Article(id=1195687995794829684, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195707415279747621, articleNumber=1001-2494(2024)03-0275-06, orderNo=null, doi=10.11669/cpj.2024.03.012, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1676217600000, receivedDateStr=2023-02-13, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1763003833005, onlineDateStr=2025-11-13, pubDate=1707321600000, pubDateStr=2024-02-08, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763008463439, onlineIssueDateStr=2025-11-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=1763003833005, onlineFirstDateStr=2025-11-13, sourceXml=null, magXml=null, createTime=1763003833005, creator=13701087609, updateTime=1763003833005, updator=13701087609, issue=Issue{id=1195707415279747621, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='3', pageStart='193', pageEnd='284', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763008462972, creator=13701087609, updateTime=1763009150406, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1195710298666611616, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195707415279747621, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1195710298670805921, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195707415279747621, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=275, endPage=280, ext={EN=ArticleExt(id=1195687996012933494, articleId=1195687995794829684, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Quality Analysis of Cyathulae Radix Based on National Drug Sampling and Testing and Some Suggestions, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To analyze the quality differences of Cyathulae Radix from different manufacturers on the market based on national drug sampling and testing in 2022, then analyze the problems and put forward suggestions to provide basis for the quality supervision and standard improvement of Cyathulae Radix. OBJECTIVE Inspection was conducted according to corresponding standards, inspection reports were issued, and then quality evaluation and analysis were conducted. At the same time, problems were found and suggestions were made based on targeted exploratory research on quality problems, standard problems and other related problems found in the inspection. RESULTS A total of 334 batches of Cyathulae Radix samples were taken. According to the standard inspection, two batches of samples were found to be substandard in character, and Cyathulae capitatae Radix was used as Cyathulae Radix. At the same time, it was found that the content determination methods in the standard were too complex, and the specified limit for content determination was too low. In the exploratory study, the unique component achybidensaponin I was detected in 27 batches of Cyathulae Radix and 7 batches exceeded the specified limit, which was mixed with Achyranthes bidentata. Plant growth regulator (paclobutrazol) was detected in 270 batches of Cyathulae capitatae Radix. The detection of heavy metals and harmful elements cadmium(Cd) in 114 batches exceeded the limit. Finally, the quality standard of Cyathulae Radix was improved, the supplementary test method was established, and the risk warning was put forward. CONCLUSION Through the national sampling inspection, the relevant problems in the prepared slices and quality standards of Cyathulae Radix are found, suggesting that the quality standards should be improved and the quality supervision of Cyathulae Radix should be strengthened.

, correspAuthors=YANG Lei, GOU Yan, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=GAO Bixing, QI Jingliang, LI Qian, GENG Zhao, ZHONG Lian, GAO Chi, DENG Xi, WANG Ying, BAO Xiaohong, YANG Lei, GOU Yan), CN=ArticleExt(id=1195688172236616277, articleId=1195687995794829684, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=基于国家药品抽检的川牛膝质量问题及建议, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 基于2022年国家药品抽检工作,分析市场上不同厂家川牛膝质量差异,分析问题并提出建议,为川牛膝的质量监管及标准提高提供依据。方法 针对所抽取川牛膝样品按照相应标准进行检测,出具检验报告书。针对检验中所发现的质量问题、标准问题及前期调研发现的相关问题进行有针对性的探索性研究,进行质量评价分析,发现问题,提出建议。结果 共抽取川牛膝样品334批。标准检验,2批样品性状不合格,存在用麻牛膝充当川牛膝使用的情况,同时发现标准收载含量测定方法过于复杂,且限度过低。探索性研究,27批川牛膝检出麻牛膝特有成分牛膝皂苷Ⅰ,7批超出规定限度,存在麻牛膝混用的情况;270批川牛膝检出植物生长调节剂(多效唑)。114批重金属及有害元素镉(Cd)检测超出限度。最后提升了川牛膝质量标准、建立了补充检验方法、提出风险警示。结论 通过此次全国抽检发现川牛膝饮片和标准中的相关问题,提示需完善标准并加强川牛膝的质量监管。

, correspAuthors=杨蕾, 苟琰, authorNote=null, correspAuthorsNote=
*杨蕾,女,博士,主任药师 研究方向:药物分析 Tel:(028) 87877181;
苟琰,女,硕士,主任中药师 研究方向:中药及民族药品种与质量研究 Tel:(028)87877195
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高必兴,男,博士 研究方向:中药及民族药品种与质量研究

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高必兴,男,博士 研究方向:中药及民族药品种与质量研究

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Inf Tradit Chin Med(中医药信息), 2018, 35(2):6-9., articleTitle=Active anticogulants in vivo of different ingredients extracted from Radix Cyathulae, refAbstract=null), Reference(id=1197101289709547621, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=null, journalName=Ch.P(2020) Vol Ⅳ(中国药典2020年版.四部), refType=null, unstructuredReference=Ch.P(2020) Vol Ⅳ(中国药典2020年版.四部)[S]. 2020:239., articleTitle=null, refAbstract=null), Reference(id=1197101289831182438, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, doi=null, pmid=null, pmcid=null, year=2013, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=TONG K, journalName=The quality assessment of Cyathula officinalis Kuan, refType=null, unstructuredReference=TONG K. The quality assessment of Cyathula officinalis Kuan[D]. Yaan: Sichuan Agricultural University, 2013., articleTitle=null, refAbstract=null), Reference(id=1197101289910874215, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, doi=null, pmid=null, pmcid=null, year=1997, volume=12, issue=4, pageStart=49, pageEnd=50, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=LIU Y P, LI Z L, CHEN H, journalName=J Chengdu Univ Tradit Chin Med, refType=null, unstructuredReference=LIU Y P, LI Z L, CHEN H, et al. Determination of polysaccharide in Cyathulae officinalis Kuan by spectrophotometry[J]. J Chengdu Univ Tradit Chin Med(成都中医药大学学报), 1997, 12(4): 49-50., articleTitle=Determination of polysaccharide in Cyathulae officinalis Kuan by spectrophotometry, refAbstract=null), Reference(id=1197101289982177384, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, doi=null, pmid=null, pmcid=null, year=2005, volume=26, issue=2, pageStart=203, pageEnd=204, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=PENG H Y, journalName=J Southwest China Norm Univ Nat Sci Ed(西南师范大学学报自然科学版), refType=null, unstructuredReference=PENG H Y. Determination of polysaccharide in Cyathulae officinalis Kuan by ultraviolet spectrophotometry[J]. J Southwest China Norm Univ Nat Sci Ed(西南师范大学学报自然科学版), 2005, 26(2): 203-204., articleTitle=Determination of polysaccharide in Cyathulae officinalis Kuan by ultraviolet spectrophotometry, refAbstract=null)], funds=[Fund(id=1197101288195403863, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, awardId=2021002, language=CN, fundingSource=四川省药品监督管理局科技计划项目资助(2021002), fundOrder=null, country=null), Fund(id=1197101288350593112, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, awardId=NMPAJGKX-2023-075, language=CN, fundingSource=国家药品监督管理局中国药品监管科学行动计划第二批重点项目资助(NMPAJGKX-2023-075), fundOrder=null, country=null), Fund(id=1197101288455450713, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, awardId=2024-KYYL-002, language=CN, fundingSource=四川省药品检验研究院院立项目资助(2024-KYYL-002), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1197101283237736457, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, xref=null, ext=[AuthorCompanyExt(id=1197101283246125066, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, companyId=1197101283237736457, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=NMPA Key Laboratory for Quality Evaluation of Chinese Patent Medicines, Sichuan Institute for Food and Drug Control, Chengdu 611731, China), AuthorCompanyExt(id=1197101283254513675, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, companyId=1197101283237736457, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=四川省药品检验研究院, 国家药品监督管理局中成药质量评价重点实验室, 成都 611731)])], figs=[ArticleFig(id=1197101287159410765, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=EN, label=Fig.1, caption=HPLC chromatogram of Cyathulae capitatae Radix(A), achybidensaponin Ⅰ(B) and Cyathulae Radix(C), figureFileSmall=djYpZumbVPReOT8GzNca2g==, figureFileBig=Xc7kiAGjFknup8SL2u9f9g==, tableContent=null), ArticleFig(id=1197101287218131022, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=CN, label=图1, caption=麻牛膝(A)、牛膝皂苷Ⅰ对照品(B)及川牛膝(C)色谱图, figureFileSmall=djYpZumbVPReOT8GzNca2g==, figureFileBig=Xc7kiAGjFknup8SL2u9f9g==, tableContent=null), ArticleFig(id=1197101287343960143, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=EN, label=Fig.2, caption=Content determination(cyasterone) frequency distribution diagram, figureFileSmall=hRfvvynYkfG4RReByVFC3g==, figureFileBig=eJ5LJ4XK4PAOttZGL48GjQ==, tableContent=null), ArticleFig(id=1197101287427846224, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=CN, label=图2, caption=含量测定(杯苋甾酮)频数分布图, figureFileSmall=hRfvvynYkfG4RReByVFC3g==, figureFileBig=eJ5LJ4XK4PAOttZGL48GjQ==, tableContent=null), ArticleFig(id=1197101287520120913, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=EN, label=Fig.3, caption=HPLC chromatograms of content determination of Cyathulae Radix by Ch.P(2020) Vol Ⅰ method

A-Agilent 5 HC C18 (4.6 mm×250 mm,5 μm); B-Waters X-Bridge C18 (4.6 mm×250 mm, 5 μm).

, figureFileSmall=MIeunSokD7BF2lrjuDvvqA==, figureFileBig=p1luxPB/8CuudFBeIUyMCg==, tableContent=null), ArticleFig(id=1197101287599812690, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=CN, label=图3, caption=药典方法测定川牛膝含量的色谱图

A-安捷伦5 HC C18(4.6 mm×250 mm,5 μm);B-沃特世X-Bridge C18 (4.6 mm×250 mm, 5 μm)。

, figureFileSmall=MIeunSokD7BF2lrjuDvvqA==, figureFileBig=p1luxPB/8CuudFBeIUyMCg==, tableContent=null), ArticleFig(id=1197101287658532947, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=EN, label=Fig.4, caption=Chromatogram for determination of Cyathulae Radix by isocratic elution with methanol and water(30∶70)

A-Thremo C18(4.6 mm×250 mm,5 μm);B-Capcell PAK MG C18 (4.6 mm×250 mm,5 μm);C-Waters X-Bridge C18(4.6 mm×250 mm,5 μm).

, figureFileSmall=bb9eRE96q7eKJhp7MqMuDw==, figureFileBig=tT6NAP69iYR2QkF+xTgpRQ==, tableContent=null), ArticleFig(id=1197101287725641812, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=CN, label=图4, caption=甲醇-水(30∶70)等度洗脱测定川牛膝含量的色谱图

A-赛默飞C18(4.6 mm×250 mm,5 μm);B-资生堂MG C18 (4.6 mm×250 mm,5 μm);C-沃特世X-Bridge C18(4.6 mm×250 mm,5 μm)。

, figureFileSmall=bb9eRE96q7eKJhp7MqMuDw==, figureFileBig=tT6NAP69iYR2QkF+xTgpRQ==, tableContent=null), ArticleFig(id=1197101287809527893, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=EN, label=Tab.1, caption=

Statistical analysis of total polysaccharide content of Cyathulae Radix under different proposed limit principles

, figureFileSmall=null, figureFileBig=null, tableContent=
Proposed limit principle 30% below average 20% below average X-2Std X-Std
Proposed limit values 10.74% 12.27% 4.40% 9.87%
Qualified batches 209 180 253 219
Satisfactory rate 81.96% 70.59% 99.22% 85.88%
Unqualified batches 46 75 2 36
Failure rate 18.04% 29.41% 0.78% 14.12%
), ArticleFig(id=1197101287893413974, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195687995794829684, language=CN, label=表1, caption=

不同拟定限度原则下的川牛膝总多糖含量测定统计分析

, figureFileSmall=null, figureFileBig=null, tableContent=
Proposed limit principle 30% below average 20% below average X-2Std X-Std
Proposed limit values 10.74% 12.27% 4.40% 9.87%
Qualified batches 209 180 253 219
Satisfactory rate 81.96% 70.59% 99.22% 85.88%
Unqualified batches 46 75 2 36
Failure rate 18.04% 29.41% 0.78% 14.12%
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基于国家药品抽检的川牛膝质量问题及建议
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高必兴 , 齐景梁 , 李倩 , 耿昭 , 钟恋 , 高驰 , 邓曦 , 王颖 , 包小红 , 杨蕾 * , 苟琰 *
中国药学杂志 | 论著 2024,59(3): 275-280
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中国药学杂志 | 论著 2024, 59(3): 275-280
基于国家药品抽检的川牛膝质量问题及建议
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高必兴, 齐景梁, 李倩, 耿昭, 钟恋, 高驰, 邓曦, 王颖, 包小红, 杨蕾*, 苟琰*
作者信息
  • 四川省药品检验研究院, 国家药品监督管理局中成药质量评价重点实验室, 成都 611731
  • 高必兴,男,博士 研究方向:中药及民族药品种与质量研究

通讯作者:

*杨蕾,女,博士,主任药师 研究方向:药物分析 Tel:(028) 87877181;
苟琰,女,硕士,主任中药师 研究方向:中药及民族药品种与质量研究 Tel:(028)87877195
Quality Analysis of Cyathulae Radix Based on National Drug Sampling and Testing and Some Suggestions
GAO Bixing, QI Jingliang, LI Qian, GENG Zhao, ZHONG Lian, GAO Chi, DENG Xi, WANG Ying, BAO Xiaohong, YANG Lei*, GOU Yan*
Affiliations
  • NMPA Key Laboratory for Quality Evaluation of Chinese Patent Medicines, Sichuan Institute for Food and Drug Control, Chengdu 611731, China
出版时间: 2024-02-08 doi: 10.11669/cpj.2024.03.012
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目的 基于2022年国家药品抽检工作,分析市场上不同厂家川牛膝质量差异,分析问题并提出建议,为川牛膝的质量监管及标准提高提供依据。方法 针对所抽取川牛膝样品按照相应标准进行检测,出具检验报告书。针对检验中所发现的质量问题、标准问题及前期调研发现的相关问题进行有针对性的探索性研究,进行质量评价分析,发现问题,提出建议。结果 共抽取川牛膝样品334批。标准检验,2批样品性状不合格,存在用麻牛膝充当川牛膝使用的情况,同时发现标准收载含量测定方法过于复杂,且限度过低。探索性研究,27批川牛膝检出麻牛膝特有成分牛膝皂苷Ⅰ,7批超出规定限度,存在麻牛膝混用的情况;270批川牛膝检出植物生长调节剂(多效唑)。114批重金属及有害元素镉(Cd)检测超出限度。最后提升了川牛膝质量标准、建立了补充检验方法、提出风险警示。结论 通过此次全国抽检发现川牛膝饮片和标准中的相关问题,提示需完善标准并加强川牛膝的质量监管。

川牛膝  /  麻牛膝  /  国家药品抽检  /  质量分析  /  多效性

OBJECTIVE To analyze the quality differences of Cyathulae Radix from different manufacturers on the market based on national drug sampling and testing in 2022, then analyze the problems and put forward suggestions to provide basis for the quality supervision and standard improvement of Cyathulae Radix. OBJECTIVE Inspection was conducted according to corresponding standards, inspection reports were issued, and then quality evaluation and analysis were conducted. At the same time, problems were found and suggestions were made based on targeted exploratory research on quality problems, standard problems and other related problems found in the inspection. RESULTS A total of 334 batches of Cyathulae Radix samples were taken. According to the standard inspection, two batches of samples were found to be substandard in character, and Cyathulae capitatae Radix was used as Cyathulae Radix. At the same time, it was found that the content determination methods in the standard were too complex, and the specified limit for content determination was too low. In the exploratory study, the unique component achybidensaponin I was detected in 27 batches of Cyathulae Radix and 7 batches exceeded the specified limit, which was mixed with Achyranthes bidentata. Plant growth regulator (paclobutrazol) was detected in 270 batches of Cyathulae capitatae Radix. The detection of heavy metals and harmful elements cadmium(Cd) in 114 batches exceeded the limit. Finally, the quality standard of Cyathulae Radix was improved, the supplementary test method was established, and the risk warning was put forward. CONCLUSION Through the national sampling inspection, the relevant problems in the prepared slices and quality standards of Cyathulae Radix are found, suggesting that the quality standards should be improved and the quality supervision of Cyathulae Radix should be strengthened.

Cyathulae Radix  /  Cyathulae capitatae Radix  /  national drug sampling and testing  /  quality analysis  /  paclobutrazol
高必兴, 齐景梁, 李倩, 耿昭, 钟恋, 高驰, 邓曦, 王颖, 包小红, 杨蕾, 苟琰. 基于国家药品抽检的川牛膝质量问题及建议. 中国药学杂志, 2024 , 59 (3) : 275 -280 . DOI: 10.11669/cpj.2024.03.012
GAO Bixing, QI Jingliang, LI Qian, GENG Zhao, ZHONG Lian, GAO Chi, DENG Xi, WANG Ying, BAO Xiaohong, YANG Lei, GOU Yan. Quality Analysis of Cyathulae Radix Based on National Drug Sampling and Testing and Some Suggestions[J]. Chinese Pharmaceutical Journal, 2024 , 59 (3) : 275 -280 . DOI: 10.11669/cpj.2024.03.012
川牛膝来源于苋科植物川牛膝(Cyathula officinalis Kuan)的干燥根,现收载于2020年版 《中国药典》一部,具有逐瘀通经、通利关节、利尿通淋之功,常用于治疗经闭癥瘕、胞衣不下、跌扑损伤、风湿痹痛、足痿筋挛、尿血血淋等病症[1]。川牛膝以种植为主,主产于四川省、重庆市及湖北省等地,四川为其道地产区,野生资源主要分布于四川省凉山彝族自治州、雅安市天全县及宝兴县等地、云南省丽江市、保山市及贵州的部分地区[2]。现有饮片主要包括川牛膝(片)及酒川牛膝,以川牛膝(片)最为多见。
前期调研发现,川牛膝存在品种与质量的问题,市场存在麻牛膝冒充或掺伪川牛膝,现有文献也有相应的记载[2-5];主产区(四川省、重庆市及湖北省)均存在农药及生长调节剂的使用情况;不同产区栽培年限及栽培方式存在着差异;产地大多为趁鲜加工;部分标准规定不合理,以上问题均可能影响川牛膝饮片的质量,故为全面探究川牛膝饮片的整体情况,结合标准检验及探索性研究,对所抽取的334批川牛膝样品进行质量分析,发现问题,提出建议,保障人民用药的安全性及有效性。
本次抽检共334批川牛膝样品,抽样地域覆盖了全国31个省、自治区、直辖市,共有256家生产企业和334家被抽样单位。被抽样单位涉及87家经营单位,208家生产单位,39家使用单位。
依据2015年版及2020年版《中国药典》一部及《浙江省中药炮制规范》2015年版[6-7]中川牛膝项下规定的项目进行全检。
采用HPLC方法,建立了麻牛膝掺伪川牛膝的鉴别方法。
结合文献[8-11]及川牛膝功效成分,增加多糖含量测定方法,采用紫外-可见分光光度法建立了以硫酸-苯酚法测定川牛膝多糖的含量测定方法,多维度综合评价川牛膝质量。
针对“2.2.1”项下标准检验中发现的标准相关的问题,按照2020年版《中国药典》四部[12]相关要求进行优化实验。
针对前期调研发现的农药及植物生长调节剂残留,重金属及有害元素的问题依据2020年版《中国药典》四部[12]规定进行检测,评估其安全性。
依据标准规定对334批川牛膝样品进行全检,发现主要的问题存在于性状,其他检验项目均合格。现将性状检验结果及原因分析如下。
334批样品中,不合格2批,不合格因素为“味苦”,与标准规定中“味甜”相悖。同时发现不同批次间性状存在较大的差异性,表现为:①片厚:2015年版及2020年版《中国药典》四部通则0213“炮制通则”所规定的“薄片”的厚度为1~2 mm,部分批次为2~4 mm,部分成段;②片形及直径:大部分为呈圆形或椭圆形,少数批次为斜切片;大部分直径0.9~1.5 cm,存在少数批次直径0.3~0.7 cm,大部分为段;③切面颜色:切面颜色有黄白色、棕黄或棕黑色;④甜度:不同批次间川牛膝饮片的口尝甜度存在着较大的差异性。
结合前期调研分析,产生上述原因主要有以下4个方面:①产地趁鲜加工:造成片厚的主要原因与产地加工相关,大部分产地趁鲜加工,未满足药品生产质量管理规范(GMP)标准操作规范,导致片厚,直接销售于生产企业,而已切片后的川牛膝,无法再继续加工为薄片,导致市场上流通的川牛膝有一定比例为厚片。同时产地趁鲜加工也会导致切面颜色加深;②川牛膝直径较小:川牛膝切片时易碎,当选择直径较小的川牛膝药材加工成川牛膝饮片,难以切成薄片,故市场上存在川牛膝段;③贮藏年限:切面的颜色除受产地加工影响外,与其贮藏的年限也存在着一定的相关性——年限越久,切面颜色越深;④产地及生长年限:川牛膝的甜度可能与产地相关,也可能与不同栽培年限相关,同时不同的产地加工方式可能也影响着川牛膝的甜度。
针对川牛膝品种问题、有效性、安全性及质量标准可控性开展了以下探索性研究。
标准检验中发现2批川牛膝味苦,与药典规定性状不符,经前期调研考证发现,味苦川牛膝基原为麻牛膝,来源于头花杯苋[Cyathula capitate (Wall.) Moq.]的干燥根。川牛膝与麻牛膝性状除味道差异外,其余均无显著性差异[2],其冒充川牛膝,可通过味道进行区分,但若掺伪,常规手段几乎无法判定。
前期预试验研究发现川牛膝与麻牛膝成分差异性较大,混淆品麻牛膝掺伪或冒充对川牛膝临床安全性及有效性均可能产生一定影响:川牛膝味甜故俗称甜牛膝,麻牛膝味苦故俗称苦牛膝,苦味是由于麻牛膝含有川牛膝几乎不含有的皂苷类成分。同时药典涉及的指标成分杯苋甾酮成分在川牛膝中的含量普遍大于麻牛膝[13],因此两者不应混用,亟需建立有效的检测方法以检查川牛膝中是否掺入麻牛膝。
本研究基于麻牛膝特有成分牛膝皂苷I建立了以HPLC检查麻牛膝掺伪川牛膝的补充检验方法,结果见图1。并已报送相关单位审核,规定本品按干燥品计算,含牛膝皂苷Ⅰ(C48H76O18)不得过0.20%。具体检验方法如下。
色谱条件与系统适用性试验:以十八烷基硅烷键合硅胶为填充剂;以乙腈-体积分数0.2%磷酸溶液(33∶67)为流动相;检测波长为205 nm。理论板数按牛膝皂苷Ⅰ峰计算应不低于3 000。
对照品溶液的制备:取牛膝皂苷Ⅰ对照品适量,精密称定,加甲醇制成每1 mL含40 μg的溶液,即得。
供试品溶液的制备:取本品粉末(过3号筛)约0.5 g,精密称定,置具塞锥形瓶中,精密加入体积分数30%甲醇25 mL,密塞,称定重量,加热回流45 min,放冷,再称定重量,用体积分数30%甲醇补足减失重量,摇匀,滤过,取续滤液,即得。
结果334批样品中,27批川牛膝检出麻牛膝特有成分牛膝皂苷Ⅰ,存在混用情况,其中有7批超出规定限度。
限度修订:前期针对334批川牛膝样品依据标准对其进行了含量测定研究,结果数据分布在0.054%~0.112%之间,其正态分布图(图2),通过正态分布图发现川牛膝中杯苋甾酮含量低于0.070%有3批,3批通过所建立“3.2.1”项下的方法均检出牛膝皂苷I,其中2批性状为味苦,已判定为不合格。334批川牛膝含量平均值为0.089%,中位值为0.088%,提示现行药典标准中杯苋甾酮不得少于0.030%,限度制定较低,无法真正反映川牛膝的内在质量。依据现有结果及相关文献[13-14],建议限度修订为不得少于0.070%。
方法优化:2020年版《中国药典》一部川牛膝含量测定中流动相值得商榷,梯度条件耐用性差,目标物在此条件下不出峰或分离度较差,见图3。研究采用HPLC方法筛选出耐用性更好的色谱条件,并进行方法学考察。结果将流动相修改为等度洗脱,流动相为甲醇-水(30∶70),各峰分离度较好,同时考察不同色谱柱的耐用性,分离度均较好,见图4
除甾酮类成分外,川牛膝多糖也为其药效物质基础之一,具有增强免疫、抗炎、抗氧化、降血脂等作用,与其功效相关[8-9]。Chen[10]研究了川牛膝多糖可保护病毒性心肌炎心肌细胞损伤并抑制细胞凋亡。Meng等[11]研究川牛膝不同浓度乙醇提取的粗多糖具有体内的抗凝血活性,均与其主要功效“活血化瘀”相关;Liu和Peng等[14-15]提出将川牛膝多糖纳入药典标准。现有标准仅针对其甾醇类成分进行了质量控制,无法反映川牛膝真正的质量。
本研究采用紫外-可见分光光度法,建立了硫酸-苯酚法测定川牛膝总多糖含量方法,对334批川牛膝样品进行检测,按均值下浮30%、均值下浮20%、均值-2倍标准差(X-2Std)、均值-1倍标准差(X-Std)4种原则拟定限度(表1),综合分析4种拟定原则下的合格批次(合格率)与不合格批次(不合格率)情况,同时根据平均值、标准差所反应的数据离散程度,最终确定以X-Std作为其多糖的标准限度,规定本品按干燥品计算,含川牛膝多糖以无水葡萄糖(C6H12O6)计,不得少于9.8%。最终所有批次的合格率为85.5%。
结合前期调研情况及2020年版《中国药典》四部通则的相关规定拟针对334批川牛膝饮片进行农药及植物生长调节剂残留筛查。参考2020年版《中国药典》四部通则2341“农药残留量测定法”,采用气相色谱-串联质谱(GC-MS/MS)和液相色谱-串联质谱(LC-MS/MS)对禁限用农药(55种)、常用农药(43种)和植物生长调节剂(10种)进行检测。结果共检出农药38种,其中禁用农药13种,包括磷胺、克百威、氯磺隆、甲拌磷、胺苯磺隆、特丁硫磷、滴滴涕、氟虫腈、对硫磷、三氯杀螨醇、除草醚、六六六及硫丹,均未超出2020年版《中国药典》四部通则0212的限量规定;检出常用农药19种,均处于较低残留水平(<0.01 mg·kg-1);检出植物生长调节剂6种,分别为多效唑、矮壮素、抑芽唑,1,3-二苯脲、烯效唑、阿特拉津,检出率为82.0%,其中多效唑检出270批,检出率为80.8%。
植物生长调节剂的检出是川牛膝中较为突出的问题,与前期调研情况基本一致。6种检出的生长调节剂,除多效唑外均处于较低残留水平。多效唑检出率为80.2%,检出结果为NA~0.32 mg·kg-1,检出率和残留量均较高。2022年3月17日,国家药监局正式发布了《中药材生产质量管理规范》,对于植物生长调节剂的使用进行了明确规定:禁止使用壮根灵、膨大素等生长调节剂调节中药材收获器官生长。目前我国关于中药材暂无这类指标的法定检测方法和限量值的相关规定,相关监管部门应加快推进法定检测方法和限量值的制定。
采用2020年版《中国药典》四部通则2321中电感耦合等离子体质谱(ICP-MS)针对铅(Pb)、镉(Cd)、砷(As)、汞(Hg)、铜(Cu)5种重金属及有害元素进行检测。参考2020年版《中国药典》四部通则9302“中药有害残留物限量制定指导原则”对重金属及有害元素限量的有关规定,即Cd≤1 mg·kg-1,Hg≤0.2 mg·kg-1,Pb≤5 mg·kg-1,Cu≤20 mg·kg-1,As≤2 mg·kg-1。结果114批次Cd元素均超出“重金属及有害元素一致性限量指导值”。
川牛膝样品Cd元素超标的原因,可能主要是由以下原因所致:首先土壤是造成重金属污染不可忽略的因素,由于人为或天然的原因,我国某些地区土壤重金属含量较高,会通过扩散作用被植物根部吸收;同时川牛膝目前主要是栽培,在种植过程中肥料也会在一定程度上造成重金属元素积累;或是存在生产运输贮藏过程中重金属污染的风险。因此,为保证用药的安全性,有必要对川牛膝中的重金属及有害元素进行控制。
通过此次川牛膝的国家药品专项抽检工作,发现涉及质量标准、品种、质量及安全性等相关问题,并针对所存在的问题进行了详细的分析,并提出了相应的解决方案。如针对标准问题修订了含量测定的条件、提升了限度;针对品种问题建立了针对麻牛膝的补充检验方法;针对质量问题增加了多糖的含量指标项;针对规范化种植和用药安全进行了农药及植物生长调节剂残留、重金属及有害元素测定。
值得注意的是,川牛膝和伪品麻牛膝的传统功效和临床应用有较大的差异,麻牛膝的急性毒性大于川牛膝,川牛膝味甜俗称甜牛膝,麻牛膝味苦俗称苦牛膝,就药效物质基础而言,苦味是由于麻牛膝含有川牛膝几乎不含有的皂苷类成分,且药典涉及的指标成分杯苋甾酮在川牛膝中的含量普遍高于麻牛膝,因此,在《中药材品种论述》中谢宗万先生即明确指出麻牛膝与川牛膝不可混用。麻牛膝冒充或掺入川牛膝使用,使其用药有效性和安全性存在一定风险。前期调研发现市场麻牛膝冒充或掺伪现象严重,收集多批次来源于药材市场、医院药房及零售药店等流通渠道的样品,采用拟定的补充检验方法对此3类来源样品检测发现,牛膝皂苷I检出率高达44.05%,以5%掺伪比例的限度计算,不合格率达30.95%,存在较大的市场风险。
此次国评抽检中发现其中80.8%川牛膝样品检出多效唑,34.1%的川牛膝样品Cd结果超过2020年版《中国药典》四部通则9302“中药有害残留物限量制定指导原则”项下Cd的一致性限量指导值1 mg·kg-1。考虑不规范种植可能对用药安全性和有效性造成一定的影响,建议生产企业加强法律法规的学习,严格把控原药材质量,加强检验人员的检测技能;严格规范生产流程;饮片生产及使用单位要加强生产、流通、使用各环节的质量管控,尤其是对川牛膝的安全性检测,包括重金属Cd及植物生长调节剂。
另外,为保证质量标准能有效控制质量,建议修订现行质量标准,优化含量测定方法、提升含量测定杯苋甾酮的限度至0.070%,同时建立行之有效的方法对麻牛膝掺伪进行控制。
  • 四川省药品监督管理局科技计划项目资助(2021002)
  • 国家药品监督管理局中国药品监管科学行动计划第二批重点项目资助(NMPAJGKX-2023-075)
  • 四川省药品检验研究院院立项目资助(2024-KYYL-002)
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2024年第59卷第3期
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doi: 10.11669/cpj.2024.03.012
  • 接收时间:2023-02-13
  • 首发时间:2025-11-13
  • 出版时间:2024-02-08
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  • 收稿日期:2023-02-13
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四川省药品监督管理局科技计划项目资助(2021002)
国家药品监督管理局中国药品监管科学行动计划第二批重点项目资助(NMPAJGKX-2023-075)
四川省药品检验研究院院立项目资助(2024-KYYL-002)
作者信息
    四川省药品检验研究院, 国家药品监督管理局中成药质量评价重点实验室, 成都 611731

通讯作者:

*杨蕾,女,博士,主任药师 研究方向:药物分析 Tel:(028) 87877181;
苟琰,女,硕士,主任中药师 研究方向:中药及民族药品种与质量研究 Tel:(028)87877195
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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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