Self-Emulsifying Drug Delivery Systems - Pharmaceutical Technology

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


Pharmaceutical Technology


Table 1
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 compounds presented interesting challenges for formulation scientists in the pharmaceutical industry. Up to 40% of new chemical entities discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds, which leads to poor oral bioavailability, high intra- and inter-subject variability, and lack of dose proportionality (1).

In the oral formulation of such compounds, a number of attempts—such as decreasing particle size, use of wetting agents, coprecipitation, and preparation of solid dispersions— have been made to modify the dissolution profile and thereby improve the absorption rate. Recently, much attention has focused on lipid-based formulations to improve the bioavailability of poorly water soluble drugs. Among many such 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-emulsifying drug delivery systems (SEDDSs).

SEDDSs are mixtures of oils and surfactants, ideally isotropic and sometimes containing cosolvents, which emulsify spontaneously to produce fine oil-in-water emulsions when introduced 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 a droplet 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 to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer 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)

  • The nature of the oil–surfactant pair
  • The surfactant concentration
  • The temperature at which self-emulsification occurs.

Oils. Oils can solubilize the lipophilic drug in a specific amount. It is the most important excipient because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract (9). Long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used in the design of SEDDSs. Modified or hydrolyzed vegetable oils have contributed widely to the success of SEDDSs owing to their formulation and physiological advantages (8). Novel semisynthetic medium-chain triglyceride oils have surfactant properties 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 between 30–60% 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 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 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 monoethyle ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role of the cosurfactant in the microemulsion systems.

Formulation of SEDDSs

With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants, to water-soluble cosolvents, 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 (11). The following should be considered in the formulation of a SEDDS:

  • The solubility of the drug in different oil, surfactants and cosolvents.
  • The selection of oil, surfactant and cosolvent based on the solubility of the drug and the preparation of the phase diagram (12).
  • The preparation of SEDDS formulation by dissolving the drug in a mix of oil, surfactant and cosolvent.

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 (13).

Mechanism of self-emulsification

According to Reiss, self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases and can be described by the equation:




Where, DG 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. The two phases of emulsion tend to separate with time to reduce the interfacial area, and subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion 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 visual evaluation. The efficiency of self-emulsification could be estimated by determining the rate of emulsification, droplet-size distribution and turbidity measurements.

Visual assessment. This may provide important information about 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-emulsification by establishing whether the dispersion reaches equilibrium rapidly and in a reproducible time.

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 (10, 18). Photon correlation spectroscopy, microscopic techniques or a Coulter Nanosizer are mainly used for the determination of the emulsion droplet size (10, 19, 20). The reduction of the droplet size to values below 50 μm leads to the formation of SMEDDSs, which are stable, isotropic and clear o/w dispersions (6).

Zeta potential measurement. This is used to identify the charge of the droplets. In conventional SEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids (17).

Determination of emulsification time. Self-emulsification time, dispersibility, appearance and flowability was observed and scored according to techniques described in H. Shen et al. (21) used for the grading of formulations.

Application

SEDDS formulation is composed of lipids, surfactants, and cosolvents. The system has the ability to form an oil-in-water emulsion when dispersed by an aqueous phase under gentle agitation. SEDDSs present drugs in a small droplet size and well-proportioned distribution, and increase the dissolution and permeability. Furthermore, because drugs can be loaded in the inner phase and delivered by lymphatic bypass share, SEDDSs protect drugs against hydrolysis by enzymes in the GI tract and reduce the presystemic clearance in the GI mucosa and hepatic first-pass metabolism. Table I shows the SEDDSs prepared for oral delivery of lipophilic drugs in recent years.

Conclusion

Self-emulsifying drug delivery systems 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 SEDDSs, which have been shown to substantially improve oral bioavailability. With future development of this technology, SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

References

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2. D.L. Burcham et al., "Improved oral bioavailability of the hypocholesterolemic DMP 565 in dogs following oral dosing in oil and glycol solutions," Biopharm. Drug Dispos. 18, 737–742 (1997).

3. T.M. Serajuddin et al., "Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersion," J. Pharm. Sci. 77, 414–417 (1988).

4. R.A. Myers and V.J. Stella, "Systemic bioavailability of penclomedine (NSC-338720) from oil-in-water emulsions administered intraduodenally to rats," Int. J. Pharm. 78, 217–226 (1992).

5. R.A. Schwendener and H. Schott, "Lipophilic 1-beta-d -arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model," J. Cancer Res. Clin. Oncol. 122, 723–726 (1996).

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," Int. J. Pharm. 106, 15–23 (1994).

7. R.N. Gursoy and S. Benita, "Self-emulsifying drug delivery systems for improved oral delivery of lipophilic drugs," Biomedicine and Pharmacotherapy 58,173-182 (2004).

8. P.P. Constantinides, "Lipid microemulsion for improving drugs dissolution and oral absorption: physical and biopharmaceutical aspects," Pharm Res. 12, 1561-1572 (1995).

9. S.M. Khoo et al., "Formulation design and bioavailability assessment of lipidic silf-emulsifying formulation of halofanitrine," International Journal of Pharmaceutics 167, 155–164 (1998).

10. N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS) with polyglycolized glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs." Int. J. Pharm. 106, 15–23 (1994).

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

12. N. Farah, J.P. Laforet and J. Denis, "Self Micro Emulsifying Drug Delivery Systems for improving dissolution of drugs: In vitro evaluations," presented by Gattefosse Patented Technology at the AAPS Annual Meeting in San Diego, November 1994.

13. S. Nazzal and M.A. Khan, "Controlled release of a self-emulsifying formulation from a tablet dosage form: Stability assessment and optimization of some processing parameters," International Journal of Pharmaceutics 315, 110–121 (2006).

14. P.P. Constantinides, "Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects," Pharm. Res. 12, 1561–72 (1995).

15. D.Q.M. Craig et al., "An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy," Int. J. Pharm. 114, 103–110 (1995).

16. N. Gursoy et al., "Excipient effects on in vitro cytotoxicity of a novel paclitaxel selfemulsifying drug delivery system," J. Pharm. Sci. 92, 2420–2427 (2003).

17. T. Gershanik and S. Benita, "Positively-charged self-emulsifying oil formulation for improving oral bioavailability of progesterone," Pharm. Dev. Technol. 1, 147–157 (1996).

18. B.D. Tarr and S.H. Yalkowsky, "Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size," Pharm. Res. 6, 40–43 (1989).

19. S.A. Charman et al., "Self-emulsifying drug delivery system: Formulation and biopharmaceutic evaluation of an investigational lipophilic compound," Pharma. Res. 9, 87 – 93 (1992).

20. R. Holm, I.H.M. Jensen, and J. Sonnergaard, "Optimization of self-microemulsifying drug delivery system using D-optimal design and the desirability function," Drug Development and Industrial Pharmacy 32, 1025 –1032 (2006).

21. H. Shen and M. Zhong, "Preparation and evaluation of self-microemulsifying drug delivery system containing atorvastatin," Journal of Pharmacy and Pharmacology 58, 1183–1191 (2006).

22. P. Patil, P. Joshi, and A. Paradkar, "Effect of formulation variables on preparation and evaluation of gelled self emulsifying drug delivery systems of ketoprofen," AAPS PharmSciTech 5 (3), 1-8 (2004).

23. H.R. Shen and M.K. Zhong, "Preparation and evaluation of selfmicroemulsifying drug delivery systems containing atorvastatin," Journal of Pharmacy and Pharmacology 58, 1183–1191 (2006).

24. Wei Ianlan et al., "Preparation and evaluation of SEDDS and SMEDDS containing Carvedilol," Drug Development and Industrial Pharmacy 31, 785–794 (2005).

25. B.K. Kang et al., "Development of self-microemulsifying drug delivery systems for oral bioavailability enhancement of simvastatin in beagle dogs," International Journal of Pharmaceutics 274, 65–73 (2004).

26. J.Y. Hong et al., "A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption," Journal of Controlled Release 110, 332–338 (2006).

27. G.S. Chaea et al., "Enhancement of the stability of BCNU using self-emulsifying drug delivery systems (SEDDS) and in vitro antitumor activity of self-emulsified BCNU-loaded PLGA wafer," International Journal of Pharmaceutics 301, 6–14 (2005).

28. T.R. Kommuru et al., "Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment," International Journal of Pharmaceutics 212, 233–246 (2001).

29. A.A. Attama et al., "The use of solid self-emulsifying systems in the delivery of diclofenac," International Journal of Pharmaceutics 262, 23–28 (2003).

30. Mauro Serratoni et al., "Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system," European Journal of Pharmaceutics and Biopharmaceutics 65, 94–98 (2007).

31. Mette Grovea et al., "Bioavailability of seocalcitol II: Development and characterisation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides," European Journal of Pharmaceutical Sciences 28, 233–242 (2006).

32. Wei Wu, Yang Wang and Li Que, "Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system," European Journal of Pharmaceutics and Biopharmaceutics 63, 288–294 (2006).

33. A.A. Date and M.S. Nagarsenker, Design and evaluation of selfnanoemulsifying drug delivery systems (SNEDDS) for cefpodoxime proxetil," International Journal of Pharmaceutics 329, 166–172 (2007).

34. E.I. Taha et al., "Preparation and in vitro characterization of selfnanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate," International Journal of Pharmaceutics 285, 109–119 (2004).

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,
Madhabhai M. Patel is a professor in the Department of Pharmaceutics, Kalol Pharmacy College, Kalol, Gujarat, India. *To whom all correspondence should be addressed.

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