title: Formulation design and in vivo evaluation of dry powder inhalation system of new vasoactive intestinal peptide derivative ([R(15, 20, 21), L(17), A(24,25), des-N(28)]-VIP-GRR) in experimental asthma/COPD model rats.
abstract: Vasoactive intestinal peptide (VIP) has been considered as a promising drug candidate for asthma and COPD because of its potent immunomodulating and anti-inflammatory activities. Recently, our group developed a new VIP derivative, [R(15, 20, 21), L(17), A(24,25), des-N(28)]-VIP-GRR (IK312548), with improved chemical and metabolic stability. In the present study, a dry powder inhaler system of IK312548 was designed for inhalation therapy with minimal systemic side effects, the physicochemical properties of which were also evaluated with a focus on morphology, particle size distribution, inhalation performance, and peptide stability. Laser diffraction and cascade impactor analysis suggested high dispersion and deposition in the respiratory organs with a fine particle fraction of 31.2%. According to UPLC/ESI-MS and circular dichroic spectral analyses, no significant changes in the purity and structure of VIP derivative were observed during preparation of respirable formulation. Anti-inflammatory properties of IK312548 respirable powder (RP) were characterized in antigen-sensitized asthma/COPD-model rats. There were marked inflammatory cells infiltrated into the lung tissues of experimental asthma/COPD-model rats; however, intratracheal administration of IK312548-RP led to significant reductions of recruited inflammatory cells in lung tissues and BALF by 72 and 78%, respectively. Thus, respirable powder formulation of IK312548 might be a promising medication for asthma, COPD, and other airway inflammatory diseases.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. onoue@u-shizuoka-ken.ac.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aoki
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsui
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kojo
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mizumoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004355:Drug Stability; D058995:Dry Powder Inhalers; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D010316:Particle Size; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; C560571:vasoactive intestinal peptide-glycyl-arginyl-arginine, arginyl(15,20,21)-leucyl(17)-alanyl(24,25)-desasparagyl(28)-; D014660:Vasoactive Intestinal Peptide