Solid self-emulsifying drug delivery systems/Asian Journal of Pharmaceutical Sciences 2009, 4(4): 240-253

Approaches for the development of solid self-emulsifying drug delivery systems and dosage forms
Suman Katteboinaa,*, V S R Chandrasekhar. Pb, Balaji. Sc
b

Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur Dist, Andhra Pradesh, India522101 Department of Pharmaceutics, Hindu College of Pharmacy, Amaravathi road, Guntur, Andhra Pradesh, India522002 c Department of Pharmaceutics, University College of Pharmaceutical Sciences, Andhra University, India530003
Received 2 March 2009; Revised 15 June 2009; Accepted 12 July 2009

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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 delivery 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 solubility and bioavailability of such drugs. One of the most popular and commercially viable formulation approaches for solving these problems is self-emulsifying drug delivery systems (SEDDS) which have attracted considerable attention from pharmaceutical scientists who want to increase the oral bioavailability of such poorly watersoluble drugs. So, we have prepared this review to
__________ *Corresponding author. Address: Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur Dist, Andhra Pradesh, India522101. Tel.: +91-9177986966; Fax:+91-9490263657 E-mail: ksumanpharma@gmail.com

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 pancreatic 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

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oil droplets lead to a faster and more uniform distribution of the drug in the gastrointestinal tract, minimizing the irritation due to contact between the drug and the gut wall [3-6]. In addition, lipids affect the oral bioavailability 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 supercritical 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.

Table 1 Lipid formulation classification system (LFCS) as described by Pouton showing typical compositions and properties of lipid-based formulations [9, 14]. Increasing Hydrophilic Typical composition (%) Triglycerides or mixed glycerides Water-insoluble surfactants (HLB<12) Water-soluble surfactants (HLB>12) Hydrophilic cosolvents Particle size of dispersion 100250 (nm) Significance of aqueous dilution Significance of digestibility Advantages Type I 100 Coarse Type II 4080 2060 100250 Solvent capacity unaffected Not crucial but likely to occur Unlikely to lose solvent capacity on dispersion Content Type IIIA 4080 2040 040 100250 Some loss of solvent capacity Not crucial but may be inhibited Type IIIB <20 2050 2050 50 100 Type IV 020 3080 050 <50

Limited Importance

Significant phase Significant phase changes and changes and potential potential loss of loss of solvent solvent capacity capacity Not required Not required

Crucial Requiremet GRAS status; simple; excellent capsule compatibility

Clear or almost clear Clear dispersion; Formulation has good dispersion; drug drug absorption solvent capacity for absorption without without digestion many drugs digestion

Disadvantages

Formulation haspoor Turbid o/w Possible loss of solvent likely loss of Likely loss of solvent solvent capacity unless dispersion (particle capacity on dispersion; solvent capacity on capacity on dispersion; drug is highly lipophilic size 0.252 m) less easily digested dispersion may not be digestible

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2.1. Type I - Non-dispersing systems Type I systems consist of formulations where the drug is in a solution of triglycerides and/or mixed glycerides or in an oil-in-water emulsion stabilised by low concentrations 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 incorporation of the required payload dose. 2.2. Type II-SEDDS: non-water soluble component systems Type II lipid formulations, referred as a self-emulsifying drug delivery systems, (SEDDS) are isotropic mixtures 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 formulations 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 efficient 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 referred to 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 hydrophilic surfactants and co solvents is increased and the lipid content is reduced. Type IIIB formulations typically achieve 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 also commonly made based on the particle size and optical clarity of the resultant dispersion. Thus, SEDDS formulations typically provide opaque dispersions with particle sizes>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 cyclosporine 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-tocopherol as an antioxidant. In contrast to the earlier Sandimmun cyclosporin formulation consisting of corn oil, 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--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 Lipid Formulation Classification System [30]. Type IV formulations 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. When compared with formulations containing simple glyceride lipids they also produce very fine dispersions when introduced in aqueous media. It has been suggested that they

Table 2 Examples of studies describing the bioavailability enhancement of PWSD after administration of SEDDS and SMEDDS formulations. Compound Win 54954 Formulation (s) SEDDS (35% drug, 40% Neobee M5 (MCT) and 25% Tagat TO) or PEG 600 solution Study design Observations Ref.

Relative BA No difference in BA but Improved [16] in dogs reproducibility, increased Cmax Increased BA and Cmax and reduced tmax from SMEDDS

Sandimmum (SEDDS: corn oil and ethanol) or neoral Relative BA (SMEDDS: Corn oil glycerides, Cremoph or RH40, PG, in humans DL-a-toco pherol and ethanol) Cyclosporine Sandimmum (SEDDS) or neoral (SMEDDS)

[17]

Increased Cmax, AUC and dose Relative BA linearity reduced food effect from [18] in humans SMEDDS Relative BA in humans Reduced intra and inter subject variability from SMEDDS [19]

Sandimmum (SEDDS) or neoral (SMEDDS)

Ontazolast

Soybean oil emuls ion drug solution in peceol drug Absolute BA BA increases of at least 10-fold suspension or two semi-solid SEDDS consisting of [20] in rats from all lipid based formulations gelucrie 44/14 and peceol in the ratios 50:50 and 80:20 SEDDS (Tween 80: Span 80: palm oil (LCT ) in a 4:2:4 Relative BA ratio) or soybean oil (LCT) solution in humans SMEDDS (40% Myvacet 9-45, 50% labrasol and 10% lauro glycol) or powder formulation SMEDDS (37% Cap ryol90 28% cremophor EL, 28% Carb itol) or tablet SEDDS (labrafil M1944CS, Tween 80 and Transcutol) and tablets Two SEDDS (Tween 80 and labrasol) or LCT solution Relative BA in dogs BA 3-fold higher from SEDDS BA 2-fold higher from SEDDS [21] [22]

Vitamin E Coenzyme Q10 Simvastatin Carvedilol Tocotrienols

Relative BA BA 1.5-fold higher from SEDDS [23] in dogs Relative BA in dogs Relative BA in humans BA 4-fold higher from SEDDS BA 2 to 3 fold higher from SEDDS [24] [25] [26] [27]

Biphenyl dimethyl SEDDS (43% Tween 80, 35% triacetin and 22% Neobee Relative BA i BA 5-fold higher from SEDDS dicarboxylate M-5 (MCT)) or powder formulation n rats Indomethacin SEDDS (70% ethyl oleate and 30% Tween 85 ) or powder formulation Relative BA in rats BA significantly increased from SEDDS

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produce rapid drug release and increased drug absorption. However, little is known about the solubilisation capacity of these systems in vivo and, in particular, whether they are equally capable of maintaining PWSD in solution during passage along the GIT when compared with 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.

and limitations of the technique are also presented. These techniques are listed in Table 3 according to the physical nature 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 into spherical 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 development of solid dosage forms such as tablets or capsules. Equipment like rotary, pressure, two-fluid or ultrasonic atomizers are available to atomize the liquid mixture and to generate droplets [31]. Most of the recent research conducted on spray cooling with lipid-based excipients used ultrasonic atomizers. The main classs of excipient used with this technique are polyoxylglycerides and, more specifically, stearoyl polyoxylglycerides Gelucire 50/13 facilitating the production of microparticles with a narrow size distribution that exhibit signinificantly enhanced drug release profiles for poorly soluble 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, solid carriers, and solubilisation of the mixture before spray drying. The solubilized liquid formulation is then atomized 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

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 enhancement with lipids. Whereever possible, the advantages

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Table 3 Considerations in selection of formulation techniques for bioavailability enhancement with lipid-based excipients. Physical property of the lipid excipients applied Liquid to solid X X X X X X X X X X Semi-solid X Formulations advantages and limits Maximum lipid Lip exposure* (%, w/w) 99 99 60 80 50 50 99 99 Maximum drug Loading (%, w/w) 50 30 50 10 80 60 20 50

Formulation techniques for solid and semi-solid formulations

Capsule filling Spray-cooling Spray drying Adsorption on solid carrier Melt granulation Melt extrusion Super critical fluid based methods Solid lipid nanoparticles

*Percentage calculated after evaporation of solvent where applicable.

from an ordinary emulsion containing a water-soluble solid carrier. The solid SMEDDS was prepared by spraydrying 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, magnesium hydroxide, talcum, crospovidone, cross-linked sodium carboxymethyl cellulose and crosslinked polymethyl methacrylate are typical solid carriers [36]. Crosslinked 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-enhancing 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 loratadine. Silicone dioxide has been used as an adsorption carrier for ketoprofen. It is also currently used in formulations of drugs like ketoprofen, ezetimibe, siramesine hydrochloride, and gentamicin. 3.2.4. Melt granulation Melt granulation is a process in which powder agglomeration is obtained through the addition of a binder that melts or softens at relatively low temperatures. As a one-step operation, melt granulation offers several advantages compared with conventional wet granulation, since liquid addition and the subsequent drying phase

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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 adaptable 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-solid excipients with high HLB, on the other hand, may be used for immediate release and bioavailability enhancement. Of these, Gelucire1, a family of vehicles derived from mixtures 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 lipidbased 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 process are 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 resulting 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 extrusion spheronization using MCC malt dextrin and copolyvidone [44]. The bioavailability of propranolol was

improved by preparing a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire 44/14 core [45]. This approach has been successfully applied to 17-estradiol and two model drugs (methyl and propyl parabens) with surfactants such as sucrose monopalmitate (Surfhope D-1616), lauroyl polyoxylglycerides (Gelucire 44/14) and polysorbate 80 (Tween 80) [46]. Applying extrusion-spheronization, 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 methods either 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 conditions. 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 dissolving 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 that have been studied with this process for controlled-release applications include glyceryl trimyristate (Dynasan 114) and stearoyl polyoxylglycerides (Gelucire 50/02) [49-50]. More recently, the technique has been successfully applied for bioavailability enhancement of carbamazepine using Vitamin E TPGS and Gelucire 44/14) [50-52]. The important considerations with this formulation 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 concerns relating 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 nanostructured lipid carriers (NLC) SLN and NLC are two types of submicron sized particles between 501000 nm composed of physiologically 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 poloxamers 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 excipient, 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 excipients with 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 formulated as an NLC using caprylic /capric triacylglycerols (as liquid lipid) as carriers[61]. Clozapine solid lipid nanoparticles have been developed using various triglycerides (trimyristin, tripalmitin and tristearin), soylecithin 95%, poloxamer 188 and stearylamine as a positive charge inducer by hot homogenization 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 spontaneously occurs in vivo or after exposure to an aqueous solution dry emulsion technology solves the stability problems associated with classic emulsions (e.g. phase separation, and contamination by microorganisms) during storage and also helps avoid the use of harmful or toxic organic solvents. Dry emulsions may be redispersed in water before use. Medium chain triglycerides are 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 developed enteric-coated dry emulsion formulations, which are potentially applicable for the oral delivery of peptide and protein drugs. These formulations consist of a surfactant, a vegetable oil, and a pH-responsive polymer, and lyophilization is used [68]. 4.2. Self-emulsifying capsules After administration of capsules containing conventional liquid SE formulations, microemulsion droplets form and subsequently disperse in the GI tract to reach sites of absorption. However, if irreversible phase separation of the microemulsion occurs, no improvement in drug absorption can be expected. Hence, sodium dodecyl sulfate has been added to SE formulations and supersaturatable SEDDS has been designed, using a small quantity of HPMC (or other polymers) in the formulations 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 silicatesX1, magnesium stearate mixing timeX2, and compression forceX3) 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 TyloxapolTM (a copolymer of alkyl phenol and formaldehyde). Polyethylene oxide was very suitable for controlledrelease 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- subject and inter-subject variability of plasma profiles and minimizing GI irritation without lowering drug bioavailability [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 waterinsoluble 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 dissolution rate and bioavailability of poorly water-soluble drugs, some manufacturing problems involving stability are continuing targets for pharmaceutical research. Serajuddin pointed 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 acidcontaining drugs, a hydroxyl-containing drug, an amidecontaining drug (phenacetin) and a drug with no protondonating 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 Chinese medicine) exhibits potent pharmacological actions including tumor suppression, and antibacterial, and antithrombotic activity. With ZTO as an oil phase, You et al. prepared solid SE sustained-release microspheres using the quasi-emulsion-solvent-diffusion method involving spherical 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 administration 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 production 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 technique involves 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 SE effect, 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 delivery of paclitaxel (PTX). These chitosan/GMO nanoparticles with bioadhesive properties and increased cellular association, were prepared by the multiple emulsion (O/W/O) solvent evaporation method. GMO enhanced the solubility of PTX and provided a foundation 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 minimizing the adverse side effects associated with chemotherapeutics 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 halflife. 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 moulding. 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 functional groups per polymer chain. Such copolymers exhibit SE 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-emulsification can be estimated by determining the rate of emulsification and droplet size distribution. The droplet size of the emulsion is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as absorption. Photon correlation spectroscopy (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 cosolvent ratios are changed in an attempt to identify the self-emulsifying regions and/or other types of dispersions. 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 characterization of SMEDDS can be made using dye solubilization, dilutability by the dispersed phase excess and

conductance measurements. Emulsion droplet polarity is also a very important factor in characterizing emulsification 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 1.03%, will yield cationic SEDDS. Thus, such systems have a positive -potential value of about 3545 mV. This positive -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 confirmed 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 manufacture, and improved stability as well as better patient compliance. Most importantly, S-SEDDS are very flexible for developing various solid dosage forms for oral and parenteral administration. Moreover, GI irritation can be avoided and controlled/sustained release of drug is achievable. It is also worth pointing out some issues which require more attention, for example the physical aging phenomenon associated with glycerides, oxidation of 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.

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