A promising synthetic citric crosslinked β-cyclodextrin derivative for antifungal drugs: Solubilization, cytotoxicity, and antifungal activity.

Effective antifungal therapy for the treatment of fungal keratitis requires a high drug concentration at the corneal surface. However, the use of natural β-cyclodextrin (βCD) in the preparation of aqueous eye drop formulations for treating fungal keratitis is limited by its low aqueous solubility. Here, we synthesized water-soluble anionic βCD derivatives capable of forming water-soluble complexes and evaluated the solubility, cytotoxicity, and antifungal efficacy of drug prepared using the βCD derivative. To achieve this, a citric acid crosslinked βCD (polyCTR-βCD) was successfully synthesized, and the aqueous solubilities of selected antifungal drugs, including voriconazole, miconazole (MCZ), itraconazole, and amphotericin B, in polyCTR-βCD and analogous βCD solutions were evaluated. Among the drugs tested, complexation of MCZ with polyCTR-βCD (MCZ/polyCTR-βCD) increased MCZ aqueous solubility by 95-fold compared with that of MCZ/βCD. The inclusion complex formation of MCZ/βCD and MCZ/polyCTR-βCD was confirmed by spectroscopic techniques. Additionally, the nanoaggregates of saturated MCZ/polyCTR-βCD and MCZ/βCD solutions were observed using dynamic light scattering and transmission electron microscopy. Moreover, MCZ/polyCTR-βCD solution exhibited good mucoadhesion, sustained drug release, and high drug permeation of porcine cornea ex vivo. Hen's Egg test-chorioallantoic membrane assay and cell viability study using Statens Seruminstitut Rabbit Cornea cell line showed that both MCZ/polyCTR-βCD and MCZ/βCD exhibited no sign of irritation and non-toxic to cell line. Additionally, antifungal activity evaluation demonstrated that all isolated fungi, including Candida albicans, Aspergillus flavus, and Fusarium solani, were susceptible to MCZ/polyCTR-βCD. Overall, the results showed that polyCTR-βCD could be a promising nanocarrier for the ocular delivery of MCZ.