Improved Bioavailability of a Water-Insoluble Drug by Inhalation of Drug-Containing Maltosyl-β-Cyclodextrin Microspheres Using a Four-Fluid Nozzle Spray Drier

• Published in: AAPS PharmSciTech Vol. 13; no. 4; pp. 1130 - 1137
• Main Authors: Ozeki, Tetsuya, Kano, Yoshihito, Takahashi, Norimitsu, Tagami, Tatsuaki, Okada, Hiroaki
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.12.2012
• Subjects: Absorption; Administration, Inhalation; Aerosols - chemistry; Animals; beta-Cyclodextrins - administration & dosage; beta-Cyclodextrins - chemistry; Biochemistry; Biological Availability; Biomedical and Life Sciences; Biomedicine; Biotechnology; Chemistry, Pharmaceutical - methods; Cyclodextrins - administration & dosage; Cyclodextrins - chemistry; Male; Maltose - administration & dosage; Maltose - analogs & derivatives; Maltose - chemistry; Microspheres; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Particle Size; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - chemistry; Pharmacology/Toxicology; Pharmacy; Powders - administration & dosage; Powders - chemistry; Rats; Rats, Sprague-Dawley; Research Article; Solubility; Technology, Pharmaceutical - methods; Water - chemistry; inhalation therapy; microparticles; water-insoluble drug; maltosyl-β-cyclodextrin; 4-fluid nozzle spray drier
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-012-9826-z

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.