Box-Behnken design-based development and optimization of potentiated antibacterial nanoemulgel for azithromycin

The topical administration of azithromycin (AZ) is hindered by its low aqueous solubility, limiting its local availability for treating acne. Develop and optimize an AZ-loaded nanoemulsion (AZ-NE) using tea tree oil (TTO) and incorporate it into a hyaluronic acid (HA) gel base to enhance solubility, residence time, and antibacterial activity against Propionibacterium acnes . A Box–Behnken design was used to optimize TTO concentration, surfactant concentration, and sonication time with respect to globule size, polydispersity index (PDI), and viscosity. The optimized AZ-NE was incorporated into HA gel (1%, 1.5%, and 2%) to form nanoemulgels (AZ-NG), which were evaluated for in vitro release, skin irritation in rats, and antibacterial efficacy. Oil concentration significantly influenced droplet size, with the optimized AZ-NE exhibiting a particle size of 58.72 nm, PDI of 0.262, and viscosity of 98.4 cp. The 1.5% HA formulation (NG2) was selected as optimal, exhibiting pseudoplastic flow with a viscosity of 1671 cp, a spreadability of 4.21 cm, a pH of 5.72, and a drug content of 99.42%. In vitro testing showed that NG2 achieved 98% drug release within 6 hours, significantly higher than that of the AZ-loaded plain gel (63%). In vivo studies revealed no skin irritation. Furthermore, AZ-NG demonstrated superior antifungal activity with a zone of inhibition of 51 mm against P. acnes, compared to 38 mm for TTO and 32 mm for AZ-plain gel. The developed AZ-TTO nanoemulgel proved effective for acne management, offering a synergistic antibacterial effect, enhanced dissolution, and safe topical application.