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 beta-cyclodextrin (beta CD) 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 beta CD derivatives capable of forming water-soluble complexes and evaluated the solubility, cytotoxicity, and antifungal efficacy of drug prepared using the beta CD derivative. To achieve this, a citric acid crosslinked beta CD (polyCTR-beta CD) was successfully synthesized, and the aqueous solubilities of selected antifungal drugs, including voriconazole, miconazole (MCZ), itraconazole, and amphotericin B, in polyCTR-beta CD and analogous beta CD solutions were evaluated. Among the drugs tested, complexation of MCZ with polyCTR-beta CD (MCZ/polyCTR-beta CD) increased MCZ aqueous solubility by 95-fold compared with that of MCZ/beta CD. The inclusion complex formation of MCZ/beta CD and MCZ/polyCTR-beta CD was confirmed by spectroscopic techniques. Additionally, the nanoaggregates of saturated MCZ/polyCTR-beta CD and MCZ/beta CD solutions were observed using dynamic light scattering and transmission electron microscopy. Moreover, MCZ/polyCTR-beta CD solution exhibited good mucoadhesion, sustained drug release, and high drug permeation of porcine cornea ex vivo. Hen's Egg testchorioallantoic membrane assay and cell viability study using Statens Seruminstitut Rabbit Cornea cell line showed that both MCZ/polyCTR-beta CD and MCZ/beta CD 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-beta CD. Overall, the results showed that polyCTR-beta CD could be a promising nanocarrier for the ocular delivery of MCZ.

Automated summary

In this study, water-soluble anionic beta-cyclodextrin derivatives were synthesized to improve the aqueous solubility of miconazole for the treatment of fungal keratitis. The results showed that the prepared complex significantly increased the solubility of miconazole and exhibited good antifungal efficacy.