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

Chaudhari, Pinal and Naik, Ranjitha and Birangal, Sumit Raosaheb and Ghate, Vivek and Lewis, Shaila A (2022) A supramolecular thermosensitive gel of ketoconazole for ocular applications: In silico, in vitro, and ex vivo studies. International Journal of Pharmaceutics, 613. pp. 1-18. ISSN 0378-5173

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The incidence of corneal fungal infections continues to be a growing concern worldwide. Ocular delivery of antifungal 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- -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 thermosensitive in 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, the in situ gel exhibited a more sustained drug release profile. The ex vivo corneal permeation studies showed higher permeation from KTZ-SBE-β-CD in situ gel (flux of ~19.11 µg/cm2 /h) than KTZ in 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

Item Type: Article
Uncontrolled Keywords: Ocular in situ gel; Ketoconazole; Molecular modeling; Cyclodextrins; Fungal keratitis
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmaceutics
Depositing User: KMC Library
Date Deposited: 17 Feb 2022 04:27
Last Modified: 17 Feb 2022 04:27
URI: http://eprints.manipal.edu/id/eprint/158306

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