Voriconazole Eye Drops with SBECD and PVA

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Fungal keratitis is one of the leading causes of blindness in developing countries. The infections are associated with ocular trauma caused by vegetative matter or soil-contaminated objects. In recent years, the rise in contact lens wearing, especially in developed nations, has also contributed to a risk factor for fungal keratitis. Filamentous fungi, such as Fusarium and Aspergillus, are the most common pathogenic microorganisms of mycotic keratitis. The treatment of fungal keratitis is complicated and challenging due to delayed diagnosis and likely unpredictable susceptibility of fungi to antifungal drugs. Moreover, only one commercial topical antifungal drug (natamycin eye drops) is available. The prescription of additional topical antifungal preparations requires a compounding pharmacy, increasing the overall treatment cost. Because fungal keratitis is likely to affect over one million people each year, a simple and precise diagnostic method plus the availability of affordable antifungal eye drops are needed.

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% w/v VCZ eye drop formulations were developed consisting of 6% w/v 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.

Hay Man Saung Hnin Soe, Khanittha Kerdpol, Thanyada Rungrotmongkol, Patamaporn Pruksakorn, Rinrapas Autthateinchai, Sirawit Wet-osot, Thorsteinn Loftsson and Phatsawee Jansook (2023) Voriconazole Eye Drops: Enhanced Solubility and Stability through Ternary Voriconazole/Sulfobutyl Ether β-Cyclodextrin/Polyvinyl Alcohol Complexes. Int. J. Mol. Sci. 2023, 24(3), 2343; https://doi.org/10.3390/ijms24032343

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