Controlled release of a water-soluble drug, captopril, by a combination of hydrophilic and hydrophobic cyclodextrin derivatives.
Parent beta-cyclodextrin (beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-CyD) form 1:1 solid complexes with an orally active angiotensin-converting enzyme inhibitor, captopril, while hydrophobic perbutanoyl-beta-CyD (TB-beta-CyD) forms a solid dispersion or solid solution with the drug. The binary system of captopril/HP-beta-CyD or captopril/TB-beta-CyD and the ternary system of captopril/TB-beta-CyD/HP-beta-CyD in different molar ratios were prepared by the kneading method, and the release behavior of the drug was investigated. The release rate of captopril from the binary HP-beta-CyD system was rather fast, whereas that from the binary TB-beta-CyD system was comparatively slower, the retarding effect being dependent on the amounts of TB-beta-CyD. The release rate from the ternary captopril/TB-beta-CyD/HP-beta-CyD system was slowed down by the addition of small amounts of HP-beta-CyD, whereas the rate became faster as the molar ratio of HP-beta-CyD further increased (>.25 molar ratio). Both water penetration studies and microscopic observation suggested that the retarding effect is attributable to a gel formation of HP-beta-CyD in the TB-beta-CyD hydrophobic matrix. It was difficult to prolong plasma levels of captopril by administering orally either the binary HP-beta-CyD or TB-beta-CyD system in dogs. On the other hand, the ternary captopril/TB-beta-CyD/HP-beta-CyD system (molar ratio of 1:0.5:0.5) gave a plasma profile comparable to that of a commercially available sustained release preparation (Captoril R). Therefore, a combination of HP-beta-CyD and TB-beta-CyD is useful for the controlled release of water-soluble drugs such as captopril.
Ikeda
Y
Y
Wakunaga Pharmaceutical Co., 1624 Shimokotachi, Kodacho, Takata-gun, Hiroshima, Japan.
Kimura
K
K
Hirayama
F
F
Arima
H
H
Uekama
K
K
D000042:Absorption; D000818:Animals; D002152:Calorimetry, Differential Scanning; D002216:Captopril / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D004285:Dogs; D016503:Drug Delivery Systems; D008297:Male; D013696:Temperature; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D047392:beta-Cyclodextrins; D002216:Captopril; C031215:betadex