Engineering the Perfect Medicated Nail Lacquer: Quality by Design–Driven Optimization Strategy for Boosting Antifungal Nail Penetration

Onychomycosis is difficult to treat because the nail plate limits antifungal penetration and many antifungal drugs show poor aqueous solubility.

This study aimed to improve transungual delivery of Terbinafine HCl (TBHCl) by combining solubility enhancement through solid dispersion (SD) using Soluplus and penetration enhancement using phosphoric acid in a nail lacquer (NL).

TBHCl solid dispersions were prepared and evaluated by FTIR, DSC, solubility, and dissolution studies. An optimized TBHCl solid dispersion-loaded nail lacquer (TBSD-NL) was developed using a Quality by Design (QbD) approach. Formulations were assessed for drying time, viscosity, peel-off, non-volatile content, water resistance, in vitro drug release, ex vivo nail permeation, antifungal activity, and skin irritation.

TBHCl solubility increased from 95.2 µg/mL (pure drug) to 702.3 µg/mL in the optimized SD (1:10 ratio), representing a 7.4-fold increase. Drug release after 2.5 h improved from 12.76% (pure drug) to 82.42% (SD). The optimized TBSD-NL showed drying time of 75 s, viscosity of 40 cps, peel-off of 5.5%, non-volatile content of 28%, and water loss of 6.2% after immersion. In vitro release at 8 h was 75% for TBSD-NL compared with 54% for marketed cream. Ex vivo permeation through goat hoof reached 60,977 µg/cm² for TBSD-NL versus 42,350 µg/cm² for marketed cream, with flux values of 118.78 µg/cm²/h and 85.09 µg/cm²/h, respectively. Zones of inhibition for TBSD-NL were 1.1 cm against Candida albicans and 1.4 cm against Aspergillus niger, higher than comparator formulations. Skin irritation score was 0.33 for erythema with no edema.

The combined use of solid dispersion and phosphoric acid significantly improved TBHCl solubility, nail permeation, and antifungal activity. The optimized TBSD-NL formulation shows potential as a topical treatment for onychomycosis.