COMPLEXATION OF STEROID-HORMONES WITH CYCLODEXTRIN DERIVATIVES - SUBSTITUENT EFFECTS OF THE GUEST MOLECULE ON SOLUBILITY AND STABILITY IN AQUEOUS-SOLUTION

被引:39
作者
ALBERS, E
MULLER, BW
机构
[1] UNIV KIEL, DEPT PHARMACEUT, GUTENBERGSTR 76-78, W-2300 KIEL 1, GERMANY
[2] BYK GULDEN LOMBERG GMBH, DEPT PHARMACEUT DEV, W-7750 CONSTANCE, GERMANY
关键词
D O I
10.1002/jps.2600810808
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The inclusion complexation of homologous derivatives of steroid hormones with cyclodextrins and 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) was investigated with regard to underlying structure-interaction relationship. The interaction was studied by phase solubility analysis and stabilization effects of complex formation with 2-HP-beta-CD. The solubilizing and stabilizing abilities of 2-HP-beta-CD were generally more effective for testosterone derivatives than for estradiol esters. Within a homologous series of steroid hormones, the steepest linear solubility isotherms were found for 17-methyl and 3-methyl derivatives. The solubilization of steroid esters by 2-HP-beta-CD depended on the structure and length of the ester side chain. The interaction of 2-HP-beta-CD with the steroids was hindered by long-chain fatty acid ester groups. With increasing length of the side chain, a decline of the isotherms occurred and the phase solubility behavior changed from linear to exponential. Contrary to expectations, benzoylation of steroids considerably decreased the guest-host interaction. The observed rates of degradation of the steroid esters were significantly reduced by 2-HP-beta-CD, depending on the chain length, and correlated well with the order found in phase solubility analysis. The degradation showed no deviations from pseudo-first-order kinetics, and the degradation mechanism was not changed because of complexation. The results suggest that interaction of 2-HP-beta-CD with steroid esters involves the ester functions of the prodrugs and is more suitable for unsubstituted guest molecules.
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页码:756 / 761
页数:6
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