a Institute of Materia Medica, Zhejiang Academy of Medical Sciences , Hangzhou , China.
Drug Deliv. 2019 Dec;26(1):63-69. doi: 10.1080/10717544.2018.1556360.
The influence of chiral excipient D-chitosan (CS) on the stereoselective release of racemic ketoprofen (rac-KET) microspheres has been investigated in comparison to those microspheres containing individual enantiomers in vitro and in vivo. Stereoselectivity was observed in vitro release test, with R-KET release slightly higher than that of S-KET, especially in 3% rac-KET loading microspheres. Stereoselectivity is dependent on the content of chiral excipient and pH of release medium. A molecular docking study between CS and KET enantiomers further revealed that S-KET has a stronger interaction with CS compared to R-KET. Moreover, the plasma concentration of KET enantiomers in rats shows substantial differences, as the plasma levels of S-KET were higher than those of R-KET. Plasma levels of enantiomers from the R-KET microspheres had similar stereoselectivity as rac-KET microspheres. The S/R ratio of rac-KET microspheres was significantly lower than that of rac-KET suspension (regular-release formulation) (p<.05), and the differences is 3-5 fold. Besides, rates of R-KET converted to S-KET exhibited differences between rac-KET microspheres and suspension. Similar results were also found between R-KET microspheres and suspension. All investigations suggest that the chitosan interacting preferentially with S-KET to R-KET significantly affect the stereoselective pharmacokinetics of rac-KET from chitosan microspheres in rats.
研究了手性赋形剂 D-壳聚糖（CS）对消旋酮洛芬（rac-KET）微球立体选择性释放的影响，并与含有单个对映体的微球进行了体外和体内比较。在体外释放试验中观察到立体选择性，R-KET 的释放略高于 S-KET，尤其是在 3%rac-KET 载药量的微球中。立体选择性取决于手性赋形剂的含量和释放介质的 pH 值。CS 和 KET 对映体之间的分子对接研究进一步表明，S-KET 与 CS 的相互作用强于 R-KET。此外，大鼠血浆中 KET 对映体浓度存在显著差异，S-KET 的血浆水平高于 R-KET。R-KET 微球的血浆水平与 rac-KET 微球具有相似的立体选择性。rac-KET 微球的 S/R 比值明显低于 rac-KET 混悬液（常规释放制剂）（p<.05），差异为 3-5 倍。此外，rac-KET 微球和混悬液之间 R-KET 转化为 S-KET 的速率存在差异。R-KET 微球和混悬液之间也存在类似的结果。所有研究均表明，CS 优先与 S-KET 相互作用，这显著影响了大鼠 CS 微球中 rac-KET 的立体选择性药代动力学。
