Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
J Pharm Sci. 2010 Feb;99(2):719-29. doi: 10.1002/jps.21861.
Three different techniques were applied to investigate aggregation of drug/cyclodextrin complexes, that is, drug permeation through semi-permeable membranes, determination of changes in the value of activity coefficients of drug/cyclodextrin complex solutions and transmission electron microscopy (TEM). The aqueous solutions studied contained gamma-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin or mixtures thereof, and hydrocortisone, amphotericin B, diclofenac sodium or indomethacin. The permeation studies indicated that drug/cyclodextrin complex monomers (i.e., unaggregated complexes) were dominating at cyclodextrin concentrations below 5% (w/v). Then formation of aggregates gradually increased with increasing cyclodextrin concentration until all increase in dissolved drug/cyclodextrin complexes was due to formation of cyclodextrin aggregates. This happened even though the observed phase-solubility diagrams were linear, that is, were of A(L)-type. The activity coefficients showed positive deviation from ideal state. This positive deviation is due to concurrent of several processes, that is, hydration, aggregation and complex formation. The observed deviations from ideality indicated that complex aggregates were formed in the aqueous complexation media. TEM pictures showed formation of aggregates in both pure aqueous cyclodextrin solutions as well as in cyclodextrin solutions that had been saturated with hydrocortisone. The aggregate diameter was between 10 and 100 nm but larger aggregates with diameter of about 200 nm were formed through assemble of smaller aggregates.
三种不同的技术被应用于研究药物/环糊精复合物的聚集，即药物透过半透膜的渗透、测定药物/环糊精复合物溶液活度系数值的变化和透射电子显微镜（TEM）。研究中使用的水溶液含有γ-环糊精、2-羟丙基-γ-环糊精或它们的混合物，以及氢化可的松、两性霉素 B、双氯芬酸钠或吲哚美辛。渗透研究表明，在环糊精浓度低于 5%（w/v）时，药物/环糊精复合物单体（即未聚集的复合物）占主导地位。然后，随着环糊精浓度的增加，聚集物逐渐增加，直到所有溶解的药物/环糊精复合物的增加都归因于环糊精聚集物的形成。尽管观察到的相溶解度图是线性的，即 A(L)-型，但仍会发生这种情况。活度系数表现出对理想状态的正偏差。这种正偏差是由于几个过程同时发生，即水合、聚集和复合物形成。观察到的偏离理想状态表明在水相络合介质中形成了复合物聚集物。TEM 图片显示，在纯水溶液中环糊精溶液以及已经被氢化可的松饱和的环糊精溶液中都形成了聚集物。聚集物的直径在 10 到 100nm 之间，但通过较小聚集物的组装形成了直径约为 200nm 的较大聚集物。
