Research Laboratories, Eastman Chemical Company, Kingsport, United States.
Eur J Pharm Biopharm. 2013 Apr;83(3):378-87. doi: 10.1016/j.ejpb.2012.11.003. Epub 2012 Nov 28.
The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®.
本系列实验的目的是改善一种难溶性弱碱性药物的溶解度和溶解/沉淀行为，以伊曲康唑为例。制备了伊曲康唑与两种常用环糊精衍生物和一种新引入的环糊精衍生物的二元包合物。将它们的溶解度和溶解行为与纯药物和市售制剂 Sporanox®进行了比较。在形成伊曲康唑/环糊精复合物的过程中，加入了一种新型的高水溶性聚合物 Soluplus®，制备了三元复合物。还研究了由伊曲康唑和 Soluplus®制成的固体分散体作为对照。对所有制剂和纯伊曲康唑进行了粉末 X 射线衍射（pX-RD）和差示扫描量热法（DSC）的固态分析。溶解度测试表明，对于所有制剂方法，用羟丙基-β-环糊精（HP-β-CD）或羟丁基-β-环糊精（HBen-β-CD）形成的伊曲康唑的水溶解度与 Soluplus®一起被证明是最有利的制剂方法。虽然市售制剂和纯药物的溶解性能非常差，但这两种三元包合物在所有测试介质中均能快速、广泛地释放伊曲康唑。利用溶解实验的结果，应用一种新开发的基于生理的药代动力学（PBPK）的计算机模拟来比较 Sporanox®的体内行为与体外研究中最有前途的三元复合物的预测性能。PBPK 建模预测，口服三元复合物制剂后，伊曲康唑的生物利用度可能会增加，特别是当伊曲康唑被制成包含 HP-β-CD 或 HBen-β-CD 和 Soluplus®的三元复合物时。
