Lindfors Lennart, Jonsson Malin, Weibull Emelie, Brasseur James G, Abrahamsson Bertil
AstraZeneca R&D, Pharmaceutical Development, Mölndal, Sweden.
Department of Mechanical Engineering, The Pennsylvania State University, University Park, Pennsylvania, 16802.
J Pharm Sci. 2015 Sep;104(9):2969-76. doi: 10.1002/jps.24487. Epub 2015 May 15.
The aim of this study was to understand and predict the influence of hydrodynamic effects in the small intestine on dissolution of primary and aggregated drug particles. Dissolution tests of suspensions with a low-solubility drug, felodipine, were performed in a Couette cell under hydrodynamic test conditions corresponding to the fed small intestine. Dissolution was also performed in the USP II apparatus at two paddle speeds of 25 and 200 rpm and at different surfactant concentrations below critical micelle concentration. The experimental dissolution rates were compared with theoretical calculations. The different levels of shear stress in the in vitro tests did not influence the dissolution of primary or aggregated particles and experimental dissolution rates corresponded very well to calculations. The dissolution rate for the aggregated drug particles increased after addition of surfactant because of deaggregation, but there were still no effect of hydrodynamics. In conclusion, hydrodynamics do not influence dissolution and deaggregation of micronized drug particles in the small intestine of this model drug. Surface tension has a strong effect on the deaggregation and subsequent dissolution. Addition of surfactants at in vivo relevant surface tension levels is thus critical for in vivo predictive in vitro dissolution testing.
本研究的目的是了解并预测小肠中的流体动力学效应对初级和聚集药物颗粒溶解的影响。在对应于进食后小肠的流体动力学测试条件下，于Couette池中对低溶解度药物非洛地平的悬浮液进行了溶出度试验。还在美国药典II装置中，以25和200转/分钟的两个桨叶转速以及低于临界胶束浓度的不同表面活性剂浓度进行了溶出度试验。将实验溶出速率与理论计算结果进行了比较。体外试验中不同水平的剪切应力并未影响初级或聚集颗粒的溶解，且实验溶出速率与计算结果非常吻合。加入表面活性剂后，由于解聚作用，聚集药物颗粒的溶出速率增加，但流体动力学仍无影响。总之，在该模型药物的小肠中，流体动力学并不影响微粉化药物颗粒的溶解和解聚。表面张力对解聚及随后的溶解有很强的影响。因此，在体内相关表面张力水平下添加表面活性剂对于体内预测性体外溶出度测试至关重要。
