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

• Published in: Drug metabolism and pharmacokinetics 2012, Vol.27 (4), p.379-387
• Main Authors: Onoue, Satomi, Kojo, Yoshiki, Aoki, Yosuke, Kawabata, Yohei, Yamauchi, Yukinori, Yamada, Shizuo
• Format: Article
• Language: English
• Subjects: Administration, Oral; amorphous; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - blood; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Area Under Curve; bioavailability; Biological Availability; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Chromatography, Liquid; Crystallization; Crystallography, X-Ray; dissolution; Drug Stability; Gastric Juice - chemistry; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Injections, Intravenous; Male; Metabolic Clearance Rate; Microscopy, Electron, Scanning; Microscopy, Polarization; Models, Biological; ortho-Aminobenzoates - administration & dosage; ortho-Aminobenzoates - blood; ortho-Aminobenzoates - chemistry; ortho-Aminobenzoates - pharmacokinetics; Polymethacrylic Acids - chemistry; Powder Diffraction; Rats; Rats, Sprague-Dawley; solid dispersion; Solubility; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Spectroscopy, Near-Infrared; Technology, Pharmaceutical - methods; tranilast
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.DMPK-11-RG-101

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 (pH1.2). 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.