title: Mucoadhesive beclomethasone microspheres for powder inhalation: their pharmacokinetics and pharmacodynamics evaluation.
abstract: The feasibility of prolonging drug action and/or reducing drug dosage using mucoadhesive beclomethasone dipropionate (BDP) microspheres for powder inhalation was investigated. BDP was spray-dried from ethanol solution or aqueous suspension systems dissolving a mucoadhesive polymer, hydroxypropylcellulose (HPC); this resulted in amorphous and crystalline BDP incorporation in the HPC microspheres (aBDP/HPC and cBDP/HPC; BDP-HPC ratio=1:4), respectively. These microspheres were administered as powder aerosols to healthy or antigen-induced, asthmatic guinea pigs, and BDP's retention in the lung (pharmacokinetics) and inhibitory duration with respect to eosinophil infiltration into the airways (pharmacodynamics) were compared to those for pure crystalline BDP (cBDP; 'control'). Both BDP/HPC microspheres were prepared within a respirable-size range of 2.5-2.9 microm. BDP's aqueous solubility was increased 25 times for aBDP/HPC, compared to crystalline counterpart. Pharmacokinetic profiles for three powders were dissolution-modulated. aBDP/HPC showed rapid BDP absorption from the lung (> or = 95% absorption for 180 min) with a greater metabolite (B17MP) formation, compared to cBDP, primarily due to the increased dissolution of amorphous BDP. In contrast, 86.0% of BDP remained at 180 min following cBDP/HPC administration, demonstrating the prolonged BDP's retention in the lung by virtue of poor dissolution (and/or release) and retarded mucociliary clearance. As a result, while cBDP (1.37 mg/kg) significantly inhibited eosinophil infiltration into the lungs of antigen-sensitized and -challenged guinea pigs for only 1-6 h, cBDP/HPC, despite a much lower drug dosage (0.25 mg/kg), was capable of maintaining such inhibitory effects for 24 h following administration. It appeared therefore that the prolonged lung retention of BDP by the use of the HPC microspheres (cBDP/HPC) was attributed to prolonging its pharmacological duration without requiring increased drug dosage.
authors.affiliation: DDS Research Laboratories, Teijin Ltd., Asahigaoka, Hino, Tokyo 191-8512, Japan. msakagam@vcu.edu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
authors.forename: Wataru
authors.initials: W
authors.lastname: Kinoshita
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Sakon
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Makino
mesh_terms: D000269:Adhesives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001507:Beclomethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008863:Microspheres; D011208:Powders
chemical_list: D000269:Adhesives; D000893:Anti-Inflammatory Agents; D011208:Powders; D001507:Beclomethasone