title: Stable dry powder inhaler formulation of tranilast attenuated antigen-evoked airway inflammation in rats.
abstract: Tranilast (TL) has been clinically used for the treatment of airway inflammatory diseases, although the clinical use of TL is limited because of its poor solubility and systemic side effects. To overcome these drawbacks, a novel respirable powder of TL (CSD/TL-RP) for inhalation therapy was developed using nanocrystal solid dispersion of TL (CSD/TL). Stability study on CSD/TL-RP was carried out with a focus on inhalation performance. Even after 6 months of storage at room temperature, there were no significant morphological changes in micronized particles on the surface of carrier particles as compared with that before storage. Cascade impactor analyses on CSD/TL-RP demonstrated high inhalation performance with emitted dose and fine particle fraction (FPF) of ca. 98% and 60%, respectively. Long-term storage of CSD/TL-RP resulted in only a slight decrease in FPF value (ca. 54%). Inhaled CSD/TL-RP could attenuate antigen-induced inflammatory events in rats, as evidenced by marked reduction of granulocytes in bronchoalveolar lavage fluid and inflammatory biomarkers such as eosinophil peroxidase, myeloperoxidase, and lactate dehydrogenase. These findings were consistent with decreased expression levels of mRNAs for nuclear factor-kappa B and cyclooxygenase-2, typical inflammatory mediators. Given these findings, inhalable TL formulation might be an interesting alternative to oral therapy for the treatment of asthma and other airway inflammatory diseases with sufficient dispersing stability.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aoki
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsui
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sato
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004339:Drug Compounding; D004355:Drug Stability; D058995:Dry Powder Inhalers; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use / Q000648:ultrastructure; D010047:Ovalbumin / Q000009:adverse effects / Q000276:immunology; D011208:Powders; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D018926:Anti-Allergic Agents; D015415:Biomarkers; D018836:Inflammation Mediators; D016328:NF-kappa B; D011208:Powders; D012333:RNA, Messenger; D062367:ortho-Aminobenzoates; D010047:Ovalbumin; D051546:Cyclooxygenase 2; C012293:tranilast