Li Zhenghua, Zhang Shuangshuang, Yan Hongxiang, Liu Jianping
Department of Pharmaceutics, China Pharmaceutical University, No.24 Tongjiaxiang, Nanjing 210009, China.
Asian J Pharm Sci. 2018 Jul;13(4):310-316. doi: 10.1016/j.ajps.2018.02.009. Epub 2018 Mar 12.
The clinical manifestations of variant angina is unevenly distributed during the 24 h, thus the performance of drugs should be tailored according to the angina circadian rhythm. Cryptotanshinone (CTN) is one of the representative bioactive lipid-soluble components of Danshen which has been commonly used for cardiovascular diseases such as angina pectoris. The aim of this study was to develop a novel CTN sustained-released pellets (CTN-SRPs) to precisely synchronize the CTN plasma concentrations with predicted occurrence of angina pectoris for angina chronotherapy. A deconvolution-based method was applied to develop and optimize the CTN-SRPs. The plasma concentration-time curve of CTN immediate-released formulation after oral administration in rats was used as the weight function. The predicted plasma concentration-time curve of CTN-SRPs simulated according to the incidence of variant angina during 24 h was used as the response function. Then the desired drug release profile of CTN-SRPs was calculated based on deconvolution using weight function and response function, and subsequently used for guiding the formulation optimization. CTN-SRPs were prepared with the combinations of PVP, poloxamer 127 and EC as matrix using fluidized bed technology. An orthogonal design was employed to obtain the optimal formulation with its release profile similar with the desired one. Pharmacokinetic studies validated that the actual plasma concentration-time curve of these optimized CTN-SRPs was similar with the predicted one. In addition, the percent errors (%PE) of CTN plasma concentrations in 8-12 h were less than 10%. In conclusion, this deconvolution-based method could be applied to adjust the performance of drugs for angina chronotherapy.
变异型心绞痛的临床表现于24小时内分布不均，因此药物的使用应根据心绞痛的昼夜节律进行调整。隐丹参酮（CTN）是丹参中具有代表性的生物活性脂溶性成分之一，常用于治疗心绞痛等心血管疾病。本研究的目的是开发一种新型的CTN缓释微丸（CTN-SRPs），使CTN的血浆浓度与预测的心绞痛发作精确同步，用于心绞痛的时辰治疗。应用基于反卷积的方法来开发和优化CTN-SRPs。以大鼠口服CTN速释制剂后的血浆浓度-时间曲线作为权重函数。根据24小时内变异型心绞痛的发生率模拟得到的CTN-SRPs的预测血浆浓度-时间曲线作为响应函数。然后基于权重函数和响应函数通过反卷积计算出CTN-SRPs所需的药物释放曲线，并随后用于指导制剂优化。采用流化床技术，以PVP、泊洛沙姆127和EC为基质组合制备CTN-SRPs。采用正交设计获得释放曲线与预期相似的最优制剂。药代动力学研究证实，这些优化后的CTN-SRPs的实际血浆浓度-时间曲线与预测曲线相似。此外，8-12小时内CTN血浆浓度的误差百分比（%PE）小于10%。总之，这种基于反卷积的方法可用于调整心绞痛时辰治疗药物的性能。
