INTRODUCTION:

Oral route has been become major route of drug delivery for the treatment of many chronic diseases. But, in recent years the formulation of poorly soluble compounds presented interesting challenges for formulation scientists in the pharmaceutical industry because up to 40% of new chemical entities discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds, which leads to poor oral bioavailability and it cause high intra- and inter-subject variability and lack of dose proportionality^1,2. In past, these problems are overcome by modifying the physicochemical properties, such as salt formation and particle size reduction of the compound may be one approach to improve the dissolution rate of the drug, but these methods have their own limitations. Again to overcome these limitations, various other formulation strategies have been adopted including the use of cyclodextrins, nanoparticles, solid dispersions and permeation enhancers³.

Indeed, in some selected cases, these approaches have been successful. In recent years, much attention has focused on lipid based formulations to improve the oral bioavailability of poor water soluble drug compounds.

In fact, the most popular approach is the incorporation of the drug compound into inert lipid vehicles such as oils, surfactant dispersions, self-emulsifying formulations, emulsions and liposomes with particular emphasis on self-emulsifying drug delivery systems (SEDDS)^1,4,5.

Self-emulsifying drug delivery systems are isotropic mixtures of oil, surfactant, co-surfactant and drug that form fine oil-in-water emulsion when introduced into aqueous medium under gentle agitation^6,7,8. These formulations spread readily in the GI tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for self-emulsification⁹. SEDDS typically produce emulsions with a droplet size between 100 and 300 nm while SMEDDS are transparent micro emulsions with a droplet size of less than 50 nm also the concentration of oil in SMEDDS is less than 20 % as compared to 40-80% in SEDDS and these are physically stable formulations that are easy to manufacture upon mild agitation followed by dilution in aqueous media such as GI fluids, these systems can form fine oil-in-water (o/w) emulsions or micro-emulsions (SMEDDS)⁵. Apart from these two approaches, the self-nanoemulsifying drug delivery system (SNEDDS), which is well known for its potential to improve the aqueous solubility and oral absorption of lipophilic drugs (Pouton et al., 2000). SNEDDS is an isotropic mixture composed of oil, surfactant, co-surfactant and drug. It can readily disperse in the aqueous environment of the gastrointestinal tract to form a ﬁne oil-in-water emulsion with a droplet size less than 100 nm under gentle agitation for improving the oral bioavailability of poorly water-soluble drugs^5,10.

These are normally prepared as liquid dosage forms that can be administered in soft or hard gelatin capsules but these are having some disadvantages. These dis-advantages are overcome by formulating as solid forms of SEDDS by extrusion/ spheronization methods⁵. Compared to conventional emulsions, these lipid based formulations are thermodynamically stable with high solubilization capacity for lipophilic drugs.

Advantages of SEDDS:

· Improvement in oral bioavailability of numerous poorly water soluble drugs by increase in specific surface area gives more efficient drug transport through the intestinal aqueous boundary layer¹¹.

· SEDDS is a good candidate for oral delivery of hydrophobic drugs with adequate solubility in oils or oil/surfactant blends^12-14.

· Small droplets of oil (<5_m) in it, improves drug dissolution through providing a large interfacial area for partitioning of the drug between the oil and GIT fluid¹⁵.

· Ease of manufacture and scale- up is one of the most important advantages that make SEDDS unique when compared to other drug delivery systems like solid dispersions, liposomes, nanoparticles etc.

· It gives reduction in inter-subject and intra-subject variability and food effects on therapeutic performance of the drug in the body¹⁶.

· SEDDS also provide the advantage of increased drug loading capacity when compared with conventional lipid solution as the solubility of poorly water soluble drugs with intermediate partition coefficient (2<log P>4) are typically low in natural lipids and much greater in amphiphilic surfactants, co surfactants and co-solvents.

Disadvantages of SEDDS:

· The high surfactant level typically present in SEDDS formulations can lead to GI side-effects.

FORMULATION:

In the formulation of self emulsified drug delivery system, includes a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants, to water-soluble co-solvents, there are many different combinations that could be formulated for encapsulation in hard or soft gelatin or mixtures which disperse to give fine colloidal emulsions¹⁷. The following should be considered in the formulation of a SEDDS. The fundamental differences between Type I, II, III and IV formulations are given in the Table 1.

TYPE I:

Type I formulations are the simplest lipid products in which the drug is dissolved in digestible oil, usually a vegetable oil or medium chain triglyceride. These are safe food substances, classed as generally regarded as safe (GRAS) by regulatory agencies and do not present a toxicological risk to formulators. The low solvent capacity of triglycerides often prevents formulation in oil, but oil solutions may be a realistic option for potent drugs or compounds with log P (octanol /water partition coefficient) >4. Solvent capacity for less hydrophobic drugs can be improved by blending triglycerides with other oily excipients which include mixed mono and di-glycerides¹⁸. When an appropriate dose of the drug can be dissolved, Type I formulation may well be the system of choice, in view of its simplicity and biocompatibility. Generally, 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. However, for readily digestible formulations this process is typically efficient and facilitates formulation dispersion and drug solubilization may be catalyzed by lipid digestion.

TYPE II:

Type II formulations (typically referred to as self-emulsifying drug delivery systems, SEDDS) are isotropic mixtures of lipids and lipophilic surfactants (HLB<12) that self-emulsify to form fine oil-in-water emulsions when introduced in aqueous media. Self-emulsification is generally obtained at surfactant contents above 25% (w/w). However, at higher surfactant contents (> 50–60% w/w depending on the materials) the progress of emulsification may be compromised by the formation of viscous liquid crystalline gels at the oil/water interface¹⁵. PWSD can be dissolved in SEDDS and encapsulated in hard or soft gelatin capsules to produce convenient single unit dosage forms. Type II formulations provide the advantage of overcoming the slow dissolution step typically observed with solid dosage forms. SEDDS generate large interfacial areas which in turn allow efficient partitioning of drug between the oil droplets and the aqueous phase from where absorption occurs^10,14. Rapid release of the drug and increased drug solubilization in the gastrointestinal lumen were suggested to be responsible for the improved drug bioavailability.

TYPE III:

Type III formulations, commonly referred to as self-micro emulsifying drug delivery systems (SMEDDS), are defined by the inclusion of hydrophilic surfactants (HLB>12) and co-solvents such as ethanol, propylene glycol and polyethylene glycol. Type III formulations can be further segregated (somewhat arbitrarily) into Type IIIA and Type IIIB formulations in order to identify more hydrophilic systems (Type IIIB) where the content of hydrophilic surfactants and co-solvents increases and the lipid content reduces. 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 given the lower lipid content. Thus SEDDS formulation typically provide opaque dispersions with particle sizes >200 nm whereas SMEDDS formulations disperse to give smaller droplets with particle sizes <200 nm and provide optically clear or slightly opalescent dispersions, more consistent with the presence of a micro-emulsion. SEDDS and SMEDDS formulations have contributed to the improvement of the oral bioavailability of several PWSD and many of these examples of a successfully marketed SMEDDS formulation is the Neoral® cyclosporine formulation. In contrast to the earlier Sandimmun® cyclosporin formulation63 which formed a coarse emulsion on dispersion into water, Neoral spontaneously forms a transparent and thermodynamically stable dispersion with a droplet size below 100 nm when introduced into an aqueous media.

TYPE IV:

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 to formulations containing simple glyceride lipids and also produce very fine dispersions when introduced in to an aqueous media. This in turn has been suggested to lead to rapid drug release and increased drug absorption. Little is known, however, as to the solubilization 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 comprising natural oils. An example of a Type IV formulation is the current capsule formulation of the HIV protease inhibitor amprenavir (Agenerase) which contains tocopherol polyethylene glycosuccinate (TPGS) as a surfactant and polyethylene glycol (PEG) 400 and propylene glycol as co-solvents¹⁹.

Excipients used in SEDDS:

In the preparation of self emulsifying drug delivery system mainly we are using the oils, surfactants and co-solvents. Self emulsification occurs only at the specific characteristics such are nature of the oil/surfactant pair, the surfactant concentration and oil/surfactant ratio and the temperature ^15,20,21.

Oils:

The oil represents one of the most important excipients in the SEDDS formulation not only because it can solubilize marked amounts of the lipophilic drug or facilitate self emulsification but also and mainly because it can increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract depending on the molecular nature of the triglyceride²². Long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used in the design of SEDDSs. Modified or hydrolyzed vegetable oils have contributed widely to the success of SEDDSs owing to their formulation and physiological advantages and their degradation products resemble the natural end products of intestinal digestion¹⁰. Novel semi synthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the regular medium- chain triglyceride¹¹.

Surfactants:

Nonionic surfactants with high hydrophilic–lipophilic balance (HLB) values are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). The usual surfactant strength ranges between 30–60% w/w of the formulation in order to form a stable SEDDS. Emulsifiers of natural origin are preferred since they are considered to be safer than the synthetic surfactants⁵. Surfactants have 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 high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules⁹.

Co-solvents:

The production of an optimum SEDDS requires relatively high concentrations (generally more than 30% w/w) of surfactants. Organic solvents such as, ethanol, propylene glycol (PG), and polyethylene glycol (PEG) are suitable for oral delivery, and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base. These solvents can even act as co-surfactants in micro-emulsion systems. On the other hand, alcohols and other volatile co-solvents have the disadvantage of evaporating into the shells of the soft gelatin, or hard, sealed gelatin capsules in conventional SEDDS leading to drug precipitation. Thus, alcohol free formulations have been designed¹⁰, but their lipophilic drug dissolution ability may be limited. Cosolvents like diethylene glycol monoethyle ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role of the cosurfactant in the microemulsion systems.

Mechanism of self-emulsification:

According to Reiss, self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. 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:

DG= S N_iP_i2s

Where, DG is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius r and s 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 forms a monolayer of emulsion droplets, and hence reduces the interfacial energy, as well as providing a barrier to prevent coalescence¹⁰.

Self-emulsifying drug delivery systems (SEDDS) should be considered to overcome problems associated with poor water solubility of drugs. These systems have a unique property: they are able to self-emulsify rapidly in the gastrointestinal ﬂuids, forming under the gentle agitation provided by gastrointestinal motion ﬁne O/W emulsions. This ﬁne O/W emulsion results in small droplets of oil dispersed in the gastrointestinal ﬂuids that provide a large interfacial area enhancing the activity of the 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. Further, in most cases the surfactant used for this kind of formulations promotes an increase on 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 at the same time intestinal epithelial permeability. Moreover, the oil droplets lead to a faster and more uniform distribution of the drug in the gastrointestinal tract, minimizing the irritation due to the contact between the drug and the gut wall^6,9,11,23. Last but not least it must be mentioned the impact of the lipids on the oral bioavailability of the drug compounds that exert their effect through several mechanisms including the protect ion of the drug from the enzymatic or chemical degradation in the oil droplets and the activation of lipoproteins promoting the transport of lipophilic drugs⁷.

PREPARATION METHODS:

Usually in olden days SEDDS are prepared in the form of liquid state that liquid SEDDS are generally enclosed by soft or hard gelatin capsules to facilitate oral administration but it produce some disadvantages, such as high production costs, low drug incompatibility and stability, drugs leakage and precipitation, capsule ageing. Irreversible drugs/ excipients precipitation may cause severe problem²⁴. More importantly, the large quantity (30–60%) of surfactants in the formulations can induce gastrointestinal (GI) irritation. To overcome these problems by preparing the solid- SEDDS, such are prepared by the incorporation of liquid SEDDS into a solid dosage form is compelling and desirable, and some solid self-emulsifying (SE) dosage forms have been initially explored, such as SE tablet and pellets^25,26.

Generally the self emulsifying formulations were prepared by dissolving the formulation specified amount of active medicament in the mixture of surfactant, oil and co-surfactant mixture at 60^◦C in an isothermal water bath. For the formulation and preparation of SEDDS some basic guidelines are needed to conform: safety, compatibility, drug solubility, efficient self-emulsification efficiency and droplet size, etc^12,27. Preparation methods of liquid SEDDS and solid SEDDS are described below.

Preparation of the liquid SEDDS:

Liquid SEDDS are prepared based on the pilot studies such as equilibrium solubility, pseudo ternary phase diagram and super saturation studies. An emulsifying system, which is in equilibrium solubility of drug (w/w), could be diluted with water (1:100) without precipitation within 2 h. The composition of the optimized blank SEDDS is 30% oil, 60% surfactant (2:1) and 10% co-surfactant²⁸.

The preparation of the SEDDS involved the following steps:

1. Mixing of oil, surfactants and co-surfactant at 50◦C with a magnetic stirrer.

2. Then dissolve drug in the blank SEDDS with stirring until to form an isotropic mixture.

3. Cooling to room temperature and equilibrating for 24 h before use.

Preparation of the solid SEDDS:

Solid SEDDS were developed mainly by adsorption of solid carriers, spray drying, melt extrusion, dry emulsion, solid dispersion etc. These solid SEDDS can be converted into pellets, tablets and capsules. SE tablets and pellets are prepared by extrusion/spheronization²⁸.

i) Solid carriers These solid carriers have property to absorb liquid/ semisolid formulation as self emulsifying system (SES). It is a simple procedure, where SES is incorporated into a free flowing powder material which has adsorption quality. The mixture is uniformly adsorbed by mixing in a blender. This solid mixture is filled into capsule or added to more excipient before compression into tablets²⁹. The above mixture was solidified to powder forms using three kinds of adsorbents: microporous calcium silicate, magnesium aluminum silicate and silicon dioxide³⁰.

ii) Spray Drying In this technique first the prepared formulation containing oil, surfactant, drug, solid carrier etc, is sprayed into a drying chamber through a nozzle. The volatile vehicles first evaporate leaving behind small solid particles. These particles are then filled into capsules or compressed into tablets.

iii) Melt extrusion This formulation technique depends on the property of the plastic mass material which can be easily extruded and spheronised with pressure. Here there is no need for addition of liquid form of excipient but a constant temperature and pressure need to be maintained³¹.

iv) Dry Emulsion It is mainly O/W emulsion, which is then converted into solid form by spray drying/solid carrier/ freeze drying^32-35.

DOSAGE FORMS FROM SELF EMULSIFYING SYSTEM:

Self emulsifying capsule: It is a capsules containing liquid or semisolid form of self emulsifying system. In the GIT, the capsules get dispersed to SES uniformly in the fluid to micron size, enhancing bioavailability. Second type of self emulsifying capsule is solid SES filled into capsule.

Self emulsifying tablets: Nazzal et al developed self‐nanoemulsified tablet dosage form of Ubiquinone. The main objectives of this study were to study effect of formulation ingredients on the release rate of Ubiquinone and to evaluate an optimized self nanoemulsified tablets formulation. The first prepared self nanoemulsion system containing Ubiquinone was prepared as nanoemulsion, this nanoemulsion was adsorbed by granular materials and then compressed to form tablets. This tablets will liquify at body temperature without agitation and at gastrointestinal conditions, agitation as peristaltic movement will lower the liquification time, resulting in faster emulsification with increased plasma concentration. Different formulation ratio shows varying dissolution profile at constant speed/agitation. These tablets showed good release profiles with acceptable tablet properties³⁶.

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 SEDDS⁵⁴.

Self emulsifying nanoparticle: Nanoparticle technology can be applied to the formulation of self emulsifying nanoparticle. One of the solvent was injection, in this method the prepared molten lipid mass contained lipid, surfactant and drug. 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 obtained³⁷.

Self emulsifying pellets: Self emulsifying formulation of progesterone presented as in pellets and the liquid form was compared with an aqueous suspension of progesterone comparative bioavailability study was performed in dogs. The in vitro dissolution tests showed that nearly 100% of progesterone dissolved within 30 min and within 5 min from capsules containing the progesterone dissolved in self emulsifying system. From the aqueous suspension, 50% of the dose was released within 60 min. They also showed that pellets administered orally to dogs were tested versus the same dose of progesterone dissolved in liquid SES in capsules or a suspension of micronized progesterone. In that SES pellets and SES solution had higher plasma levels of progesterone at each time point as compared to the aqueous suspension of progesterone³⁸.

Franceschinis et al developed a method of producing self‐emulsifying pellets by wet granulation. Here they first developed a binder solution containing an oil(mono and diglycerides), polysorbate 80 and model drug nimesulide in different proportion. This oil surfactant mixture was stirred then added to water to form Self‐ emulsifying system. Second step was to prepare granules from microcrystalline cellulose and lactose in a granulator. These binder solutions were sprayed on to the granules and pellets were formed by increasing the speed of the granulator. Pellets were able to generate significantly smaller droplets with respect to corresponding emulsions³⁹. Serratoni et al presented controlled drug release from self‐emulsifying pellets. The prepared self emulsifying system were formed by mixing oil surfactant 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 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 compared⁴⁰.

Self emulsifying beads: Self emulsifying system can be formulated as a solid dosage form by using less excipient. Patil and Paradkar discovered that deposition of SES into microporous polystyrene beads was done by solvent evaporation. Porous polystyrene beads with complex internal void structures were typically produced by co-polymerising 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 PPB⁴¹.

CHARACTERISATION OF SEDDS:

The prepared SEDDS are characterized for the physicochemical properties of the formulations. The characteristics of both liquid SEDDS and solid SEDDS are discussed below.

Droplet size determination:

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 ^9,42. The possible explanation to the enhanced absorption could be that the smaller the droplet size, the larger the interfacial surface area, which facilitate and improve drug absorption. Moreover, some authors have paid much attention to the drug solubilization capacity in the lipid formulations when dilution and digestion in the GIT, which would inﬂuence the subsequent dispersion and absorption of drug^43,44,45. Photon correlation spectroscopy (PCS) is a useful method for determination of emulsion droplet size especially when the emulsion properties do not change upon inﬁnite aqueous dilution, a necessary step in this method. However, microscopic techniques should be employed at relatively low dilutions for accurate droplet size evaluation⁵.

Assessment of self emulsification:

The USP 24 rotating paddle apparatus was used to evaluate the efficiency of self-emulsiﬁcation of different mixtures. One gramme of each mixture was added to 200 ml of distilled water with gentle agitation condition provided by a rotating paddle at 70 rpm and at a temperature o f 37^oC. The process of self-emulsiﬁcation was visually monitored for the rate of emulsiﬁcation and for the appearance of the produced emulsions.

Size and shape analysis of pellets:

The shape of pellets was evaluated within the 800–1000 m fraction by a digital microscope, with an optical zoom of 40×0.17 and an eye piece of 10×22. A set of standard sieves agitated for 20 min with a sieve shaker was used for performing the size analysis of 100 g of the produced pellets⁴⁶. Shape analysis was performed on 1000 pellets within the 1000–1400m fraction using a stereomicroscope, digital camera and image analysis software.

Determination of emulsifying time:

The emulsiﬁcation time of SEDDS was determined according to Unite d State Pharmacopeia (USP) XXIII, dissolution apparatus II.

In brief, 0.5 mL of each formulation was added drop wise to 500 mL of puriﬁed water at 37^oC Gentle agitation was provided by a standard stainless steel dissolution paddle rotating at 50 rpm. The emulsiﬁcation time was assessed visually as reported by Bachynsky et al⁴⁷.

Zeta potential determination:

The emulsion stability is directly related to the magnitude of the surface charge^48,49,50. The zeta potential of the diluted SEDDS formulations was measured using a Zeta Meter System. The SEDDS were diluted with a ratio of 1:2500 (v/v) with distilled water and mixed for 1 min using a magnetic stirrer. Measuring the zeta potential in simulated gastric ﬂuid (SGF) was a challenge due to the high speciﬁc conductance of the media that restricts the maximum tolerated voltage applied through the cell. The measured zeta potential in simulated intestinal ﬂuid (SIF) was not signiﬁcantly different from the zeta potential measured in distilled water. Based on the above we favored the use of distilled water as a commonly used diluent in zeta potential measurements. Zeta potential of each SEDDS was determined in triplicate.

Polarity of emulsion droplet:

Emulsion droplet polarity is also a very important factor in characterizing emulsiﬁcation efficiency (Shah NH et al 1994). The HLB, chain length and degree of unsaturation of the fatty acid, molecular weight of the hydrophilic portion and concentration of the emulsiﬁer have an impact on the polarity of the oil droplets. Polarity represents the afﬁnity of the drug compound for oil and/or water and the type of forces formed. Rapid release of the drug into the aqueous phase is promoted by polarity.

The charge on the oil droplets of SEDDS is another property that needs to be assessed⁵. Melting properties and polymorphism of lipid or drug in SES may be established by X- ray diffraction and differential scanning calorimetry.

PHARMACEUTICAL APPLICATIONS OF SEDDS:

SEDDS are a promising approach for the formulation of drug compounds with poor aqueous solubility. So the numerous hydrophobic and poorly water soluble drugs are prepared in the form of SEDDS are given below. The potential for lipidic self-emulsifying drug delivery systems (SEDDS) to improve the oral bioavailability of a poorly absorbed, antimalarial drug

(Halofantrine, HF) has been investigated in fasted beagles in 1998. The lipid based formulations of HF-base afforded a 6-8 fold improvement in absolute oral bioavailability relative to previous data of the solid HF⁵¹. SEDDS also shows signiﬁcant improvement of the bioavailability of phenytoin that may solve some of the inter-subject and intra-subject variability of phenytoin if used in human trials⁵². The oral bioavailability of dexibuprofen was enhanced by a novel solid Self-emulsifying drug delivery system (SEDDS), in this the plasma concentrations of drug in solid SEDDS were signiﬁcantly twofold higher than that of dexibuprofen powder (P < 0.05)⁵³.

A supersaturable self-emulsifying drug delivery system (S-SEDDS) of paclitaxel was developed employing HPMC as a precipitation inhibitor with a conventional SEDDS formulation. A pharmacokinetic study showed that the paclitaxel S-SEDDS formulation produces approximately a 10-fold higher maximum concentration (Cmax) and a 5-fold higher oral bioavailability (F 9.5%) compared with that of the orally administered Taxol formulation (F 2.0%) and the SEDDS formulation without HPMC (F 1%)⁴³. Examples of SEDDS designed for the oral delivery of lipophilic drugs are given the Table no: 2.

CONCLUSION:

Self-emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability by emulsification of lipophilic drugs gives faster dissolution rates and absorption. With future development of this technology, SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

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Received on 22.06.2010 Modified on 02.07.2010

Research J. Pharm. and Tech. 4(2): February 2011; Page 175-181

Formulation Type	Composition	Characteristics	Advantages	Dis-advantages
Type I	Oils without surfactants (e.g. tri-, di-and mono-glycerides)	Non-dispersing, requires digestion	GRAS status; simple; excellent capsule compatibility	Formulation has poor solvent capacity unless drug is highly lipophilic
Type II	Oils and water insoluble surfactants	SEDDS formed without water soluble components	Unlikely to lose solvent capacity on dispersion	Turbid o/w dispersion (particle size 0.25-2 µm)
Type III	Oils, surfactants, co-solvents (both water insoluble and water soluble excipient)	SEDDS/SMEDDS formed with water soluble components	Clear or almost clear dispersion; drug absorption without digestion	Possible loss of solvent capacity on dispersion; less easily digested
Type IV	Water-soluble surfactants and co-solvents (no oils)	Formulation disperses typically to form a micellar solution	Formulation has good solvent capacity for many drugs	Likely loss of solvent capacity on dispersion; may not be digestible

Type of delivery system	Oil	Surfactant(s)	Drug compound
SEDDS Solid	A mixture of mono- and diglycerides of oleic acid	polyglycolyzed mono-, di- and triglycerides (HLB = 14), Tween 80 (HLB = 15)	Ontazolast
SEDDS (Sandimme)	Olive oil	Polyglycolyzed glycerides	CsA
SEDDS	Medium chain saturated fatty acids, peanut oil	Medium chain mono- and diglycerides. Tween 80, PEG25 glyceryl trileate, poly glycolyzed glycerides (HLB=6-9)	A naphthalene derivative
SEDDS	Medium chain saturated fatty acids	PEG25 glyceryl trioleate	5-(5-(2,6-dichloro-4-(dihydro-2 oxazolyl) phenoxy)pentyl)-3 methyl isoxazole)
SEDDS (+ve charged)	Ethyl oleate	Tween 80	CsA
SEDDS (+ve charged)	Ethyl oleate	Tween 80	Progesterone
SEDDS	Myvacet 9-45 or Captex 200	Labrosol(HLB=14) or Labrofac CM10(HLB=10), lauroglycol (HLB=4)	CoQ₁₀
SEDDS (Norvir)	Oleic acid	Polyoxyl 35 castor oil	Ritonavir
SEDDS (Fortovase)	Oleic acid –di alfa tocopherol	Medium chain mono- and diglycerides.	Saquinavir