A novel surfactant aided micellar system of oxidation inhibitors in clotrimazole bioadhesive gel: development, characterization, in vitro and in vivo antifungal evaluation against Candida clinical isolates

Abstract

Clotrimazole (CLZ) is a widely used antifungal agent with poor aqueous solubility, which requires the development of new delivery systems to improve its therapeutic activity. However, butylatedhydroxy anisole (BHA) and butylatedhydroxy toluene (BHT) have been known as potential antioxidants with antimicrobial properties. In an attempt to develop a better formulation with an antifungal profile, a surfactant aided antioxidant micellar system was dispersed within a clotrimazole gel formulation. Initially, the gel library was prepared and subjected to in vitro evaluation. Based on in vitro release and kinetic profiles, the best three formulations were selected for further analysis. Moreover, in vitro antifungal activity (MIC) and fractional inhibitory concentration index (FICI) against different drug resistant and susceptible Candida isolates were carried out and directed to the best among the 27 formulations. The optimized best selected formulation was thereafter evaluated via morphology studies and in vivo antifungal evaluation. Morphology studies depicted the distribution of micellar structures within the polymeric gel network as well as the contact activity mechanism against Candida albicans. The physicochemical characterization showed that average micellar size was lower than ∼160 nm, low polydispersity index, negative zeta potential and gel pH 6.9. After 60 days, no significant change was observed within the formulation. Photostability studies revealed that antioxidants eminently inhibit the drug degradation under UV radiation with improved drug stability. In addition, in vivo antifungal activity was investigated on experimentally induced cutaneous infection in immunosuppressed Sprague Dawley (SD) rats. The in vivo study confirmed the maximum therapeutic efficacy, as the lowest number of cfu ml⁻¹ was recorded. Conclusively, this study provide a good skin targeting effect and may be promising for stable and effective topical delivery of CLZ offering a maintained localized effect.