Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phyathai Road, Pathumwan, Bangkok 10330, Thailand.
Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phyathai Road, Pathumwan, Bangkok 10330, Thailand.
Int J Mol Sci. 2023 Jan 25;24(3):2343. doi: 10.3390/ijms24032343.
Voriconazole (VCZ) is a broad-spectrum antifungal agent used to treat ocular fungal keratitis. However, VCZ has low aqueous solubility and chemical instability in aqueous solutions. This study aimed to develop VCZ eye drop formulations using cyclodextrin (CD) and water-soluble polymers, forming CD complex aggregates to improve the aqueous solubility and chemical stability of VCZ. The VCZ solubility was greatly enhanced using sulfobutyl ether β-cyclodextrin (SBEβCD). The addition of polyvinyl alcohol (PVA) showed a synergistic effect on VCZ/SBEβCD solubilization and a stabilization effect on the VCZ/SBEβCD complex. The formation of binary VCZ/SBEβCD and ternary VCZ/SBEβCD/PVA complexes was confirmed by spectroscopic techniques and in silico studies. The 0.5% / VCZ eye drop formulations were developed consisting of 6% / SBEβCD and different types and concentrations of PVA. The VCZ/SBEβCD systems containing high-molecular-weight PVA prepared under freeze-thaw conditions (PVA-H hydrogel) provided high mucoadhesion, sustained release, good ex vivo permeability through the porcine cornea and no sign of irritation. Additionally, PVA-H hydrogel was effective against the filamentous fungi tested. The stability study revealed that our VCZ eye drops provide a shelf-life of more than 2.5 years at room temperature, while a shelf-life of only 3.5 months was observed for the extemporaneous Vfend eye drops.
伏立康唑（VCZ）是一种广谱抗真菌药物，用于治疗眼部真菌性角膜炎。然而，VCZ 在水溶液中的水溶性低，化学稳定性差。本研究旨在开发使用环糊精（CD）和水溶性聚合物的 VCZ 滴眼剂配方，形成 CD 复合聚集体以提高 VCZ 的水溶性和化学稳定性。磺丁基醚-β-环糊精（SBEβCD）极大地提高了 VCZ 的溶解度。聚乙烯醇（PVA）的加入对 VCZ/SBEβCD 的增溶具有协同作用，并对 VCZ/SBEβCD 复合物具有稳定作用。通过光谱技术和计算机研究证实了二元 VCZ/SBEβCD 和三元 VCZ/SBEβCD/PVA 复合物的形成。开发了由 6%/SBEβCD 和不同类型和浓度的 PVA 组成的 0.5%/VCZ 滴眼剂配方。在冻融条件下制备的含有高分子量 PVA 的 VCZ/SBEβCD 体系（PVA-H 水凝胶）提供了高黏膜附着力、持续释放、通过猪角膜的良好体外渗透和无刺激迹象。此外，PVA-H 水凝胶对测试的丝状真菌有效。稳定性研究表明，我们的 VCZ 滴眼剂在室温下的保质期超过 2.5 年，而临时配制的 Vfend 滴眼剂的保质期仅为 3.5 个月。
