FORMULATION AND EVALUATION OF A CLOTRIMAZOLELOADED ETHOSOMAL GEL FOR ENHANCED TRANSDERMAL ANTIFUNGAL ACTIVITY

Abstract

Background: Fungal infections represent a substantial global health burden, affecting nearly one billion people worldwide. Clotrimazole, a broad-spectrum antifungal agent, has been a cornerstone of topical therapy; however, its clinical utility is significantly constrained by poor dermal bioavailability and inadequate penetration through the stratum corneum when delivered via conventional formulations. Objective: The present study aimed to formulate and evaluate a clotrimazole-loaded ethosomal gel for enhanced transdermal antifungal activity. Methods: Clotrimazole-loaded ethosomes were prepared using the mechanical dispersion method with varying concentrations of phospholipids and ethanol. A 3² factorial design was employed to optimize formulation variables. The optimized ethosomes were characterized for vesicle size, zeta potential, surface morphology, and drug entrapment efficiency. Following optimization, ethosomes were incorporated into a Carbopol 934 gel base. The resulting ethosomal gel was evaluated for pH, viscosity, in vitro drug release, ex vivo skin permeation, antifungal activity, and stability studies. Results: The optimized ethosomal formulation exhibited a vesicle size of 202.8 ± 4.8 nm, zeta potential of −83.6 ± 0.96 mV, and drug entrapment efficiency of 98.42 ± 0.15%. Transmission electron microscopy confirmed uniformly spherical vesicles with intact bilayer structures. The ethosomal gel demonstrated pH of approximately 8.0 and viscosity of 73,200 cps. In vitro drug release studies revealed approximately 92% cumulative drug release over 8 hours, with data best fitting the Higuchi model, indicating diffusion-controlled release. Ex vivo skin permeation studies showed significantly higher cumulative permeation (88.53%) and steadystate flux (3.39 μg/cm²/min) compared to conventional ethosomal gel (1.57 μg/cm²/min) and marketed formulation (1.13 μg/cm²/min). Antifungal activity evaluation against Candida albicans revealed a zone of inhibition of 34.6 ± 0.57 mm for the ethosomal gel, significantly superior to conventional liposomal gel (29.6 ± 0.57 mm) and marketed cream (19.0 ± 1.00 mm). Stability studies demonstrated good storage stability with drug content exceeding 90% of initial values at both accelerated (40°C) and long-term (25°C) storage conditions for 3 months. Conclusion: The developed clotrimazole-loaded ethosomal gel represents a promising nanocarrier-based strategy for enhanced transdermal delivery of clotrimazole. The formulation successfully overcame the limitations of conventional topical formulations by improving drug permeation, sustaining drug release, and enhancing antifungal efficacy. The excellent physicochemical properties, superior skin permeation, potent antifungal activity, and good stability suggest that the ethosomal gel could serve as a viable alternative to conventional topical formulations for the effective management of superficial fungal infections.