title: Strategic application of self-micellizing solid dispersion technology to respirable powder formulation of tranilast for improved therapeutic potential.
abstract: OBJECTIVE
  The present study aimed to develop an inhalable self-micellizing solid dispersion of tranilast (SMSD/TL) using poly[MPC-co-BMA] to improve the therapeutic potential and safety.
  
  
  METHODS
  The safety of poly[MPC-co-BMA] in lungs was assessed using rat lung epithelium-derived L2 cells. SMSD/TL and respirable powder of SMSD/TL (SMSD/TL-RP) were prepared using a wet milling system and jet mill, respectively. The physicochemical properties of TL formulations were characterized in terms of dissolution, morphology, and particle size. Pharmacological and pharmacokinetic studies were also conducted on inhaled SMSD/TL-RP.
  
  
  RESULTS
  The lactate dehydrogenase level from L2 cells treated with poly[MPC-co-BMA] was lower than that with polysorbate 80, a positive control. SMSD/TL showed enhanced dissolution behavior of TL. The jet milled SMSD/TL particles easily separated from the lactose carrier, and the particle size was suitable for inhalation. Compared with RP of TL, inhaled SMSD/TL-RP (100 μg-TL/rat) could more strongly suppress the inflammatory responses in antigen-sensitized rats. The TL level in plasma after intratracheal administration of SMSD/TL-RP at a pharmacological effective dose (100 μg-TL/rat) was ca. 4.2-fold lower than that after oral administration of TL solution at a clinical dose (1.67 mg/kg).
  
  
  CONCLUSIONS
  SMSD/TL-RP might be an attractive dosage form to improve the anti-inflammatory effects and safety of TL.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamic, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamic, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kojo
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamic, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yakushiji
authors.affiliation: Department of Pharmaceutical Physicochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Yuminoki
authors.affiliation: Department of Pharmaceutical Physicochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamic, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: onoue@u-shizuoka-ken.ac.jp.
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D002626:Chemistry, Pharmaceutical / Q000379:methods; D007785:Lactose / Q000737:chemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D008823:Micelles; D010316:Particle Size; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000378:metabolism; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D062367:ortho-Aminobenzoates / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D018926:Anti-Allergic Agents; D008689:Methacrylates; D008823:Micelles; D011208:Powders; D062367:ortho-Aminobenzoates; D010767:Phosphorylcholine; C079200:poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate); C012293:tranilast; D007785:Lactose
keywords: Anti-inflammatory effect; Poly[MPC-co-BMA]; Respirable powder; Self-micellizing solid dispersion; Tranilast