In vitro/in vivo characterization of nanocrystalline formulation of tranilast with improved dissolution and hepatoprotective properties.
The present study was undertaken to develop a nanocrystalline formulation of tranilast (NC/TL), an acidic anti-inflammatory agent, with the aim of improving its biopharmaceutical and hepatoprotective properties. NC/TL was prepared by wet-mill technology, and its physicochemical properties were characterized in terms of morphology, crystallinity, particle size distribution, stability and dissolution. Even after the storage of NC/TL for 8 weeks under accelerated conditions, there were no significant transitions in the crystalline form, crystallinity and particle size distribution of wet-milled TL. The nanosized TL particles could be immediately dispersed when the NC/TL was introduced into aqueous medium, and the NC/TL exhibited significant improvement in the dissolution behavior even under acidic conditions, compared with crystalline TL and a physical mixture of TL and polymer (PM/TL). The hepatoprotective effects of orally dosed TL formulations were evaluated in a carbon tetrachloride (CCl4)-treated rat model of acute liver injury. In a rat model of acute liver injury, repeated treatment with NC/TL (2 mg TL/kg) every 12h led to marked attenuation of hepatic damage as evidenced by decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and total reactive oxygen species levels. However, PM/TL was found to be less effective, and the difference in efficacy between NC/TL and PM/TL should be attributable to the highly enhanced dissolution behavior of NC/TL. Strategic application of NC formulation technology might be an efficacious approach for enhancing the therapeutic potential of TL to treat liver dysfunction.
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address: onoue@u-shizuoka-ken.ac.jp.
Satomi
S
Onoue
Kiyoshi
K
Yamamoto
Yohei
Y
Kawabata
Shizuo
S
Yamada
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D001219:Aspartate Aminotransferases / Q000097:blood; D001702:Biopharmaceutics / Q000379:methods; D002251:Carbon Tetrachloride; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004355:Drug Stability; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012995:Solubility; D062367:ortho-Aminobenzoates / Q000737:chemistry*
D000893:Anti-Inflammatory Agents; D011108:Polymers; D017382:Reactive Oxygen Species; D062367:ortho-Aminobenzoates; D002251:Carbon Tetrachloride; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C012293:tranilast
Dissolution; Hepatoprotection; Nanocrystalline formulation; Stability; Tranilast; Wet-milling system