title: A new agglomerated KSR-592 beta-form crystal system for dry powder inhalation formulation to improve inhalation performance in vitro and in vivo.
abstract: A new agglomerated KSR-592 (steroid) beta-form needle-like crystals with lactose system for dry powder inhalation (DPI) was developed to improve inhalation performance with Jethaler. The drug agglomerates were prepared by the method of spherical agglomeration in liquid so as to control the particle size and the mechanical strength of agglomerates by changing the agitation speed of the agglomeration system. The agglomerates mixed with lactose particles for the DPI formulation were effectively disintegrated into respirable fine particle in the milling chamber of the device (Jethaler) when inhaled. The DPI formulation with these agglomerates exhibited ideal fluidity and provided a larger fine particle fraction (FPF: 29.7%) than the formulation with agglomerates consisting of alpha-form (plate-like) crystals (24.5%). The air-flow rate of inhalation had no effect on the disintegration properties of these agglomerates, suggesting a reliable inhalation performance in vivo. Further, an in vivo test of the aerosolized KSR-592 (beta-form) crystals having the same particle size distribution as those in the aerosol produced by Jethaler was conducted by means of a dry powder inhalation testing system using Brown Norway rats. Inhaled KSR-592 (beta-form) crystals were found to be uniformly deposited in the lungs of Brown Norway rat sensitized by ovalbumin (OA) and suppressed the increase in eosinophil number in the lungs after OA challenge.
authors.affiliation: Pharmaceutical Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1 Kashiwabara, Hotaka-machi Minamiazumi, Nagano 399-8304, Japan. kazuhiko_ikegami@pharm.kissei.co.jp
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ikegami
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawashima
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kazuki
authors.initials: K
authors.lastname: Mimura
authors.forename: Den-ichi
authors.initials: D
authors.lastname: Momose
authors.forename: Kiyohisa
authors.initials: K
authors.lastname: Ouchi
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens / Q000633:toxicity; D000731:Androstanes / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000737:chemistry; D004804:Eosinophils / Q000187:drug effects; D007114:Immunization; D007958:Leukocyte Count; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D010316:Particle Size; D011208:Powders; D051381:Rats; D011914:Rats, Inbred BN; D013499:Surface Properties
chemical_list: D000485:Allergens; D000731:Androstanes; D018927:Anti-Asthmatic Agents; C473300:KSR592; D011208:Powders; D010047:Ovalbumin