesive SE pellets have been prepared [47-48].

3.2.6. Supercritical fluid based methods

Lipids may be used in supercritical fluid based methodseither for coating of drug particles, or for producing solid dispersions. The coating process entails dispersing the drug particles as powder in a supercritical fluid containing one or more dissolved coating materials. The solubility of the coating material(s) is sustained initially by elevated pressure and temperature condi-tions. The coating process is subsequently facilitated by a gradual reduction in pressure and temperature leading to reduced solubility of the coating material in the supercritical fluid allowing gradual deposition onto the drug particles, to form coating layer(s). The supercritical fluid of choice is supercritical carbon dioxide [49-50]. The process for obtaining solid particles entails dissolv-ing the drug and lipid-based excipient(s) in an organic solvent such as methanol and then in a supercritical fluid, followed by lowering the temperature and pressure conditions to reduce their solubility in the fluid [51-53]. Examples of lipid-based or lipid-related excipients thathave been studied with this process for controlled-releaseapplications include glyceryl trimyristate (Dynasan™ 114) and stearoyl polyoxylglycerides (Gelucire® 50/02) [49-50]. More recently, the technique has been success-fully applied for bioavailability enhancement of carba-mazepine using Vitamin E TPGS and Gelucire® 44/14) [50-52]. The important considerations with this formula-tion technique are i) the solubility of the formulation components in the supercritical fluid, ii) the integrity/stability of the active substance under the process

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conditions, and iii) the energy or environmental concernsrelating to the evaporation of solvents if applicable. Compared with other methods, it has one of the highest potentials for lipid exposure and a relatively lower drug loading capacity and so is best suited for highly potent, low-dose drugs.

3.2.7. Solid lipid nanoparticles (SLN) and nano-structured lipid carriers (NLC)

SLN and NLC are two types of submicron sizedparticles between 50–1000 nm composed of physio-logically tolerated lipid components which are in the solid state at room temperature. These submicron carriers can be classified according to their inner structure: SLN have a solid core while NLC have a liquid core. The classic components of SLN are glyceryl dibehenate (Compritol® 888 ATO) as solid lipid matrix and poloxa-mers 188 (Pluronic® F68) or polysorbates 80 (Tween® 80) as surfactant. SLN are produced by high-pressure homogenization of the solid matrix and drug with an aqueous solution of the aforementioned surfactants. NLC, on the other hand, are reservoir systems derived from SLN to increase the drug loading capacity inside the system. They typically contain a liquid lipid exci-pient, such as medium chain triglycerides, in addition to the classic SLN components. They have been mainly used for controlled-release applications via the oral [54], intravenous [55] or topical route [56-60]. SLN offer unique advantages in that they can be prepared free of organic solvents and with a wide range of lipid excipientswith different properties, applied to drugs requiring high lipid exposure (up to 99%lipid loading), for high content uniformity, and for high drug loading capacity (up to 50% reported). Coenzyme Q10 has been formu-lated as an NLC using caprylic /capric triacylglycerols (as liquid lipid) as carriers[61].

Clozapine solid lipid nanoparticles have been deve-loped using various triglycerides (trimyristin, tripalmitinand tristearin), soylecithin 95%, poloxamer 188 and stearylamine as a positive charge inducer by hot homo-genization followed by ultrasonication and paclitaxal SLN have been formulated [62].

4. Dosage forms of S-SEDDS

4.1. Dry emulsions

Dry emulsions are powders in which emulsion spon-taneously occurs in vivo or after exposure to an aqueoussolution dry emulsion technology solves the stabilityproblems associated with classic emulsions (e.g. phaseseparation, and contamination by microorganisms) during storage and also helps avoid the use of harmful or toxic organic solvents. Dry emulsions may be re-dispersed in water before use. Medium chain triglyceridesare commonly used as the oil phase for these emulsions. Dry emulsion formulations are typically prepared from oil/ water (O/W) emulsions containing a solid carrier (such as lactose or maltodextrin) in the aqueous phase by rotary evaporation [63], freeze-drying [64] or spray drying [65-67]. Dry emulsions can be used for further preparation of tablets and capsules. To promote the bioavailability of the poorly soluble drug, amlodipine, oleyl polyoxylglycerides (Labrafil® M 1944 CS) were used as the lipophilic phase of the dry emulsion. Most recently, nimodipine dry emulsions have been prepared using Dextran 40 as a water-soluble solid carrier. The most exciting finding in this field is the newly developedenteric-coated dry emulsion formulations, which are potentially applicable for the oral delivery of peptide and protein drugs. These formulations consist of a sur-factant, a vegetable oil, and a pH-responsive polymer, and lyophilization is used [68].

4.2. Self-emulsifying capsules

After administration of capsules containing conven-tional liquid SE formulations, microemulsion droplets form and subsequently disperse in the GI tract to reachsites of absorption. However, if irreversible phase sepa-ration of the microemulsion occurs, no improvement in drug absorption can be expected. Hence, sodium dodecylsulfate has been added to SE formulations and super-saturatable SEDDS has been designed, using a small quantity of HPMC (or other polymers) in the formu-lations to prevent drug precipitation by generating and

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maintaining a supersaturated state in vivo. These contain a reduced amount of surfactant, thereby minimizing any GI side effects [69-70]

4.3. Self-emulsifying sustained/controlled-release tablets

Combinations of lipids and surfactants offer great potential for preparing SE tablets and a great deal of research has been carried out. Nazzal and Khan have evaluated the effect of some processing parameters (colloidal silicates—X1, magnesium stearate mixing time—X2, and compression force—X3) on hardness and coenzymum Q10 (CoQ10) dissolution from tablets of eutectic-based SMEDDS. The optimized conditions (X1 = 1.06%, X2 = 2 min, X3 = 1670 kg) were achieved by a face-centered cubic design [71]. In order to reduce significantly the amount of solidifying excipients required for transformation of SEDDS into solid dosage forms, a gelled SEDDS has been developed by Patil et al. In their study, colloidal silicon dioxide (Aerosil 200) was selected as a gelling agent for the oil-based systems, which served the dual purpose of reducing the amount of required solidifying excipients and aiding the slowing down of drug release [72].

SE tablets are of great use in avoiding adverse effects, as described by Schwarz in a clinical application. Incorporation of indomethacin (or other hydrophobic NSAID), for example, in SE tablets may increase its penetration efficacy through the GI mucosal membranes, potentially reducing GI bleeding. In these studies, the SES was composed of glycerol monolaurate and Tylo-xapolTM (a copolymer of alkyl phenol and formaldehyde). Polyethylene oxide was very suitable for controlled-release matrices. The resultant SE tablets consistently maintained a higher active ingredient concentration in blood plasma over the same time period compared with a non-emulsifying tablet [73]. The latest advance in research involving SE tablets is the SE osmotic pump tablet, where an elementary osmotic pump system was chosen as the SES carrier. It has outstanding features such as stable plasma concentrations and a controllable drug release rate, allowing a bioavailability of 156.8% relative to commercial carvedilol tablets [74].

4.4. Self-emulsifying sustained/controlled-release pellets

Pellets, as a multiple unit dosage form, possess many advantages over conventional solid dosage forms, such as flexibility of manufacture, reducing the intra- subjectand inter-subject variability of plasma profiles and mini-mizing GI irritation without lowering drug bioavail-ability [75]. Thus, it is very appealing to combine the advantages of pellets with those of SEDDS by SE pellets. Serratoni et al. prepared SE controlled-release pellets by incorporating drugs into SES that enhanced the rate of release, while coating pellets with a water-insoluble polymer reduced the rate of drug release. Pellets were prepared by extrusion/spheronization and contained two water-insoluble model drugs (methyl and propyl parabens); SES contained mono-diglycerides and polysorbate 80. This research demonstrated that combinations of coating and SES could control in vitro drug release by providing a range of release rates; also, the presence of the SEDDS did not affect the ability of the polymer film to control drug dissolution [76]. The study of SE sustained-release matrix pellets showed the successful formulations could be obtained with glyceryl palmito-stearate (Gelucire 54/02) and glyceryl behenate (Gelucire 70/02) [77].

4.5. Self-emulsifying solid dispersions

Although solid dispersions can increase the dissolu-tion rate and bioavailability of poorly water-soluble drugs,some manufacturing problems involving stability are continuing targets for pharmaceutical research. Serajuddinpointed out that these difficulties could be overcome by the use of SE excipients [78-79]. SE excipients, like Gelucire1 44/14, Gelucire 50/02, Labrasol, Transcutol and TPGS (tocopheryl polyethylene glycol 1000 succinate), have been widely used to solve the same problem [78-81]. Gupta et al. prepared SE solid dispersion granules using the hot-melt granulation method for seven drugs, including four carboxylic acid-containing drugs, a hydroxyl-containing drug, an amide-containing drug (phenacetin) and a drug with no proton-donating groups (progesterone) in which Gelucire 50/13

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was used as the dispersion carrier, while Neusilin US2 was used as the surface adsorbent [41].

4.6. Self-emulsifying beads

In an attempt to transform SES into a solid form with minimum amounts of solidifying excipients, Patil and Paradkar investigated SES as microchannels of porous polystyrene beads (PPB) using the solvent evaporation method. PPB with complex internal void structures are typically produced by copolymerizing styrene and divinyl benzene, and their research concluded that PPB are potential carriers for solidification of SES, with sufficiently high SES to PPB ratios required for the solid form [82] .

4.7. Self-emulsifying sustained-release microspheres

Zedoary turmeric oil (ZTO; a traditional Chinesemedicine) exhibits potent pharmacological actions includ-ing tumor suppression, and antibacterial, and antithrom-botic activity. With ZTO as an oil phase, You et al. prepared solid SE sustained-release microspheres usingthe quasi-emulsion-solvent-diffusion method involvingspherical crystallization. The ZTO release behaviour was controlled by the ratio of hydroxypropyl methylcellulose acetate succinate to Aerosil 200 in the formulation, and the plasma concentration time-profiles after oral admi-nistration to rabbits showed a bioavailability of 135.6% compared with the conventional liquid SEDDS [83].

4.8. Self-emulsifying nanoparticles

Nanoparticle techniques have been used in the pro-duction of SE nanoparticles. Solvent injection is one of these techniques in which the lipid, surfactant and drugs are melted together, then injected drop-wise into a stirred non-solvent. The resulting SE nanoparticles are then obtained by filtration and dried. This approach produced nanoparticles of about 100 nm with a high drug loading efficiency of 74% [84]. A second techniqueinvolves sonication emulsion-diffusion-evaporation, which allowed the co-loading 5-fluorouracil (5-FU) and

antisense EGFR (epidermal growth factor receptor) plasmids in biodegradable PLGA/O-CMC nanoparticles. The mixture of PLGA (poly-lactide-co-glycolide) and O-CMC (O-carboxmethyl-chitosan) exhibited an SEeffect, without surfactant stabilizer. Eventually, the 5-FU and plasmid encapsulation efficiencies were as high as 94.5% and 95.7%, respectively, and the 5-FU release activity from such nanoparticles was sustained for as long as three weeks [85]. Trickler et al. developed a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the deli-very of paclitaxel (PTX). These chitosan/GMO nano-particles with bioadhesive properties and increased cellular association, were prepared by the multipleemulsion (O/W/O) solvent evaporation method. GMOenhanced the solubility of PTX and provided a founda-tion for chitosan aggregation, while providing nearly 100% loading and entrapment efficiencies for PTX. This approach allows the use of lower doses of PTX to achieve an effective therapeutic window, thus minimizingthe adverse side effects associated with chemotherapeu-tics like PTX [86].

4.9. Self-emulsifying suppositories

Some investigators have shown that S-SEDDS can increase not only GI adsorption but also rectal/vaginal adsorption [87]. Glycyrrhizin given by the oral route barely achieves therapeutic plasma concentrations, but satisfactory therapeutic levels for the treatment of chronic hepatic diseases can be achieved by the use of either vaginal or rectal SE suppositories.

4.10. Self-emulsifying implants

Research into SE implants has greatly increased the use and application of S-SEDDS. As an example, 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine, BCNU) is a chemotherapeutic agent used to treat malignant brain tumors. Its effectiveness was hindered by its short half-life. In order to enhance its stability compared with itsrelease from poly (d, l-lactide-co-glycolide) (PLGA) wafer implants, SES was formulated with tributyrin,

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Cremophor RH 40 (polyoxyl 40 hydrogenated castor oil) and Labrafil 1944 (polyglycolyzed glyceride). Then, the self-emulsified BCNU was fabricated into wafers with a flat and smooth surface by compression mould-ing. Ultimately, SES increased the in vitro half-life of BCNU up to 130 min compared with 45 min with intact BCNU. The in vitro release of BCNU from SE PLGA wafers was prolonged up to 7 d. Such wafers had higher in vitro anti-tumor activity and were less susceptible to hydrolysis than wafers without SES [88]. Loomis invented copolymers having a bioresorbable region, a hydrophilic region and at least two cross-linkable func-tional groups per polymer chain. Such copolymers exhibitSE properties without the requirement of an emulsifying agent. These copolymers can be used as good sealants for implantable prostheses [89].

5. Characterization of SEDDS

The primary means of self-emulsification assessment is visual evaluation. The efficiency of self-emulsificationcan be estimated by determining the rate of emulsificationand droplet size distribution. The droplet size of the emulsion is a crucial factor in self-emulsification perform-ance because it determines the rate and extent of drugrelease as well as absorption. Photon correlation spectro-scopy (PCS) is a useful method for determination of emulsion droplet size The reduction of droplet size to values below 50 nm leads to the formation of SMEDDS, which are stable, isotropic and clear O/W dispersions. Pseudo-ternary phase diagrams, in which the ratio of two or more of the components is kept constant while typically three other excipient concentrations are varied, can be constructed to describe such systems [90].

Normally, the oil, surfactant and co-surfactant or co-solvent ratios are changed in an attempt to identify the self-emulsifying regions and/or other types of disper-sions. Finally, appropriate experimental conditions (optimum excipient concentrations) are established by means of ternary diagram studies allowing formulation of the required SEDDS and/or SMEDDS. The charac-terization of SMEDDS can be made using dye solubi-lization, dilutability by the dispersed phase excess and

conductance measurements. Emulsion droplet polarity is also a very important factor in characterizing emulsifi-cation efficiency. The HLB, chain length and degree of unsaturation of the fatty acid, molecular weight of the hydrophilic portion and concentration of the emulsifier affect the polarity of the oil droplets.

Polarity represents the affinity of the drug for oil and/or water and the type of forces formed. Rapid release of the drug into the aqueous phase is promoted by is polarity. The charge of the oil droplets of SEDDS is another property that should be assessed although the charge of the oil droplets in conventional SEDDS is negative due to the presence of free fatty acids, incorporation of a cationic lipid, such as oleylamine at a concentration range of 1.0−3%, will yield cationic SEDDS. Thus, such systems have a positive ξ-potential value of about 35−45 mV. This positive ξ-potential value is preserved following the incorporation of the drug compounds.

6. Conclusion

SEDDS are a promising approach for the formulation of drugs with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDS, which have been shown to substantially improve oral BA. As mentioned above, numerous studies have con-firmed that S-SEDDS substantially improve the solubility/dissolution, absorption and bioavailability of poorly water-soluble drugs. As alternatives for conventional forms, liquid SEDDS, S-SEDDS are superior offering reduced production costs, simplified industrial manu-facture, and improved stability as well as better patient compliance. Most importantly, S-SEDDS are very flexi-ble for developing various solid dosage forms for oral and parenteral administration. Moreover, GI irritation can be avoided and controlled/sustained release of drugis achievable. It is also worth pointing out some issueswhich require more attention, for example the physical aging phenomenon associated with glycerides, oxidationof vegetable oils, and interaction between drugs and excipients. Selection of suitable excipients is the main hurdle to be overcome when developing S-SEDDS. At

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present, drugs including Cyclosporine A, Ritonavir, and Saquinavir, which are designed as SEDDS, are readily available on the market. As nearly 40% of new drug compounds are hydrophobic, it appears that more drug products will be formulated as SEDDS in the very near future. Thus, these aspects are the major areas for future research into S-SEDDS.

References

[1] C. Lipinski, Poor aqueous solubility an industry wide problem in drug discovery. Am. Pharm. Rev., 2002: 82-85.

[2] G. L. Amidon, H. Lennernas, V. P. Shah, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res., 1995, 12: 413-420.

[3] M. G. Wakerly, C .W. Pouton, B. J. Meakin. Evaluation of the self-emulsifying performance of a non-ionic surfactant-vegetable oil mixture. J Pharm Pharmacol., 1987, 39:6.

[4] M. G. Wakerly, C. W. Pouton, B. J. Meakin, et al. Self-emulsification of vegetable oil non- ionic surfactant mixtures. ACS Symp Ser., 1986, 242-255.

[5] S. A. Charman, W. N. Charman, M. C. Rogge, et al. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res., 1992, 9: 87-93.

[6] N. H. Shah, M. T. Carvagal, C. L. Patel, et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J Pharm., 1994, 106: 15-23.

[7] R. Neslihan Gursoy, Simon Benita. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs, Biomedecine & Pharmacotherapy Volume 58, Issue 3, April 2004, Pages 173-182.

[8] P. P. Constantinides Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res., 1995, 12: 1561-1572.

[9] C. W. Pouton. Lipid formulations for oral administration of drugs: nonemulsifying, self-emulsifying and self-microemulsifying drug delivery systems. Eur. J. Pharm. Sci., 2000, 11: S93-S98.

[10] C. W. Pouton. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the Lipid Formulation Classification System, Eur. J. Pharm. Sci., 2006, 29: 278-287.

[11] P. J. Carrigan, T. R. Bates. Biopharmaceutics of drugs administered in lipid-containing dosage forms: GI absorption of griseofulvin from an oil in water emulsion in the rat. J. Pharm. Sci., 1973, 62: 1476-1479.

[12] R. A. Myers, V. J. Stella, Systemic bioavailability of penclomedine (NSC-338720) from oil-in-water emulsions administered intraduodenally to rats, Int. J. Pharm., 1992, 78: 217-226.

[13] C. W. Pouton. Formulation of self-emulsifying drug delivery systems, Adv. Drug Deliver. Rev., 1997, 25: 47-58.

[14] C.W. Pouton. Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. Int. J. Pharm., 1985, 27: 335-348.

[15] J. F. Cuine, C. L. McEvoy, W. N. Charman, et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs, J. Pharm. Sci., 2008, 97: 993-1010.

[16] T. Gershanik, S. Benita. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs, Eur. J. Pharm. Sci. Biopharm., 2000, 50: 179-188.

[17] S. A. Charman, W. N. Charman, M. C. Rogge, Self-emulsifying drug delivery systems: formulation and evaluation of an investigational lipophilic compound, Pharm. Res., 1992, 9: 87-93.

[18] A. K. Trull, K. K. C. Tan, L. Tan, et al. Enhanced absorption of new oral cyclosporin microemulsion formulation, Neoral, in liver transplant recipients with external biliary diversion. Transplant. Proc., 1994, 26: 2977-2978.

[19] E. A. Mueller, J. M. Kovarik, J. B. Van Bree, et al. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharm. Res., 1994, 11: 301-304.

[20] J. M. Kovarik, E. A. Mueller, J. B. Van Bree, et al. Reduced inter- and intra individual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J. Pharm.Sci., 1994, 83: 444-446.

[21] D. J. Hauss, S. E. Fogal, J. V. Ficorilli, et al. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J. Pharm. Sci., 1998, 87: 164-169.

[22] T. Julianto, K. H. Yuen, A. Mohammad Noor. Improved bioavailability of vitamin E with a self emulsifying formulation. Int. J. Pharm., 2000, 200: 53-57.

[23] T. R. Kommuru, B. Gurley, M. A. Khan, et al. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int. J. Pharm., 2001, 212: 233-246.

[24] B. K. Kang, J. S. Lee, S. K. Chon, et al. Development of self-micro emulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int. J. Pharm., 2004, 274: 65-73.

[25] L. Wei, P. Sun, S. Nie, et al. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev. Ind. Pharm., 2005, 31: 785-794.

[26] S. P. Yap, K. H. Yuen. Influence of lipolysis and droplet size on tocotrienol absorption from self emulsifying formulations, Int. J. Pharm., 2004, 281: 67-78.

[27] C. K. Kim, Y. J. Cho, Z. G. Gao. Preparation and evaluation of biphenyl dimethyl dicarboxylate microemulsions for oral delivery. J. Control. Release, 2001, 70: 149-155.

[28] J. Y. Kim, Y. S. Ku. Enhanced absorption of indomethacin after oral or rectal administration of a self emulsifying system containing indomethacin to rats. Int. J. Pharm., 2000, 194: 81-89.

Page 13: Approaches+for+the+Development+of+Solid+Self Emulsifying++Drug+Delivery+Systems+and+Dosage+Forms+ (1)

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[29] R.G. Strickley, Solubilizing excipients in oral and injectable formulations, Pharm. Res., 2004, 21: 201-230.

[30] C.W. Pouton, Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system, Eur. J. Pharm. Sci., 2006, 29: 278-287.

[31] L. Rodriguez, N. Passerini, C. Cavallari, et al. Description and preliminary evaluation of a new ultrasonic atomizer for spray-congealing process. Int. J. Pharm., 1999, 183: 133-143.

[32] N. Passerini, B. Albertini, B. Perissuti, et al. Evaluation of melt granulation and ultrasonic spray congealing as techniques to enhance the dissolution of praziquantel, Int. J. Pharm., 2006, 318: 92-102.

[33] C. Cavallari, L. Rodriguez, B. Albertini, et al. Thermal and fractal analysis of diclofenac/Gelucire 50/13 microparticles obtained by ultrasound-assisted atomization. J. Pharm. Sci., 2005, 94.

[34] T. Yi, J. L. Wan, H. B. Xu, et al. A new solid self-microemulsifying formulation prepared by spray-drying to improve the oral bioavailability of poorly water soluble drugs. Eur. J. Pharm. Biopharm., 2008, 70: 439-444.

[35] Y. Ito, T. Kusawake, M. Ishida, et al. Oral solid gentamicin preparation using emulsifier and adsorbent. J. Control. Release, 2005, 105: 23-31.

[36] C. Fabio, C. Elisabetta. Pharmaceutical composition comprising a water/oil/ water double microemulsion incorporated in a solid support. WO2003/013421.

[37] L. Boltri. Enhancement and modification of etoposide release from crospovidone particles loaded with oil-surfactant blends. Pharm. Dev. Technol., 1997, 2: 373-381.

[38] N. Venkatesan, J. Yoshimitsu, Y. Ito, et al. Liquid filled nanoparticles as a drug delivery tool for protein therapeutics. Biomaterials, 2005, 26: 7154-7163.

[39] A. Seo, P. Holm, H. G. Kristensen, et al. The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer. Int. J. Pharm., 2003, 259: 161-171.

[40] M. K. Gupta, D. Goldman, R. H. Bogner, et al. Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent. Pharm. Dev. Technol., 2001, 6: 563-572.

[41] M. K. Gupta, Y. C. Tseng, D. Goldman, et al. Hydrogen bonding with adsorbent during storage governs drug dissolution from solid-dispersion granules. Pharm. Res., 2002, 19: 1663-1672.

[42] V. Jannin, J. Musakhanian, D. Marchaud. Approaches for the development of solid and semi-solid lipid-based formulations. Adv. Drug. Deliv. Rev., 2008, 60: 734-746.

[43] G. Verreck, M. E. Brewster. Melt extrusion-based dosage forms: excipients and processing conditions for pharmaceutical formulations. Bull. Tech. Gattefosse., 2004, 97: 85-95.

[44] S. Nazzal, M. Nutan, A. Palamakula, et al. Optimization of a self-nanoemulsified tablet dosage form of Ubiquinone using response surface methodology: effect of formulation ingredients. Int. J. Pharm., 2002, 240: 103-114.

[45] E. Mehuys, J. P. Remon Human bioavailability of propranolol from a matrix-in-cylinder system with a HPMC-GelucireR core. J. Control. Release, 2005, 107: 523-536.

[46] S. Hulsmann, T. Backensfeld, S. Keitel, et al. Melt extrusion-an alternative method for enhancing the dissolution rate of 17-bestradiol hemihydrate. Eur. J. Pharm. Biopharm., 2000, 49: 237-242.

[47] A. Abdalla and K. Mader Preparation and characterization of a self-emulsifying pellet formulation. Eur. J. Pharm. Biopharm., 2007, 66: 220-226.

[48] T. Iosio, D. Voinovich., M. Grassi, et al. Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: influence of formulation variables and preliminary study on the in vivo absorption. Eur. J. Pharm. Biopharm., 10.1016/j.ejpb., 2007,11.014.

[49] C. Thies, I. Ribeiro Dos Santos, J. Richard, et al. A supercritical fluid-based coating technology. 1: process considerations, J. Microencapsul., 2003, 20: 87-96.

[50] I. Ribeiro Dos Santos, C. Thies, J. Richard, et al. A supercritical fluid bases coating technology. 2: solubility considerations. J. Microencapsul., 2003, 20: 97-109.

[51] S. Sethia, E. Squillante. Physicochemical characterization of solid dispersions of carbamazepine formulated by supercritical carbon dioxide and conventional solvent evaporation method. J. Pharm. Sci., 2002, 91: 1948-1957.

[52] S. Sethia, E. Squillante. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods, Int. J. Pharm., 2004, 272: 1-10.

[53] S. Sethia, E. Squillante. In vitro-in vivo evaluation of supercritical processed solid dispersions: permeability and viability assessment in Caco-2 cells. J. Pharm. Sci., 2004, 93: 2985-2993.

[54] L. D. Hu, X. Tang, F. Cui. Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs, J. Pharm. Pharmacol., 2004, 56: 1527-1535.

[55] Y. Wang, Y. Deng, S. Mao, et al. Characterization and body distribution of beta-elemene solid lipid nanoparticles (SLN). Drug Dev. Ind. Pharm., 2005, 31: 769-778.

[56] E. Gavini, V. Sanna, R. Sharma, et al. Solid lipid microparticles (SLM) containing juniper oil as anti-acne topical carriers: preliminary studies. Pharm. Dev. Technol., 2005, 10: 479-487.

[57] M. Ricci, C. Puglia, F. Bonina, C. D. Di Giovanni, et al. Evaluation of indomethacin percutaneous absorption from nanostructured lipid carriers (NLC): in vitro and in vivo studies, J. Pharm. Sci., 2005, 94: 1149-1159.

[58] R. Sivaramakrishnan, C. Nakamura, W. Mehnert, et al. Glucocorticoid entrapment into lipid carriers. Characterisation by parelectric spectroscopy and influence on dermal uptake. J. Control. Release, 2004, 97: 493-502.

[59] E. B. Souto, S. A. Wissing, C. M. Barbosa, et al. Comparative study between the viscoelastic behaviors of different lipid nanoparticle formulations. J. Cosmet. Sci., 2004, 55: 463-471.

[60] E. B. Souto, R. H. Muller. SLN and NLC for topical delivery of ketoconazole. J. Microencapsul., 2005, 22: 501-510.

[61] Veerawat Teeranachaideekul, B. Eliana, H. Souto Rainer Muller. Cetyl palmitate-based NLC for topical delivery of Coenzyme Q10-development, physicochemical characterization and in vitro release studies European J. Pharm. Biopharm., 2007, 67: 141-148.

[62] Kopparam Manjunath, Vobalaboina Venkateswarlu. Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administration. J. Control. Release, 2005, 107: 215-228.

[63] S. L. Myers, M. L. Shively. Preparation and characterization of emulsifiable glasses: oil-in-water and water-in-oil-in-water emulsion. J. Colloid Interface Sci., 1992, 149: 271-278. [64] J. Bamba, G. Cavé, Y. Bensouda, et al. Cryoprotection

of emulsions in freeze-drying: freezing process analysis.

Page 14: Approaches+for+the+Development+of+Solid+Self Emulsifying++Drug+Delivery+Systems+and+Dosage+Forms+ (1)

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1

Drug. Dev. Ind. Pharm., 1995, 21: 1749-1760.[65] K. L. Christensen, G. P. Pedersen, H. G. Kristensen

Technical optimization of redispersible dry emulsions. Int. J. Pharm., 2001, 212: 195-202.

[66] T. Hansen, P. Holm, K. Schultz. Process characteristics and compaction of spray-dried emulsions containing a drug dissolved in lipid. Int. J. Pharm., 2004, 287: 55-66.

[67] D. J. Jang, E. J. Jeong, H. M. Lee, et al. Improvement of bioavailability and photostability of amlodipine using redispersible dry emulsion. Eur. J. Pharm. Sci., 2006, 28: 405-411.

[68] E. Toorisaka, M. Hashida, N. Kamiya, et al. An enteric-coated dry emulsion formulation for oral insulin delivery. J. Control Release, 2005, 107: 91-96.

[69] P. Gao, W. Morozowich. Development of supersaturatable selfemulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert. Opin. Drug. Discov., 2006, 3: 97-110.

[70] P. Gao, B. D. Rush, W. P. Pfund, et al. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J. Pharm. Sci., 2003, 92: 2386-2398.

[71] S. Nazzal, and M.A. Khan, Controlled release of a self-emulsifying formulation from a tablet dosage form: stability assessment and optimization of some processing parameters. Int. J. Pharm., 2006, 315: 110-121.

[72] P. Patil, P. Joshi, A. Paradkar Effect of formulation variables on preparation and evaluation of gelled self-emulsifying drug delivery system (SEDDS) of ketoprofen.AAPS Pharm. Sci. Tech., 10.1208/pt050342 http://www.aapspharmscitech.org/articles/pt0503/pt050342/pt050342.pdf.

[73] S. Joseph. Solid self-emulsifying dosage form for improved delivery of poorly soluble hydrophobic compounds and the process for preparation thereof. US Pat 20030072798.

[74] L. L. Wei. Investigations of a novel self-emulsifying osmotic pump tablet containing carvedilol. Drug. Dev. Ind. Pharm., 2007, 33: 990-998.

[75] R. Gandhi, C. Lal Kaul, R. Panchagnula. Extrusion and spheronization in the development of oral controlled-release dosage forms. PSTT, 1999, 2: 160-170.

[76] M. Serratoni, S. Newton, A. Booth, Clarke. Controlled drug release from pellets containing water insoluble drugs dissolved in a self-emulsifying system. Eur. J. Pharm. Biopharm., 2007, 65: 94-98.

[77] J. Hamdani, A.J. Moes, K. Anighi Physical and thermal characterizations of Precirol and Compritol as lipophilic

glycerides used for the preparation of controlled-release matrix pellets. Int. J. Pharm., 2003, 260: 47-57.

[78] A. T. M. Serajuddin. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci., 1999, 88: 1058-1066.

[79] M. Vasanthavada, A. T. M. Serajuddin. Lipid-based self-emulsifying solid dispersions. In oral lipid-based formulations: enhancing bioavailability of poorly water-soluble drugs (Hauss, D. J., ed.), pp. Informa Healthcare, 2007, 149-184.

[80] A. T. Serajuddin, P. C. Sheen, D. Mufson, et al. Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions. J. Pharm. Sci., 1998, 77: 414-417.

[81] S. M. Khoo, C. J. H. Porter, W. N. Charman. The formulation of halofantrine as either non-solubilising PEG 6000 or solubilising lipid based solid dispersions: physical stability and absolute bioavailability assessment. Int. J. Pharm., 2000, 205: 65-78.

[82] P. Patil, A. Paradkar. Porous polystyrene beads as carriers for self-emulsifying system containing loratadine. AAPS Pharm. Sci. Tech., 2006, 10.1208/0pt07012 http://www.aaps-

pharm-scitech.org/articles/pt0701/pt070128/pt070128.pdf.[83] J. You. Study of the preparation of sustained-release

microspheres containing zedoary turmeric oil by the emulsion-solvent-diffusion method and evaluation of the self-emulsification and bioavailability of the oil. Colloid. Surf. B., 2006, 48: 35-41.

[84] A. A. Attama, M. O. Nkemnele. In vitro evaluation of drug release from self micro-emulsifying drug delivery systems using a biodegradable homolipid from Capra hircus. Int. J. Pharm., 2005, 304: 4-10.

[85] Y. X. Hu. Preparation and evaluation of 5-FU/PLGA/gene nanoparticles. Key Eng. Mat., 2005, 288-289: 147-150.

[86] W. J. Trickler, A. A. Nagvekar, A. K. Dash. A novel nanoparticle formulation for sustained paclitaxel delivery. AAPS Pharm. Sci. Tech., 2008, 10.1208/s12249-008-9063-7

[87] J. Y. Kim, Y.S. Ku. Enhanced absorption of indomethacin after oral or rectal administration of a self-emulsifying system containing indomethacin to rats. Int. J. Pharm., 2000, 194: 81-89

[88] G. S. Chae, J. S. Lee, S. H. Kim, et al. Enhancement of the stability of BCNU using self-emulsifying drug delivery systems (SEDDS) and in vitro antitumor activity of self-emulsified BCNU-loaded PLGA wafer. Int. J. Pharm., 2005, 301: 6-14.