TY - JOUR
T1 - Voriconazole-Cyclodextrin Supramolecular Ternary Complex-Loaded Ocular Films for Management of Fungal Keratitis
AU - Suvarna, Pooja
AU - Chaudhari, Pinal
AU - Birangal, Sumit
AU - Mallela, Lakshmi Sruthi
AU - Roy, Sanhita
AU - Koteshwara, Ananthamurthy
AU - Aranjani, Jesil Mathew
AU - Lewis, Shaila Angela
N1 - Funding Information:
The authors are grateful to the Manipal College of Pharmaceutical Sciences (MCOPS) and the Manipal Academy of Higher Education (MAHE) for providing the necessary facilities for carrying out the research work. The authors are thankful to the Central Instrumentation Facility (CIF, Manipal) for providing the 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 American Chemical Society.
PY - 2022/1/3
Y1 - 2022/1/3
N2 - Fungal keratitis is one of the leading causes of ophthalmic mycosis affecting the vision due to corneal scarring. Voriconazole (VRC) is the most preferred azole antifungal agent for treating ocular mycotic infections. Ocular drug delivery is challenging due to the shorter corneal residence time of the formulation requiring frequent administration, leading to poor patient compliance. The present study aimed at improving the solubility, transcorneal permeation, and efficacy of voriconazole via the formation of cyclodextrin-based ternary complexes and incorporation of the complex into mucoadhesive films. A phase solubility study suggested a ∼14-fold improvement in VRC solubility, whereas physicochemical characterization confirmed the inclusion of VRC in the cyclodextrin inner cavity. In silico docking studies were performed to predict the docking conformation and stability of the inclusion complex. Complex-loaded films showed sustained release of voriconazole from the films and improved transcorneal permeation by ∼4-fold with an improved flux of 8.36 μg/(cm2 h) for ternary complex-loaded films compared to 1.86 μg/(cm2 h) for the pure VRC film. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and hen's egg-chorioallantoic membrane test (HET-CAM) assays confirmed that the complexes and ocular films were nonirritant and safe for ocular administration. The antifungal study performed using Aspergillus fumigatus and Fusarium oxysporum suggested improved antifungal activity compared to the pure drug film. In conclusion, the supramolecular cyclodextrin ternary complex proved to be a promising strategy for enhancing the solubility and permeability and augmenting the antifungal activity of voriconazole in the management of fungal keratitis.
AB - Fungal keratitis is one of the leading causes of ophthalmic mycosis affecting the vision due to corneal scarring. Voriconazole (VRC) is the most preferred azole antifungal agent for treating ocular mycotic infections. Ocular drug delivery is challenging due to the shorter corneal residence time of the formulation requiring frequent administration, leading to poor patient compliance. The present study aimed at improving the solubility, transcorneal permeation, and efficacy of voriconazole via the formation of cyclodextrin-based ternary complexes and incorporation of the complex into mucoadhesive films. A phase solubility study suggested a ∼14-fold improvement in VRC solubility, whereas physicochemical characterization confirmed the inclusion of VRC in the cyclodextrin inner cavity. In silico docking studies were performed to predict the docking conformation and stability of the inclusion complex. Complex-loaded films showed sustained release of voriconazole from the films and improved transcorneal permeation by ∼4-fold with an improved flux of 8.36 μg/(cm2 h) for ternary complex-loaded films compared to 1.86 μg/(cm2 h) for the pure VRC film. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and hen's egg-chorioallantoic membrane test (HET-CAM) assays confirmed that the complexes and ocular films were nonirritant and safe for ocular administration. The antifungal study performed using Aspergillus fumigatus and Fusarium oxysporum suggested improved antifungal activity compared to the pure drug film. In conclusion, the supramolecular cyclodextrin ternary complex proved to be a promising strategy for enhancing the solubility and permeability and augmenting the antifungal activity of voriconazole in the management of fungal keratitis.
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U2 - 10.1021/acs.molpharmaceut.1c00746
DO - 10.1021/acs.molpharmaceut.1c00746
M3 - Article
AN - SCOPUS:85121920230
SN - 1543-8384
VL - 19
SP - 258
EP - 273
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 1
ER -