title: Improved bioavailability of a water-insoluble drug by inhalation of drug-containing maltosyl-β-cyclodextrin microspheres using a four-fluid nozzle spray drier.
abstract: We previously developed a unique four-fluid nozzle spray drier that can produce water-soluble microspheres containing water-insoluble drug nanoparticles in one step without any common solvent between the water-insoluble drug and water-soluble carrier. In the present study, we focused on maltosyl-β-cyclodextrin (malt-β-CD) as a new water-soluble carrier and it was investigated whether drug/malt-β-CD microspheres could improve the bioavailability compared with our previously reported drug/mannitol (MAN) microspheres. The physicochemical properties of bare drug microparticles (ONO-2921, a model water-insoluble drug), drug/MAN microspheres, and drug/malt-β-CD microspheres were evaluated. In vitro aerosol performance, in vitro dissolution rate, and the blood concentration profiles after intratracheal administration were compared between these formulations. The mean diameter of both drug/MAN and drug/malt-β-CD microspheres was approximately 3-5 μm and both exhibited high aerosol performance (>20% in stages 2-7), but drug/malt-β-CD microspheres had superior release properties. Drug/malt-β-CD microspheres dissolved in an aqueous phase within 2 min, while drug/MAN microspheres failed to dissolve in 30 min. Inhalation of drug/malt-β-CD microspheres enhanced the area under the curve of the blood concentration curve by 15.9-fold than that of bare drug microparticles and by 6.1-fold than that of drug/MAN microspheres. Absolute bioavailability (pulmonary/intravenous route) of drug/malt-β-CD microspheres was also much higher (42%) than that of drug/MAN microspheres (6.9%). These results indicate that drug/malt-β-CD microspheres prepared by our four-fluid nozzle spray drier can improve drug solubility and pulmonary delivery.
authors.affiliation: Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, 467-8603, Japan. ozekit@phar.nagoya-cu.ac.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ozeki
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kano
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Takahashi
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okada
mesh_terms: D000042:Absorption; D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry*; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003505:Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D008320:Maltose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D008863:Microspheres; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D011208:Powders / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014867:Water / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000336:Aerosols; D003505:Cyclodextrins; D004364:Pharmaceutical Preparations; D011208:Powders; D047392:beta-Cyclodextrins; C433303:maltosyl-cyclodextrin; D014867:Water; D008320:Maltose