抄録
The solubility of cyclosporin A (CYA), an immunosuppressive drug, in water increased with a rise in hydrophilic cyclodextrin (CyD) concentrations, forming higher-order complexes. The solubilizing ability of hydrophilic CyDs for CYA increased in the order γ-CyD<β-CyD<α-CyD<<2, 6-dirnethyl-β-CyD(DM-β-CyD)≈DM-α-CyD. The oral bioavailability of CYA was increased about 4.5-fold by the complexation with DM-CyDs, and the variation of CYA absorption from gastrointestinal tracts was significantly decreased. On the other hand, the lymphatic transfer of CYA was hardly affected by the hydrophilic CyDs including DM-CyDs. Acylated β-CyDs that all hydroxyl groups of β-CyD are substituted with acetyl, butanoyl and octanoyl groups, were used as slow release carriers for CYA. When CYA/acylated β-CyDs complexes were administered orally, both plasma and lymph concentrations of CYA were prolonged up to at least 36 h, although the bioavailability decreased particularly for the butanoyl and octanoyl β-CyDs complexes. Interestingly, triacetyl-β-CyD complex increased both plasma and lymph concentrations of CYA compared with drug alone. The oral administration of CYA as an olive oil solution significantly enhanced the lymph levels of CYA. The CYA/olive oil solution in combination with HP-CyDs, especially HP-γ-CyD, further increased plasma and lymph levels of CYA. These results suggest that DM-CyDs are particularly useful in improving the oral bioavailability of CYA, while hydrophobic acylated β-CyDs are useful as a prolonged-release carrier for CYA. The CYA/olive oil solution in combination with HP-γ-CyD was proved to facilitate the lymphatic transfer of CYA.
