Background: Isoconazole nitrate (ISN), an antifungal agent that inhibits ergosterol synthesis by blocking lanosterol 14α-demethylation, is widely used to treat candidiasis, and improving its skin retention and permeability can enhance its therapeutic efficacy. Therefore, we developed an ISN nanoparticle (ISN-NP) gel by wet-bead milling in the presence of methylcellulose (MC). Methods: These ISN nanoparticles were incorporated into a carboxypolymethylene hydrogel (Carbopol). The ISN concentration was measured using HPLC, and Wistar rats and Candida albicans were used to evaluate skin absorption and antifungal activity, respectively. Results: The ISN-NP gel exhibited a particle size distribution ranging from 60 to 220 nm, with the nanoparticles remaining stable. In addition, the ISN-NP gel demonstrated superior antifungal activity against Candida albicans. The Carbopol gel maintained appropriate viscosity and physical stability, and the ISN nanoparticles were released from the gel. Compared with microparticle-based gels (ISN-MP gels), the ISN-NP gel showed significantly enhanced drug release and transdermal permeation, with 1.54- and 1.7-fold increases, respectively. Conclusions: These findings indicate that incorporating ISN nanoparticles (nanocrystalline ISN) into a Carbopol-based gel matrix provides a promising strategy to enhance the topical delivery of this poorly water-soluble antifungal drug. Overall, this nanogel system represents a valuable platform for transdermal delivery in clinical applications.
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