title: Inhalable sustained-release formulation of long-acting vasoactive intestinal peptide derivative alleviates acute airway inflammation.
abstract: The present study was undertaken to develop a respirable sustained-release powder (RP) formulation of long-acting VIP derivative, [Arg(15, 20, 21), Leu(17)]-VIP-GRR (IK312532), using PLGA nanospheres (NS) with the aim of improving the duration of action. NS formulation of IK312532 (IK312532/NS) was prepared by an emulsion solvent diffusion method in oil, and a mixture of the IK312532/NS and erythritol was jet-milled and mixed with lactose carrier to obtain the IK312532/NS-RP. Physicochemical properties were characterized focusing on appearance, particle size, and drug release, and in vivo pharmacological effects were assessed in antigen-sensitized rats. The IK312532/NS with a diameter of 140 nm showed a biphasic release pattern in distilled water with ca. 20% initial burst for 30 min and a sustained slow release up to ca. 55% for 24h. Laser diffraction analysis demonstrated that IK312532/NS-RP had fine dispersibility and suitable particle size for inhalation. In antigen-sensitized rats, insufflated IK312532/NS-RP (10 μg of IK312532/rat) could suppress increases of granulocyte recruitment and myeloperoxidase in pulmonary tissue for up to 24h after antigen challenge, although IK312532-RP at the same dose was less effective with limited duration of action. From these findings, newly prepared IK312532/NS-RP might be of clinical importance in improving duration of action and medication compliance for treatment of airway inflammatory diseases.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan. onoue@u-shizuoka-ken.ac.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsui
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kuriyama
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kojo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mizumoto
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Karaki
authors.forename: Atsukazu
authors.initials: A
authors.lastname: Kuwahara
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects; D008171:Lung Diseases / Q000188:drug therapy; D008297:Male; D054118:Nanospheres; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; C511374:vasoactive intestinal peptide-GRR, Arg(15,20,21)-Leu(17)-; D014660:Vasoactive Intestinal Peptide; D009195:Peroxidase