Development and Evaluation of Clotrimazole-Loaded Nanoemulgel for Enhanced Topical Antifungal Delivery

Background: Clotrimazole is a widely used topical imidazole antifungal; however, its physicochemical properties and limited skin penetration can restrict effective drug delivery from conventional topical formulations. Nanoemulgel systems offer a promising approach by combining the nanoscale characteristics of nanoemulsions with the prolonged residence and improved application properties of a gel base. Objective: The present study aimed to develop and optimize a clotrimazole-loaded nanoemulgel for enhanced topical drug delivery, skin permeation, skin retention, and antifungal activity. Methods: Preformulation studies of clotrimazole included organoleptic characterization, solubility, melting point, and partition coefficient determination. Based on solubility screening, oleic acid, Tween 80, and Transcutol P were selected as the oil, surfactant, and co-surfactant, respectively. Pseudo-ternary phase diagrams were constructed, and six nanoemulsion formulations (F1–F6) were prepared using high-speed homogenization followed by ultrasonication. The optimized nanoemulsion was incorporated into Carbopol 934 gel to prepare four nanoemulgel formulations (NG1–NG4). Formulations were evaluated for physicochemical characteristics, in-vitro drug diffusion and release kinetics. The optimized nanoemulgel was further assessed for ex-vivo skin permeation and retention and antifungal activity against Candida albicans and Aspergillus niger. Results: Clotrimazole exhibited maximum solubility in oleic acid (82.45 ± 1.24 mg/mL), Tween 80 (95.64 ± 1.42 mg/mL), and Transcutol P (108.52 ± 1.63 mg/mL). Formulation F5 showed the smallest droplet size (98.4 ± 1.82 nm) and lowest polydispersity index (0.164 ± 0.005), and was selected as the optimized nanoemulsion. Among the nanoemulgels, NG4 demonstrated superior performance, with 96.82 ± 0.58% drug diffusion at 12 h. Drug-release analysis showed the best fit with the Higuchi model (R² = 0.989), while the Korsmeyer–Peppas diffusion exponent (n = 0.684) indicated non-Fickian release. Compared with conventional clotrimazole gel, NG4 exhibited higher 12-h drug permeation (624.48 ± 1.58 vs. 436.26 ± 1.32 µg/cm²), flux (52.84 ± 1.06 vs. 36.42 ± 1.12 µg/cm²/h), and skin retention (246.82 ± 1.94 vs. 128.46 ± 2.08 µg/cm²). NG4 also produced larger zones of inhibition against C. albicans (31.8 ± 0.72 mm) and A. niger (28.4 ± 0.68 mm) than the conventional gel. Conclusion: The optimized clotrimazole-loaded nanoemulgel demonstrated favorable physicochemical characteristics, controlled drug release, enhanced skin permeation and retention, and improved antifungal activity compared with the conventional formulation. The developed nanoemulgel therefore represents a promising topical delivery system for improving the therapeutic performance of clotrimazole.