附子理中丸大蜜丸、水蜜丸和浓缩丸3种剂型的化学特征关键质量属性辨识研究  

Identification of critical quality attributes with chemical characteristics of three dosage forms of Fuzi Lizhong Dami Pills,Shuimi Pills and Nongsuo Pills

作　　者：杨莎莎 林夏 郝怡雯 周航 张月 高子希 谢福玉 张星 傅超美[1] 张臻[1] YANG Shasha;LIN Xia;HAO Yiwen;ZHOU Hang;ZHANG Yue;GAO Zixi;XIE Fuyu;ZHANG Xing;FU Chaomei;ZHANG Zhen(State Key Laboratory of Southwestern Chinese Medicine Resources,School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China)

机构地区：[1]成都中医药大学药学院,西南特色中药资源国家重点实验室,四川成都611137

出　　处：《中草药》2024年第9期2955-2966,共12页Chinese Traditional and Herbal Drugs

基　　金：四川省科技计划重点研发项目(2020YFS0567);四川省科技厅四川省科技计划项目(2021YJ0251);四川省中医药管理局科学技术研究专项(2023MS600);成都中医药大学杏林学者青基人才专项(QJRC2022027)。

摘　　要：目的 建立附子理中丸(FuziLizhongPills,FLP)处方的大蜜丸(DamiPills,FLP-D)、水蜜丸(Shuimi Pills,FLPS)及浓缩丸(Nongsuo Pills,FLP-N)的HPLC指纹图谱,同时测定7种药效成分含量,寻找FLP处方与剂型关联的化学特征关键质量属性。方法 采用分层抽样法结合研究实际,随机抽取市售FLP-D 30批,FLP-S 12批,FLP-N 12批,建立以上54批FLP的HPLC指纹图谱,并同时测定甘草苷、苯甲酰新乌头原碱、党参炔苷、6-姜酚、白术内酯Ⅲ、白术内酯Ⅰ、10-姜酚7种有效成分含量;利用主成分分析(principal component analysis,PCA)和偏最小二乘法-判别分析(partial least square s-discriminant analysis,PLS-DA)方法对FLP-D、FLP-S和FLP-N各自的HPLC指纹图谱特征峰及7种有效成分进行分析。结果 FLP-D、FLP-S和FLP-N的HPLC指纹图谱分别标定出20、25、20个特征峰,通过PCA和PLS-DA,筛选出14个差异性标志物,其中8、9、12、17、18、25号峰来自甘草,29、32号峰来自干姜,22号峰来自白术。含量测定结果表明,甘草苷、苯甲酰新乌头原碱、6-姜酚、白术内酯Ⅲ、白术内酯Ⅰ在FLP-D、FLP-S和FLP-N中的含量差异显著,其中6-姜酚为变量重要性投影(variable importance in projection,VIP)值>1.0的差异性标志物。结论 建立的HPLC指纹图谱与多成分同时测定方法能有效评价FLP-D、FLP-S和FLP-N的化学成分差异;识别出的14个差异性标志物可作为区分FLPD、FLP-S和FLP-N的潜在化学特征关键质量属性;甘草苷、苯甲酰新乌头原碱、白术内酯Ⅲ、白术内酯Ⅰ可作为区分FLPD与FLP-N或区分FLP-S与FLP-N的化学特征关键质量属性,6-姜酚可作为同时区分FLP-D、FLP-S和FLP-N 3种不同剂型的化学特征关键质量属性。为进一步完善FLP系列制剂的质量标准提供了参考,同时为解决同方异剂中药的质控指标同质化问题提供了新思路。Objective To find the chemical critical quality attributes(CQAs)associated with the dosage form characteristics of Fuzi Lizhong Pills(FLP,附子理中丸)by establishing HPLC fingerprints of Dami Pills(FLP-D),Shuimi Pills(FLP-S)and Nongsuo Pills(FLP-N)and determining contents of seven effective components.Methods According to the stratified sampling method and research requirement,30 batches of FLP-D,12 batches of FLP-S and 12 batches of FLP-N were randomly selected from the market.The HPLC fingerprints of 54 batches of FLP were establishe.The contents of seven effective components,including liquiritin,benzoylmesaconine,lobetyolin,6-gingerol,atractylenolide III,atractylenolide I,and 10-gingerol were simultaneously determined.Principal component analysis(PCA)and partial least squares-discriminant analysis(PLS-DA)were used to analyze the HPLC fingerprint characteristic peaks of FLP-D,FLP-S and FLP-N and seven active components.Results There were 20 characteristic peaks in the fingerprints of FLP-D,25 characteristic peaks in FLP-S,and 20 characteristic peaks in FLP-N.A total of 14 differential markers were determined by PCA and PLS-DA.Among them,peaks 8,9,12,17,18 and 25 originated from Gancao(Glycyrrhizae Radix et Rhizoma),peaks 29 and 32 originated from Ganjiang(Zingiberis Rhizoma),and peak 22 originated from Baizhu(Atractylodis Macrocephalae Rhizoma).The contents of liquiritin,benzoylmesaconine,6-gingerol,atractylenolide III and atractylenolide I in FLP-D,FLP-S and FLP-N were significantly different.The compound 6-gingerol was a differential marker with variable importance in projection(VIP)value>1.0.Conclusions The established HPLC fingerprint and multi-component simultaneous determination method can effectively evaluate the chemical composition differences of FLP-D,FLP-S and FLP-N.The identified14 differential markers could be the potential CQAs of FLP-D,FLP-S and FLP-N.Liquiritin,benzoylmesaconine,atractylenolide III and atractylenolide I could be used as CQAs to distinguish FLP-D and FLP-N,or FLP-S and FLP-N.

关 键 词：附子理中丸 HPLC 指纹图谱 甘草苷 苯甲酰新乌头原碱 党参炔苷 6-姜酚 白术内酯Ⅲ 白术内酯Ⅰ 10-姜酚 剂型差异 化学特征关键质量属性 主成分分析 偏最小二乘法-判别分析 差异性标志物 

分 类 号：R283.6[医药卫生—中药学]