Physicochemical and Pharmacokinetic Characterization of Amorphous Solid Dispersion of Tranilast with Enhanced Solubility in Gastric Fluid and Improved Oral Bioavailability

Abstract

In the present study, amorphous solid dispersion (ASD) formulations of tranilast (TL) with 8 hydrophilic polymers were prepared by a solvent evaporation method with the aim of improving dissolution behavior in gastric fluid and thereby enhancing oral bioavailability. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, drug-polymer interaction, and stability. Of all TL formulations, ASD formulation with Eudragit EPO exhibited the highest improvement in dissolution behavior with a 3,000-fold increase in the first-order dissolution rate under acidic conditions (pH 1.2). Spectroscopic studies using infrared and near-infrared analyses revealed the drug-polymer interaction in the Eudragit EPO-based ASD formulation. On the basis of dissolution, crystallinity, and stability data, the maximum allowable drug load in the Eudragit EPO-based ASD formulation was deduced to be ca. 50%. Pharmacokinetic profiling of orally dosed TL formulations in rats was also carried out using UPLC/ESI-MS. After oral administration of the Eudragit EPO-based ASD formulation in rats, enhanced TL exposure was observed with an increase of oral bioavailability by 19-fold, and the variation of AUC was ca. 4 times lower than that with crystalline TL. With these data, the ASD approach could be a viable formulation strategy for enhancing the wettability and oral bioavailability of TL, resulting in improved therapeutic potential of TL for the treatment of inflammatory diseases.