INTRODUCTION:

Oral route is preferred for drug administration; however, more than 40% of new chemical entities exhibit poor aqueous solubility, resulting in unsatisfactory oral drug delivery. SEDDS possess potential to improve oral bioavailability of poorly water soluble drugs^1,2.

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.

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, polyvinyl pyrrolidone (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 colorimetry or X-ray crystallography. In this type of case SEDD system is a good option^3,4.

Advantages^5,6,7.

1. High drug solubilization capacity and Onset of action of SEDDS is quick

2. Good termodynamic stability and Protect the drug from enzymatic hydrolysis.

3. Improvement in oral bioavailability.

4. Improve drug loading capacity.

5. Reduce the intrasubject and intersubject variability and food effects.

6. Useful for drug targeting toward specific absorption window.

7. The SEDDS offer ease in manufacture and scale-up.

8. Control of delivery profile.

9. Drug loading capacity is higher in SEDDS, than other lipid/oil based formulation.

10. Lipid digestion process has no influence on SEDD.

Disadvantages:

1. Lack of in vitro model for assessment of the formulations.

2. Chemical instabilities of drugs and high surfactant concentrations.

3. These formulations potentially are dependent on digestion prior to release the drug.

4. Traditional dissolution methods do not work, because these formulation potentially are dependent on digestion prior to release of the drug.

Mechanism of Self-Emulsification:

Conventional emulsions are formed by mixing two immiscible liquids namely water and oil stabilized by an emulsifying agent. When an emulsion is formed surface area expansion is created between the two phases. The emulsion is stabilized by the surfactant molecules that form a film around the internal phase droplet. In conventional emulsion formation, the excess surface free energy is dependent on the droplet size and the interfacial tension. If the emulsion is not stabilized using surfactants, the two phases will separate reducing the interfacial tension and the free energy. In case of SEDDS, the free energy of formation is very low and positive or even negative which results in thermodynamic spontaneous emulsification. It has been suggested that self emulsification occurs due to penetration of water into the Liquid Crystalline (LC) phase that is formed at the oil/surfactant-water interface into which water can penetrate assisted by gentle agitation during self-emulsification. After water penetrates to a certain extent, there is disruption of the interface and a droplet formation. This LC phase is considered to be responsiblefor the high stability of the resulting nanoemulsion against coalescence.

Self emulsifying processes are related to the free energy, ΔG⁸given by:

ΔG=ΣN π r2 σ

Where,

N=Number of droplets with radius r

σ=Interfacial energy

Types of SEDDS:

On the basis of the water solubility of components, types are

(A) Non-water soluble Component Systems:

These systems are isotropic mixtures of lipids and lipophillic surfactants having HLB value less than 12 that self emulsify to form fine oil in water emulsion in aqueous medium. Self emulsification is generally obtained at a surfactant level above 25% w/w. But at a surfactant level of 50-60% w/w the emulsification process may be compromised by formation of viscous liquid crystalline gels at the oil/water interface. This system is also known as Type-II SEDDS according to lipid formulation classification System (LFCS).Poorly water soluble drugs can be incorporated in SEDDS and encapsulated in capsules (hard or soft gelatin) to produce convenient single unit dosage forms. These systems offer advantages-

· They are able to generate large interfacial areas which cause efficient partitioning of drug between oil droplets and the aqueous phase.

· They can overcome the slow dissolution step typically observed with solid dosage forms.

(B) Water soluble component system:

These systems are formulated by using hydrophilic surfactants with HLB more than 12 and co solvents such as Ethanol, Propylene Glycol and Polyethylene glycols. Type III SEDDS are commonly known as self micro-emulsifying drug delivery systems (SMEDDS).

Type III formulations can be further divided into type III A and Type III B formulations in order to identify more hydrophilic forms. In Type IIIB, the content of hydrophilic surfactants and co solvents is increased and lipid content is reduced. The distinction between SEDDS and SMEDDS formulation is commonly based on particle size and optical clarity of resultant dispersion. Thus SEDDS formulations typically provide opaque dispersions with particle size greater than 100 nm while SEDDS disperse to give small droplets with particle size less than 100 nm and provide optically clear or slightly opalescent dispersions. SEDDS and SMEDDS have played an important role in the improvement of solubility as well as bioavailability of drugs with poor aqueous solubility. An example of the marketed SMEDDS formulation is Neoral Cyclosporine formulation in which corn oil, derived mono, di and triglycerides were used as lipid phase, cremophor RH 40 as surfactant, propylene glycol and ethanol as co solventalong with α- tocopherol as an antioxidant. Neoral spontaneously forms a transparent and thermo-dynamically stable dispersionwith droplet size below 100 nm when introduced into an aqueous medium.SEDDS may be solid or liquid in nature and they may be formulated into tablets, capsules, pellets, solid dispersions, microspheres, nanoparticles or dry emulsions^9,10,11.

Formulation of SEDDS:

SEDDS are composed of oil, hydrophilic surfactant, and a co-solvent. The process of self-emulsificationis only specific to certain combinations of pharmaceutical excipients. It depends on the type of oil and surfactant pair, their ratios, the surfactant concentration and the temperature at which self-emulsification occurs. The primary step during formulation of a SEDDS is the identification of these specific combinations of excipients and construct a phase diagram which shows various concentrations of excipients that possess self-emulsification. Mutual miscibility of these excipients is also important for producing a stable liquid formulation. Long chain triglycerides (LCT) are usually immiscible with hydrophilic surfactants and co-solvents. Polar oils such as mixed glycerides show an affinity towards hydrophilic surfactants and thus are miscible with the surfactant and also aids in self-dispersion of the formulation. The diversity of chemical nature of lipids used may lead to immiscibility on long-term storage, so it is essential to perform physical stability tests on the formulation. If waxy excipients are used, they should be melted before weighing and then mixed with other liquid excipients. With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants to water soluble co-solvents, there are many different combinations that could be formulated for encapsulation in hard or soft gelatin or mixtures which disperse to give fine colloidal emulsions. 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 and the preparation of the phase diagram

3. The preparation of SEDDS formulation by dissolving the drug in a mixture of oil, surfactant and co-solvent. The addition of a drug to a 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 prolonged SEDDS, formulation is made by adding the polymer or gelling agent.

Excipients used in SEDDS:

Pharmaceutical acceptability of excipients and the toxicity issues of the components used makes the selection of excipients really critical. There is a great restriction as which excipients to be used. Early studies revealed that the SEDDS process is specific to the nature of the oil/surfactant pair, the surfactant concentration and oil/surfactant ratio, the concentration and nature of co-surfactant and surfactant/co-surfactant ratio and the temperature at which self-microemulsification occurs. These important discoveries were further supported by the fact that only very specific combinations of pharmaceutical excipients led to efficient self- microemulsifying systems.

Oils:

The oil represents one of the most important excipients in the SEDDS formulation not only because it can solubilize the required dose 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.Both long and medium chain triglyceride (LCT and MCT) 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 excipients choice for the development of SEDDS are not frequently selected due to their poor ability to dissolve large amounts of lipophilic drugs. 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. E.g. Cotton seed oil, Soybean oil, Corn oil, Sunflower oil, Castor oil etc.

Co-solvant:

The production of an optimum SEDDS requires relatively high concentrations (generally more than 30% w/w) of surfactants, thus the concentration of surfactant can be reduced by incorporation of co-surfactant. Role of the co-surfactant together with the surfactant is to lower the interfacial tension to a very small even transient negative value. At this value the interface would expand to form fine dispersed droplets, and subsequently adsorb more surfactant and surfactant/co-surfactant until their bulk condition is depleted enough to make interfacial tension positive again. This process known as 'spontaneous emulsification' forms the microemulsion. However, the use of co-surfactant in self emulsifying systems is not mandatory for many non-ionic surfactants. The selection of surfactant and co-surfactant is crucial not only to the formation of SEDDS, but also to solubilization of the drug in the SEDDS. 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 and can act as co-surfactant in the self emulsifying drug delivery systems, although alcohol- free self-emulsifying microemulsions have also been described in the literature. Indeed, such systems may exhibit some advantages over the previous formulations when incorporated in capsule dosage forms, since alcohol and other volatile co-solvents 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. Hence, proper choice has to be made during selection of components¹².

Surfactants:

Several compounds exhibiting surfactant properties may be employed for the design of self-emulsifying systems, but the choice is limited as very few surfactants are orally acceptable. 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 oleate. 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 surfactants 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. The lipid mixtures with higher surfactant and co-surfactant/oil ratios lead to the formation of SMEDDS. There is a relationship between the droplet size and the concentration of the surfactant being used. In some cases, increasing the surfactant concentration could lead to droplets with smaller mean droplet size, this could be explained by the stabilization of the oil droplets as a result of the localization of the surfactant molecules at the oil-water interface. On the other hand, in some cases the mean droplet size may increase with increasing surfactant concentrations^13.This phenomenon could be attributed to the interfacial disruption elicited by enhanced water penetration into the oil droplets mediated by the increased surfactant concentration and leading to ejection of oil droplets into the aqueous phase. The surfactants used in these formulations are known to improve the bioavailability by various mechanisms including: improved drug dissolution, increased intestinal epithelial permeability, increased tight junction permeability and decreased/inhibited pglycoprotein drug efflux. However, the large quantity of surfactant may cause moderate reversible changes in intestinal wall permeability or may irritate the GI tract. Formulation effect and surfactant concentration on gastrointestinal mucosa should ideally be investigated in each case.

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. Nonionic surfactants

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.

Cationic surfactants:

Where the hydrophilic group carries a positive charge. Example: quaternary ammonium halide.

Ampholytic surfactants:

(also called zwitter ionic surfactants) Contain both a negative and a positive charge. Example: sulfobetaines.

Nonionic 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) polysorbatet (Tweens)^14,15,16.

Co-surfactant:

In SMEDDS, generally co-surfactant of HLB value 10-14 is used. Hydrophilic co-surfactants

Are preferably alcohols of intermediate chain length such as hexanol, pentanol and octanol which are known to reduce the oil water interface and allow the spontaneous formulation of micro emulsion. E.g. Span, Capyrol 90, Capmul.

METHOD OF PREPARATION:

A) Solidification techniques for transforming liquid/semisolid44: Various solidification techniques are as listed below;

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:

A) Heating of the semisolid excipient to at least 20˚C above its melting point.

B) Incorporation of the active substances (with stirring).

C) Capsule filling with the molt cooling to room temperature. For liquid formulations, it involves a two-step process.

D) Filling of the formulation into the capsules followed by sealing of the body and cap of the capsule, either by banding or by micro spray sealing.

B) Spray drying:

Essentially, this technique involves the preparation of a formulation by mixing lipids, surfactants, drug, solid carriers, and solubilization of the mixture before spray drying. The solubilized liquid formulation is then atomized into a spray of droplets. The droplets are introduced into a drying chamber, where the volatile phase (e.g. the water contained in an emulsion) evaporprepared into tablet pattern and the drying chamber design are selected according to the drying characteristic the product and powder specification.

C) Adsorption to solid carriers:

Free flowing powders may be obtained from liquid SE formulations by adsorption to solid carriers. The adsorption process is simple and just involves addition of the liquid On to carriers by mixing in a blender.

D) Melt granulation:

Melt granulation is a process in which powder agglomeration is obtained through the addition of a binder that melts or softens at relatively low temperatures.

E) Melt extrusion/extrusion spheronization:

Melt extrusion is a solvent-free process that allows high drug loading (60%), as well as content uniformity. Extrusion is a procedure of product of uniform shape and density, by forcing it through a die under controlled temperature, product flow, and pressure conditions¹⁷.

Evaluation of SEDDS:

The very essence of SEDDS is self-emulsification, which is primarily assessed visually. The various ways to characterize SEDDS are compiled below.

1. Equilibrium phase diagram: Although self emulsification is a dynamic non equilibrium process involving interfacial phenomena, information can be obtained about self-emulsification using equilibrium phase behavior.

2. Turbidity measurement: This identifies efficient self-emulsification by establishing whether the dispersion reaches equilibrium.

Rapidly and in a reproducible time. These measurements are carried out on turbidity meters, most commonly the Hach turbidity meter and the Orbeco-Helle turbidity meter.

3. Droplet size: 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 emulsion. Photon correlation spectroscopy, microscopic techniques or a Coulter Nano-sizer are mainly used for the determination of the emulsion droplet size. Electron microscopic studies: Freeze-fracture electron microscopy has been used to study surface characteristics of dispersed systems.

4. Zeta potential measurement: This is used to identify the charge of the droplets. In conventional SEDDS, the charge on an oil droplet is negative because of the presence of free fatty acids.

5. Determination of emulsification time: The process of self-emulsification was observed using light microscopy. The mechanism of emulsification involved erosion of a fine cloud of small particles from the surface of large droplets, rather than a progressive reduction in droplet size.

6. Liquefaction time: This test is designed to estimate the time required by solid SEDDS to melt in vivo in the absence of agitation to simulated GI conditions.

7. Small-angle neutron scattering: Small-angle neutron scattering can be used to obtain information on the size and shape of the droplets.

8. Small-angle X-ray scattering: Small-angle X-ray scattering is capable of delivering structural information of macromolecules between 5 and 25 nm, of repeat distances in partially ordered systems of up to 150 nm. It is used for the determination of the microscale or nanoscale structure of particle systems in terms of such parameters as averaged particle sizes, shapes, distribution and surface-to-volume ratio^18-28.

Applications:

A. Solid self-emulsifying drug systems:

Solid self-emulsifying drug delivery used for the development of tablets using a liquid SEDDS for a poorly water-soluble drug. A high content of liquid SEDDS can be loaded (up to 70%) onto a carrier which not only maintains good flow ability but also enables the production of tablets with good cohesive properties and good content uniformity in both capsules and tablets. This clearly expands the options available to the formulator.

B. Enhancement of solubility:

If drug is incorporated in SEDDS, it increases the solubility because it circumvents the dissolution step in case of Class-II drug (Low solubility/high permeability). A SEDDS formulation of a poorly water soluble drug candesartancilexetil was formulated for directly filling in hard gelatin capsules for oral administration. The results from the study show the utility of SEDDS to enhance solubility and dissolution of sparingly soluble compounds.

C. Protection against biodegradation:

SEDDS have ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors and protect these from enzymatic degradation.

D. Super saturable SEDDS (SEDDS):

The high surfactant level typically present in S-SEDDS formulations can lead to GI side-effects and a new class of super saturable formulations, including super saturable SEDDS (S-SEDDS) formulations, have been designed and developed to reduce the surfactant side-effects and achieve rapid absorption of poorly soluble drugs. The S-SEDDS approach is to generate a protracted supersaturated solution of the drug when the formulation is released from an appropriate dosage form into an aqueous medium. Surper saturation is intended to increase the thermodynamic activity to the drug beyond its solubility limit and, therefore, to result in an increased driving force for transit into and across the biological barrier .The SEDDS formulations contain a reduced level of surfactant and a polymeric precipitation inhibit or to yield and stabilize a drug in a temporarily supersaturated state. Hydroxypropyl methylcellulose (HPMC) and related cellulose polymers are well recognized for their propensity to inhibit crystallization and there by generate and maintain the supersaturated state for prolonged time periods.

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 products for converting liquids into powders–which can then be processed into powder fill capsules or tablet. 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.

CONCLUSION:

SMEDDS formulation can be optimized for the delivery of hydrophobic compounds with drug loading; minimum surfactant concentration and proper infinite dilution can be achieved without drug precipitation. Self-emulsifying drug delivery system can be use for the formulations of drugs compounds with poor aqueous stability. Development of this technology SEDDS will continue to enable novel applications in drug delivery system. SEDDS have been shown to be reasonably successful in improving the oral bioavailability of poorly water-soluble and Traditional preparation of SEDDS involves dissolution of drugs in oils and their blending with suitable solubilizing agents.

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Received on 05.03.2018 Modified on 13.04.2018

Res. J. Pharma. Dosage Forms and Tech.2018; 10(3):200-206.

DOI: 10.5958/0975-4377.2018.00031.9