Formulation and development of thymoquinone-loaded ufasome hydrogel for effective treatment of onychomycosis

Chronic fungal nail infections like onychomycosis are challenging to treat due to drug resistance, long treatment durations, and poor nail penetration of conventional antifungals. Here, we report the formulation and evaluation of a thymoquinone-loaded ufasome hydrogel (TQ-UFs-Gel) designed for enhanced transungual delivery. TQ-UFs were prepared by thin-film hydration of sodium oleate and cholesterol, optimized via a central composite design to yield vesicles ~ 191.50 ± 0.23 nm in size with 80.05 ± 0.34% entrapment efficiency and PDI 0.18 ± 0.32. The hydrogel was formed by incorporating TQ-UFs into 1% Carbopol 940. Physicochemical characterization included pH, spreadability, viscosity, texture profile analysis, in vitro release (Franz diffusion), ex vivo bovine hoof permeation, nail clipping drug loading, and HET-CAM irritation testing. The optimized TQ-UFs-Gel exhibited shear-thinning behavior (viscosity 987 → 387 cP), pH 5.9 ± 0.23, spreadability 8.7 ± 0.12 cm, and firmness 191.7 g. In vitro release showed a biphasic profile (39.90% in 2 h; 90.10% in 24 h), fitting the Korsmeyer-Peppas model (R² = 0.9537). Ex vivo studies demonstrated 95.20 ± 0.8% cumulative permeation and flux 3.29 µg/cm²/h, versus 70.30 ± 0.2% and 2.97 µg/cm²/h for control gel. Nail clipping analysis confirmed increased TQ loading (1.43 µg/mg vs. 0.68 µg/mg for free TQ). Antifungal assays against Trichophyton mentagrophytes showed a significant CFU reduction for TQ-UFs compared to free drug, and HET-CAM tests indicated minimal irritation (IrS 0.41 ± 1.20). TQ-UFs-Gel demonstrated sustained release, enhanced nail permeation, and antifungal activity with low irritation potential, supporting its potential as a transungual delivery system for onychomycosis treatment.