Formulation and in vivo Evaluation of a Self-Microemulsifying Drug Delivery System of Dutasteride

Abstract

This study aimed to develop an effective formulation to improve the solubility and oral absorption of dutasteride by using a self-microemulsifying drug delivery system (SMEDDS). We used the d-optimal mixture design as a tool for developing an optimized SMEDDS formulation with excellent physicochemical characteristics such as mean particle size of <100 nm and percentage of drug dissolved at 15 min, >80%. An optimized dutasteride-loaded SMEDDS formulation consisted of 39.80% Capryol^TM 90, 25.90% Cremophor^® EL, and 34.30% Transcutol^® HP and showed an emulsion droplet size of about 35.3 nm. Approximately 90% of dutasteride from the SMEDDS dissolved at 10 min in dissolution media of pH 1.2 and 6.8. Furthermore, pharmacokinetic studies in rats indicated that compared to the raw drug, the optimized SMEDDS formulation significantly improved the oral absorption of dutasteride. Therefore, preliminary results from our study suggest that the dutasteride-loaded self-microemulsifying formulation has a great potential for clinical application.

Key words

dutasteride - self-microemulsifying drug delivery system - bioavailability - pharmacokinetics

• References

• 1 Gisleskog PO, Hermann D, Hammarlund-Udenaes M et al. The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination. Br J Clin Pharmacol 1999; 47: 53-58
• 2 Evans HC, Goa KL. Dutasteride. Drugs Aging 2003; 20: 905-916
• 3 Andriole G, Bruchovsky N, Chung LW et al. Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol 2004; 172: 1399-1403
• 4 U.S. Food Drug Administration “Application Number: 21-319.”:  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21319_Duagen_biopharmr_P1.pdf cited 20 Dec 2012
• 5 Baek IH, Kim MS. Improved supersaturation and oral absorption of dutasteride by amorphous solid dispersions. Chem Pharm Bull 2012; 60: 1468-1473
• 6 Park SJ, Choo GH, Hwang SJ et al. Quality by Design: Screening of Critical Variables and Formulation Optimization of Eudragit E Nanoparticles Containing Dutasteride. Arch. Pharm Res 2013; http://dx.doi.org/10.1007/s12272-013-0064-z
• 7 Kim CK, Park JS. Solubility enhancers for oral drug delivery: can chemical structure manipulation be avoided?. Am J Drug Deliv 2005; 2: 113-130
• 8 Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 2004; 58: 173-182
• 9 Patel D, Sawant KK. Self micro-emulsifying drug delivery system: formulation development and biopharmaceutical evaluation of lipophilic drugs. Curr Drug Deliv 2009; 6: 419-424
• 10 Subramanian N, Ray S, Ghosal SK et al. Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib. Biol Pharm Bull 2004; 27: 1993-1999
• 11 Basalious EB, Shawky N, Badr-Eldin SM. SNEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I: development and optimization. Int J Pharm 2010; 391: 203-211
• 12 Pawar SK, Vavia PR. Rice germ oil as multifunctional excipient in preparation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus. AAPS PharmSciTech 2012; 13: 254-261
• 13 Dixit AR, Rajput SJ, Patel SG. Preparation and bioavailability assessment of SMEDDS containing valsartan. AAPS PharmSciTech 2010; 11: 314-321
• 14 Vonderscher J, Meinzer A. Rationale for the development of Sandimmune Neoral. Transplant Proc 1994; 26: 2925-2927
• 15 Kohli K, Chopra S, Dhar D et al. Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability. Drug Discov Today 2010; 15: 958-965
• 16 Thi TD, Van Speybroeck M, Barillaro V et al. Formulate-ability of ten compounds with different physicochemical profiles in SMEDDS. Eur J Pharm Sci 2009; 38: 479-488
• 17 Awotwe-Otoo D, Zidan AS, Rahman Z et al. Evaluation of anticancer drug-loaded nanoparticle characteristics by nondestructive methodologies. AAPS PharmSciTech 2012; 13: 611-622
• 18 Kaul G, Huang J, Chatlapalli R et al. Quality-by-design case study: investigation of the role of poloxamer in immediate-release tablets by experimental design and multivariate data analysis. AAPS PharmSciTech 2011; 12: 1064-1076
• 19 Jin SJ, Yoo YH, Kim MS et al. Paroxetine hydrochloride controlled release POLYOX matrix tablets: screening of formulation variables using Plackett-Burman screening design. Arch Pharm Res 2008; 31: 399-405
• 20 Kim MS, Kim JS, You YH et al. Development and optimization of a novel oral controlled delivery system for tamsulosin hydrochloride using response surface methodology. Int J Pharm 2007; 341: 97-104
• 21 Lee YL, Kim MS, Park MY et al. Quality by design: understanding the formulation variables and optimization of metformin hydrochloride 750 mg sustained release tablet by Box–Behnken design. J Pharm Invest 2012; 42: 213-220
• 22 El-Malah Y, Nazzal S, Khanfar NM. D-optimal mixture design: optimization of ternary matrix blends for controlled zero-order drug release from oral dosage forms. Drug Dev Ind Pharm 2006; 32: 1207-1218
• 23 Eriksson L, Johansson E, Wikström C. Mixture design — design generation, PLS analysis, and model usage. Chemometr Intell Lab 1998; 43: 1-24
• 24 Mura P, Furlanetto S, Cirri M et al. Optimization of glibenclamide tablet composition through the combined use of differential scanning calorimetry and d-optimal mixture experimental design. J Pharm Biomed Anal 2005; 37: 65-71
• 25 Ramakrishna NV, Vishwottam KN, Puran S et al. Selective and rapid liquid chromatography – tandem mass spectrometry assay of dutasteride in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 809: 117-124
• 26 Singh AK, Chaurasiya A, Singh M et al. Exemestane loaded self-microemulsifying drug delivery system (SMEDDS): development and optimization. AAPS PharmSciTech 2008; 9: 628-634
• 27 Zhang L, Zhu W, Yang C et al. A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting. Int J Nanomedicine 2012; 7: 151-162
• 28 Yan YD, Kim JA, Kwak MK et al. Enhanced oral bioavailability of curcumin via a solid lipid-based self-emulsifying drug delivery system using a spray-drying technique. Biol Pharm Bull 2011; 34: 1179-1186
• 29 Myers RH, Montgomery DC. Response surface methodology: process and product optimization using designed experiments. John Wiley & Sons; New York: 2002: 273-286
• 30 Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur J Pharm Sci 2000; 11: S93-S98
• 31 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
• 32 Cornaire G, Woodley J, Hermann P et al. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm 2004; 278: 119-131
• 33 Sha X, Yan G, Wu Y et al. Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. Eur J Pharm Sci 2005; 24: 477-486
• 34 Dahan A, Hoffman A. The effect of different lipid based formulations on the oral absorption of lipophilic drugs: The ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats. Euro J Pharm Biopharm 2007; 67: 96-105