SELF EMULSIFYING DRUG DELIVERY SYSTEM: AN APPROACH TO IMPROVE THE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS

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1 572 P a g e International Standard Serial Number (ISSN): International Journal of Universal Pharmacy and Bio Sciences 3(3): May-June 2014 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89*** Pharmaceutical Sciences ICV 5.13*** REVIEW ARTICLE!!! SELF EMULSIFYING DRUG DELIVERY SYSTEM: AN APPROACH TO IMPROVE THE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS Dain K Thankachen*, Manju Maria Mathews, Prof. John Joseph Nirmala College of Pharmacy, Muvattupuzha,Kerala. KEYWORDS: Co-surfactant, Oil, Self emulsifying drug delivery system (SEDDS), Surfactant. For Correspondence: Dain K Thankachen* Address: Department of Pharmaceutics Nirmala College of Pharmacy Ernakulam, Kerala, India. E- mail: dainkaduppil@gmail.com ABSTRACT Oral route is the easiest and most convenient route for drug administration. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility. This may lead to high inter- and intra subject variability, lack of dose proportionality and therapeutic failure. 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 formulation with sufficient bioavailability. Self-emulsifying drug delivery system (SEDDS) has gained more attention for enhancement of oral bio-availability of poorly water soluble and lipophilic drugs with reduction in dose. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles. SEDDS are ideally an isotropic mixture of oil, surfactants, solvents and sometimes cosolvents/surfactants. The principal characteristic of these systems is their ability to form fine emulsions (or micro-emulsions) in gastrointestinal tract (GIT) with mild agitation provided by gastric mobility. Purpose of this review article is to provide brief outline of self emulsifying drug delivery system as a promising approach to effectively tackle the problem of poorly soluble molecules along with the associated problems & its potential to increase the bioavailability of poorly soluble drugs.

2 573 P a g e International Standard Serial Number (ISSN): INTRODUCTION: One of the most popular and commercially viable delivery approaches used to improve the solubility and bioavailability of poorly water soluble drugs is self-emulsifying drug delivery system (SEDDS) 1. Self-emulsifying drug delivery systems (SEDDS) are a vital tool in solving low bioavailability issues of poorly soluble drugs. The use of SEDDS to improve the bioavailability of poorly water soluble drugs was first reported in 1982 by Pouton. In his work, he identified an effective self emulsifying system composed of Miglyol 812 (M812, medium chain triglyceride, MCT) and Tween 85 (T85, polyoxyethelene-20-sorbitan trioleate). SEDDS are formulated with mixtures of lipid vehicles and non-ionic surfactants in the absence of water, and are assumed to exist as transparent isotropic solutions. They are able to self emulsify rapidly in the aqueous media, such as gastrointestinal(gi) fluids, forming fine oil-in-water (o/w) emulsions/lipid droplets or micro emulsions(smedds) under the gentle agitation provided by gastro-intestinal motion and are suitable for oral delivery in soft and hard gelatin or hard hydroxypropylmethylcellulose (HPMC) capsules 2. Hydrophobic drugs can be dissolved in these systems, enabling them to be administered as a unit dosage form for per-oral administration.when such a formulation is released into the lumen of the gut, it disperses to form a fine emulsion. The drug, therefore, remains in solution in the gut, avoiding the dissolution step that frequently limits the absorption rate of hydrophobic drugs from the crystalline state 1. SEDDSs typically produce emulsions with a droplet size between nm while self-micro-emulsifying drug delivery systems (SMEDDSs) form transparent micro-emulsions with a droplet size of less than 50 nm, on dilution with physiological fluid 2. Fine oil droplets would pass rapidly from the stomach and promote wide distribution of the drug throughout the GI tract, thereby minimizing the irritation frequently encountered during extended contact between bulk drug substances and the gut wall 1. The self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. The ease of emulsification could be associated with the ease of water penetrating into the various liquids crystalline or gel phases formed on the surface of the droplet. When compared with emulsions, which are sensitive and metastable dispersed forms, SEDDS are physically stable formulations that are easy to manufacture. The spontaneous formation of emulsion presents the drug in a dissolved form and the resultant small droplet size provide a large interfacial area for diffusion 3. The SEDDS formulation has been well accepted for drugs with poor aqueous solubility and high permeability, classified as Class II drugs by Biopharmaceutic classification system (BCS) system 4. For lipophilic

3 574 P a g e International Standard Serial Number (ISSN): drugs with dissolution-limited oral absorption, these systems may offer an improvement in the rate and extent of absorption and more reproducible plasma concentration profiles 3. Self emulsifying formulations are normally prepared as liquid which possesses some disadvantages, for example, high production costs, low stability and portability, low drug loading and few choices of dosage forms. Irreversible drugs/excipients precipitation may also be problematic. More importantly, the large quantity (30-60%) of surfactants in the formulations can induce GI irritation. To address these problems, transformation of SEDDS in solid dosage forms by addition of large amounts of solidifying excipients (adsorbents and polymers) have been reported 1. ADVANTAGES 1. Improvement in oral bioavailability enabling reduction in dose: SEDDS is a novel approach to improve the water solubility and ultimately bioavailability of lipophilic drugs. The ability of SEDDS to present the drug to GIT in globule size between nm and subsequent increase in specific area enables more efficient drug transport through the intestinal aqueous boundary layer leading to improvement in bioavailability. 2. Ease of manufacture and scale-up: SEDDS require very simple and economical manufacturing facilities like simple mixer with agitator and volumetric liquid filling equipment for large-scale manufacturing. 3. Reduction in inter-subject and intra-subject variability and food effects: SEDDS offer reproducibility of plasma profile. 4. Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT: One unique property that makes SEDDS superior as compared to the other drug delivery systems is their ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors and their ability to offer protection from enzymatic hydrolysis Fine oil droplets empty rapidly from the stomach and promote wide distribution of the drug throughout the intestinal tract and thereby minimizing irritation frequently associated with extended contact of drugs and gut wall More consistent temporal profiles of drug absorption. 7. Selective targeting of drug(s) toward specific absorption window in GIT. 8. Protection of drug(s) from the hostile environment in gut. 9. High drug payloads 7.

4 575 P a g e International Standard Serial Number (ISSN): DISADVANTAGES 1. Conventional SEDDS, which are mostly prepared in a liquid form and orally administered in soft or hard gelatin capsules, can make some limitations such as high production costs, low drug incompatibility and stability, drugs leakage and precipitation, capsule ageing. Then incorporation of liquid SEDDS into a solid dosage form is compelling and desirable The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations. The large quantity of surfactant in self-emulsifying formulations (30-60%) irritates GIT. 3. Volatile cosolvents in the conventional self-emulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs The traditional dissolution method does not work, because these formulations potentially are dependent on digestion prior to release of the drug 9. FACTORS AFFECTING OF SEDDS: 1. Nature and dose of the drug: Drugs which are administered at very high dose are not suitable for unless they have extremely good solubility in at least one of the components of SEDDS, preferably lipophilic phase. The drugs which have limited or less solubility in water and lipids are most difficult to deliver by SEDDS. The ability of SEDDS to maintain the drug in solubilised form is greatly influenced by the solubility of the drug in oil phase. 2. Solubility of drug: The ability of SEDDS to maintain the drug in solubilised form is greatly influenced by the solubility of the drug in oily phase. If the surfactant and co-surfactant contribute to a greater extent for solubilisation then there is risk of precipitation. 3. Polarity of the lipophilic phase: The polarity of lipid phase is one of the factors that govern the release of the drug from the micro-emulsion. HLB, chain length, degree of unsaturation of the fatty acid, molecular weight of the hydrophilic portion and concentration of the emulsifier govern polarity of the droplets. The polarity reflects the affinity of the drug for oil and/or water, and the type of forces formed. The high polarity will promote a rapid rate of release of the drug into the aqueous phase. The highest release was obtained with the formulation that had oil phase with highest polarity CRITERIA OF DRUG PROPERTIES: 9 BCS (Bio-pharmaceutical classification system) classifies the drug based on solubility and permeability of a drug. Mainly Class 2 (Low Solubility, High Permeability) is used for SEDDS. Ex.

5 576 P a g e International Standard Serial Number (ISSN): Glibenclamide, Azithromycin,Danazol, Phenytoin, Dapsone, Carbamazepine, Nifedipine, Carvedilol, Chlorpromazine, Cisapride, Ciprofloxacin. COMPOSITION OF SEDDS The self-emulsifying process depend on 11 ; The nature of the oil surfactant pair The surfactant concentration and surfactant/ cosurfactant ratio. The temperature at which self emulsification occurs. Oils: Oils can solubilize the lipophilic drug in a specific amount. It is the most important excipient because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract 12. Long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used in the design of SEDDS. Unmodified edible oils provide the most `natural' basis for lipid vehicles, but their poor ability to dissolve large amounts of hydrophobic drugs and their relative difficulty in efficient self-emulsification markedly reduce their use in SEDDS. In contrast, modified or hydrolyzed vegetable oils have contributed widely to the success of the above systems. Novel semi synthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the regular medium- chain triglyceride 12. Nature of oil is very important in the formation of SEDDS. Chemical structure of the oil components and interactions of these components with the various enzymes, surfactants and proteins associated with digestion and absorption process, for example, fatty acid chain length is important factor for chylomicron formation. Short and medium chain acids are predominantly absorbed by portal blood system while longer chain fatty acid may be re-esterified in the cell lining the small intestine and absorbed via the lymphatics. The absorption enhancement is greater when using unsaturated fatty acids. M. Cheema et al reported that a greater degree of unsaturation led to a more rapid onset of lipoprotein synthesis as a result of faster absorption or greater affinity of fatty acid binding to protein because unsaturated fatty acids have lower melting points as compared to saturated with increasing fluidity. Liquid crystal formation from oil depends on oil polarity, which would influence the emulsification process. Very polar or non-polar oils tend to form poor emulsions. Miglyol 812 and 840 both have intermediate polarity which shows favourable emulsification properties with Tween85. Solubility of the drug in the oil-surfactant mixture is very important whereas solubility of drug in vegetable oil is not a problem. The simplest

6 577 P a g e International Standard Serial Number (ISSN): and most desirable formulation may well be a simple oil solution which is self emulsified in the gut during digestion 13. Examples include mineral oil, vegetable oil, silicon oil, lanolin, refined animal oil, fatty acids and mono-/di-/tri-glycerides. Fractionated coconut oil and palm seed oil (medium-chain triglycerides) Corn oil, Olive oil, Sesame oil, Soybean oil, Peanut oil (long chain triglycerides) 2 Surfactant: The choice of surfactants is limited because very few surfactants are orally acceptable. The most widely used surfactants are nonionic surfactants with high hydrophilic lipophilic balance (HLB) value. The surfactants used in SEDDS include Tween, Span, Labrasol, Labrafac CM 10, Cremophore. The usual surfactant strength ranges between 30 60% w/w of the formulation in order to form a stable SEDDS. Surfactants having a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively large amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules 11. The lipid mixtures with higher surfactant and cosurfactant/oil ratios lead to the formation of self-micro emulsifying formulations(smedds). The surfactants used in these formulations will improve the bioavailability by various mechanisms including: improved drug dissolution, increased intestinal epithelial permeability, increased tight junction permeability and decreased/inhibited p-glycoprotein drug efflux 4. A large quantity of surfactant may irritate the GI tract. Thus, the safety aspect of the surfactant vehicle should be carefully considered in each case. Co-solvents: Co-solvents dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base and can act as co-surfactant in the self emulsifying drug delivery systems. The co-solvents includes Transcutol (Diethylene glycol monoethyl ether), Polyethylene glycol 400, Glycerol, Propylene glycol, Ethanol, Polyoxyethylene, Propylene carbonate, Tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol) 7. The production of an optimum SEDDS requires relatively high surfactant concentration (usually more than30%w/w), however the use of co-surfactant in self emulsifying systems is not mandatory for many non-ionic surfactants. Other excipients:

7 578 P a g e International Standard Serial Number (ISSN): Oil soluble antioxidants include α-tocopherol, β-carotene, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), propylgallate and ascorbylpalmitate 2. MECHANISM OF SELF EMULSIFICATION Self emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion 14. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases and can be described by the equation; ΔG = Σ N π r 2 σ Where, ΔG is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets, r is the radius of droplets and σ represents the interfacial energy. The two phases of emulsion tend to separate with time to reduce the interfacial area and subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion droplets and hence reduce the interfacial energy as well as providing a barrier to prevent coalescence. In the case of self-emulsifying systems, the free energy required to form the emulsion is either very low and positive, or negative (then, the emulsification process occurs spontaneously) 15. In self emulsifying system the interfacial tension is made sufficiently low that interfacial energy become comparable and lowers their entropy of dispersion and free energy of formation become zero or negative. Thus the main driving force of SSEF is ultra low interfacial tension, which is achieved by using two or more emulsifier in combination, but sometime single nonionic surfactant may work. The ease of emulsification is suggested to be related to the ease of water penetration into various liquid crystal (LC) or gel phase formed on the surface of the droplet The addition of binary mixture (nonionic surfactant/ oil) water interface is formed between oil and continuous aqueous phase. This is followed by solubilization of water within oil phase as a result of aqueous penetration through interface. This will occur until the solubilization limit is reached close interphase which lead to dispersed LC phase so in the end all globule in close proximity will be LC which mainly depend on surfactant concentration in binary mixture 19. The presence of the drug may alter the emulsion characteristics, possibly by interacting with the liquid crystalline phase 20. METHOD OF PREPARATION: A) Solidification techniques for transforming liquid/semisolid: Various solidification techniques are listed below;

8 579 P a g e International Standard Serial Number (ISSN): ) Capsule filling with liquid and semisolid self-emulsifying formulations: Capsule filling is the simplest and the most common technology for the encapsulation of liquid or semisolid SE formulations for the oral route. For semisolid formulations, it is a four-step process: A) Heating of the semisolid excipient to at least 20 C above its melting point. B) Incorporation of the active substances (with stirring). C) Capsule filling with the molten mixture and D) Cooling to room temperature. For liquid formulations, it involves a two-step process. Filling of the formulation into the capsules followed by sealing of the body and cap of the capsule, either by banding or by micro spray sealing 21. B) Spray drying: Essentially, this technique involves the preparation of a formulation by mixing lipids, surfactants, drug, solid carriers, and solubilization of the mixture before spray drying. The solubilized liquid formulation is then atomized into a spray of droplets. The droplets are introduced into a drying chamber, where the volatile phase (e.g. the water contained in an emulsion) evaporates forming dry particles under controlled temperature and airflow conditions. Such particles can be further prepared 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 specification. C) Adsorption to solid carriers: Free flowing powders may be obtained from liquid SE formulations by adsorption to solid carriers. The adsorption process is simple and just involves addition of the liquid on 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 22. 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 23. Crosslinked polymers create a favourable environment to sustain drug dissolution and also assist in slowing down drug reprecipitation 24. Nanoparticle adsorbents include porous silicon dioxide (Sylysia 550), carbon nanotubes, carbon nanohorns, fullerene, charcoal and bamboo charcoal 25. At present, colloidal silicon dioxide is widely used as an adsorbing agent for various drugs like ketoprofen, ezetimibe, and Siramesine hydrochloride. It has been reported that porous polystyrene

9 580 P a g e International Standard Serial Number (ISSN): beads can be used as carriers for a self-emulsifying system containing loratadine. Silicone dioxide has been used as an adsorption carrier for ketoprofen. D) 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. E) Melt extrusion/extrusion spheronization: Melt extrusion is a solvent-free process that allows high drug loading (60%) 21, 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 26. The size of the extruder aperture determines the approximate size of the resulting spheroids. The extrusionspheronization process is commonly used in the pharmaceutical industry to make uniformly sized spheroids (pellets). EVALUATION: A) Thermodynamic stability studies: The physical stability of a lipid based formulation is also crucial to its performance, which can be adversely affected by precipitation of the drug in the excipient matrix. In addition, poor formulation physical stability can lead to phase separation of the excipient, affecting not only formulation performance, but visual appearance as well. In addition, incompatibilities between the formulation and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or incomplete release of drug. a) Heating cooling cycle: Six cycles between refrigerator temperature (4 O C) and 45 O C with storage at each temperature of not less than 48 hr is studied. Those formulations, which are stable at these temperatures, are subjected to centrifugation test. b) Centrifugation: Passed formulations are centrifuged thaw cycles between 21 O C and +25 O C with storage at temperature for not less than 48 hr is done at 3500 rpm for 30 min. Those formulations that does not show any phase separation are taken for the freeze thaw stress test. c) Freeze thaw cycle: Three freeze for the formulations. Those formulations passed this test showed good stability with no phase separation, creaming, or cracking. B) Dispersibility test The efficiency of self-emulsification of oral nano or micro emulsion is assessed using a standard USP XXII dissolution apparatus II. One milliliter of each formulation was added to 500 ml of water at 37 ± C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle

10 581 P a g e International Standard Serial Number (ISSN): agitation. The in vitro performance of the formulations is visually assessed using the following Grading system: Grade A: Rapidly forming (within 1 min) nanoemulsion, having a clear or bluish appearance. Grade B: Rapidly forming, slightly less clear emulsion, having a bluish white appearance. Grade C: Fine milky emulsion that formed within 2 min. Grade D: Dull, grayish white emulsion having slightly oily appearance that is slow to emulsify (longer than 2 min). Grade E: Formulation, exhibiting either poor or minimal emulsification with large oil globules present on the surface. Grade A and Grade B formulation will remain as nanoemulsion when dispersed in GIT. While formulation falling in Grade C could be recommend for SEDDS formulation. C) Turbidimetric Evaluation Nepheloturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quantity of Selfemulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on magnetic hot plate at appropriate temperature, and the increase in turbidity is measured, by using a turbidimeter. However, since the time required for complete emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of emulsification) D) Viscosity Determination The SEDDS system is generally administered in soft gelatin or hard gelatin capsules. So, it can be easily pourable into capsules and such systems should not be too thick. The rheological properties of the micro emulsion are evaluated by Brookfield viscometer. This viscosities determination conform whether the system is w/o or o/w. If the system has low viscosity then it is o/w type of the system and if a high viscosity then it is w/o type of the system. E) Droplet Size Analysis and Particle Size Measurements The droplet size of the emulsions is determined by photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles) using a Zetasizer able to measure sizes between 10 and 5000 nm. Light scattering is monitored at 25 C at a 90 angle, after external standardization with spherical polystyrene beads. The nanometric size range of the particle is retained even after 100 times dilution with water which proves the system s compatibility with excess water.

11 582 P a g e International Standard Serial Number (ISSN): F) Refractive Index and Percent Transmittance Refractive index and percent transmittance proved the transparency of formulation. The refractive index of the system is measured by refractometer by putting a drop of solution on slide and comparing it with water (1.333). The percent transmittance of the system is measured at particular wavelength using UV-spectrophotometer by using distilled water as blank. If refractive index of system is similar to the refractive index of water (1.333) and formulation have percent transmittance > 99 percent, then formulation have transparent nature. G) Electro Conductivity Study The SEDD system contains ionic or non-ionic surfactant, oil, and water. This test is performed for measurement of the electro conductive nature of system. The electro conductivity of resultant system is measured by electro conductometer. In conventional SEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids. H) In vitro Diffusion Study In vitro diffusion studies are carried out to study the drug release behavior of formulation from liquid crystalline phase around the droplet using dialysis technique. I) Drug Content Drug from pre-weighed SEDDS is extracted by dissolving in suitable solvent. Drug content in the solvent extract was analyzed by suitable analytical method against the standard solvent solution of drug. BIOPHARMACEUTICAL ASPECTS 30 The ability of lipids and/or food to enhance the bioavailability of poorly water soluble drugs is well known. Although incompletely understood, the currently accepted view is that lipids may enhance bioavailability via a number of potential mechanisms, including: 1. Alterations (reduction) in gastric transit, thereby slowing delivery to the absorption site and increasing the time available for dissolution. 2. Increases in effective luminal drug solubility. The presence of lipids in the GI tract stimulates an increase in the secretion of bile salts (BS) and endogenous biliary lipids including phospholipids (PL) and cholesterol (CH), leading to the formation of BS/PL/CH intestinal mixed micelles and an increase in the solubilisation capacity of the GI tract. However, intercalation of administered (exogenous) lipids into these BS structures either directly (if sufficiently polar), or secondary to digestion, leads to swelling of the micelle structures and a further increase in solubilisation capacity.

12 583 P a g e International Standard Serial Number (ISSN): Stimulation of intestinal lymphatic transport. For highly lipophilic drugs, lipids may enhance the extent of lymphatic transport and increase bioavailability directly or indirectly via a reduction in first-pass metabolism. 4. Changes in the biochemical barrier function of the GI tract. It is clear that certain lipids and surfactants may attenuate the activity of intestinal efflux transporters, as indicated by the p- glycoprotein efflux pump, and may also reduce the extent of enterocyte based metabolism. 5. Changes in the physical barrier function of the GI tract. Various combinations of lipids, lipid digestion products and surfactants have been shown to have permeability enhancing properties. For the most part, however, passive intestinal permeability is not thought to be a major barrier to the bioavailability of the majority of poorly water-soluble, and in particular, lipophilic drugs. RECENT ADVANCEMENTS IN SEDDS Self-emulsifying sustained/controlled-release tablets Combinations of lipids and surfactants have presented great potential of preparing self-emulsifying tablets that have been widely researched. After evaluation the effect of some processing parameters (colloidal silicates X 1, magnesium stearate mixing time X 2, and compression force X 3 ) on hardness and coenzyme Q10 (CoQ10) dissolution from tablets of eutectic-based SMEDDS. The optimized conditions (X 1 = 1.06%, X 2 = 2 min, X 3 = 1670 kg) were achieved by a face-centered cubic design 31. 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 excipeints and aiding in slowing down of the drug release 32. Self-emulsifying capsules: After administration of capsules containing conventional liquid SE formulations, micro emulsion droplets form and subsequently disperse in the GI tract to reach sites of absorption. However, if irreversible phase separation of the micro emulsion occurs, an improvement of drug absorption cannot be expected. For handling this problem, sodium dodecyl sulfate was added into the SE formulation 33. With the similar purpose, the super saturatable SEDDS was designed, using a small quantity of hydroxyl propyl methyl cellulose (HPMC) (or other polymers) in the formulation to prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo. This system contains a reduced amount of a surfactant, thereby minimizing GI side effects The

13 584 P a g e International Standard Serial Number (ISSN): SEDDS formulations, empty soft gelatin capsules were filled with the formulation using a syringe and sealed with hot gelatin. Besides liquid filling, liquid self emulsifying ingredients also can be filled into capsules in a solid or semisolid state obtained by adding solid carriers. Self-emulsifying nanoparticle: Nanoparticle technology can be applied to the formulation of self emulsifying nanoparticles. Solvent injection is one of these techniques. In this method, the lipid, surfactant and drugs were melted together. This lipid molten mass was injected drop wise into a non solvent system. This is filtered and dried to get nanoparticles. By this method 100 nm size particle with 70-75% drug loading efficiency was obtained 36. Second technique is sonication emulsion diffusion evaporation; by this method co-load 5-flurouracil and antisense EGFR (epidermal growth factor receptor) plasmids into biodegradable PLGA/O-CMC nanoparticles. The mixture of PLGA (poly-lactide-coglycolide) and O-CMC (O-carboxmethylchitosan) had a SE effect, with no additional surfactant required 37. 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 increased cellular association and was prepared by multiple emulsion (o/w/o) solvent evaporation methods 38. Self-emulsifying sustained/controlled-release pellets To formulate and prepare SEDDS, there were some basic guidelines needed to conform: safety, compatibility, drug solubility, efficient self-emulsification efficiency and droplet size, etc. 39. Pellets, as a multiple unit dosage form, possess many advantages over conventional solid dosage forms, such as flexibility of manufacture, reduction of intrasubject and intersubject variability of plasma profiles and minimizing GI irritation without lowering drug bioavailability. Thus, it seems very appealing to combine the advantages of pellets with those of SEDDS by SE pellets. Spherical pellets with low friability and self-emulsifying properties can be produced by the standard extrusion/spheronization technique. The pellets are capable of transferring lipophilic compounds into the aqueous phase and have a high potential to increase the bioavailability of lipophilic drugs 40. M. Serratoni et al. presented controlled drug release from self-emulsifying pellets. The prepared self emulsifying system were formed by mixing oilsurfactant within solublised drug in appropriate concentrations, because higher quantity of drug incorporated into SES, could be precipitated when diluted with water. This SES was added into damp mass of microcrystalline cellulose and lactose monohydrate, water was then added to the prepared wet mass for extrusion-spheronization to form

14 585 P a g e International Standard Serial Number (ISSN): pellets. These pellets were coated by hydrophilic polymers namely ethyl cellulose then coated by aqueous solution of hydroxypropylmethyl cellulose in a fluid bed coater. The ability of this formulation to enhance dissolution of the model drug, where dissolution results for the uncoated pellets containing methyl or propyl parabens with and without the addition of self emulsifying system were compared 41. Self-emulsifying microsphere: You et al. formulated solid SE sustained-release microspheres using the quasi-emulsion solvent diffusion method for the spherical crystallization technique. Zedoary turmeric oil release behavior could be controlled by the ratio of hydroxypropyl methylcellulose acetate succinate to Aerosil 200 in the formulation. The plasma concentration time profiles were achieved after oral administration of such microspheres into rabbits, with a bioavailability of 135.6% with respect to the conventional liquid SEDDS 42. Self-emulsifying beads: Self emulsifying system can be formulated as a solid dosage form by using less excipients. Patil and Paradkar discovered that deposition of SES into the microchannels of porous polystyrene beads(ppb) was done by solvent evaporation. Porous polystyrene beads with complex internal void structures were typically produced by copolymerising styrene and divinyl benzene. It is inert and stable over a wide range of ph, temperature and humidity. Geometrical features, such as bead size and pore architecture of PPB, were found to govern the loading efficiency and in vitro drug release from SES-loaded PPB 43. Self-emulsifying suppositories: Some investigators proved that Solid-SEDDS could increase not only GI adsorption but also rectal/vaginal adsorption 44. Glycyrrhizin, which, by the oral route, barely achieves therapeutic plasma concentrations, can obtain satisfactory therapeutic levels for chronic hepatic diseases by either vaginal or rectal SE suppositories. The formulation included glycyrrhizin and a mixture of a C6 C18 fatty acid glycerol ester and a C6 C18 fatty acid macrogol ester 45. Self emulsifying solid dispersions: Solid dispersions could increase the dissolution rate and bioavailability of poorly water soluble drugs but still some manufacturing difficulties and stability problems existed. Serajuddin pointed out that these difficulties could be surmounted by the use of SE excipients SE excipients like Gelucire 144/14, Gelucire 150/02, Labrasol I1, Transcuto I1 and TPGS (tocopheryl polyethylene glycol 1000 succinate) have been widely used in this field Gupta et al. prepared SE solid

15 586 P a g e International Standard Serial Number (ISSN): 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 50/13was used as the dispersion carrier, while Neusilin US2 was used as the surface adsorbent 50. APPLICATIONS: Improvement in Solubility and bioavailability: If drug is incorporated in SEDDS, it increases the solubility because it circumvents the dissolution step in case of Class-II drug (Low solubility/high permeability). Ketoprofen, a moderately hydrophobic non steroidal anti-inflammatory drug (NSAID), is a drug of choice for sustained release formulation but it has has high potential for gastric irritation during chronic therapy. Also because of its low solubility, ketoprofen shows incomplete release from sustained release formulations. It is reported that the complete drug release from sustained release formulations containing ketoprofen in nano crystalline form 51. This formulation enhanced bioavailability due to increase the solubility of drug and minimizes the gastric irritation. Also incorporation of gelling agent in SEDDS sustained the release of Ketoprofen. In SEDDS, the lipid matrix interacts readily with water, forming a fine particulate Oil in-water (o/w) emulsion. The emulsion droplets will deliver the drug to the gastrointestinal mucosa in the dissolved state readily accessible for absorption. Therefore, increase in AUC i.e. bioavailability and Cmax is observed with many drugs when presented in SEDDS. Protection against Biodegradation: The ability of self emulsifying drug delivery system to reduce degradation as well as improve absorption may be especially useful for drugs, for which both low solubility and degradation in the GI tract contribute to a low oral bioavailability. Many drugs are degraded in physiological system, may be because of acidic PH in stomach, enzymatic degradation or, hydrolytic degradation etc. Such drugs when presented in the form of SEDDS can be well protected against these degradation processes as liquid crystalline phase in SEDDS might be act as barrier between degradating environment and the drug. Controlling the release of drug: Different formulation approaches that have been sought to achieve sustained release, increase the bioavailability, and decrease the gastric irritation of ketoprofen include preparation of matrix pellets of nano-crystalline ketoprofen, sustained release ketoprofen microparticles and floating oral ketoprofen systems and transdermal systems of ketoprofen. Preparation and stabilization of nano-

16 587 P a g e International Standard Serial Number (ISSN): crystalline or improved solubility forms of drug may pose processing, stability, and economic problems. This problem can be successfully overcome when Ketoprofen is presented in SEDDS formulation. This formulation enhanced bioavilability due to increase the solubility of drug and minimizes the gastric irritation. Also incorporation of gelling agent in SEDDS sustained the release of Ketoprofen 9. CONCLUSION Self-emulsifying drug delivery system is a promising approach to improve solubility, absorption and bioavailability of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDS, which have been shown to substantially improve oral bioavailability. SEDDS has the flexibility to develop into different solid dosage form. With future development of this technology, SEDDS will continue to enable novel applications in drug delivery and solve deficiency associated with the delivery of poorly soluble drugs. Thus this field required further exploration and research so as to bring out commercially available self emulsifying formulation. REFERENCES: 1. Roop K Khar, Vyas SP, Farhan J Ahmad, Gaurav K Jain. Lachman/Lieberman s The Theory and Practice of Industrial Pharmacy. 4 edn. CBS publishers; New Delhi; Mohsin K, Shahba A A and Alanazi F K,(2012), Lipid Based Self Emulsifying Formulations for Poorly Water Soluble Drugs-An Excellent Opportunity. Indian Journal of Pharmaceutical Education and Research,46(2), Bhargava P, Bhargava S, and Daharwal S J,(2011), Self Emulsifying Drug Delivery System: An approach to improve the solubility of poorly water soluble drug. Advanced Research in Pharmaceuticals & Biologicals,1(1), Patel P A, Chaulang G M, Akolkotkar A, Mutha S S, Hardikar S R and Bhosale A V,(2008), Self Emulsifying Drug Delivery System: A Review. Research J. Pharm. and Tech,1(4), Charman S A,(1992), Self emulsifying drug delivery systems: Formulation and biopharmaceutics evaluation of an investigational lipophilic compound. Pharm Res, 9 (1), Pouton C W, (1985), Self-emulsifying drug delivery system: Assessment of the efficiency of emulsification. Int J Pharm,27,

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