PARP抑制剂HD199胶囊的研制

Optimization of fabrication technology of the PARP inhibitor HD199

为了克服新型二磷酸腺苷核糖多聚酶PARP抑制剂HD199原料药流动性不佳、黏度大的问题,本文开发出工艺简单易行、方便调整剂量、质量可控的临床研究使用HD199胶囊剂。通过研究助流剂微粉硅胶和稀释剂种类及用量对HD199粉体性质和溶出度的影响,考察原辅料相容性及工艺重现性,筛选确定HD199胶囊的处方组成。HD199流动性和填充性明显改善,HD199休止角由55.5°降低到45.6°,压缩度由44.4%下降到30.7%;原辅料相容性好,各实验条件下,所研究的各种辅料对HD199的稳定性几乎没有影响,有关物质的改变与API相似;优选的处方组成为HD199/微粉硅胶/乳糖/硬脂酸镁(质量比为1∶0.075∶1.5∶0.025)。研制的HD199胶囊溶出行为理想,工艺重现性佳,适于放大生产。

This paper aimed to solve the problem of poor fluidity of HD199,a new PARP(poly ADP-ribose polymerase)inhibitor,and to prepare quality-controllable HD199 capsules with simple and feasible process for phase I clinical studies.The formulation of HD199 capsules was studied by investigating the effects of excipient type and quantity on the powder characters and dissolution profiles.The rest angle of HD199 decreased from 55.5°to 45.6°and the compressibility decreased from 44.4% to 30.7%.Compatibility of raw materials and process reproducibility were also studied.Under various test conditions,the studied excipients had little effect on the stability of HD199,and the change of related substances was similar to that of API.The optimized formulation with good compatibility was as follows:HD199/colloidal silicon dioxide/lactose/magnesium stearate(mass fraction was 1∶0.075∶1.5∶0.025).HD199 capsules,which had high dissolution rate with good reproducibility,were successfully prepared and suitable for scale-up production.