中药注射剂（丹红注射液）“量-稳-活-代”多维“质控markers”的辨析研究

Quality control study on Traditional Chinese Medicine Injection (TCMI) is significant mission of the drug safety reevaluation. The composition of TCMI is complex. The key issue for the quality control study of TCMI is how to choose appropriate quantitative indexes, which has influences on the safety and effectiveness of drug in clinical practice. Focusing on this issue, our research group has proposed the scientific hypothesis: the 'quality control markers' (QC markers) of TCMI should be representative constituents with superior pharmacokinetic properties, therapeutic activity and stability in preparation. Danhong injection (DHI) was chosen as a research model, which was systematically studied on the chemical material basis, content, stability, activity and pharmacokinetic properties of DHI. Then a multi-dimensional network (content-stability-activity-pharmacokinetic) was established. The selection criteria of "QC markers" is according to the regression area and the uniformity degree of dimensional score of the constituents in the multi-dimensional network. We would choose the constituents with larger regression area and favorable uniformity degree (showed high content, excellent stability, pharmacokinetic behavior and pharmacological activity) as optimal "QC markers" of DHI. This research integrated different perspectives and multiple dimensions to evaluate constituents whether owned the property of "QC markers", and established the foundation for the quality control of DHI. Besides, the research provided a novel strategy for the quality control study of TCM formulae.

中药注射剂质量控制研究是安全性再评价的重要内容。中药注射液成分复杂，如何选择合适的质控指标是其质量控制的关键，直接影响药物临床应用的安全性和有效性。针对此问题，本课题提出“中药注射液的‘质控markers’应是注射液的代表性成分，具有制剂条件下较好的稳定性、与药物疾病治疗作用相关的活性、良好的药动学属性”的科学假说，以丹红注射液为研究对象，系统研究化学物质基础、成分含量、稳定性、活性、药代动力学属性并构建多元网络回归分析法，以化合物在多元网络中回归面积和维度得分均一度作为“质控markers”的选择依据，选取回归面积大、均一度好（即：含量高、稳定性好、活性强、药动学属性好）的化合物作为丹红注射液的“质控markers”。该研究从不同层面、多个维度系统评价化合物是否具有“质控markers”的属性，为丹红注射液的质量控制奠定了基础，为其他中药注射液的质量控制研究提供了新的研究思路。

中药质量控制是中药质量系统评价研究的关键，含量测定是中药质量控制的核心，中药质控指标的选择是含量测定的基础。本项目围绕中药注射液“质控markers”辨析这一中药质量控制的关键问题，以丹红注射液为研究对象，开展了“质控markers”的辨析方法研究。系统开展了丹红注射液化学成分群研究、多成分含量测定研究、稳定性（高温稳定性和强光稳定性）研究、抗氧化活性和抗血小板聚集活性研究。在此基础上，构建了基于“含量–稳定性–活性”的“蛛网模式”方法并应用于丹红注射液“质控markers”辨析研究中，优选了丹红注射液的“质控markers”。该研究为丹红注射液质量标准的构建提供了充分的科学依据；项目研究成果写入了《丹红注射液临床应用中国专家共识》，并由中国中西医结合学会脑心同治专业委员会发布；课题组研究人员受邀在国内外重要学术期刊发表一系列“质控markers”研究综述文章。基于“蛛网模式”的“质控markers”辨析模式也拓展应用于丹红注射液活性组分筛选研究中，建立了基于抗氧化活性的“三元网络评价模式”。该研究发表文章7篇，其中SCI论文3篇；申请专利3项，其中授权专利2项；培养研究生3名。完成了项目任务书规定的各项考核指标。