INTRODUCTION:

The oral route is the preferred route for chronic drug therapy. Numerous potent lipophilic drugs exhibit low oral bioavailability due to their poor aqueous solubility properties. For this class of compounds, defined by Amidon et al. as `low solubility/high permeability class П, dissolution in the environmental lumen is the rate-controlling step in the absorption process¹. Efforts are ongoing to enhance the oral bioavailability of lipophilic drugs in order to increase their clinical efficacy. The most popular approach is the incorporation of the active lipophilic component into inert lipid vehicles², such as oils³, surfactant dispersions^4,5, self-emulsifying formulations^6.,7, emulsions ^8,9 and liposomes¹⁰, with every formulation approach having its special advantages and limitations.

Efficacy of lipophilic drug is often hindered due to their poor aqueous solubility leading to low absorption after in vivo administration. A part of the administered dose is absorbed and reaches the pharmacological site of action and remainder causes toxicity and undesirable side effects due to unwanted biodistribution. Enhancement in drug efficacy and lowering of drug toxicity could be achieved through encapsulation and delivery the drug in lipid based delivery system.

The concept of drug delivery system has emerged to minimize the toxic side effects of drug, to broaden their application, to expand modes of their administration and to solve absorption problems. The twentieth century has witnessed a remarkable growth in drug development and the newly developed drugs are mostly lipophilic compound with poor aqueous solubility, which limits their efficacy and bioavailability. solubilization, encapsulation, and delivery of these drugs using lipid based and biocompatible systems are likely to furnish better absorption, by way of lower dose, reduced frequency of administration, and improved therapeutic index.

During the last two decades colloidal vehicles^11-20(liposomes, niosomes, microemulsion, organogels and nanocapsules) have been explored and they have emerged as prospective system for drug delivery. These self-organizing systems often lead to improvement in the therapeutics index of the lipophilic drugs through increased solubilization and modification of their pharmacokinetic profiles. For fruitful uses of this system in pharmacy, tolerance towards additives, stability over wide temperature range, low viscosity, small size biodegradability, and easy elimination from the body are some of the essential criteria. Also, the size of the encapsulated particles needs to be controlled to avoid capillary blockage and hence submicron-sized entities are preferred .Development, characterization and biological studies on “biocompatible micro emulsion” have become a thrust area of research as they satisfy most of the required criteria. Development characterization and biological studies on “ “biocompatible micro emulsion” as potential vehicles for drug delivery^21-29has become thrust area of research as they satisfy most of the required criteria^30-38

Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, and sometimes containing co-solvents, which emulsify spontaneously to produce fine oil-in-water emulsions when introduced into aqueous phase under gentle agitation^{6, 7,39,40,41.}Recently, SEDDS have been formulated using medium chain tri-glyceride oils and nonionic surfactants, the latter being less toxic. Upon peroral administration, these systems form fine emulsions (or micro-emulsions) in gastro-intestinal tract (GIT) with mild agitation provided by gastric mobility^{.42, 43} Potential advantages of these systems include enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of drug(s) toward specific absorption window in GIT, and protection of drug(s) from the hostile environment in gut^{.44, 45}

The process of self-emulsification proceeds through formation of liquid crystals (LC) and gel phases. Release of drug from SEDDS is highly dependent on LC(liquid crystal) formed at the interface, since it is likely to affect the angle of curvature of the droplet formed and the resistance offered for partitioning of drug into aqueous media⁴⁶. Effect of LC will be more prominent for semisolid or solid SEDDS because LC phases are formed in-situ, and the drug diffuses through LC phases into aqueous media.

In the present topic, focus will be on lipid based drug delivery systems (e.g. Self-Emulsifying Drug Delivery systems (SEDDS)). Emulsion particles can be of either micro- or nano- size, depending on the composition of the system. These formulations circumvent the dissolution step in the gastro-intestinal tract, but are still dependent on digestion.

NEED OF SEDDS:

Oral delivery of poorly water-soluble compounds is to pre-dissolve the compound in a suitable solvent and fill the formulation into capsules. The main benefit of this approach is that pre-dissolving the compound overcomes the initial rate limiting step of particulate dissolution in the aqueous environment within the GI tract. However, a potential problem is that the drug may precipitate out of solution when the formulation disperses in the GI tract, particularly if a hydrophilic solvent is used (e.g. polyethylene glycol). If the drug can be dissolved in a lipid vehicle there is less potential for precipitation on dilution in the GI tract, as partitioning kinetics will favor the drug remaining in the lipid droplets^.47

Another strategy for poorly soluble drugs is to formulate in a solid solution using a water-soluble polymer to aid solubility of the drug compound. For example, polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG 6000) have been used for preparing solid solutions with poorly soluble drugs. One potential problem with this type of formulation is that the drug may favor a more thermodynamically stable state, which can result in the compound crystallizing in the polymer matrix. Therefore the physical stability of such formulations needs to be assessed using techniques such as differential scanning calorimetry or X-ray crystallography. In this type of case SEDD system is a good option.

Potential advantages of these systems include;

1. Enhanced oral bioavailability enabling reduction in dose,

2. More consistent temporal profiles of drug absorption,

3. Selective targeting of drug(s) toward specific absorption window in GIT,

4. Protection of drug(s) from the hostile environment in gut.

5. Control of delivery profiles

6. Reduced variability including food effects

7. Protective of sensitive drug substances

8. High drug payloads

9. Liquid or solid dosage forms

MECHANISM OF SELF-EMULSIFICATION:

The process by which self-emulsification takes place is not yet well understood. However, according to Reiss ⁴⁸, 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 equation⁴⁸

Where, G 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. 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, the emulsification process occurs spontaneously). Emulsification requiring very little input energy involves destabilization through contraction of local interfacial regions. For emulsification to occur, it is necessary for the

Table: 2 Relative bioavailability of lipid based formulation of hydrophobic drugs

Drug name

Species tested

Test Product

Reference Product

Increase in AUC

Formulation

AUC

(Mean ± S.D)

Formulation

AUC (Mean ± S.D)

Vitamin E log p 9.96

Cyclosporin (log p 4.29)

Halofantrine (log p 9.20)

Atovaquone (log p 5.3)

Danazol (log p 4.53)

Ontazolast (log p 4.00)

Atorvastatin 9log p 6.26)

Human

Dogs

Rats

Dogs

Tween 80, Span 80 and Vitamin E dissolved in palm oil in the proportion 4:2:4 to form SEDDS

SMEDDS,

Nerol soft gelatin capsules

SEDDS, MCT

SEDDS, LCT

Solution in lipid + ethanol

SMEDDS,

Lipid+ Cremophor EL+ ethanol

SMEDDS, LCT

SMEDDS, MCT

Lipid solution, LCT

SEDDS, 1:1 mix of Gelucine 44/14 and peceol

SEDDS, 8:2 mix of Gelucine 44/14 and peceol

SEDDS, peceol

Emulsion,Soyabean oil +Tween 80

SMEDDS, Labrafil, Camphor RH 40, Proplylene glycol

SMEDDS, Estol, Cremophor RH 40, PG

SMEDDS, Labrafac, Cremophor RH 40, PG

AUC_0-∞= 210.7±63µg/mL

AUC_0-∞ = 5313±1956 h ng/mL

AUC_0-∞-6973±2388 h ng/mL

AUC_o-73h = 31.8±9.3 h µg/mL

AUC_0-73 h = 31.8 ±8.4 h µg/mL

AUC_0-10 h = 270.5±38.5 h ng/mL

AUC_0-10 hr = 47.7±29.5 h ng/mL

AUC_0-10h = 340.2±64.4 h ng/mL

AUC_0-8 hr = 752±236 h ng/mL

AUC_{0-
8} hr = 877±104 h ng/mL

AUC_0-8 hr = 528±68 h ng/mL

AUC_0-8 hr =1003±270 h ng/mL

AUC_0-24 hr= 2613±367.6 h ng/mL

AUC_0-24 h = 2568.3±408 h ng/mL

AUC_0-24 hr = 2520.81±308.4 h ng/mL

Natophenol soft gelatin capsules

SEDDS, Sand immune soft gelatin capsules

SMEDDS, MCT

Aqueous suspension

Micronised powder

Aqueous suspension, Tween 80 + HPMC

Lipitor tablets 10 mg

AUC_0-∞ = 94± 80 h µg/mL

AUC_0-∞ =5426±2481 h ng/mL

AUC_0-73 h = 9.4±1 h µg/mL

AUC_0-10 h = 35.3±5.2 h ng/mL

AUC_0-8h= 65±15 h ng/mL

AUC0-24 h = 1738±207.9 h ng/mL

AUC_0-24 h = 1738±207.9 h ng/mL

AUC _0-24h = 1738±207.9 h ng/mL

2 fold

6.5 fold

None

1.3 fold

3.4 fold

7 fold

1.3 fold

9 fold

11 fold

13 fold

8 fold

15 fold

1.5 fold

1.5 hr

Abbreviation: LCT-Long Chain triglcerides; MCT- Medium Chain triglycerides; PG-proplylene glycol

series of SEDDS system containing drug in various oil and surfactant. Then, in vitro self-emulsification properties and droplet size analysis of these formulations upon their addition to water under mild agitation conditions is studied. Pseudo-ternary phase diagram is constructed, identifying the efficient self-emulsification region. From these studies, an optimized formulation is selected and its bio-availability is compared with a reference formulation ^45.

The efficiency of oral absorption of the drug compound from the SEDDS depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification ability. Thus, only very specific pharmaceutical excipient combinations will lead to efficient self-emulsifying systems.

SMEDDS are distinguished from SEDDS by the much smaller emulsion droplets produced on dilution, resulting in a transparent or translucent solution. SMEDDS generally contain relatively high concentrations of surfactant (typically 40-60% w/w), and regularly contain hydrophilic co-solvents (e.g. propylene glycol, polyethylene glycols). They are often described as micro-emulsion pre-concentrates, as the micro-emulsion is formed on dilution in aqueous media⁵⁶

When developing lipid based formulations the following parameters are believed to be important;

· The solubility of drug in the formulation as such and upon dispersion (for SEDDS),

· The rate of digestion (for formulations susceptible to digestion) and possibly

· The solubilization capacity of the digested formulation^.

Oils:

Both long- and medium-chain triglyceride (MCT) oils with different degrees of saturation have been used for the design of self-dispersing formulations. 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^{40, 57, 58}. Since they exhibit formulative and physiological advantages. These excipients form good emulsification systems, with a large number of non-ionic surfactants approved for oral administration, while their degradation products resemble the end products of intestinal digestion. MCTs were preferred in the earlier self-emulsifying formulations^39,59. Because of higher Fluidity, better solubility properties and self-emulsification ability, but evidently, they are considered less attractive compared to the novel semi-synthetic medium chain derivatives⁴⁰ which can be defined rather as amphiphilic compounds exhibiting surfactant properties. In such cases, the more lipophilic surfactant may play the role of the hydrophilic oil in the formulation^40,43. Solvent capacity for less hydrophobic drugs can be improved by blending triglycerides with mono- and di-glycerides.⁴⁵

Surfactants

Non-ionic surfactants with a relatively high hydrophilic± lipophilic balance (HLB) were advocated for the design of self-dispersing systems, where the various liquid or solid ethoxylated polyglycolyzed glycerides and polyoxyethylene 20 oleate (Tween 80) are the most frequently used excipients. Emulsifiers derived from natural sources are expected to be safer than synthetic ones and are recommended for SDLF (self dispersed lipid formulation) use^40,58,60,61, despite their limited ability to self-emulsify. Non-ionic surfactants are known to be less toxic compared to ionic surface-active agents, but they may cause moderate reversible changes in intestinal wall permeability^{6, 62}. Amemiya et al. proposed a new vehicle based on a fine emulsion using minimal surfactant content (3%) to avoid the potential toxicological problems associated with high surfactant concentration ⁶³. The usual surfactant concentration in self-emulsifying formulations required to form and maintain an emulsion state in the GI tract ranged from 30 to 60% w/w of the formulation. 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.

The high HLB and subsequent hydrophilicity of surfactants is necessary for the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous environment, providing a good dispersing/selfemulsifying performance. The surface-active agents are amphiphilic by nature, and they are therefore usually able to dissolve and even solubilize relatively high quantities of the hydrophobic drug. The latter is of prime importance for preventing precipitation within the GI lumen and for the prolonged existence of the drug molecules in soluble form, which is vital for effective absorption ⁵⁹. The lipid mixtures with higher surfactant and co-surfactant/oil ratios lead to the formation of self-micro emulsifying formulations (SMEDDS)^40,64,65,66. Formulations consisting only of the surfactant mixture may form emulsions or microemulsions (when surfactants exhibit different low and high HLB) ⁴³, micelle solution or, in some particular cases, niosomes, which are non-ionic, surfactant-based bilayer vehicles⁶⁷.

Co-solvents

Relatively high surfactant concentrations (usually more than 30% w/w) are needed in order to produce an effective self-emulsifying system. Organic solvents, suitable for oral administration (ethanol, propylene glycol (PG), polyethylene glycol (PEG), etc.) may help to dissolve large amounts of either the hydrophilic surfactant or the drug in the lipid base. These solvents sometimes play the role of the co-surfactant in the micro emulsion systems, although alcohol- free self-emulsifying microemulsions have also been described in the literature ⁴⁰. Indeed, such systems may exhibit some advantages over the previous formulations when incorporated in capsule dosage forms, since alcohol and other volatile co-solvents comprised in the conventional self-emulsifying formulations are known to migrate into the shells of soft gelatin, or hard, sealed gelatin capsules, resulting in the precipitation of the lipophilic drug. On the other hand, the lipophilic drug dissolution ability of the alcohol free formulation may be limited. Drug release from the formulation increased with increasing amount of co-surfactant. Various examples of surfactant, co-solvents and oil are given in table 1.

EVALUATION:

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.

1. Heating cooling cycle: Six cycles between refrigerator temperature (4⁰C) and 45⁰C with storage at each temperature of not less than 48 h is studied. Those formulations, which are stable at these temperatures, are subjected to centrifugation test.

2. Centrifugation: Passed formulations are centrifuged thaw cycles between 21 ⁰C and +25 ⁰C with storage at each temperature for not less than 48 h 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.

3. Freeze thaw cycle: Three freeze for the formulations.

Those formulations passed this test showed good stability with no phase separation, creaming, or cracking.⁶⁸

Dispersibility test

The efficiency of self-emulsification of oral nano or micro emulsion is assessed using a standard USP XXII dissolution apparatus 2. One milliliter of each formulation was added to 500 mL of water at 37 ± 0.5 ⁰C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle 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.⁶⁸

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)^{44, 69}

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 micro emulsion are evaluated by Brookfield viscometer. This viscosities determination conform 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 high viscosities then it is w/o type of the system.^{44, 69}

Droplet Size Analysis 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.^{44, 69}

Refractive Index and Percent Transmittance

Refractive index and percent tranmittance proved the transparency of formulation. The refractive index 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 at particular wavelength 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.

Electro conductivity Study

The SEDD system contains ionoc 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.

In Vitro Diffusion Study

In vitro diffusion studies is performed to study the release behavior of formulation from liquid crystalline phase around the droplet using dialysis technique.⁴⁴

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.

DRAWBACK OF SEDDS

One of the obstacles for the development of self-emulsifying drug delivery systems (SEDDS) and other lipid-based formulations is the lack of good predicative in vitro models for assessment of the formulations. Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug. To mimic this, an in vitro model simulating the digestive processes of the duodenum has been developed. This in vitro model needs further development and validation before its strength can be evaluated. Further development will be based on in

vitro - in vivo correlations and therefore different prototype lipid based formulations needs to be developed and tested in vivo in a suitable animal model. Future studies will address the development of the in vitro model.

APPLICATION:

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-П drug (Low solubility/high permeability).

Ketoprofen, a moderately hydrophobic (log P 0.979) non-steroidal anti-inflammatory drug (NSAID), is a drug of choice for sustained release formulation has high potential for gastric irritation during chronic therapy. Also because of its low solubility, ketoprofen shows incomplete release from sustained release formulations. Vergote et al. (2001) reported complete drug release from sustained release formulations containing ketoprofen in nanocrystalline form.⁷⁰

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,⁷⁰ sustained release ketoprofen microparticles⁷¹ and formulations⁷¹, floating oral ketoprofen systems⁷², and transdermal systems of ketoprofen^.73

Preparation and stabilization of nano-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.

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 gastro-intestinal mucosa in the dissolved state readily accessible for absorption. Therefore, increase in AUC i.e. bioavailability and C_max is observed with many drugs when presented in SEDDS. These drugs are listed in table 2 & 3.

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 an act as barrier between degradating environment and the drug.

Acetylsalicylic acid (Log P = 1.2, Mw=180), a drug that degrades in the GI tract because it is readily hydrolyzed to salicylic acid in an acid environment. When the drug was formulated in a Galacticles™ Oral Lipid Matrix System (SEDDS formulation) and compare with a commercial formulation, it showed the good plasma profile as compare to reference formulation. . The oral bioavailability of undegraded acetylsalicylic acid is improved by 73% by the Galacticles™ Oral Lipid Matrix System formulation compared to the reference formulation. This suggests that the SEDDS formulation has a capacity to protect drugs from degradation in the GI tract⁴³

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 minimise gastrointestinal surfactant side effects.

Oral drug delivery systems are designed address the varied challenges in oral delivery of numerous promising compounds including poor aqueous solubility, poor absorption, and large molecular size. These are both liquid and powder-in-capsule products comprising our self-emulsifying liquid crystalline nano-particles (LCNP) technology (featuring Cubosome®, Hexosome®, and Flexosome™).

Liquid crystalline nano-particles (LCNPs) are excellent solubilizers. Compared with conventional lipid or non-lipid carriers, LCNPs show high drug carrier capacity for a range of sparingly water-soluble drugs. For drugs susceptible to in vivo degradation, such as peptides and proteins, LCNP vehicles protect the sensitive drug from enzymatic degradation. The LCNP systems also address permeability limitations by exploiting the lipid-mediated absorption mechanism. For water-soluble peptides typical bioavailability enhancements range from twenty to more than one hundred times. In an alternative application large proteins have been encapsulated for local activity in the gastrointestinal tract.

LCNP carriers can be combined with controlled-release and targeting functionalities. The particles are designed to form in situ at a controlled rate, which enables an effective in vivo distribution of the drug. LCNP carriers can also be released at different absorption sites, for example in the upper or lower intestine, which is important for drugs that have narrow regional absorption windows. SMEDDS” composition of PNU156804 that showed a good chemical stability and a higher

bioavailabibty with respect to a conventional formulation.⁷⁵

FUTURE TREND

In relation to formulation development of poorly soluble drugs in the future, there are now techniques being used to convert liquid/semi-solid SEDDS and SMEDDS formulations into powders and granules, which can then be further processed into conventional 'powder-fill' capsules or even compressed into tablets. Hot melt granulation is a technique for producing granules or pellets, and by using a waxy solubilising agent as a binding agent, up to 25% solubilising agent can be incorporated in a formulation. There is also increasing interest in using inert adsorbents, such as the Neusilin (Fuji Chemicals) and Zeopharm (Huber) products for converting liquids into powders – which can then be processed into powder fill capsules or tablets.

But to obtain solids with suitable processing properties, the ratio of SEDDS to solidifying excipients must be very high⁷⁶, which seems to be practically non-feasible for drugs having limited solubility in oil phase. In this regard, it was hypothesized that the amount of solidifying excipients required for transformation of SEDDS in solid dosage forms will be significantly reduced if SEDDS is gelled. Colloidal silicon dioxide (Aerosil 200) is selected as a gelling agent for the oil based systems, which may serve the dual purpose of reducing the amount of solidifying excipients required and aiding in slowing drug release

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Received on 11.09.2008 Modified on 18.10.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008; Page 313-323

Compound	Observation after Study	Reference
Win 54954	No difference in BA but improved reproducibility, increased C max	39
Cyclosporin	Increased BA and C max and reduced T max from SMEDDS	77
	Increased Cmax, AUC and dose linearity and reduced food effect ffrom SMEDDS	78
	Reduced intra- and inter-subject variability from SMEDDS	79
Halofantrine	Trend to higher BA from LCT SMEDDS	80
Ontazolast	BA increase of at least 10- fold from all lipid based formulations	58
Vitamin E	BA 3- fold higher from SEDDS	81
Coenzyme Q₁₀	BA 2- fold higher from SEDDS	82
Ro-15-0778	BA 3- fold higher from SEDDS when compared with other formulations	43
Simvastatin	BA 1.5 fold higher from SMEDDS	83
Biphenyl Dimethyl Dicarboxylate	BA 5- fold higher from SEDDS	84
Indomethacin	BA singnificantly increased from SEDDS	85
Progesterone	BA 9- fold higher from SEDDS	86
Tocotrienols	BA 2-3 fold higher from SEDDS	87
Danazol	BA from LCT solution and LC-SMEDDS 7- fold and 6- fold higher than that from MC-SMEDDS	88
Carvediol Solvent green 3	BA 4- fold higher from SEDDS BA 1.7-fold higher from SMEDDS	89 90
Silymarin	BA approximately 2-and 50- fold higher from SMEDDS	91
Atorvastatin Itraconazole Atovaquone Seocalcitol	BA significantly increased from all SMEDDS Increased BA and reduced food effect BA 3-fold higher from SMEDDS BA LC-SMEDDS=MC-SMEDDS	92 93 94 95
PNU-91325	5-6 fold enhancement in oral bioavailability for super saturable cosolvent, S-SEDDS, and Tween 80 formulations relative to cosolvent	75
Model Compounds inclunding disopyramide, ibuprofen, Ketoprofen, and Tolbutamide	Improved BA relative to the suspension formulations for either or both of the liquid microemulsion and SEDDS formulation in all cases	96