Physicochemical characterization of a new crystal form and improvements in the pharmaceutical properties of the poorly water-soluble antiosteoporosis drug 3,9-bis(N,N-dimethylcarbamoy-loxy)-5H-benzofuro[3,2-c]quinoline-6-one (KCA-098) by solid dispersion with hydroxypropylcellulose.
The present study was undertaken to improve the oral absorption of KCA-098, an antiosteoporosis drug. In this study, the form 2 of KCA-098 was used as a desirable crystal form for pharmaceutical formation among three kinds of crystal forms, 1, 2, and 3. Solid dispersions of KCA-098 with hydroxypropylcellulose (HPC) or poly(vinylpyrrolidone) (PVP) were prepared by the solvent method. The physicopharmaceutical properties of the solid dispersions were characterized by powder x-ray diffraction, FTIR spectroscopy, and differential scanning calorimetry (DSC). The powder x-ray diffractograms suggest that KCA-098 in the HPC-SL solid dispersion existed in a partial crystalline state as a new crystal form that could be produced by recrystallization from the solvent. Dissolution from the solid dispersions was markedly enhanced in comparison with that of the drug alone. The dissolution enhancement was observed to be greater for the solid dispersion with HPC-SL than for that with PVP. The KCA-098/HPC-SL (1:2) solid dispersion capsule showed a 3.5-fold increase in the initial concentration and 2.5-fold increase in initial concentration of dissolved drug after 60 min, compared with the values for a physical mixture of KCA-098 (form 2)/lactose (1:2). The in vivo absorption of the drug was investigated after oral administration of KCA-098 or its solid dispersion. The area under the plasma concentration curve of KCA-098 after oral administration of the KCA-098/HPC-SL (1:2) solid dispersion capsule was three-fold greater than that for the drug itself.
Yamada
T
T
Pharmaceutical Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
Saito
N
N
Anraku
M
M
Imai
T
T
Otagiri
M
M
D000042:Absorption; D000818:Animals; D002482:Cellulose / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D003375:Coumestrol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics; D003460:Crystallization; D004285:Dogs; D008297:Male; D010024:Osteoporosis / Q000188:drug therapy*; D011208:Powders; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
D011208:Powders; C088191:KCA 098; D002482:Cellulose; C008079:hydroxypropylcellulose; D003375:Coumestrol