Enhanced antifungal therapy for cutaneous candidiasis: Development, evaluation, and optimization of luliconazole-loaded transethosomal gel.

Cutaneous candidiasis, a widespread opportunistic fungal infection primarily caused by Candida albicans, accounts for 1% of outpatient and 7% of inpatient dermatology consultations. The rise in antifungal resistance due to genetic mutations in Candida species has complicated therapeutic outcomes and increased mortality rates. This study aimed to develop a more effective topical therapy by formulating Luliconazole (LCZ), a potent imidazole antifungal limited by poor solubility and skin penetration, into a Transethosomal gel (LCZ-TEG) for enhanced delivery and efficacy. LCZ-loaded Transethosomes (LCZ-TESs) were developed and subsequently incorporated into a hydroxypropyl methylcellulose (HPMC) gel base. Utilizing a Box-Behnken design (BBD) within a Quality by Design (QbD) framework, the formulation was optimized by evaluating the impact of LCZ load, Tween 80 concentration, and ethanol content. The optimized LCZ-TEG formulation demonstrated a high correlation between predicted and experimental values, with a particle size (PS) of 111.90 nm, a polydispersity index (PDI) of 0.072, a zeta potential (ZP) of +49.40 mV, and a 95.00% drug entrapment efficiency (EE), with a sustained-release profile. Ex vivo studies indicated that the LCZ-TESs significantly outperformed free LCZ in skin permeation. This was corroborated by confocal laser scanning microscopy (CLSM), which revealed that LCZ-TESs exhibited stronger and deeper fluorescence signals, reaching a skin depth of 179 µm compared to only 84 µm for the rhodamine B-free solution. Furthermore, in vitro antifungal testing demonstrated a 1.40-fold increase in the zone of inhibition (ZOI) compared to the marketed Lucoz® cream. In vivo studies in a Candida-infected rat model showed a 1.50-fold reduction in treatment duration with the LCZ-TEG formulation. These findings suggest that the developed LCZ-TEG significantly improves the solubility, skin penetration, and antifungal efficacy of luliconazole, supporting its potential as a promising, efficient, and targeted therapy for cutaneous candidiasis.