SELF-MICRO EMULSIFYING DRUG DELIVERY SYSTEMS (SMEDDS): A REVIEW ON PHYSICO-CHEMICAL AND BIOPHARMACEUTICAL ASPECTS
Nearly 40% of new drug candidates exhibit low solubility in water, which is a challenge in development of optimum oral solid dosage form in terms of formulation design and bioavailability of new pharmaceutical products. Many strategies have been used to overcome these problems either by means of modifying the solubility or maintaining the drug in dissolved form throughout gastric transit time. Much attention has focused on lipid solutions, emulsions and emulsion pre-concentrates, which can be prepared as physically stable formulations suitable for encapsulation of such poorly soluble drugs. Recently, self-micro emulsifying drug delivery systems (SMEDDS) especially have attracted increasing interest primarily becauseÂ these are physically stable, easy to manufacture, can be filled in soft gelatin capsules and then will generate a drug containing micro-emulsion with a large surface area upon dispersion in the gastrointestinal tract. The emulsions will further facilitate the absorption of the drug due via intestinal lymphatic pathway and by partitioning of drug into the aqueous phase of intestinal fluids. In the present review, an overview of SMEDDS as a key technology for formulating lipophilic drugs and various factors that potentially affect the oral bioavailability of such drugs are presented.
Keywords: Low solubility, Oral bioavailability, Self-micro emulsion, Intestinal lymphatic pathway.
2. Mundhe AV, Fuloria NK, Biyani KR, Cocrystalization: an alternative approach for solid modification, Journal of Drug Delivery and Therapeutics. 2013; 3(4):166-172.
3. Shelke PV, Dumbare AS, Gadhave MV, Jadhav SL, Sonawane AA, Gaikwad DD, Formulation and evaluation of rapidly dis integrating film of amlodipine bes ylate, Journal of Drug Delivery & Therapeutics; 2012; 2(2):72-75.
4. Abdalla A, Sandra K, Mader K. A new self-emulsifying drug delivery system (SEDDS) for poorly soluble drugs: characterization, dissolution, in vitro digestion and incorporation into solid pellets. Eur J Pharm Sci 2008; 35(5):457-464.
5. Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 2006; 29(3e4):278e287.
6. Chandel P, Kumari R, Kapoor A, Liquisolid technique: an approach for enhancement of solubility, Journal of drug delivery and therapeutics, 2013; 3(4):131-137
7. Miryala V, Kurakula M, Self-nano emulsifying drug delivery systems (SNEDDS) for oral delivery of atorvastatinâ€“formulation and bioavailability studies, Journal of Drug Delivery & Therapeutics, 2013; 3(3):131-142.
8. Singh J, Walia M, Harikumar SL, Solubility enhancement by solid dispersion method: a review, Journal of drug delivery and Therapeutics, 2013; 3(5):148-155.
9. Dalvi PB, Gerange AB, Ingale PR, Solid dispersion: strategy to enhance solubility, Journal of Drug Delivery and Therapeutics. 2015; 5(2):20-28.
10. Aungst BJ. Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism. J Pharm Sci 1993; 82:979-987.
11. Shah DP, Patel B, Shah C, Nanosuspension technology: A innovative slant for drug delivery system and permeability enhancer for poorly water soluble drugs, Journal of Drug Delivery and Therapeutics, 2015; 5(1):10-23.
12. Venkatesh, G. et al. In vitro and in vivo evaluation of self-microemulsifying drug delivery system of buparvaquone. Drug Dev. Ind. Pharm. 2010; 36:735â€“745.
13. Gursoy, R.N. and Benita, S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed. Pharmacother. 2004; 58:173â€“182.
14. Singh, B. et al. Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications. Crit. Rev. Ther. Drug Carrier Syst. 2009; 26:427â€“521.
15. Charman WN, Stella VJ. Transport of lipophilic molecules by the intestinal lymphatic system. Adv Drug Del Rev. 1991; 7:1-14.
16. Porter CJ, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007; 6:231-248.
17. Sanghai B, Aggarwal G, HariKumar SL, Solid self microemulsifying drug deliviry system: a review, Journal of Drug Delivery and Therapeutics. 2013; 3 (3):168-174
18. Dhakar RC, Maurya SD, Saluja V. From formulation variables to drug entrapment efficiency of microspheres: A technical review, Journal of Drug Delivery & Therapeutics. 2012; 2(6):128-133.
19. de Smidt PC et al. Intestinal absorption of penclomedine from lipid vehicles in the conscious rat: contribution of emulsification versus digestibility. Int J Pharm 2004; 270: 109â€“118.
20. Shah NH, Carvajal MT, Patel CI, Infeld MH, Malick AW. Selfemulsifying drug delivery systems (SEDDS) with polyglycolysed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J Pharm . 1994; 106:15-23.
21. Charman SA, Charman WN, Rogge MC , Wilson TD , Dutko FJ , Pouton CW . Self-emulsifying drug delivery systems: formulation andbiopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res. 1992; 9 : 87 - 93 .
22. Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and â€˜self microemulsifying â€™ drug delivery systems. Eur J Pharm Sci . 2000; 11:S93 - S98
23. Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int J Pharm. 2001; 212:233 â€“ 246
24. Oâ€™Driscoll, C.M. and Griffin, B.T. Biopharmaceutical challenges associated with drugs with low aqueous solubility â€“ the potential impact of lipid-based formulations. Adv. Drug Deliv. Rev. 2008; 60:617â€“624
25. Kohli K, Chopra S, Dhar D, Arora S, Khar RK, Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability, Drug Discovery Today, 2010; 15(21/22):958-965.
26. Pouton CW, J. H. C. Porter, Formulation of lipid-based delivery systems for oral administration: Materials, methods and strategies, Adv. Drug Deliver. Rev. 2008; 60:625â€“637; DOI: 10.1016/j.addr.2007.10.010.
27. Small DM. A classification of biologic lipids based upon their interaction in aqueous systems. J Am Oil Chem Soc 1968; 45: 108â€“119.
28. Cao Y, Marra M, Anderson BD. Predictive relationships for the effects of triglyceride ester concentration and water uptake ons olubility and partitioning of small molecules into lipid vehicles. J Pharm Sci 2004; 93:2768â€“79.
29. Prajapati NH, Patel DP, Patel NG, Dalrymple DM, Serajuddin AT. Effect of difference in fatty acid chain lengths of medium chain lipids on lipid/surfactant/water phase diagrams and drug Solubility. J Excipients Food Chem. 2011Í¾ 2:73.
30. El Laithy HM, ElShaboury KM. The development of cutinalipogels and gel micromeulsion for topical administration of fluconazole. AAPS PharmSciTech. 2002Í¾ 3:E35. [PMCID: PMC2751344] [PubMed: 12916929]
31. Patel AR, Vavia PR. Preparation and in vivo evaluation of SMEDDS (Self Microemulsifying Drug Delivery System) containing fenofibrate. AAPS J. 2007Í¾ 9:E344â€“52. [PMCID: PMC2751486] [PubMed: 18170981]
32. Yanez JA, Wang SW, Knemeyer IW, Wirth MA, Alton KB. Intestinal lymphatic transport for drug delivery. Adv Drug Deliv Rev. 2011Í¾ 63:923â€“42. [PubMed: 21689702]
33. Stegemann S, Leveiller F, Franchi D, de Jong H, LindÃ©n H. When poor solubility becomes an issue: From early stage to proof of concept. Eur J Pharm Sci. 2007Í¾ 31:249â€“61. [PubMed: 17616376]
34. Pouton CW. Formulation of selfemulsifying drug delivery systems. Adv Drug Deliv Rev. 1997Í¾ 25:47â€“ 58.
35. Patravale VB, Date AA. Microemulsions: Pharmaceutical Applications. In: Stubenrauch C, editor. Microemulsions: Background, New Concepts, Applications, Perspectives. United Kingdom: Blackwell Publishing LtdÍ¾ 2009. pp. 259â€“93.
36. Malcolmson C, Satra C, Kantaria S, Sidhu A, Lawrence MJ. Effect of oil on the level of solubilization of testosterone propionate into nonionic oilinwater microemulsions. J Pharm Sci. 1998Í¾ 87:109â€“16. [PubMed: 9452978].
37. Grovea M, Mullertzb A, Bioavailability of seocalcitol II: development and characterization of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides, Eur. J. Pharm. Sci. 2006; 28:233â€“234; DOI: 10.1016/j.ejps.2006.02.005.
38. Khoo SM, Humberstone AJ, Porter CJH, Edwards GA, Charman WN, Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine, Int. J. Pharm. 1998; 167:155â€“164; DOI: 10.1016/S03785173(98)00054-4.
39. Porter CJ, Kaukonen AM, Boyd BJ, Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation, Pharm. Res. 2004; 8:1405â€“1412; DOI: 10.1023/B:PHAM.0000036914.22132.cc.
40. Stuchlik M, WÃ¡k S, Lipid-based vehicle for oral drug delivery, Biomed. Pap. 2001; 145:17â€“26.
41. Constantinides PP, Lipid for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects, Pharm. Res. 1995; 12:1561â€“1572; microemulsions DOI: 10.1023/A: 1016268311867.
42. Constantinides PP, Scalart JP, Formulation and physical characterization of water-in-oil microemulsions containing long- versus medium-chain glycerides, Int. J. Pharm. 1997; 158:57â€“68; DOI: 10.1016/S0378-5173(97)00248-2.
43. Swenson ES, Milisen WB, Curatolo W, â€œIntestinal permeability enhancement: efficacy, acute local toxicity, and reversibility,â€ Pharmaceutical Research, vol. 1994; 11(8):1132â€“ 1142.
44. Hauss DJ, â€œOral lipid based Formulations-Enhancing the Bioavailablity of Poorly water soluble drugs,â€ in Drugs and Pharmaceutical Sciences, 2007; 170:1â€“339, Informa healthcare, NC, USA.
45. Wang L, Dong J, Chen J, Eastoe J, Li X, â€œDesign and optimization of a new self-nanoemulsifying drug delivery system,â€ Journal of Colloid and Interface Science, 2009; 330(2):443â€“448.
46. Shah SR, Parikh RH, Chavda JR et al., â€œSelf-nanoemulsifying drug delivery system of glimepiride: design, development, and optimization,â€ PDA Journal of Pharmaceutical Science and Technology, 2013; 67(3):201â€“213.
47. Pouton CW, â€œSelf-emulsifying drug delivery systems: assessment of the efficiency of emulsification,â€ International Journal of Pharmaceutics, vol. 1985; 27(2-3):335â€“348.
48. Ozawa K, Olsson U, Kunieda H, Oil-induced structural change in nonionic microemulsions. J. Dispersion Sci. Technol., 1986; 22:119-124. CrossRef | Direct Link
49. Meinzer, A. et al. Microemulsion: a suitable galenical approach for the absorption enhancement of low soluble compounds? BT Gattefosse 1995; 88:21â€“26
50. Reiss, H. Entropy induced dispersion of bulk liquids. J. Colloid Interface Sci. 1975; 53:61â€“70
51. Craig D.Q. et al. An investigation into the mechanism of self emulsification using particle size analysis and low frequency dielectric spectroscopy. Int. J. Pharm. 1995; 114:103â€“110
52. Pouton, C.W. et al. Self-emulsifying systems for oral delivery of drugs. International Symposium on Control Release Bioactive Materials pp. 1987; 113â€“114.
53. Gursoy, N. et al. Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery system. J. Pharm. Sci. 2003; 92:2411â€“2418.
54. Palamakula A. Khan M.A. Evaluation of cytotoxicity of oils used in coenzyme Q10 self-emulsifying drug delivery systems (SEDDS). Int. J. Pharm. 2004; 273:63â€“73.
55. Goddeeris C. et al. Light scattering measurements on microemulsions: estimation of droplet sizes. Int. J. Pharm. 2006; 312:187â€“195.
56. Vyas S.P., Khar R.K. Submicron emulsion. In Targeted and Controlled Drug Delivery Novel Carriers Systems. CBS Publishers and Distributors, 2002; pp. 291â€“294.
57. Fatouros DG et al. Morphological observations on a lipid-based drug delivery system during in vitro digestion. Eur J Pharm Sci 2007; 31:85â€“94.
58. Greiner RW, Evans DF. Spontaneous formation of a water-continuous emulsion from water-in-oil microemulsion. Langmuir 1990; 6: 1793â€“1796.
59. Humberstone AJ, Charman WN. Lipid-based vehicles for the oral delivery of poorly water-soluble drugs. Adv Drug Deliv Rev 1997; 25:103â€“28.
60. Pramod K, Peeyush K, Rajeev K, Nitish K, Rakesh K. An overview of lipid based formulation for oral drug delivery. Drug Inv Today 2010; 2:390â€“5.
61. Driscoll CMO. Lipid based formulations for intestinal lymphatic delivery. Eur J Pharm Sci 2002; 15:405â€“15.
62. Hauss DJ, Fogal SE, Ficorilli JV, Price CA, Roy T, Jayaraj AA, Keirns JJ, Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor, J. Pharm. Sci. 1998; 87:164-169.
63. Charman WN, Lipid vehicle and formulation effects on intestinal lymphatic drug transport, in: W.N. Chasmar, V.J. Stella (Eds.), Lymphatic Transport of Drugs, CRC Press, Boca Raton, FL, 1992, pp. 113-179.
64. Hauss DJ, Mehta SC, Radebaugh GW, Targeted lymphatic transport and modiÂ®ed systemic distribution of CI-976, a lipophilic lipidregulator drug, via a formulation approach, Int. J. Pharm. 1994; 108:85-93.
65. Dintaman JM, Silverman JA. Inhibition of P-glycoprotein by Dï€alphaâˆ’tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharm Res 1999; 16:1550â€“6.
66. Chervinsky DS, Brecher BL, Hoelcle MJ. Cremophor EL enhances taxol efficacy in a multidrug resistant C1300 neuroblastoma cell line. Anticancer Res 1993; 13:93â€“6.
67. Hunt JN, Knox MT. A relation between the chain length of fatty acids and the slowing of gastric emptying. J Physiol 1968; 194:327â€“36.
68. Wagnera D, Langguth HS, Hanafy A, Koggela A, Langguth P. Intestinal drug efflux: formulation and food effects. Adv Drug Del Rev 2001; 50(Suppl. 1):S13â€“31.
69. Erlanson-Albertsson C. Pancreatic colipase. Structural and physiological aspects. Biochim. Biophys. Acta 1992; 1125:1â€“7.
70. Borgstrom, B. On the mechanism of pancreatic lipolysis of glycerides. Biochim. Biophys. Acta 1954; 13:491â€“504.
71. van den Bosch H., Postema N. M., de Haas G. H. & van Deenen L. L. On the positional specificity of phospholipase A from pancreas. Biochim. Biophys. Acta 1965; 98:657â€“659.
72. Kalepun S, Manthina M, Padavala V, Oral lipid-baseddrugdeliverysystems â€“ an overview, Acta Pharmaceutica Sinica B, 2013; 3(6):361â€“372.
73. Gershkovich P, Hoffman A. Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins. Eur J Pharm Sci 2007; 32:24â€“32.
74. Holm R, Porter CJH, Edwards GA, MÃ¼llertz A, Kristensen HG, Charman WN. Examination of oral absorption and lymphatic transport of halofantrine in a tripleâˆ’cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. Eur J Pharm Sci 2003; 20:91â€“7.
75. Narang AS, Delmarre D, Gao D. Stable drug encapsulation in micelles and microemulsions. Int J Pharm. 2007Í¾ 345:9â€“25. [PubMed: 17945446]
76. Rane SS, Anderson BD. What determines drug solubility in lipid vehicles: Is it predictable? Adv Drug Deliv Rev. 2008Í¾ 60:638â€“56. [PubMed: 18089295]
77. Oâ€™Driscoll CM, Griffin BT. Biopharmaceutical challenges associated with drugs with low aqueous solubilityThe potential impact of lipidbased formulations. Adv Drug Deliv Rev. 2008Í¾ 60:617â€“24. [PubMed: 18155800]
78. Benet L. The drug effluxâ€metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 2001; 50: S3â€S11.
79. Yu L, Bridgers A, Polli J, Vickers A, Long S, Roy A, Winnike R, Coffin M. Vitamin Eâˆ’TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability. Pharm Res 1999; 16:1812â€“7.
80. Woo JS, Lee CH, Shim CK, Hwang Sâˆ’C. Enhanced oral bioavailability of paclitaxel by co-administration of the P-glycoprotein inhibitor KR30031. Pharm Res 2003; 20:24â€“30.
81. Swenson ES, Curatolo WJ. Means to enhance penetration. Adv Drug Del Rev 1992; 8:39â€“92.
82. Jackson MJ. Drug transport across gastrointestinal epithelial. Physiology of the Gastrointestinal Tract. New York: Rave Press; 1987. p. 1597â€“621.
83. Kim HJ,Yoon KA, Hahn M, Park ES, Chi SC. Preparation and in vitro evaluation of self-microemulsifying drug delivery systems containing idebenone. Drug Dev Ind Pharm 2000; 26:523â€“9.
84. Asadujjaman MD, Mishuk AU, Novel approaches in lipid based drug delivery systems, Journal of Drug Delivery and Therapeutics,2013; 3(4):124-130.
85. Meinzer A, Mueller E, Vonderscher J. Microemulsion â€“ a suitable galenical approach for the absorption enhancement of low soluble compounds? B T Gattefosse 1995; 88:21â€“6.
86. W. C. Pouton, Properties and uses of common formulation lipids, surfactants and co-solvents, in AAPS, Workshop, March 2007.
87. Levy MY, Benita S. Drug release from submicronized o/w emulsion: a new in vitro kinetic evaluation model. Int J Pharm 1990; 66:29â€“37.
88. Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int J Pharm 2001; 212:233â€“46.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (SeeÂ The Effect of Open Access).