title: 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.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. onoue@u-shizuoka-ken.ac.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kojo
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aoki
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002853:Chromatography, Liquid; D003460:Crystallization; D018360:Crystallography, X-Ray; D004355:Drug Stability; D005750:Gastric Juice / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008855:Microscopy, Electron, Scanning; D008859:Microscopy, Polarization; D008954:Models, Biological; D011109:Polymethacrylic Acids / Q000737:chemistry; D033362:Powder Diffraction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D019265:Spectroscopy, Near-Infrared; D013678:Technology, Pharmaceutical / Q000379:methods; D062367:ortho-Aminobenzoates / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011109:Polymethacrylic Acids; D062367:ortho-Aminobenzoates; C518398:Eudragit E PO; C012293:tranilast