Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
Mol Pharm. 2022 Jan 3;19(1):258-273. doi: 10.1021/acs.molpharmaceut.1c00746. Epub 2021 Dec 20.
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 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. 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/(cm h) for ternary complex-loaded films compared to 1.86 μg/(cm 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 and 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.
真菌性角膜炎是影响视力的主要眼部真菌感染原因之一，主要是由于角膜瘢痕形成。伏立康唑（VRC）是治疗眼部真菌感染的首选唑类抗真菌药物。由于配方在角膜中的停留时间较短，需要频繁给药，导致患者顺应性差，眼部药物输送具有挑战性。本研究旨在通过形成环糊精基三元配合物并将配合物掺入粘弹性膜中来提高伏立康唑的溶解度、经角膜渗透和疗效。相溶解度研究表明，VRC 的溶解度提高了约 14 倍，而物理化学特性确证了 VRC 被包入环糊精的内腔。对接研究进行了对接构象和包合物稳定性的预测。载药膜显示出伏立康唑从膜中的持续释放，并改善了经角膜渗透，与纯 VRC 膜相比，三元配合物载药膜的渗透通量提高了约 4 倍，达到 8.36μg/（cm h）。3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐（MTT）和鸡胚绒毛尿囊膜试验（HET-CAM）证实，配合物和眼部膜无刺激性，可安全用于眼部给药。使用 和 进行的抗真菌研究表明，与纯药物膜相比，复合药物具有更好的抗真菌活性。总之，超分子环糊精三元配合物被证明是一种有前途的策略，可提高伏立康唑的溶解度和渗透性，并增强其在治疗真菌性角膜炎中的抗真菌活性。
