These fine emulsions disperse readily in GIT providing large surface area for drug absorption with minimum GIT irritation. SEDDS can be easily formulated with little energy input and are more stable than conventional emulsions. The following figure has shown all the possible approaches to improve the oral bioavailability.

Thus, self emulsifying system offers an excellent vehicle for the formulation of poorly water soluble drugs with dissolution rate limited absorption ⁷. Many researchers have reported various rational applications of SEDDS for delivering and targeting lipophilic drugs, e.g., coenzyme Q10, vitamin E, halofantrine and cyclosporin A ⁸.

Solid self emulsifying drug delivery system (S-SEDDS) have been extensively exploited in recent years, as they frequently represent more effective alternative to conventional liquid SEDDS. From the perspective of dosage forms, S-SEDDS mean solid dosage forms with self-emulsification properties ^{6, 9}.

ADVANTAGES OF SEDDS:^{1, 5, 10, 11}

ü Control of delivery profile.

ü More consistent drug absorption.

ü Protection of sensitive drugs substances.

ü Protection of drugs from the gut environment.

ü Enhanced oral bioavailability enabling reduction in dose.

ü Selective targeting of drug toward specific absorption window in GIT.

DRAWBACK OF SEDDS: ^{2, 4, 11}

ü Chemical instabilities of drugs.

ü The large quantity of surfactant in self-emulsifying formulations (30-60%) irritates.

ü Need of different prototype lipid based formulations to be developed and tested in vivo in a suitable animal model.

ü 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.

MECHANISM OF SELF-EMULSIFICATION:

The process by which self emulsification takes place is not yet well understood. However, 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. In addition, the free energy of a conventional emulsion formation is a direct function of the energy required to create a new surface between the two phases and can be described by equation,

Where, G = free energy associated with the process (ignoring the free energy of mixing), N = number of droplets, r = radius, = represents the interfacial energy.

With time, the two phases of the emulsion will tend to separate, in order to reduce the interfacial area, and subsequently, the free energy of the systems. Therefore, the emulsions resulting from aqueous dilution are stabilized by conventional emulsifying agents, which form a monolayer around the emulsion droplets, and hence, reduce the interfacial energy, as well as providing a barrier to 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, emulsification process occurs spontaneously) ^{12, 13, 14}.

According to Wakerly et al., the addition of a binary mixture (oil/non ionic surfactant) to water results in interface formation between the oil and aqueous-continuous phases, followed by the solubilization of water within the oil phase owing to aqueous penetration through the interface. This will occur until the solubilization limit is reached close to the interface. Further aqueous penetration will result in the formation of the dispersed LC (Liquid Crystal) phase.

As the aqueous penetration proceeds, eventually all material close to the interface will be LC, the actual amount depending on the surfactant concentration in the binary mixture. Once formed, rapid penetration of water into the aqueous cores, aided by the gentle agitation of the self-emulsification process, causes interface disruption and droplet formation. The high stability of these self-emulsified systems to coalescence is considered to be due to the LC interface surrounding the oil droplets ^{15, 16}.

Later, Craig et al. used the combination of particle size analysis and low frequency dielectric spectroscopy (LFDS) to examine the self-emulsifying properties of a series of Imwitor 742 (a mixture of mono- and diglycerides of capric and caprylic acids)/Tween 80 systems. The dielectric studies provided evidence that the formation of the emulsions may be associated with LC formation, although the relationship was clearly complex. The above technique also pointed out that the presence of the drug may alter the emulsion characteristics, possibly by interacting with the LC phase ^{17,
18, 19}.

EXCIPIENTS USED IN SEDDS:

Self emulsiﬁcation has been shown to be speciﬁc to the nature of the oil/surfactant pair; the surfactant concentration and oil/surfactant ratio; and the temperature at which self emulsiﬁcation occurs. In support of these facts, it has also been demonstrated that only very speciﬁc pharmaceutical excipient combinations could lead to efficient self emulsifying systems.

1. OILS:

The oil represents one of the most important excipients in the SEDDS formulation. Both long and medium chain triglyceride oils with different degrees of saturation have been used for the design of self-emulsifying formulations. Furthermore, edible oils which could represent the logical and preferred lipid excipient choice for the development of SEDDS are not frequently selected due to their poor ability to dissolve large amounts of lipophilic drugs ⁷. Modiﬁed or hydrolyzed vegetable oils have been widely used since these excipients form good emulsiﬁcation systems with a large number of surfactants approved for oral administration and exhibit better drug solubility properties. They offer formulative and physiological advantages and their degradation products resemble the natural end products of intestinal digestion. Novel semi synthetic medium chain derivatives, which can be deﬁned as amphiphilic compounds with surfactant properties, are progressively and effectively replacing the regular medium chain triglyceride oils in formulations^{6, 12}.

2. SURFACTANTS:

Several compounds exhibiting surfactant properties may be employed for the design of self-emulsifying systems, the most widely recommended ones being the non-ionic surfactants with a relatively high hydrophilic−lipophilic balance (HLB). The commonly used emulsiﬁers are various solid or liquid ethoxylated polyglycolyzed glycerides and polyoxyethylene 20 oleate (Tween 80) ³. Safety is a major determining factor in choosing a surfactant. Emulsiﬁers of natural origin are preferred since they are considered to be safer than the synthetic surfactants. However, these excipients have a limited self-emulsiﬁcation capacity. Non-ionic surfactants are less toxic than ionic surfactants but they may lead to reversible changes in the permeability of the intestinal lumen. Usually the surfactant concentration ranges between 30 and 60% w/w in order to form stable SEDDS. It is very important to determine the surfactant concentration properly as large amounts of surfactants may cause GI irritation ⁹.

The surfactant involved in the formulation of SEDDS should have a relatively high HLB and hydrophobicity so that immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media (good self-emulsifying performance) can be achieved. For an effective absorption, the precipitation of the drug compound within the GI lumen should be prevented and the drug should be kept solubilized for a prolonged period of time at the site of absorption. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. There is a relationship between the droplet size and the concentration of the surfactant being used^{13, 20}. The below table no. 1 contains all the examples of surfactants, co-surfactant, and co-solvent which used in commercial formulations.

3. CO-SOLVENTS:

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 also act as co-surfactants in microemulsion systems ²¹. 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 designed, but their lipophilic drug dissolution ability may be limited^22,
23.

FORMULATION OF SEDDS:

SEDDS is critical because the drug interferes with the self emulsification process to a certain extent, which leads to a change in the optimal oil–surfactant ratio. So, the design of an optimal SEDDS requires Preformulation solubility and phase-diagram studies. In the case of the prolonged SEDDS, formulation is made by adding the polymer or gelling agent ¹⁴.

The method of making self emulsifying drug delivery system for increasing the bioavailability of a drug and/or pharmaceutical ingredient by emulsifying the drug with the self emulsifying excipient includes various steps as described below.

1. Phase behaviour (Phase Diagram) of three, component systems of oil, water and surfactant are often represented by isothermal triangular phase diagrams ²².

2. Solubilizing a poorly water-soluble drug and/or pharmaceutical ingredient, in a mixture of surfactant, cosurfactant and solvent.

3. Now mix the oil phase suitably prepared, if necessary, by heating or other preparatory means, to the solubilized drug formulation and thoroughly mixed.

4. The emulsion can then be added to a suitable dosage form such as soft or hard filled gelatin capsules and allowed to cool²³.

The table no. 2 had shown the example of bioavailability enhancement of poorly soluble drug after administration through SEDDS formulations.

METHODS TO EVALUATE SELF-EMULSIFYING PERFORMANCES:

1. 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.

5. a. Heating cooling cycle: Six cycles between refrigerator temperature (4⁰C) and at 45⁰C 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 21⁰C and 25⁰C with storage at each 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 ^{19, 24, 25}.

Table: 2 Example of bioavailability enhancement of poorly soluble drug after administration through SEDDS formulations ¹⁹

Cyclosporin	Carvediol
Halofantrine	Danazol
Ontazolast	Seocalcitol
Vitamin E	Silymarin
Atovaquone	Atorvastatin
Indomethacin	Itraconazole
Simvastatin	Coenzyme Q10
Progesteron	Biphenyl Dimethyl,Dicarboxylate

2. Dispersibility test:

The efficiency of self-emulsification is assessed of oral nano or micro using a standard USP XXII dissolution apparatus II. One millilitre of each formulation was added to 500 ml of water at 37±0.5⁰C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle agitation ²⁶. 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, greyish 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 ^{27, 28, 29}.

3. Turbidimetric Evaluation:

Nepheloturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quantity of Self-emulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on magnetic plate at ambient temperature, and the increase in turbidity is measured 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) ^{30, 31}.

4. 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 system should not too thick to create a problem. The rheological properties of the emulsion are evaluated by Brookfield viscometer. These viscosity determinations confirm whether the system is w/o or o/w. If 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 ^{32, 33}.

5. Droplet Size Analysis:

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 ^{34,
35, 36}.

6. Refractive Index and Percent Transmittance:

Refractive index and percent transmittance proved the transparency of formulation. The R.I of the system is measured by refractometer by placing drop of solution on slide and it compare with water (1.333). The percent transmittance of the system is measured using UV-spectrophotometer keeping 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 ³².

7. Electro conductivity Study:

The SEDDS contains ionic or non-ionic surfactant, oil, and water. So, this test is used to measure the electoconductive nature of system. The electro conductivity of resultant system is measured by electoconductometer ³⁵.

8. In vitro Diffusion Study:

In vitro diffusion studies are performed to study the release behaviour of formulation from liquid crystalline phase around the droplet using dialysis technique ³⁶.

9. 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 ¹².

10. Determination of self microemulsification time:

The emulsification time of SMEDDS was determined according to USP 22, dissolution apparatus II. 100 to 500mg of each formulation added drop wise to 500 ml purified water at 37˚C. Gentle agitation was provided by a standard stainless steel dissolution paddle rotating at 50 r/min. Emulsification time was assessed visually ^{17, 37}.

11. In vivo study:

P. Patil et al., show the effect of test formulation, on plasma lipid profiles was determined by comparison with reference formulation. Blood samples were collected under light ether anaesthesia by retro orbital puncture at predetermined time intervals, viz., before treatment, and after 5, 10, 15 and 21days in anticoagulated (EDTA-treated) glass vials. Plasma was separated by centrifugation at 3000 rpm for 25 min and stored frozen until further use.

T.R. Kommuru et al., carried out the bioavailability of two formulations of CoQ10, an optimized self-emulsifying formulation and a powder ﬁlled capsule formulation, were compared in dogs (coonhounds) ^8,
37.

RECENTS IN SELF-EMULSIFYING DRUG DELIVERY SYSTEM:

Traditional preparation of SEDDS involves dissolution of drugs in oils and their blending with suitable solubilizing agents. However, SE formulations are normally prepared as liquids that produce 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. Furthermore, incompatibility problems with the capsule shell are common ¹.

More importantly, the large quantity (30–60%) of surfactants in the formulations can induce gastrointestinal (GI) irritation. To address these problems, S-SEDDS have been investigated, as alternative approaches. Such systems require the solidiﬁcation of liquid self-emulsifying (SE) ingredients to powders/nanoparticles to create various solid dosage forms. (SE tablets and pellets etc).

Thus, S-SEDDS combine the advantages of SEDDS (i.e. enhanced solubility and bioavailability) with those of solid dosage forms. (e.g. low production cost, convenience of process control, high stability and reproducibility, better patient compliance)

To date, there have been some studies that mainly focus on the preparation and characterization of a single, solid SE dosage form, yet relatively few that introduce S-SEDDS in a systemic way, especially with respect to dosage form development and preparation techniques ². The following table no. 3 contains all the marketed formulations by self-emulsifying systems.

SOLID SELF-EMULSIFYING DRUG DELIVERY SYSTEM:

SEDDS are usually, however, 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 frequently represent more effective alternatives to conventional liquid SEDDS. From the perspective of dosage forms, S-SEDDS mean solid dosage forms with self-emulsiﬁcation properties. S-SEDDS focus on the incorporation of liquid/semisolid SE ingredients into powders/nanoparticles by different solidiﬁcation techniques (e.g. adsorptions to solid carriers, spray drying, melt extrusion, nanoparticles technology, and so on). Such powders/nanoparticles, which refer to SE (Self Emulsifying) nanoparticles/dry emulsions/solid dispersions, are usually further processed into other solid SE dosage forms, or, alternatively, ﬁlled into capsules (i.e. SE capsules). SE capsules also include those capsules into which liquid/semisolid SEDDS are directly ﬁlled without any solidifying excipient.

In the 1990s, S-SEDDS were usually in the form of SE capsules, SE solid dispersions and dry emulsions, but other solid SE dosage forms have emerged in recent years, such as SE pellets/tablets, SE microspheres/nanoparticles and SE suppositories/implants ^{1, 11, 38}.

SOLIDFICATION TECHNIQUES FOR TRANSFORMING LIQUID/SEMISOLID SEDDS TO S-SEDDS:^{1, 2, 38 – 47}

1. 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:

(i) Heating of the semisolid excipient to at least 20⁰C above its melting point

(ii) Incorporation of the active substances (with stirring)

(iii) Capsule ﬁlling with the molten mixture and

(iv) Cooling to room temperature.

For liquid formulations, it involves a two-step process:

(i) Filling of the formulation into the capsules

(ii) Sealing of the body and cap of the capsule, either by banding or by microspray sealing.

In parallel with the advances in capsule technology proceeding, liquid Oros technology (Alza Corporation) has been designed for controlled delivery of insoluble drug substances or peptides. This system is based on osmotic principles and is a liquid SE formulation system. It consists of an osmotic layer, which expands after coming into contact with water and pumps the drug formulation through an oriﬁce in the hard or soft capsule.

A primary consideration in capsule ﬁlling is the compatibility of the excipients with the capsule shell. The liquid/semisolid lipophilic vehicles compatible with hard capsules were listed by Cole et al. The advantages of capsule ﬁlling are simplicity of manufacturing; suitability for low dose highly potent drugs and high drug loading (up to 50% (w/w)) potential ^{1, 38}.

2. 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 air ﬂow pattern and the drying chamber design are selected according to, drying characteristics of the product and powder speciﬁcation ^{39,
40, 41}.

3. 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 formulation onto 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 ^{42, 43}.

Solid carriers can be microporous inorganic substances, high surface area colloidal inorganic adsorbent substances, cross linked polymers or nanoparticles adsorbents, for example, silica, silicates, magnesium trisilicate, magnesium hydroxide, talcum, crospovidone, cross linked sodium carboxymethyl cellulose and crosslinked polymethyl methacrylate. Cross linked polymers create a favourable environment to sustain drug dissolution and also assist in slowing down drug reprecipitation. Nanoparticle adsorbents comprise porous silicon dioxide (Sylysia 550), carbon nanotubes, carbon nanohorns, fullerene, charcoal and bamboo charcoal ^{44, 45}.

4. Melt granulation:

Melt granulation is a process in which powder agglomeration is obtained through the addition of binders that melts or softens at relatively low temperatures. As a ‘one-step’ operation, melt granulation offers several advantages compared with conventional wet granulation, since the liquid addition and the subsequent drying phase are omitted. Moreover, it is a good alternative to the use of solvent ^{2, 46}.

The main parameters that control the granulation process are impeller speed, mixing time, binder particle size, and the viscosity of the binder. A wide range of solid and semisolid lipids can be applied as meltable binders. The 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 usually used before, probably owing to its SE property. Other lipid-based excipients evaluated for melt granulation to create solid SES include lecithin, partial glycerides, or polysorbates.

The melt granulation process was usually used for adsorbing SES (lipids, surfactants, and drugs) onto solid neutral carriers (mainly silica and magnesium aluminometa silicate) ^{47, 48}.

5. Melt extrusion/extrusion spheronization:

Melt extrusion is a solvent free process that allows high drug loading (60%), as well as content uniformity. Extrusion is a procedure of converting a raw material with plastic properties into a product of uniform shape and density, by forcing it through a die under controlled temperature, product ﬂow, and pressure conditions. The size of the extruder aperture will determine the approximate size of the resulting spheroids. The extrusion–spheronization process is commonly used in the pharmaceutical industry to make uniformly sized spheroids (pellets) ⁴⁵.

The extrusion–spheronization process requires the following steps: dry mixing of the active ingredients and excipients to achieve a homogeneous powder; wet massing with binder; extrusion into extrudate; spheronization from the extrudate to spheroids of uniform size; drying; sifting to achieve the desired size distribution and coating (optional).

In the wet masses comprising SES (polysorbate 80 and mono-/ di-glycerides), lactose, water and MCC, the relative quantities of SES and water had a signiﬁcant effect on the extrusion force, size spread, disintegration time, and surface roughness of pellets. Studies suggested that the maximum quantity of this SES that can be solidiﬁed by extrusion spheronization occupies 42% of the dry pellet weight. Generally, the higher the water level, the longer the disintegration time. The rheological properties of wet masses may be measured by an extrusion capillary. It has been shown that SES containing wet mass with a wide range of rheological characteristics can be processed, but a single rheological parameter cannot be used to provide complete characterization of how well it can be processed by extrusion–spheronization.

Applying extrusion–spheronization, SE pellets of diazepam and progesterone and bi-layered cohesive SE pellets have been prepared ^{1, 49}.

DOSAGE FORM DEVELOPMENT OF S-SEDDS:

1. Dry emulsions:

Dry emulsions are powders from which emulsion spontaneously occurs in vivo or when exposed to an aqueous solution. Dry emulsions can be useful for further preparation of tablets and capsules.

Dry emulsion formulations are typically prepared from oil/water (O/W) emulsions containing a solid carrier (lactose, maltodextrin, and so on) in the aqueous phase by rotary evaporation, freeze-drying or spray drying. Myers and Shively obtained solid state glass emulsions in the form of dry ‘foam’ by rotary evaporation, with heavy mineral oil and sucrose. Such emulsiﬁable glasses have the advantage of not requiring surfactant. In freeze-drying, a slow cooling rate and the addition of amorphous cryoprotectants have the best stabilizing effects, while heat treatment before thawing decreases the stabilizing effects. The technique of spray drying is more frequently used in preparation of dry emulsions. The O/W emulsion was formulated and then spray-dried to remove the aqueous phase. The most exciting ﬁnding in this ﬁeld ought to be the newly developed enteric-coated dry emulsion formulation, which is potentially applicable for the oral delivery of peptide and protein drugs. This formulation consisted of a surfactant, a vegetable oil, and a pH-responsive polymer, with lyophilization used. Recently, Cui et al. prepared dry emulsions by spreading liquid O/W emulsions on a ﬂat glass, then dried and triturated to powders ^{2,
40, 45}.

2. Self-emulsifying capsules:

Besides liquid ﬁlling, liquid SE ingredients also can be ﬁlled into capsules in a solid or semisolid state obtained by adding solid carriers (adsorbents, polymers etc). As an example, a solid PEG matrix can be chosen. The presence of solid PEG neither interfered with the solubility of the drug, nor did it interfere with the process of self-microemulsiﬁcation upon mixing with water ⁴⁵.

Oral administration of SE capsules has been found to enhance patient compliance compared with the previously used parenteral route. For instance, low molecular weight heparin (LMWH) used for the treatment of venous thrombo-embolism was clinically available only via the parenteral route. So, oral LMWH therapy was investigated by formulating it in hard capsules. LMWH was dispersed in SMEDDS and thereafter the mixture was solidiﬁed to powders using three kinds of adsorbents: microporous calcium silicate (Florite TM RE); magnesium aluminium silicate (NeusilinTM US2) and silicon dioxide (Sylysia TM 320). Eventually these solids were ﬁlled into hard capsules. In another study, such adsorbents were also applied to prepare SE tablets of gentamicin that, in clinical use, was limited to administration as injectable or topical ^{1, 48}.

3. Self-emulsifying sustained/controlled-release tablets:

Inclusion of indomethacin (or other hydrophobic NSAID), for example, into 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 Tyloxapol TM (a copolymer of alkylphenol and formaldehyde).

Polyethylene oxide successfully illustrated its suitability for controlled release matrices. The resultant SE tablets consistently maintained a higher active ingredient concentration in blood plasma over the same time frame compared with a non-emulsifying tablet.

The newest advance in the research ﬁeld of SE tablet is the SE osmotic pump tablet, where the elementary osmotic pump system was chosen as the carrier of SES ⁴⁰.

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 intrasubject and intersubject variability of plasma proﬁles and minimizing GI irritation without lowering drug bioavailability.

Pellets were prepared by extrusion/spheronization and contained two water insoluble model drugs, SES contained mono-diglycerides and Polysorbate 80 ⁴¹.

5. Self-emulsifying solid dispersions:

Although solid dispersions could increase the dissolution rate and bioavailability of poorly water soluble drugs, some manufacturing difficulties and stability problems existed but can be solved by the use of SE excipients. These excipients have the potential to increase further the absorption of poorly water-soluble drugs relative to previously used PEG solid dispersions and may also be ﬁlled directly into hard gelatin capsules in the molten state, thus obviating the former requirement for milling and blending before ﬁlling.

SE excipients like Gelucire144/14, Gelucire1 50/02, Labrasol 1, Transcutol 1 and TPGS (tocopheryl polyethylene glycol 1000 succinate) have been widely used. For example, prepared SE solid dispersion granules using the hot-melt granulation method drugs, including phenacetin and progesterone were chosen ⁴⁹.

6. Self-emulsifying beads:

In an attempt to transform SES into a solid form with minimum amounts of solidifying excipients, Patil and Paradkar investigated loading SES into the microchannels of porous polystyrene beads (PPB) using the solvent evaporation method. PPB with complex internal void structures is typically produced by copolymerizing styrene and divinyl benzene. They are inert, stable over a wide pH range and to extreme conditions of temperature and humidity ⁴⁰.

7. Self-emulsifying nanoparticles:

Nanoparticle techniques have been useful in the production of SE nanoparticles. There are two methods Solvent injection and sonication.

Solvent injection is the method in which the lipid, surfactant and drugs were melted together, and injected drop wise into a stirred non-solvent. The resulting SE nanoparticles were thereafter ﬁltered out and dried. This approach yielded nanoparticles (about 100 nm) with a high drug loading efficiency of 74%.

A second technique is that of sonication emulsion–diffusion–evaporation, by which is co-loading of 5-ﬂuorouracil (5-FU) and antisense EGFR (epidermal growth factor receptor) plasmids in biodegradable PLGA/O-CMC nanoparticles was realized ⁴⁸.

The mixture of PLGA (poly-lactide-co-glycolide) and O-CMC (O-carboxymethyl-chitosan) had a SE effect, with no need to add another 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 could be sustained for as long as three weeks.

Recently, Trickler et al. developed a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of paclitaxel (PTX) ¹.

8. Self-emulsifying suppositories:

Some investigators proved that S-SEDDS could increase not only GI adsorption but also rectal/vaginal adsorption.

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 self emulsifying suppositories ⁴⁵.

9. Self-emulsifying implants:

Research into SE implants has greatly enhanced the utility and application of S-SEDDS. An example, 1, 3-bis (2-chloroethyl)-1- nitrosourea (carmustine or BCNU) is a chemotherapeutic agent used to treat malignant brain tumors. However, its effectiveness was hindered by its short half-life. In order to enhance its stability compared with that released from PLGA (poly d, l-lactide-co-glycolide) wafer implants, SES was formulated with tributyrin, Cremophor RH 40 (polyoxyl 40 hydrogenated castor oil) and Labraﬁl 1944 (polyglycolyzed glyceride).

Then the self-emulsiﬁed BCNU was fabricated into wafers with ﬂat and smooth surface by compression molding. Ultimately, SES increased in vitro half-life of BCNU up to 130 min contrasted with 45 min of intact BCNU. In vitro release of BCNU from SE PLGA wafers were prolonged up to 7 days. Such wafers had higher in vitro antitumor activity and were less susceptible to hydrolysis than those wafers devoid of SES ^{2, 41, 50}.

FUTURE PROSPECTS:

Thus, this novel delivery system has made easy the delivery of lipophilic drugs orally which increases its bioavailability due to its small particle droplets. There is still a long way to go, however, before more SEDDS formulations appear on the market.

Because there exist some fields of SEDDS to be further exploited, such as studies about human bioavailability and establishment of an in vitro/in vivo correlation. The Solid Self Emulsifying Drug Delivery System, aspects should represent the major future working directions for developing S-SEDDS. The fact that almost 40% of the new drug compounds are hydrophobic in nature implies that studies with SEDDS and S-SEDDS will continue, and more drug compounds formulated and as early as possible will reach the pharmaceutical market in the future.

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 SEDDS, which have been shown to substantially improve oral bioavailability. With future development of this technology, SEDDS will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

Supersaturable SEDDS contain a reduced amount of a surfactant and a water-soluble cellulosic polymer (or other polymers) to prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo. The S-SEDDS formulations can result in enhanced oral absorption as compared with the related self-emulsifying drug delivery systems (SEDDS) formulation and the reduced surfactant levels may minimize gastrointestinal surfactant side effects.

The recent, Solid-self emulsifying drug delivery systems (S-SEDDS) are very flexible method to develop various dosage forms for orally and parenterally administration, and which is superior in reducing cost, simplifying industrial manufacture and improving stability as well as patient compliance. Thus, these aspects should represent the major future working directions for S-SEDDS.

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Received on 23.04.2012 Modified on 18.05.2012

Research J. Pharm. and Tech. 5(6): June 2012; Page 736-745

Excipient Name (commercial name)	Examples of commercial products in which it has been used
Surfactants/co-surfactants
Polysorbate 20 (Tween 20)	Targretin soft gelatin capsule
Polysorbate 80 (Tween 80)	Gengraf hard gelatin capsule
Sorbitan monooleate (Span 80)	Gengraf hard gelatin capsule
Polyoxy-35-castor oil(Cremophor RH40)	Gengraf hard gelatin capsule, Ritonavir soft gelatin capsule
Polyoxy-40- hydrogenated castor oil (Cremophor RH40)	Nerol soft gelatin capsule, Ritonavir oral solution
Polyoxyethylated glycerides (Labrafil M 2125 Cs)	Sandimmune soft gelatin capsules
Polyoxyethlated oleic glycerides (Labrafil M1944 Cs)	Sandimmune oral solution
D-alpha Tocopheryl polyethylene glycol 1000 succinate	Agenerage Soft gelatin capsule, Agenarage oral solution
Co-solvents
Ethanol	Nerol soft gelatin Capsule, Nerol Oral Solution, Gengraf hard gelatin Capsule, Sandimmune soft gelatin Capsule, Sandimmune oral solution
Glycerin	Nerol soft gelatin Capsule, Sandimmune soft gelatin Capsules
Polypylene glycol	Nerol soft gelatin Capsule, Nerol Oral Solution, Lamprene soft gelatin capsule, Agenerage Oral solution , Gengraf hard gelatin capsule
Polyethylene glycol	Targretin soft gelatin capsule, Gengraf hard gelatin capsule, Agenerase soft capsule, Agenerase oral solution
Lipid ingredients
Corn oilmono,di,,tri-glycerides	Nerol soft gelatin Capsule, Nerol Oral Solution
DL-alpha-Tocopherol	Nerol Oral Solution, Fortavase soft gelatin capsule
Fractionated triglyceride of coconut oil (medium-chain triglyceride)	Rocaltrol soft gelatin capsule, Hectrol soft gelatin capsule
Fractionated triglyceride of palm seed oil (medium-chain triglyceride)	Rocatrol oral solution
Mixture of mono-and di-glycerides of caprylic/capric acid	Avodat soft gelatin capsule
Medium chain mono-and di-glycerides	Fortavase soft gelatin capsule
Corn oil	Sandimmune soft gelatin capsule, Depakene capsule
Olive oil	Sandimmune oral solution
Oleic acid	Ritonavir soft gelatin capsule, Norvir soft gelatin capsule
Sesame oil	Marinol soft gelatin capsule
Hydrogenated soyabean oil	Accutane soft gelatin capsule,Vesanoid soft gelatin capsule
Hydrogenated vegetable oils	Accutane soft gelatin capsule,Vesanoid soft gelatin capsule
Soyabean oil	Accutane soft gelatin capsule
Peanut oil	Prometrium soft gelatin capsule
Beeswax	Vesanoid soft gelatin capsule

Product Name	Compound	Dosage form	Indication
Juvela®	Tocopherol nicotinate	Soft gelatin capsule	Hypertension, Hyperlipidemia
Selbex®	Teprenone	Hard gelatin capsule	Acute gastritis
Sandimmun®	Cyclosporine A/II	Soft gelatin capsule	Immuno suppressant
Restandol®	Testosterone undecanote	Soft gelatin capsule	Hormone replacement therapy
Agenerase®	Amprenavir	Soft gelatin capsule	HIV antiviral
Lipirex®	Fenofibrate	Hard gelatin capsule	Antihyper-lipoproteinemic
Infree®	Indomethacin farnesil	Hard gelatin capsule	Anti-inflammatory and analgesic
Epadel®	Ethyl icosapentate	Soft gelatin capsule	Hyperlipidemia
Rocaltrol®	Calcitriol	Soft gelatin capsule	Calcium regulator
Gengraf®	Cyclosporin A/III	Hard gelatin capsule	Immuno suppressant
Convulex®	Valproic acid	Soft gelatin capsule	Antiepileptic
Targretin®	Bexarotene	Soft gelatin capsule	Antineoplastic
Glakay®	Menatetrenone	Soft gelatin capsule	Osteoporosis
Fenogal®	Fenofibrate	Hard gelatin capsule	HIV antiviral
MXL®	Morphine sulfate	Hard gelatin capsule	Analgesic