Enhanced Efinaconazole Permeation and Activity Against Trichophyton rubrum and Trichophyton mentagrophytes with a Self-Nanoemulsifying Drug Delivery System

<b>Background</b>: Onychomycosis responds poorly to topical therapy, and efinaconazole (EFN) has low aqueous solubility. <b>Methods</b>: This study aimed to develop a 10% <i>w</i>/<i>w</i> EFN self-nanoemulsifying system (SNEDDS) with improved solubility, permeation, antifungal activity, and stability. Excipients were screened by EFN saturation solubility. An MCT oil/Solutol HS 15/Labrafil M2125 CS SNEDDS (5/75/20, <i>w</i>/<i>w</i>) was optimized via a pseudo-ternary diagram. Characterization included droplet size, PDI, and zeta potential, morphology, and drug-excipient compatibility. Solubility was measured across pH. Permeation of EFN SNEDDS vs. EFN suspension was tested by Franz diffusion cells. Antifungal activity against <i>Trichophyton rubrum</i> and <i>Trichophyton mentagrophytes</i> was assessed by paper-disc diffusion, and hyphal damage on human nails was examined by SEM. Stability was studied for six months under room, accelerated, and stress conditions. <b>Results</b>: The optimized SNEDDS formed sub-50 nm droplets with low polydispersity and favourable zeta potential. Solubility was maintained across pH, and cumulative permeation increased 13.6-fold versus suspension. Paper-disc assays showed larger inhibition zones at lower EFN doses. SEM on human nails revealed marked hyphal destruction. TEM confirmed spherical nanoemulsion droplets. FT-IR showed no new peaks, supporting compatibility. Particle size, PDI, zeta potential, and drug content remained stable over six months under all storage conditions. <b>Conclusions</b>: A 10% <i>w</i>/<i>w</i> EFN SNEDDS enhanced solubility, transungual permeation, and antifungal efficacy while maintaining robust stability, supporting its potential as an ethanol-free therapy for onychomycosis.