A supramolecular thermosensitive gel of ketoconazole for ocular applications: In silico, in vitro, and ex vivo studies

Abstract

The incidence of corneal fungal infections continues to be a growing concern worldwide. Ocular delivery of anti-fungal drugs is challenging due to the anatomical and physiological barriers of the eye. The ocular bioavailability of ketoconazole (KTZ), a widely prescribed antifungal agent, is hampered by its limited aqueous solubility and permeation. In the study, the physicochemical properties of KTZ were improved by complexation with sulfobutylether-β-cyclodextrin (SBE-β-CD).KTZ-SBE-β-CD complex was studied in silico with docking and dynamics simulations, followed by wet-lab experiments.The optimized KTZ-SBE-β-CD complex was loaded into a thermosensitivein situ gel to increase corneal bioavailability. The supramolecular complex increased the solubility of KTZ by 5-folds and exhibited a 10-fold increment in drug release compared to the pure KTZ. Owing to the diffusion, thein situ gel exhibited a more sustained drug release profile. Theex vivocorneal permeation studies showed higher permeation from KTZ-SBE-β-CD in situ gel (flux of ∼19.11 µg/cm²/h) than KTZin situ gel (flux of ∼1.17 µg/cm²/h). The cytotoxicity assays and the hen's egg chorioallantoic membrane assay (HET-CAM) confirmed the formulations' safety and non-irritancy. In silico guided design of KTZ-SBE-β-CD inclusion complexes successfully modified the physicochemical properties of KTZ. In addition, the loading of the KTZ-SBE-β-CD complex into an in situ gel significantly increased the precorneal retention and permeation of KTZ, indicating that the developed formulation is a viable modality to treat fungal keratitis.

Keywords: Cyclodextrins; Fungal keratitis; Ketoconazole; Molecular modeling; Ocular in situ gel.