I. INTRODUCTION:

Oral route has been the major route of drug delivery for the chronic treatment of many diseases. However, oral delivery of 50% of the drug compounds is hampered because of the high lipophilicity of the drug itself. Nearly 40% of new drug candidates exhibit low solubility in water, which leads to poor oral bioavailability, high intra- and inter-subject variability and lack of dose proportionality.¹ Thus, for such compounds, the absorption rate from the gastrointestinal (GI) lumen is controlled by dissolution.² Modification of 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.³ Particle size reduction may not be desirable in situations where handling difficulties and poor wettability are experienced for very fine powders.⁴ To overcome these drawbacks, various other formulation strategies have been adopted including the use of cyclodextrins, nanoparticles, solid dispersions and permeation enhancers.^1,5 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 poorly 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 for-mutations, emulsions and liposomes with particular emphasis on self-emulsifying drug delivery systems (SEDDS).^6,7

Self-emulsifying drug delivery systems (SEDDS) are relatively newer lipid-based technological innovations with immense promise in oral bioavailability enhancement of drugs. These formulations have shown to reduce the slow and incomplete dissolution of a drug, facilitate the formation of its solubilized phase, increase the extent of its transportation via intestinal lymphatic system, and bypass the P-gp efflux, thereby augmenting drug absorption from the GI tract.Self-emulsifying formulations are isotropic mixtures of drug, lipids (natural or synthetic oils) and emulsifiers (solid or liquid), usually with one or more of hydrophilic co-solvents/co-emulsifiers.⁸ Verily, SEDDS is a broad term typically producing emulsions with a droplet size ranging between a few nanometers to several microns. Depending upon the size of globules, they are basically the concentrated microemulsions, nanoemulsions or their pre-concentrates.⁹ Self-microemulsified drug delivery system (SMEDDS) indicates the formulations forming transparent microemulsions with the oil droplet size range between 100 and 250 nm. Self-nanoemulsified drug delivery system (SNEDDS) is relatively a recent term indicating the globule size less than 100 nm.¹⁰

Mechanism of self-emulsification

The mechanism by which self-emulsification occurs is not yet well understood. Nevertheless, it has been suggested that self-emulsification takes place when the entropy change favouring dispersion is greater than the energy required to increase the surface area of the dispersion.¹¹The free energy of a conventional emulsion formulation is a direct function of the energy required to create a new surface between the oil and water phases. The two phases of the emulsion tend to separate with time to reduce the interfacial area and thus the free energy of the systems. The conventional emulsifying agents stabilize emulsions resulting from aqueous dilution by forming a monolayer around the emulsion droplets, reducing the interfacial energy and forming a barrier to coalescence. On the other hand, emulsification occurs spontaneously with SEDDS because the free energy required to form the emulsion is either low and positive or negative.¹² It is necessary for the interfacial structure to show no resistance against surface shearing in order for emulsification to take place. The ease of emulsification was suggested to be related to the ease of water penetration into the various LC or gel phases formed on the surface of the droplet.^13,14,15 The interface between the oil and aqueous continuous phases is formed upon addition of a binary mixture (oil/non-ionic surfactant) to water. This is followed by the solubilisation of water within the oil phase as a result of aqueous penetration through the interface. This will occur until the solubilisation limit is reached close to the interphase. Further aqueous penetration will lead to the formation of the dispersed LC phase. In the end, everything that is in close proximity with the interface will be LC, the actual amount of which depends on the surfactant concentration in the binary mixture. Thus, following gentle agitation of the self-emulsifying system, water will rapidly penetrate into the aqueous cores and lead to interface disruption and droplet formation. As a consequence of the LC interface formation surrounding the oil droplets, SEDDS become very stable to coalescence. Detailed studies have been carried out to determine the involvement of the LC phase in the emulsion formation process. Also, particle size analysis and low frequency dielectric spectroscopy (LFDS) were utilized 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 results suggested that there might be a complex relationship between LC formation and emulsion formation. Moreover, the presence of the drug compound may alter the emulsion characteristics, probably by interacting with the LC phase. Nevertheless, the correlation between the LC formation and spontaneous emulsification has still not been established.^16,17

ADVANTAGES OF SEDDS¹⁸

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.

EXCIPIENTS USED IN SEDDS

1. Oil

2. Surfactant

3. Co solvent / Co surfactant

4. Others components

1. 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 triglyceride.^19-22 Both long and medium chain triglyceride oils with different degrees of saturation have been used for the design of self-emulsifying formulations.

E.g. - Corn oil, olive oil, soybean oil, hydrolysed corn oil.

2. Surfactant

Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule. The four main groups of surfactants are defined as follows,

1. Anionic surfactants

2. Cationic surfactants

3. Ampholytic surfactants

4. Non-ionic surfactants

1 Anionic Surfactants, where the hydrophilic group carries a negative charge such as carboxyl (RCOO-), sulphonate(RSO3 -) or sulphate (ROSO3 -).Examples: Potassium laurate, sodium lauryl sulphate.

2 Cationic surfactants, where the hydrophilic group carries a positive charge. Example: quaternary ammonium halide.

3 Ampholytic surfactants (also called zwitterionic surfactants) contain both a negative and a positive charge. Example: sulfobetaines.

4 Non-ionic surfactants, where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O).

Examples: Sorbitan esters (Spans), polysorbates (Tweens).

Nonionic surfactants with high hydrophilic lipophilic balance (HLB) values are used in formulation of SMEDDS. The usual surfactant strength ranges between 30-60% w/w of the formulation in order to form a stable SMEDDS. Surfactants having a high HLB and hydrophilicity assist 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 amount of hydrophobic drug compounds.²³

3. Cosolvents

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.²⁴These solvents can even act as co surfactants in micro emulsion systems. Alternately alcohols and other volatile cosolvents have the disadvantage of evaporating into the shells of the soft gelatin or hard sealed gelatin capsules in conventional SEDDS leading to drug precipitation.

4. Other Components

Other components might be pH adjusters, flavours, and antioxidant agents. Indeed a characteristic of lipid products, particularly those with unsaturated lipids show peroxide formation with oxidation. Free radicals such as ROO., RO., and .OH can damage the drug and induce toxicity. Lipid peroxides may also be formed due to auto-oxidation, which increases with unsaturation level of the lipid molecule. Hydrolysis of the lipid may be accelerated due to the pH of the solution or from processing energy such as ultrasonic radiation. Lipophilic antioxidants (e.g. α-tocopherol, propyl gallate, ascorbylpalmitate or BHT) may therefore be required to stabilize the oily content of the SEDDS.

FORMULATION OF SEDDS

Drugs with low aqueous solubility present a major challenge during formulation as their high hydrophobicity prevents them from being dissolved in most approved solvents. The novel synthetic hydrophilic oils and surfactants usually dissolve hydrophobic drugs to a greater extent than conventional vegetable oils. The addition of solvents, such as ethanol, PG and PEG may also contribute to the improvement of drug solubility in the lipid vehicle.²⁵ With a large variety of liquid or waxy excipients available ranging from oils through lipids, hydrophobic and hydrophilic surfactant to water soluble co solvent, there are many different combinations that could be formulated for encapsulation in hard or soft gelatin or mixture which disperse to give fine colloidal emulsions.²⁶ The following should be considered in the formulation of a SMEDDS.

1 The solubility of the drug in different oil, surfactants and co solvents

2 The selection of oil, surfactant and co solvent based on the solubility of the drug

3 Preparation of the phase diagram.

4 The preparation of SMEDDS formulation by dissolving the drug in a mixture of oil, surfactant and co solvent.²⁷

TERNARY DAIGRAM

The use of pseudo ternary diagrams is not recent. This technique was mainly used to map the micro emulsion areas (composition ranges).²⁸ Pseudo ternary phase diagram is used to map the optimal composition range for three key excipients according to the resulting droplet size following self-emulsification, stability upon dilution and viscosity.

CONSTRUCTION OF PHASE DIAGRAM

A Titration method is employed to construct phase diagram. Mixture of oil with surfactant is prepared at different ratios (e.g. 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9, 0:10) into different vials. A small amount of water in 5 % (w /w) increments is added into the vials. Following each water addition the mixture in vials is centrifuged for 2 to 3 minute and is incubated at 25⁰ C for 48 hrs with gentle shaking. The resulting mixture is evaluated by visual and microscopy observation. For phase diagram the micro emulsion is the region of clear and isotropic solution.²⁹Coarseemulsion is the region of cloudy dispersion.

CHARACTERIZATION OF SEDDS

The primary means of self-emulsification assessment is visual evaluation. The efficiency of self-emulsification could be estimated by determining the rate of emulsification, droplet size distribution and turbidity measurement .³⁰

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 also visual appearance. In addition, incompatibilities between the formulation and the gelatin capsule shell can lead to brittleness or deformation delayed disintegration or incomplete release of drug.³¹

1 Heating cooling cycle: Six cycles between refrigerators temperature (4°C) and (45°C) 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°C and 25°C with storage at each temperature for not less than 48 h is done at 3500 rpm for 30 min. Those formulations that do not show any phase separation are taken for the freeze thaw stress test.

3 Freeze thaw cycle: Three freeze thaw cycles for the formulations. Those formulations pass this test show good stability with no phase separation, creaming or cracking.

Dispersability test

The efficiency of self-emulsification of oral nano or micro emulsion is assessed using a standard USP XXII dissolution apparatus 2. One millilitre of each formulation is added to 500 ml of water at 37 ± 0.5°C. A standard stainless steel dissolution paddle rotating at 50 rpm provides gentle agitation. The in vitro performance of the formulations is visually assessed using the following grading system.³¹

Grade A: Rapidly forming (within 1 min) Nano emulsion having a clear or bluish appearance.

Grade B: Rapidly forming slightly less clear having a bluish white appearance.

Grade C: Fine milky emulsion that forms within 2 min.

Grade D: Dull grayish white emulsion having slightly oily appearance that is slow to emulsify.

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.

Bioavailability study

Based on the self-emulsification properties, particle size data and stability of micro emulsion the formulation is selected for bioavailability studies.³¹The in vivo study is performed to quantify the drug after administration of the formulation. The plasma profiles of the drug in experimental animals following oral administration of the conventional tablet and SEDDS form are compared. Pharmacokinetic parameters of the maximum plasma concentration (Cmax) and the corresponding time (Tmax) for the drug following oral administration are calculated. The area under the concentration–time curve (AUC0→24 h) is estimated according to the linear trapezoidal rule. The relative bioavailability (BA) of SEDDS form to the conventional table is calculated using the following Equation

Relative BA (%) = (AUC test / AUC reference) X (Dose reference / Dose test)

Turbidimetric evaluation

This is done to identify efficient self-emulsification by establishing whether the dispersion reaches equilibrium rapidly and in a reproducible time. 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 turbidometer. 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).³²

Viscosity determination

The SEDDS system is generally administered in soft gelatin or hard gelatin capsules. Therefore, it should be easily pourable into capsules and such system should not be too thick to create a problem. The rheological properties of the micro emulsion/ nano emulsion are evaluated by Brookfield Viscometer. This viscosity determination confirms 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 viscosity then it is w/o type of the system.³²

Droplet size and Particle size measurement

This is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as the stability of the SEDDS. The droplet size of the SEDDS is determined by photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles)which can 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.

Refractive index and Percent transmission

Refractive index and percent transmittance proves the transparency of formulation. The refractive index of the system is measured by refractometer by placing drop of solution on slide and it is compared with water.

The percent transmittance of the system is measured at particular wavelength using UV-Vis spectrophotometer keeping distilled water as blank. If refractive index of system is similar to the refractive index of water and formulation has percent transmittance >99 percent then formulation has transparent nature.³²

Zeta potential measurement

This is used to identify the charge of the droplets. In conventional SEDDS, the charge on an oil droplet is negative due to presence of free fatty acids.³²

Yield of the sedds

The SEDDS formed is filtered from the solvent, dried in the desiccators and weighed to get the yield of the SEDDS formulated per batch. Percentage yield can be calculated by formula

% recovery = --------------------X 100

W2 + W3

Where,

W1 is the weight of the SEDDS formulated.

W2 weight of the drug added.

W3 is the weight of the lipid and surfactant used as the starting material.

Drug encapsulation efficiency³²

The quantities of the drugs theoretically contained in the SEDDS were compared with the quantity actually obtained, from the drug content studies i.e. the quantity loaded into the SEDDS formulated. To get the drug encapsulation efficiency equation used for calculation is,

ADC

EE (%) =--------------X 100

TDC

Where,

ADC is the actual drug content.

TDC is the theoretical drug content.

RECENT ADVANCEMENTS IN SEDDS³⁴

Now a day for stability or easy administration of SEDDS formulation various dosage form are researched. Such as Self-emulsifying sustained/ controlled release tablets, Self-emulsifying capsules, Self emulsifying suppositories, microemulsion drug delivery, self- emulsifying nanoparticles, self-emulsifying sustained/ controlled release pellets. In relation to formulation development of poorly soluble drug in future, there are now techniques being used to convert liquid/ semisolid SEDDS formulation into powders and granules, which can prepared by novel technique such as spray drying by spray dryer, freeze drying. Spray drying is most acceptable technique due to the final yield, easy manufacturing, time saving technique.

CONCLUSIONS:^35-39

SEDDS 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 improve oral bioavailability substantially. The efficiency of the SEDDS formulation is case−specific in most instances; thus, composition of the SEDDS formulation should be determined very carefully. Since a relatively high concentration of surfactants is generally employed in the SEDDS formulation, toxicity of the surfactant being used should be taken into account. In fact, a compromise must be reached between the toxicity and self-emulsification ability of the surfactant that is considered for use. The size and charge of the oil droplet in the emulsion formed are two other important factors that affect GI absorption efficiency.

Currently, several formulations have been developed to produce modified emulsified formulations as alternatives to conventional SEDDS. These include, but are not limited to, Self-microemulsion formulations, surfactant dispersions, preformulated freeze−dried emulsions, microencapsulated emulsions, lipid/cross−linked polymericmatrices, self-emulsifiable pellets, and solid self-emulsifying systems (self-emulsifying tablets). All these formulations will produce fine oil droplets or micelle dispersions upon aqueous dilution.

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Received on 10.03.2014 Modified on 15.04.2014

Res. J. Pharm. Dosage Form. and Tech. 6(2):April- June 2014; Page 134-139

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Neoral®	Cyclosporine A/I	SGC	Novartis	Immune suppressant
Norvir®	Ritonavir	SGC	Abbott lab.	HIV antiviral
Fortovase®	Saquinavir	SGC	Hoffmann.la Roche Inc.	HIV antiviral
Agenerase®	Amprenavir	SGC	Glaxosmithkline	HIV antiviral
Rocaltrol®	Calcitriol	SGC	Roche Inc.	Calcium regulator
Gengraf®	Cyclosporine A/III	HGC	Abbott Lab.	Immuno suppressant
Lipirex®	fenofibrate	HGC	Genus Lab.	Antihyperlipoproteinemic