目的 国家药典委员会于2017年6月在网上公示了达肝素钠、依诺肝素钠、那屈肝素钙3类低分子肝素标准征求意见稿,作为2020年版《中国药典》拟新增品种,为保证标准的顺利实施,急需建立首批低分子肝素相对分子质量国家对照品及相对分子质量系统适用性对照品。方法 以WHO第2次低分子肝素相对分子质量测定用对照品(2^nd international standard low molecular weight heparin for molecular weight calibration,批号05/112)为低分子肝素相对分子质量对照品,采用公示标准中“相对分子质量与相对分子质量分布”检查法,对低分子肝素相对分子质量国家对照品待标品(批号:140820-201801)、达肝素钠国家对照品待标品(批号:140811-201801)、依诺肝素钠国家对照品待标品(批号:140810-201801)、那屈肝素钙国家对照品待标品(批号:140812-201801)进行相对分子质量与相对分子质量分布测定,由全国13个药检所及低分子肝素生产厂家实验室协作标定。结果 对低分子肝素相对分子质量国家对照品待标品相对分子质量600~18 000的18个点百分面积进行标定,对实验室内误差进行考察,13个实验室中有2个实验室(7号、9号)部分点的标准差(standard deviation,SD)为1%～2%,其余11个实验室的SD值均小于1%。对实验室间误差进行考察,18个数据点的SD值均小于1%,相对标准偏差(RSD)除小分子部分的两个点均小于5%。对达肝素钠、依诺肝素钠、那屈肝素钙国家对照品待标品重均相对分子质量进行标定,实验室内SD值为4~110,RSD小于2.5%,实验室间SD值小于30, RSD小于1%。结论 经国家药品标准物质委员会审定后批准,低分子肝素相对分子质量国家对照品待标品(批号:140820-201801),附带宽分布标样表;达肝素钠国家对照品待标品(批号:140811-201801),重均相对分子质量6 268;依诺肝素钠国家对照品待标品(批号:140810-201801),重均相对分子质量4 435;那屈肝素钙国家对照品待标品(批号:140812-201801),重均相对分子质量4 832,可以用于低分子肝素相对分子质量与相对分子质量分布检查使用。

OBJECTIVE In June 2017, the National Pharmacopoeia Committee published on the internet the draft of national standards for dalteparin sodium、enoxaparin sodium and nadroparin calcium. As the new monographs to be added to the Chinese Pharmacopoeia in 2020. To establish the first batch national standards of low molecular weight calirant、dalteparin sodium、enoxaparin sodium and nadroparin calcium for system suitability. METHODS A national collaborative study involving thirteen laboratories had taken place, organized by National Institutes for Food and Drug Control(NIFDC)to provide supporting data for the establishment of the 1^st national standards of low molecular weight heparin for molecular weight calibrant、dalteparin sodium、 enoxaparin sodium and nadroparin calcium for system suitability of molecular weight determinations. The molecular weight determination methods in draft standards were used in the national collaborative study. The 2^nd international standard low molecular weight heparin for molecular weight calibration(05/112) were used as molecular weight calibrant. The candidate national standards of low molecular weight heparin for molecular weight calibration (140820-201801) and the candidate dalteparin sodium(140811-201801)、 enoxaparin sodium(140810-201801)、 nadroparin calcium(140812-201801)for system suitability of molecular weight determination were tested in the study. RESULTS The cumulative percent of peak area at the 18 molecular points from 600-18 000 of the candidate national standard of low molecular weight heparin for molecular weight calibration (140820-201801) were calculated. Based on the statistical analysis, the candidate gave low intra- and inter-laboratories variations.Of all 13 laboratories, standard deviations (SD) of two laboratories ranged from 1% to 2%,the others were less than 1%.Between laboratories, SD were all less than 1%,relative standard deviation(RSD) were all less than 5% except two points of the small molecular. The intra-lab SD of the test to determine the molecular weight of the candidate dalteparin sodium(140811-201801)、 enoxaparin sodium(140810-201801)、 nadroparin calcium(140812-201801)for system suitability of molecular weight determination was between 4 and 110,RSD was less than 2.5%. The inter-lab SD were less than 30, RSD was less than 1.0%. CONCLUSION After the examination of the expert committee on pharmaceutical standardization, the candidate (140820-201801) was approved as the first national standard of low molecular weight heparin for molecular weight calibration, the broad standard table is also provided the broad standard table. The candidate(140811-201801) is approved as the first national standard of dalteparin sodium for system suitability of molecular weight determination, with an assigned molecular weight (Mw) of 6 268. The candidate(140810-201801) is approved as the first national standard of enoxaparin sodium for system suitability of molecular weight determination, with an assigned molecular weight (Mw) of 4 435. The candidate(140812-201801) was approved as the first national standard of nadroparin calcium for system suitability of molecular weight determination, with an assigned molecular weight (Mw) of 4 832.