Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs.
The purpose of the present study was to investigate the effects of particle size on the dissolution and oral absorption of cilostazol. Three types of suspensions having different particle size distributions were prepared of the hammer-milled, the jet-milled cilostazol crystals and the NanoCrystal spray-dried powder of cilostazol. In vitro dissolution rate of cilostazol was significantly increased by reducing the particle size. The dissolution curves of the cilostazol suspensions were in good agreement with the simulation based on the Noyes-Whitney equation. The bioavailability of cilostazol after oral administration to dogs was increased with reducing the particle size. While positive food effect on the absorption was observed for the suspensions made of the hammer-milled and the jet-milled crystals, no significant food effect was found for the suspension made of the NanoCrystal cilostazol spray-dried powder. These results could be qualitatively predicted from the in vitro dissolution data using the bio-relevant media, FaSSIF and FeSSIF. In conclusion, the NanoCrystal technology is found to be efficient to improve the oral bioavailability of cilostazol and to avoid the food effect on the absorption.
Jinno
Jun-ichi
J
Otsuka Pharmaceutical Co., Ltd., 224-18 Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0182, Japan.
Kamada
Naoki
N
Miyake
Masateru
M
Yamada
Keigo
K
Mukai
Tadashi
T
Odomi
Masaaki
M
Toguchi
Hajime
H
Liversidge
Gary G
GG
Higaki
Kazutaka
K
Kimura
Toshikiro
T
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D000077407:Cilostazol; D004285:Dogs; D005215:Fasting / Q000378:metabolism; D007408:Intestinal Absorption; D049329:Nanostructures / Q000737:chemistry; D010316:Particle Size; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011208:Powders; D012995:Solubility; D013535:Suspensions; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014867:Water / Q000737:chemistry
D010975:Platelet Aggregation Inhibitors; D011208:Powders; D013535:Suspensions; D013777:Tetrazoles; D014867:Water; D000077407:Cilostazol