Ritesh B. Patel is a lecturer in the Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Gujarat, India, 

Ritesh B. Patel

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).

The self-emulsifying process is depends on: (7)

The nature of the oilâsurfactant pair 

The temperature at which self-emulsification occurs. 

 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).

 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 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.

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 solubility of the drug in different oil, surfactantsand cosolvents. 

The selection of oil, surfactant and cosolvent based onthe solubility of the drug and the preparation of thephase diagram (12). 

The preparation of SEDDS formulation by dissolvingthe drug in a mix of oil, surfactant and cosolvent. 

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).

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).

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.

 This may provide important informationabout the self-emulsifying and microemulsifying property of the mixture and about the resulting dispersion (15,16,17).

 This is to identify efficient self-emulsificationby establishing whether the dispersion reachesequilibrium rapidly and in a reproducible time.

 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).

 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).

 Self-emulsification time, dispersibility, appearance and flowability was observed andscored according to techniques described in H. Shen 

(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.

1. P.P. Bhatt, "Osmotic drug delivery systems for poorly solubledrugs," 

The Drug Delivery Companies Report Autumn/Winter 2004

2. D.L. Burcham et al., "Improved oral bioavailability of the hypocholesterolemicDMP 565 in dogs following oral dosing in oil and glycol solutions," 

3. T.M. Serajuddin et al., "Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug fromsolid dispersion," 

4. R.A. Myers and V.J. Stella, "Systemic bioavailability of penclomedine(NSC-338720) from oil-in-water emulsions administeredintraduodenally to rats," 

5. R.A. Schwendener and H. Schott, "Lipophilic 1-beta-d -arabinofuranosylcytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemiamodel," 

6. N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS)with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs," 

7. R.N. Gursoy and S. Benita, "Self-emulsifying drug delivery systemsfor improved oral delivery of lipophilic drugs," 

8. P.P. Constantinides, "Lipid microemulsion for improving drugsdissolution and oral absorption: physical and biopharmaceuticalaspects," 

9. S.M. Khoo et al., "Formulation design and bioavailability assessmentof lipidic silf-emulsifying formulation of halofanitrine,"

10. N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS)with polyglycolized glycerides for improving in vitro dissolutionand oral absorption of lipophilic drugs." 

11. J.R. Crison and G.L. Amidon, "Method and formulation for increasingthe bioavailability of poorly water-soluble drugs," USPatent No. 5,993,858, issued November 30, 1999.

12. N. Farah, J.P. Laforet and J. Denis, "Self Micro Emulsifying DrugDelivery Systems for improving dissolution of drugs: In vitroevaluations," presented by Gattefosse Patented Technology atthe AAPS Annual Meeting in San Diego, November 1994.

13. S. Nazzal and M.A. Khan, "Controlled release of a self-emulsifyingformulation from a tablet dosage form: Stability assessmentand optimization of some processing parameters," 

14. P.P. Constantinides, "Lipid microemulsions for improving drugdissolution and oral absorption: physical and biopharmaceuticalaspects," 

15. D.Q.M. Craig et al., "An investigation into the mechanisms ofself-emulsification using particle size analysis and low frequencydielectric spectroscopy," 

16. N. Gursoy et al., "Excipient effects on in vitro cytotoxicity of anovel paclitaxel selfemulsifying drug delivery system," 

17. T. Gershanik and S. Benita, "Positively-charged self-emulsifyingoil formulation for improving oral bioavailability of progesterone,"

18. B.D. Tarr and S.H. Yalkowsky, "Enhanced intestinal absorptionof cyclosporine in rats through the reduction of emulsion dropletsize," 

19. S.A. Charman et al., "Self-emulsifying drug delivery system: Formulationand biopharmaceutic evaluation of an investigational lipophilic compound," 

20. R. Holm, I.H.M. Jensen, and J. Sonnergaard, "Optimization ofself-microemulsifying drug delivery system using D-optimaldesign and the desirability function," 

Drug Development and Industrial Pharmacy 

21. H. Shen and M. Zhong, "Preparation and evaluation of self-microemulsifyingdrug delivery system containing atorvastatin,"

22. P. Patil, P. Joshi, and A. Paradkar, "Effect of formulation variableson preparation and evaluation of gelled self emulsifyingdrug delivery systems of ketoprofen," 

23. H.R. Shen and M.K. Zhong, "Preparation and evaluation of selfmicroemulsifyingdrug delivery systems containing atorvastatin,"

24. Wei Ianlan et al., "Preparation and evaluation of SEDDS andSMEDDS containing Carvedilol," 

25. B.K. Kang et al., "Development of self-microemulsifying drug delivery systems for oral bioavailability enhancement of simvastatinin beagle dogs," 

26. J.Y. Hong et al., "A new self-emulsifying formulation of itraconazolewith improved dissolution and oral absorption," 

27. G.S. Chaea et al., "Enhancement of the stability of BCNU using self-emulsifying drug delivery systems (SEDDS) and in vitro antitumoractivity of self-emulsified BCNU-loaded PLGA wafer,"

28. T.R. Kommuru et al., "Self-emulsifying drug delivery systems(SEDDS) of coenzyme Q10: formulation development and bioavailabilityassessment," 

29. A.A. Attama et al., "The use of solid self-emulsifying systems inthe delivery of diclofenac," 

30. Mauro Serratoni et al., "Controlled drug release from pellets containingwater-insoluble drugs dissolved in a self-emulsifying system,"

European Journal of Pharmaceutics and Biopharmaceutics 

31. Mette Grovea et al., "Bioavailability of seocalcitol II: Developmentand characterisation of self-microemulsifying drug delivery systems(SMEDDS) for oral administration containing medium andlong chain triglycerides," 

European Journal of Pharmaceutical Sciences 

32. Wei Wu, Yang Wang and Li Que, "Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system," 

33. A.A. Date and M.S. Nagarsenker, Design and evaluation of self nanoemulsifying drug delivery systems (SNEDDS) for cefpodoximeproxetil," 

34. E.I. Taha et al., "Preparation and in vitro characterization of self nanoemulsified drug delivery system (SNEDDS) of all-trans-retinolacetate," 

 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, 

 is a professor in the Department of Pharmaceutics, Kalol Pharmacy College, Kalol, Gujarat, India.

*To whom all correspondence should be addressed.

Articles

This review article explains how self-emulsifying drug delivery systems can increase the solubility and bioavailability of poorly soluble drug.