Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Gasthuisberg O&N2, Herestraat 49, Box 921, 3000 Leuven, Belgium.
Eur J Pharm Sci. 2009 Oct 8;38(3):270-8. doi: 10.1016/j.ejps.2009.08.002. Epub 2009 Aug 15.
Solid dispersions were successfully prepared by co-spray-drying of TPGS-stabilized itraconazole nanosuspensions with Aerosil200, followed by heat treatment of the powders. The itraconazole/Aerosil200 weight ratios amounted to 50/50, 30/70, 40/60 and 20/80. The itraconazole content of the powders was close to the expected value, with relative errors between 0.3% and 7.8%. X-ray powder diffraction (XRPD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) evaluation on the powders revealed the formation of amorphous itraconazole and the absence of glassy itraconazole. Dissolution of the powders was enhanced compared to crystalline and glassy itraconazole (a 2-dimensional structured form of itraconazole). However, no clear trend could be observed between drug loading and dissolution performance of the solid dispersions. Upon storage, conversion to crystalline itraconazole was observed for the 50/50 powder based on XRPD, SSNMR and DSC measurements. Although the 40/60 powder remained X-ray amorphous upon storage, DSC did reveal that a small fraction (7.5+/-1.6% after 10 months of storage) of itraconazole crystallized upon storage. For the 30/70 and 20/80 dispersions, no crystallization could be seen. After 10 months of storage, important changes in the dissolution behavior of the powders were observed. A decrease in dissolution performance was seen for the 50/50 dispersion, which could be attributed to the crystallization of itraconazole. On the other hand, the 40/60, 30/70 and 20/80 dispersions showed an increase in dissolution rate (more than 60% after 10 min). Although not completely clear at this stage, adsorption of itraconazole onto the Aerosil200 surface during storage might be responsible for this behavior. Finally, in vivo experiments were performed in the rat. Oral bioavailability of the 30/70 dispersion was, although lower compared to the marketed Sporanox formulation, significantly enhanced compared to the crystalline drug.
固体分散体通过 TPGS 稳定的伊曲康唑纳米混悬液与 Aerosil200 的共喷雾干燥成功制备，然后对粉末进行热处理。粉末中伊曲康唑/Aerosil200 的重量比为 50/50、30/70、40/60 和 20/80。粉末中伊曲康唑的含量接近预期值，相对误差在 0.3%至 7.8%之间。粉末的 X 射线粉末衍射（XRPD）、固态 NMR（SSNMR）和差示扫描量热法（DSC）评估表明形成了无定形伊曲康唑，不存在玻璃态伊曲康唑。与结晶态和玻璃态伊曲康唑（伊曲康唑的二维结构形式）相比，粉末的溶解性能得到了提高。然而，在药物负载和固体分散体的溶解性能之间没有观察到明显的趋势。在储存过程中，基于 XRPD、SSNMR 和 DSC 测量，发现 50/50 粉末向结晶伊曲康唑转化。尽管 40/60 粉末在储存时仍保持 X 射线无定形，但 DSC 确实表明在储存过程中有一小部分（储存 10 个月后为 7.5+/-1.6%）伊曲康唑结晶。对于 30/70 和 20/80 分散体，没有观察到结晶。储存 10 个月后，观察到粉末溶解行为的重要变化。50/50 分散体的溶解性能下降，这可能归因于伊曲康唑的结晶。另一方面，40/60、30/70 和 20/80 分散体的溶解速率增加（10 分钟后超过 60%）。尽管在现阶段还不完全清楚，但在储存过程中伊曲康唑吸附到 Aerosil200 表面可能是导致这种行为的原因。最后，在大鼠中进行了体内实验。30/70 分散体的口服生物利用度虽然低于市售 Sporanox 制剂，但与结晶药物相比，显著提高。
