QbD based antifungal drug-loaded ophthalmic liposomal formulation for the management of fungal keratitis: In vitro, ex vivoand in vivopharmacokinetic studies

An attempt has been made for controlling the drug release of antifungal drug fluconazole (FCZ) thereby formulating nanoliposomes (NLs) with increasing residence time by applying QbD approach. FCZ, an antifungal agent, having a low partition coefficient (logP 0.5) exhibits limited bioavailability due to washing off by tear fluid calls for repeated administration of dose; narrowing patient compliance. Box-Behnken design was applied for formulating thin-film hydration-based liposomes bearing FCZ; considering lipid amount, sonication time, and hydration time as independent variables. FCZ loaded NLs (FCZ-NLs) were optimized on the basis of particle size (268 ± 3.6 nm), ζ potential (−23.15 ± 3.12 mV), and % entrapment efficiency (69.75 ± 4.45%). The amount of cryoprotectant for lyophilization was also optimized. Zero-order release kinetics was close-fitting and higher ex-vivopermeation flux was observed for FCZ-NLs compared to marketed formulation. No hemolysis and ocular irritation were observed in a preclinical study. AUC (0–∞),MRT, and drug availability above the MIC of FCZ-NLs were increased up to 2.36, 3.05, and 4.57 folds, respectively as compared to the marketed formulation. The optimized FCZ-NLs could be further exploited as a potential ocular drug delivery system.