中药大品种制造关键质量属性表征:空间分布均匀度质量属性的同仁牛黄清心丸贵细药混合过程控制可视化方法研究  

Critical quality attribute assessment of big brand traditional Chinese medicine:visualization of blending process for rare medicines in Tongren Niuhuang Qingxin Pills based on spatial distribution uniformity

作　　者：张芳语 林玲 曾敬其 祝明利 陆影 张瀚 李倩倩[1,2] 马丽娟 姚璐[3] 吴志生[1,2] ZHANG Fang-yu;LIN Ling;ZENG Jing-qi;ZHU Ming-li;LU Ying;ZHANG Han;LI Qian-qian;MA Li-juan;YAO Lu;WU Zhi-sheng(School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 102488,China;Engineering Research Center of Chinese Medicine Production and New Drug Development,Ministry of Education,Beijing 102488,China;National Engineering Research Center for R&D of TCM Multiingredient Drugs,Institute of Science,Beijing Tongrentang Co.,Ltd.,Beijing 100079,China)

机构地区：[1]北京中医药大学中药学院,北京102488 [2]中药制药与新药开发教育部工程研究中心,北京102488 [3]北京同仁堂股份有限公司科学研究所中药复方新药开发国家工程研究中心,北京100079

出　　处：《中国中药杂志》2021年第7期1585-1591,共7页China Journal of Chinese Materia Medica

基　　金：国家重点研发计划项目(2019YFC1711200,2018YFC1706901);国家自然科学青年基金项目(82003959);国家博士后基金项目(2020M670240);国家“重大新药创制”科技重大专项(2018ZX09201011);国家自然科学基金优秀青年基金项目(82022073);国家自然科学基金项目(81773914)。

摘　　要：贵细药的空间分布均匀度是同仁牛黄清心丸过程控制的关键质量属性。以同仁牛黄清心丸混合过程生产真实世界样品为研究对象,采集大小为180 pix×180 pix的高光谱成像,共32400个数据点的样本。采用光谱角匹配法(spectral angle mapping,SAM)、经典最小二乘法(classic least square,CLS)和混合调谐匹配滤波法(mixture tuned matched filtering,MTMF),建立混合中间体的贵细药辨识模型。结果表明MTMF模型有更高的识别精度,因此基于MTMF模型辨识了混合中间体的贵细药空间分布。进一步结合直方图法,评价混合中间体的贵细药均匀度。数据显示,混合中间体中人工牛黄、人工麝香、冰片、羚羊角、水牛角浓缩粉的标准偏差值分别为4.78,6.5,3.48,1.96,3.00;方差分别为22.8,42.3,12.1,3.82,9.00;偏度值分别为1.26,1.71,0.06,-0.86,1.04,最终结果表明混合中间体中冰片、羚羊角、水牛角浓缩粉混合较为均匀,人工牛黄次之,人工麝香混合均匀度较差。建立了同仁牛黄清心丸混合过程生产真实世界的贵细药空间分布均匀度可视化方法,为中药大品种混合过程质量控制方法研究提供依据。The spatial distribution uniformity of valuable medicines is the critical quality attribute in the process control of Tongren Niuhuang Qingxin Pills.With the real world sample of the mixed end-point powder of Tongren Niuhuang Qingxin Pills as the research object,hyperspectral imaging technology was used to collect a total of 32400 data points with a size of 180 pix×180 pix.Spectral angle matching(SAM),classical least squares and mixed tuned matched filtering(MTMF)were used to identify the spatial distribution of rare medicines.MTMF model showed higher identification accuracy,therefore the spatial distribution of the blended intermediates was identified based on the MTMF model.The histogram method was also used to evaluate the spatial distribution uniformity of rare medicines.The results showed that the standard deviation was 4.78,6.5,3.48,1.96,and 3.00 respectively for artificial bezoar,artificial musk,Borneol,Antelope horn and Buffalo horn;the variance was 22.8,42.3,12.1,3.82,and 9.00,and the skewness was 1.26,1.71,0.06,-0.86,and 1.04,respectively.The final results showed that the most even blending was achieved in concentrated powder of Borneol,Antelope horn and Buffalo horn,followed by artificial bezoar,and last artificial musk.A visualization method was established for quality attributes of distribution uniformity in blending process of Tongren Niuhuang Qingxin Pills.It could provide evidences of quality control methods in the mixing process of big brand traditional Chinese medicine.

关 键 词：中药大品种 关键质量属性 同仁牛黄清心丸 贵细药混合均匀度 高光谱成像 生产真实世界 

分 类 号：R284[医药卫生—中药学]