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This review article explains how self-emulsifying drug delivery systems can increase the solubility and bioavailability of poorly soluble drug.
Self-emulsifying drug delivery systems (SEDDSs) have gained exposure for their ability to increase solubility and bioavailability of poorly soluble drugs. SEDDSs are isotropic mixtures of oils and surfactants, sometimes containing cosolvents, and can be used for the design of formulations in order to improve the oral absorption of highly lipophilic compounds. SEDDSs emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation. SEDDS can be orally administered in soft or hard gelatine capsules and form fine, relatively stable oil-in-water emulsions upon aqueous dilution. This article presents an overview of SEDDSs and their applications.
In recent years, the formulation of poorly soluble compoundspresented interesting challenges for formulationscientists in the pharmaceutical industry. Up to 40% of newchemical entities discovered by the pharmaceutical industryare poorly soluble or lipophilic compounds, which leads topoor oral bioavailability, high intra- and inter-subject variability,and lack of dose proportionality (1).
In the oral formulation of such compounds, a number ofattempts-such as decreasing particle size, use of wettingagents, coprecipitation, and preparation of solid dispersions-have been made to modify the dissolution profile andthereby improve the absorption rate. Recently, much attentionhas focused on lipid-based formulations to improve thebioavailability of poorly water soluble drugs. Among manysuch delivery options, like incorporation of drugs in oils (2),surfactant dispersion (3), emulsions (4) and liposomes (5),one of the most popular approaches are the self-emulsifyingdrug delivery systems (SEDDSs).
SEDDSs are mixtures of oils and surfactants, ideally isotropicand sometimes containing cosolvents, which emulsify spontaneously to produce fine oil-in-water emulsions whenintroduced into an aqueous phase under gentle agitation. Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for selfemulsification.These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption (6). SEDDSs typically produce emulsions with a droplet size between 100–300 nm while self-microemulsifying drug delivery systems (SMEDDSs) form transparent microemulsions with adroplet size of less than 50 nm. When compared with emulsions,which are sensitive and metastable dispersed forms, SEDDSs are physically stable formulations that are easy tomanufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems mayoffer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles (7).
Composition of SEDDSs
The self-emulsifying process is depends on: (7)
Oils. Oils can solubilize the lipophilic drug in a specificamount. It is the most important excipient because it canfacilitate self-emulsification and increase the fraction of lipophilicdrug transported via the intestinal lymphatic system,thereby increasing absorption from the GI tract (9).Long-chain triglyceride and medium-chain triglyceride oilswith different degrees of saturation have been used in thedesign of SEDDSs. Modified or hydrolyzed vegetable oilshave contributed widely to the success of SEDDSs owing totheir formulation and physiological advantages (8). Novelsemisynthetic medium-chain triglyceride oils have surfactantproperties and are widely replacing the regular medium-chain triglyceride (9).
Surfactant. Nonionic surfactants with high hydrophilic–lipophilic balance (HLB) values are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore,etc.). The usual surfactant strength ranges between30–60% w/w of the formulation in order to form a stable SEDDS. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w dropletsand/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they candissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules (10).
Cosolvents. Cosolvents like diehylene glycol monoethyleether (transcutol), propylene glycol, polyethylene glycol,polyoxyethylene, propylene carbonate, tetrahydrofurfurylalcohol polyethylene glycol ether (Glycofurol), etc., mayhelp to dissolve large amounts of hydrophilic surfactantsor the hydrophobic drug in the lipid base. These solventssometimes play the role of the cosurfactant in the microemulsionsystems.
Formulation of SEDDSs
With a large variety of liquid or waxy excipients available,ranging from oils through biological lipids, hydrophobic andhydrophilic surfactants, to water-soluble cosolvents, thereare many different combinations that could be formulatedfor encapsulation in hard or soft gelatin or mixtures whichdisperse to give fine colloidal emulsions (11).The following should be considered in the formulation ofa SEDDS:
The addition of a drug to a SEDDS is critical because thedrug interferes with the self-emulsification process to a certainextent, which leads to a change in the optimal oil–surfactant ratio. So, the design of an optimal SEDDS requirespreformulation-solubility and phase-diagram studies. In thecase of prolonged SEDDS, formulation is made by adding the polymer or gelling agent (13).
Mechanism of self-emulsification
According to Reiss, self-emulsification occurs when theentropy change that favors dispersion is greater than theenergy required to increase the surface area of the dispersion.The free energy of the conventional emulsion is a directfunction of the energy required to create a new surfacebetween the oil and water phases and can be described bythe equation:
Where, DG is the free energy associated with the process(ignoring the free energy of mixing), N is the number ofdroplets of radius r and s represents the interfacial energy.The two phases of emulsion tend to separate with time toreduce the interfacial area, and subsequently, the emulsion isstabilized by emulsifying agents, which form a monolayer ofemulsion droplets, and hence reduces the interfacial energy,as well as providing a barrier to prevent coalescence (14).
Characterization of SEDDSs
The primary means of self-emulsification assessment is visualevaluation. The efficiency of self-emulsification couldbe estimated by determining the rate of emulsification,droplet-size distribution and turbidity measurements.
Visual assessment. This may provide important informationabout the self-emulsifying and microemulsifying property of the mixture and about the resulting dispersion (15,16,17).
Turbidity Measurement. This is to identify efficient self-emulsificationby establishing whether the dispersion reachesequilibrium rapidly and in a reproducible time.
Droplet Size. This is a crucial factor in self-emulsificationperformance because it determines the rate and extent of drug release as well as the stability of the emulsion (10,18). Photon correlation spectroscopy, microscopic techniques ora Coulter Nanosizer are mainly used for the determinationof the emulsion droplet size (10,19,20). The reduction of the droplet size to values below 50 µm leads to the formationof SMEDDSs, which are stable, isotropic and clear o/wdispersions (6).
Zeta potential measurement. This is used to identify the chargeof the droplets. In conventional SEDDSs, the charge on anoil droplet is negative due to presence of free fatty acids(17).
Determination of emulsification time. Self-emulsification time, dispersibility, appearance and flowability was observed andscored according to techniques described in H. Shen et al. (21) used for the grading of formulations.
SEDDS formulation is composed of lipids, surfactants, andcosolvents. The system has the ability to form an oil-in-wateremulsion when dispersed by an aqueous phase under gentleagitation. SEDDSs present drugs in a small droplet size andwell-proportioned distribution, and increase the dissolutionand permeability. Furthermore, because drugs can beloaded in the inner phase and delivered by lymphatic bypassshare, SEDDSs protect drugs against hydrolysis by enzymesin the GI tract and reduce the presystemic clearance in theGI mucosa and hepatic first-pass metabolism. Table I showsthe SEDDSs prepared for oral delivery of lipophilic drugsin recent years.
Self-emulsifying drug delivery systems are a promising approachfor the formulation of drug compounds with pooraqueous solubility. The oral delivery of hydrophobic drugscan be made possible by SEDDSs, which have been shownto substantially improve oral bioavailability. With futuredevelopment of this technology, SEDDSs will continue toenable novel applications in drug delivery and solve problemsassociated with the delivery of poorly soluble drugs.
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Ritesh B. Patel* is a lecturer and Rakesh P. Patel is an assistant professor, both in the Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Gujarat, India, firstname.lastname@example.org
Madhabhai M. Patel is a professor in the Department of Pharmaceutics, Kalol Pharmacy College, Kalol, Gujarat, India.
*To whom all correspondence should be addressed.