Colloids and Surfaces B: Biointerfaces 76 (2010) 410–420 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe Vikas Bali, Mushir Ali, Javed Ali ∗ Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India article info Article history: Received 25 September 2009 Received in revised form 16 November 2009 Accepted 21 November 2009 Available online 5 December 2009 Keywords: Nanoemulsion Oral bioavailability Ezetimibe Pseudoternary phase diagram Solubility Stability abstract The present study aimed at developing an optimal nanoemulsion of ezetimibe and evaluating its stabil- ity, pharmacodynamic and pharmacokinetic potential. Solubility of ezetimibe was determined in various vehicles. Surfactants and cosurfactants were grouped in two different combinations to construct pseu- doternary phase diagrams. Formulations were selected from the o/w nanoemulsion region and were subjected to various thermodynamic stability and dispersibility tests. Optimized formulations were char- acterized for their percentage transmittance, refractive index, viscosity, droplet size and zeta potential. Release rate of optimized formulations was determined using an in vitro dissolution test. The formulation used for assessment of lipid lowering potential and bioavailability contained Capryol 90 (10%, v/v), Tween 20 (33.33%, v/v), PEG 400 (16.67%, v/v), double distilled water (40%, v/v). The release of drug from the nanoemulsion formulations was extremely significant (p < 0.001) in comparison to the drug suspension. More than 60% of the drug was released in the initial 1 h of the dissolution study in comparison to the drug suspension. The value of total cholesterol in the group administered with the formulation PF1 was highly significant (p < 0.001) with respect to the group administered with the suspension of the drug. The plasma concentration time profile of ezetimibe from nanoemulsion represented greater improve- ment of drug absorption than the marketed formulation and simple drug suspension. The shelf life of the nanoemulsion was found to be 5.94 years at room temperature. The present study established nanoemul- sion formulation to be one of the possible alternatives to traditional oral formulations of ezetimibe to improve its bioavailability. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Ezetimibe is the first member of a novel class of lipid lowering agents that selectively inhibits the absorption of biliary and dietary cholesterol as well as related phytosterols from the intestine with- out affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe is a class II molecule as per Biopharmaceutics Classification System (BCS). It is a highly lipophilic molecule having log p (octanol/water) of 4.5. Due to its highly hydrophobic character, ezetimibe exhibits highly erratic and very low-dissolution profile in the gastrointestinal fluids [1]. Its bioavailability is highly variable [2]. Moreover, its absolute bioavailability cannot be determined since the drug is virtually insoluble in aqueous media suitable for injection. Ezetimibe exhibits moderate intersubject variability in its pharmacokinetics with coefficient of variation ranging from 34% to 43% and 32% to 37% for C max and AUC respectively [3]. Researchers have tried various methods to overcome these limitations [1,4,5]. It was hypothesized that formulating a nanoemulsion would help to ∗ Corresponding author. Tel.: +91 9811312247; fax: +91 11 26059688x5307. E-mail addresses: jali@jamiahamdard.ac.in, javedaali@yahoo.com (J. Ali). reduce the intersubject variability observed in the pharmacokinet- ics of ezetimibe since nanoemulsions have been reported to make the plasma concentration profiles and bioavailability of drugs more reproducible [6,7]. Ezetimibe being a class II molecule as per BCS, solubility of the drug will be the limiting step in the absorption process. In earlier studies, the in vitro drug release studies on the optimized formu- lation have been reported in 0.5% (w/v) solution of sodium lauryl sulphate at 75 rpm [4,5]. This may lead to confounding interpreta- tion of the release profile since in the presence of a wetting agent, the exact solubilisation potential of the system developed with the aim of increasing solubility of a poorly water-soluble drug may not be fully exhibited. In order to have better interpretation of the relationship between the phase behaviour of the mixture and its composition and to aid in the better selection of the formulation, a more exhaustive study was carried out where the concentra- tion of both oil and S mix (mixture of surfactant and cosurfactant in specific volume ratios) were varied from 10% to 90% (v/v) in comparison to previously reported studies involving only 10–30% (w/w) of oil [4,5]. Significant increase in the mean globule size of formed nanoemulsion upon dilution reported in earlier studies could adversely affect the release of the drug from the developed 0927-7765/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfb.2009.11.021