Ketoconazole-Loaded Cationic Nanoemulsion: In Vitro–Ex Vivo–In Vivo Evaluations to Control Cutaneous Fungal Infections

[Image: see text] An attempt has been made to optimize ketoconazole (KTZ)-loaded cationic nanoemulsion for topical delivery followed by in vitro, ex vivo, and in vivo evaluations. Central composite design suggested a total of 13 outcomes at 3 factors and 2 levels against 6 responses. Formulations were characterized for globular size, polydispersity index, pH, ζ potential, % entrapment efficiency (% EE), and drug content. Moreover, the optimized KTZ-CNM13 was compared against drug suspension (KTZ-SUS), commercial cream, and anionic nanoemulsion for in vitro drug release, ex vivo permeation, in vitro hemolysis, antifungal assay, in vivo dermal irritancy, and long-term stability. KTZ-CNM13 was found to have a low size (239 nm), an optimal ζ potential (+22.7 mV), a high % EE (89.1%), a spherical shape, a high drug content (98.9%), and a high numerical desirability value (1.0). In vitro drug release behavior of KTZ from KTZ-CNM13 was 7.54- and 1.71-folds higher than those of KTZ-ANM13 and KTZ-SUS, respectively, at 24 h. The permeation rate values were ordered as KTZ-CNM13 > KTZ-ANM13 > KTZ-MKT > KTZ-SUP due to various studied factors. High values of zone of inhibition for KTZ-CNM13 were observed against Candida albicans, Candida glabrata, Candida tropicalis, and Candida krusei as compared to KTZ-SUS. In vitro hemolysis and in vivo irritation studied confirmed the safety concern of the nanoemulsion at the explored composition. Long-term stability result revealed a stable product at the explored temperature for a year. Conclusively, cationic nanoemulsion is a promising approach to deliver KTZ for high permeation and therapeutic efficacy.