Controlled release of a water-soluble drug, captopril, by a combination ofhydrophilic and hydrophobic cyclodextrin derivatives

Parent beta-cyclodextrin (beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-C yD) form 1:1 solid complexes with an orally active angiotensin-converting e nzyme 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-CJID or captopril/TB-beta-CyD and the ternary s ystem of captopril/TB-beta-CyD/HP-beta-CyD in different molar ratios were p repared by the kneading method, and the release behavior of the drug was in vestigated. The release rate of captopril from the binary HP-beta-CyD syste m was rather fast, whereas that from the binary TB-beta-CyD system was comp aratively 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 i ncreased (>0.25 molar ratio). Both water penetration studies and microscopi c 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 diff icult 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, th e 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 sus tained release preparation (Captoril R(R)). Therefore, a combination of HP- beta-CyD and TB-beta-CyD is useful for the controlled release of water-solu ble drugs such as captopril. (C) 2000 Elsevier Science B.V. All rights rese rved.