Formulation, Optimization, And Comparative Evaluation of Voriconazole-Loaded Transdermal Gel Incorporating Penetration Enhancers: A Qbd-Based Approach for Enhanced Skin Permeation and Antifungal Efficacy

Voriconazole, a broad-spectrum antifungal agent, exhibits limitations associated with systemic administration, including variable bioavailability and adverse effects. The present study aimed to develop and optimize a transdermal gel system incorporating chemical penetration enhancers to improve skin permeation, dermal deposition, and antifungal efficacy. Voriconazole-loaded gels were formulated using a Carbomer 940–HPMC polymeric system with cosolvents and hydroxypropyl-β-cyclodextrin for solubility enhancement. Penetration enhancers including oleic acid, isopropyl myristate, menthol, and Transcutol® P were incorporated and optimized using a Quality by Design (QbD) approach employing Box–Behnken design. The optimized formulation demonstrated significantly enhanced ex vivo permeation, with steady-state flux reaching 156.2 µg/cm²/h, along with improved permeability coefficient and reduced lag time. In vitro release studies indicated controlled drug release following first-order kinetics (R² = 0.992) and Higuchi diffusion behavior. Antifungal studies revealed superior activity against Candida albicans and Aspergillus niger, with minimum inhibitory concentration as low as 1 µg/mL. Cytocompatibility studies confirmed acceptable safety with cell viability above 85%. Stability studies indicated minimal changes over three months under ICH conditions. The study concludes that the optimized transdermal gel represents a promising alternative for effective and safe antifungal therapy.