TY - JOUR
T1 - A supramolecular thermosensitive gel of ketoconazole for ocular applications
T2 - In silico, in vitro, and ex vivo studies
AU - Chaudhari, Pinal
AU - Naik, Ranjitha
AU - Sruthi Mallela, Lakshmi
AU - Roy, Sanhita
AU - Birangal, Sumit
AU - Ghate, Vivek
AU - Balladka Kunhanna, Sarojini
AU - Lewis, Shaila A.
N1 - Funding Information:
The authors are grateful to the Department of Biotechnology (DBT), Government of India for providing Senior Research Fellowship (BT/PR26970/NNT/28/1509/2017) to Chaudhari P., and Manipal College of Pharmaceutical Sciences (MCOPS) and Manipal Academy of Higher Education (MAHE) for providing necessary facilities for carrying out the research work. The authors are thankful to Central instrumentation facility (CIF, Manipal) for providing characterization facility. The authors would like to acknowledge Manipal - Schrödinger Centre for Molecular Simulations, MCOPS, Manipal for providing facilities to conduct the in silico studies.
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2022/2/5
Y1 - 2022/2/5
N2 - 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 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.
AB - 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 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.
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U2 - 10.1016/j.ijpharm.2021.121409
DO - 10.1016/j.ijpharm.2021.121409
M3 - Article
AN - SCOPUS:85121935568
SN - 0378-5173
VL - 613
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
M1 - 121409
ER -