Perdomo-López I, Rodríguez-Pérez A I, Yzquierdo-Peiró J M, White A, Estrada E G, Villa T G, Torres-Labandeira J J
Departamento de Farmacia e Tecnoloxía Farmacéutica, Facultade de Farmacia, Universidade de Santiago de Compostela, Campus Sur, E-15782 Santiago de Compostela, Spain.
J Pharm Sci. 2002 Nov;91(11):2408-15. doi: 10.1002/jps.10237.
This study investigated the effects of the complexation of sertaconazole nitrate with different cyclodextrin (CD) derivatives (alpha-CD, beta-CD, gamma-CD, hydroxypropyl-beta-CD, and hydroxypropyl-gamma-CD) on the aqueous solubility and antimycotic activity of the drug. Phase solubility studies indicated that the solubility of sertaconazole in enzyme-free simulated gastric- and enzyme-free simulated enteric fluids was significantly increased in the presence of cyclodextrins. The observed order of solubility increasing effect was: gamma-CD > HPgamma-CD > HPbeta-CD > beta-CD > alpha-CD. Solid-state sertaconazole-cyclodextrin complexes were prepared by freeze drying, and characterized by X-ray powder difractometry, differential scanning calorimetry (DSC), and infrared spectroscopy (FTIR). Freeze-dried complexes showed markedly higher solubility than both physical mixtures and sertaconazole alone. The antimycotic activities of sertaconazole-cyclodextrin complexes in solution were evaluated by inhibition zone assays with Candida albicans. The activity ranking agrees with the solubility ranking observed for these complexes, with the gamma-CD-sertaconazole complex showing the strongest antimycotic activity. Finally, molecular modeling studies were carried out using the MM2 force field method, for complexes in vacuum and in water. This enable indentification of the preferred orientation of sertaconazole in the gamma-CD cavity and of the main structural features responsible for the enhancement of its solubility and antimycotic activity.
本研究考察了硝酸舍他康唑与不同环糊精（CD）衍生物（α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精和羟丙基-γ-环糊精）络合对该药物的水溶性和抗真菌活性的影响。相溶解度研究表明，在环糊精存在下，舍他康唑在无酶模拟胃液和无酶模拟肠液中的溶解度显著增加。观察到的溶解度增加效果顺序为：γ-环糊精＞羟丙基-γ-环糊精＞羟丙基-β-环糊精＞β-环糊精＞α-环糊精。通过冷冻干燥制备了固态舍他康唑-环糊精络合物，并通过X射线粉末衍射、差示扫描量热法（DSC）和红外光谱（FTIR）进行了表征。冷冻干燥的络合物显示出比物理混合物和单独的舍他康唑明显更高的溶解度。通过白色念珠菌抑菌圈试验评估了溶液中舍他康唑-环糊精络合物的抗真菌活性。活性排名与这些络合物观察到的溶解度排名一致，γ-环糊精-舍他康唑络合物显示出最强的抗真菌活性。最后，使用MM2力场方法对真空和水中的络合物进行了分子建模研究。这使得能够确定舍他康唑在γ-环糊精腔内的优选取向以及负责增强其溶解度和抗真菌活性的主要结构特征。
