Characterization and pharmacokinetic study of itraconazole solid dispersions prepared by solvent-controlled precipitation and spray-dry methods.

Abstract

Solid dispersion formulations have attracted attention to improve solubility and bioavailability of water-insoluble drugs. In this study, the variation of solubility and bioavailability by different preparation methods were studied using itraconazole (ITZ) solid dispersions. Itraconazole solid dispersions were prepared by a solvent-controlled precipitation method (SCPM) using HPMCAS-LF, HCl antisolvent or a spray-drying method (SDM) for comparison. Dissolution tests by pH transition and pharmacokinetic study using male Sprague Dawley rats were conducted. Itraconazole solid dispersion dissolution tests by pH transition exhibited better dissolution compared to naive ITZ, limited dissolution in acidic conditions and a burst release at neutral pH. The ITZ solid dispersions by SCPM indicated a smaller-sized particle dispersion, limited dissolution at acidic pH and a higher release at neutral pH compared to those by SDM, suggesting that the increased protonation of anionic polymers and HPMCAS-LF by acidic antisolvent could form a tighter hydrophobic aggregation with ITZ in solid dispersions. ITZ solid dispersion prepared by SCPM also showed improved ITZ absorption in male Sprague Dawley rats compared to SDM and naïve ITZ. This study suggests that the SCPM method can be widely used for solid dispersion preparations due to improved dissolution and PK profile.