Development, Box-Behnken Optimization, and Evaluation of Itraconazole Nanocrystal-Loaded Bioadhesive Nail Lacquer for Enhanced Transungual Delivery and Improved Antifungal Activity against Trichophyton rubrum

Abstract

The present study aimed to develop and optimize an itraconazole nanocrystal-loaded bioadhesive nail lacquer for improved transungual delivery. Itraconazole nanocrystals were prepared by wet media milling using Poloxamer 407 as stabilizer. A three-factor, three-level Box-Behnken design was used to study the effects of Poloxamer 407 concentration, milling speed, and milling time on particle size, polydispersity index, and apparent saturation solubility. The optimized nanocrystals showed a particle size of 192.1 ± 3.4 nm, PDI of 0.202 ± 0.009, zeta potential of −21.8 ± 1.6 mV, and apparent saturation solubility of 21.1 ± 0.6 µg/mL. Nanocrystallisation markedly improved itraconazole dissolution. The optimized nanocrystals were incorporated into an HPMC E15-based bioadhesive nail lacquer containing PEG 400 and thioglycolic acid. The formulation showed acceptable drug content, drying time, viscosity, film properties, and adhesion. Ex vivo permeation studies showed a steady-state flux of 1.48 ± 0.09 µg/cm²/h and nail drug retention of 286.7 ± 17.5 µg/g. The optimized formulation produced 2.39-fold higher flux than conventional itraconazole lacquer. Confocal microscopy and SEM supported enhanced nail penetration. Antifungal activity against Trichophyton rubrum was also improved. The formulation remained stable during 3 months of storage. These findings support nanocrystal-loaded bioadhesive nail lacquer as a promising approach for localized itraconazole delivery in onychomycosis.