Novel micelle formulations to increase cutaneous bioavailability of azole antifungals Y.G. Bachhav 1 , K. Mondon 1 , Y.N. Kalia, R. Gurny, M. Möller ⁎ School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland abstract article info Article history: Received 24 October 2010 Accepted 6 March 2011 Available online 11 March 2011 Keywords: Antifungal Azole Polymeric micelle Skin deposition Substituted polylactides Follicular delivery Efficient topical drug administration for the treatment of superficial fungal infections would deliver the therapeutic agent to the target compartment and reduce the risk of systemic side effects. However, the physicochemical properties of the commonly used azole antifungals make their formulation a considerable challenge. The objective of the present investigation was to develop aqueous micelle solutions of clotrimazole (CLZ), econazole nitrate (ECZ) and fluconazole (FLZ) using novel amphiphilic methoxy-poly(ethylene glycol)- hexyl substituted polylactide (MPEG-hexPLA) block copolymers. The CLZ, ECZ and FLZ formulations were characterized with respect to drug loading and micelle size. The optimal drug formulation was selected for skin transport studies that were performed using full thickness porcine and human skin. Penetration pathways and micellar distribution in the skin were visualized using fluorescein loaded micelles and confocal laser scanning microscopy. The hydrodynamic diameters of the azole loaded micelles were between 70 and 165 nm and the corresponding number weighted diameters (d n ) were 30 to 40 nm. Somewhat surprisingly, the lowest loading efficiency (b 20%) was observed for CLZ (the most hydrophobic of the three azoles tested); in contrast, under the same conditions, ECZ was incorporated with an efficiency of 98.3% in MPEG-dihexPLA micelles. Based on the characterization data and preliminary transport experiments, ECZ loaded MPEG- dihexPLA micelles (concentration 1.3 mg/mL; d n b 40 nm) were selected for further study. ECZ delivery was compared to that from Pevaryl® cream (1% w/w ECZ), a marketed liposomal formulation for topical application. ECZ deposition in porcine skin following 6 h application using the MPEG-dihexPLA micelles was N 13-fold higher than that from Pevaryl® cream (22.8 ± 3.8 and 1.7 ± 0.6 μg/cm 2 , respectively). A significant enhancement was also observed with human skin; the amounts of ECZ deposited were 11.3 ± 1.6 and 1.5 ± 0.4 μg/cm 2 , respectively (i.e., a 7.5-fold improvement in delivery). Confocal laser scanning microscopy images supported the hypothesis that the higher delivery observed in porcine skin was due to a larger contribution of the follicular penetration pathway. In conclusion, the significant increase in ECZ skin deposition achieved using the MPEG-dihexPLA micelles demonstrates their ability to improve cutaneous drug bioavailability; this may translate into improved clinical efficacy in vivo. Moreover, these micelle systems may also enable targeting of the hair follicle and this will be investigated in future studies. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The incidence of mycoses especially superficial fungal infections is increasing and according to a recent report more than 25% of the world's population is affected [1,2]; disease progression is more rapid and severity increased in patients with compromised immune function [3]. Host immunity can be impaired during infancy, in old age, by pregnancy, by disease, e.g. diabetes mellitus, or through the administration of antibiotics and glucocorticoids [4]. Azole antifungals such as clotrimazole (CLZ), econazole nitrate (ECZ) and fluconazole (FLZ) are the first line treatments for various fungal infections [5]. Topical therapy is desirable since, in addition to targeting the site of infection, it reduces the risk of systemic side effects. In general, azole antifungals tend to be highly lipophilic (although there are exceptions (e.g., FLZ)) and they can readily partition into the lipid-rich intracellular space in the stratum corneum; the challenge is to develop a simple stable formulation that facilitates drug release into the skin [6]. Given the desirable properties of aqueous formulations and the lipophilic character and poor water solubility of azoles, it was decided to investigate polymeric micelles as a drug carrier system. Due to their stability, size and ability to incorporate significant amounts of hydrophobic drugs in their core, these systems seem to be well-suited for use with azole antifungals. In previous studies, micelle formula- tions using two novel amphiphilic methoxy-poly(ethylene glycol)- hexyl-substituted poly(lactides) (MPEG-hexPLA) block copolymers, mono- and di-hexyl-substituted (MPEG-monohexPLA and –dihexPLA, respectively) demonstrated their ability to incorporate several poorly water soluble drugs with high loading efficiencies [7–9]. The present Journal of Controlled Release 153 (2011) 126–132 ⁎ Corresponding author at: Department of Pharmaceutics, University of Geneva, University of Lausanne, 30 Quai Ernest Ansermet, CH 1211 Geneva 4, Switzerland. Tel.: +41 22 379 3132; fax: +41 22 379 6567. E-mail address: Michael.Moeller@unige.ch (M. Möller). 1 Both authors have equally contributed to this work. 0168-3659/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2011.03.003 Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel