Seidlitz Anne, Schick Wiebke, Reske Thomas, Senz Volkmar, Grabow Niels, Petersen Svea, Nagel Stefan, Weitschies Werner
Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, 17487 Greifswald, Germany.
Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, 17487 Greifswald, Germany.
Eur J Pharm Biopharm. 2015 Jun;93:328-38. doi: 10.1016/j.ejpb.2015.04.016. Epub 2015 May 1.
In this study drug release from the CYPHER™ stent, the gold standard in drug-eluting stent therapy until the end of its marketing in 2011/2012, was systematically evaluated using different in vitro release tests. The test systems included incubations setups, the reciprocating holder apparatus (USP7), the flow-through cell apparatus (USP4) and the vessel-simulating flow-through cell (vFTC) specifically designed for stent testing. The results obtained show a large variability regarding the fractions released into the media after 7d ranging from 38.6% ± 4.5% to 74.6% ± 1.2%. The lowest fraction released was observed in the vFTC and the highest in an incubation setup with frequently changed media of a volume of 2 mL. Differences were even observed when using fairly similar and simple incubations setups with mere changes of the media volume, under maintenance of sink conditions, and of the vessel geometry. From these data it can be concluded, that in vitro release even from a slow releasing drug-eluting stent is greatly influenced by the experimental conditions and care must be taken when choosing a suitable setup. Comparison of the obtained in vitro release profiles to published in vivo data did not result in a distinct superiority of any of the tested methods regarding the predictability for the situation in vivo due to large differences in the reported in vivo data. However, this comparison yielded that the release observed in vitro using the 2 mL incubation setup and the reciprocating holder apparatus may be faster than the reported in vivo release. The results of this study also emphasize the necessity to use highly standardized release tests when comparisons between results from different experiments or even different labs are to be performed. In this context, the compendial methods are most likely offering the highest degree of standardization.
在本研究中，使用不同的体外释放试验对CYPHER™支架（在2011年/2012年其上市结束前一直是药物洗脱支架治疗的金标准）的药物释放进行了系统评估。测试系统包括孵育装置、往复式支架装置（USP7）、流通池装置（USP4）以及专门为支架测试设计的血管模拟流通池（vFTC）。所获得的结果显示，7天后释放到培养基中的分数存在很大差异，范围从38.6%±4.5%到74.6%±1.2%。在vFTC中观察到释放分数最低，而在培养基体积为2 mL且频繁更换的孵育装置中释放分数最高。即使在维持漏槽条件和容器几何形状不变的情况下，仅改变培养基体积，使用相当相似且简单的孵育装置时也观察到了差异。从这些数据可以得出结论，即使是从缓释药物洗脱支架进行体外释放，也会受到实验条件的极大影响，在选择合适的装置时必须谨慎。将获得的体外释放曲线与已发表的体内数据进行比较，由于所报道的体内数据存在很大差异，因此在预测体内情况方面，没有任何一种测试方法具有明显优势。然而，这种比较表明，使用2 mL孵育装置和往复式支架装置在体外观察到的释放可能比所报道的体内释放更快。本研究结果还强调，当要对不同实验甚至不同实验室的结果进行比较时，必须使用高度标准化的释放试验。在这种情况下，药典方法最有可能提供最高程度的标准化。
