Itraconazole solid dispersion prepared by a supercritical fluid technique: preparation, in vitro characterization, and bioavailability in beagle dogs

Abstract

Xuezhi Yin,1,3 Linda Sharon Daintree,2 Sheng Ding,3 Daniel Mark Ledger,2 Bing Wang,3 Wenwen Zhao,2 Jianping Qi,1 Wei Wu1 1Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery of Ministry of Education, Shanghai, 2Crystec Pharma Tianjin Research Centre, Tianjin, 3Changzhou Pharmaceutical Factory, Changzhou, People’s Republic of China Abstract: This research aimed to develop a supercritical fluid (SCF) technique for preparing a particulate form of itraconazole (ITZ) with good dissolution and bioavailability characteristics. The ITZ particulate solid dispersion was formulated with hydroxypropyl methylcellulose, Pluronic F-127, and l-ascorbic acid. Aggregated particles showed porous structure when examined by scanning electron microscopy. Powder X-ray diffraction and Fourier transform infrared spectra indicated an interaction between ITZ and excipients and showed that ITZ existed in an amorphous state in the composite solid dispersion particles. The solid dispersion obtained by the SCF process improved the dissolution of ITZ in media of pH 1.0, pH 4.5, and pH 6.8, compared with a commercial product (Sporanox®), which could be ascribed to the porous aggregated particle shape and amorphous solid state of ITZ. While the solid dispersion did not show a statistical improvement (P=0.50) in terms of oral bioavailability of ITZ compared with Sporanox®, the Cmax (the maximum plasma concentration of ITZ in a pharmacokinetic curve) of ITZ was raised significantly (P=0.03) after oral administration. Thus, the SCF process has been shown to be an efficient, single step process to form ITZ-containing solid dispersion particles with good dissolution and oral bioavailability characteristics. Keywords: gas anti-solvent, dissolution, HPMC, Pluronic F-127, ascorbic acid, in vivo