Abstract

This work reports the first systematic formulation strategy guided by Quality-by-Design principles to create an ultra-deformable ethosomes-based nanocarrier for luliconazole (LCZ). The approach addresses the long-standing barriers of poor solubility, limited skin penetration, and rapid drug clearance in dermatophytosis therapy. A Box-Behnken design identified the optimal composition, including phospholipid (PL 90G), Span® 20, and ethanol: propylene glycol, yielding highly elastic nanosized vesicles (196.97 ± 1.57 nm; PDI 0.158 ± 0.03) with exceptional PDE (91.0 %) and sustained release (62 % over 12 h). Incorporation into a Carbopol 980 gel conferred favourable shear-thinning behaviour, enhanced spreadability, and superior texture over a marketed 1 % LCZ cream (MKT-LF). Ex vivo permeation across rat skin demonstrated a 2.4-fold higher flux and 11.3-fold greater cutaneous deposition than MKT-LF, attributed to synergistic vesicle deformability and ethanol-induced fluidization of stratum corneum. LCZ-UDEs demonstrated deep epidermal penetration of intact fluorescently labelled vesicles. Dermatokinetic profiling revealed a 3.4-fold increase in epidermal AUC 0-12, prolonged half-life, and delayed Tmax, indicating enhanced skin retention. Antifungal assays demonstrated a two-fold reduction in MIC, and rapid fungicidal kinetics against Trichophyton rubrum compared with LCZ solution and MKT-LF. Biocompatibility studies validated >90 % HaCaT cell viability, no haemolysis, and absence of dermal irritation. Sustained intradermal LCZ levels minimized sub-therapeutic exposure that drives fungal resistance. By uniting nanoscale vesicle engineering, ethanol-enhanced skin permeation, and QbD-optimized composition, this study delivers a stable, safe, and efficacious topical nanoplatform with potential to transform dermatophytosis management and mitigate antifungal resistance.