Thermosensitive and mucoadhesive in situ ocular gel for effective local delivery and antifungal activity of itraconazole nanocrystal in the treatment of fungal keratitis

Itraconazole is a lipophilic drug, which limits its absorption for ocular administration. This study focused on the incorporation of itraconazole into nanocrystalline carrier system with stabilizer Pluronic (R) F127 and was further formulated into thermosensitive in situ ocular gel. Itraconazole nanocrystals (ITZ-NCs) were fabricated using media milling method with ultra-small-scale device. The obtained nanocrystals were observed to have a better in vitro activity against C. albicans (CA) compared to free itraconazole suspension in water. Furthermore, the optimization of the thermosensitive ocular gel formula was carried out with a central composite design, using three types of polymers, namely Pluronic (R) F127, Pluronic (R) F68, and hydroxypropyl methylcellulose (HPMC). After being dispersed into the optimized thermosensitive gel base, ITZ-NCs did not alter in terms of physical characteristics. Ex vivo ocularkinetic studies on infected porcine eye models showed a better profile of the optimized formula of thermosensitive in situ ocular gel when compared to standard gel base. Importantly, the ex vivo antifungal activity of these preparations was also increased, with a 93% decrease in the CA population observed after 48 h in infected porcine eye model. Altogether, this work has provided evidence of a novel approach in developing more advanced treatments for fungal keratitis.

Automated summary

This study focused on incorporating itraconazole into nanocrystalline carrier system with Pluronic (R) F127 stabilizer and formulating it into thermosensitive in situ ocular gel, showing improved antifungal activity against Candida albicans. The optimized gel base demonstrated better therapeutic effect on infected porcine eye models, with a 93% decrease in the CA population after 48 hours.