摘要
目的制修订和完善我国低分子肝素国家标准,提高国产低分子肝素产品的质量与质控水平,为低分子肝素作为《中国药典》2015年版新增品种做准备。方法征集国产及进口原研厂家样品及相关资料,包括11个厂家的27批原料药,13个厂家的49批注射剂。查阅国内外相关标准及文献,对生产企业实地调研,进行大量实验。根据我国低分子肝素产品的生产工艺,对低分子肝素进行分类管理,重点关注结构确证、相对分子质量与相对分子质量分布、抗FⅩa与抗FⅡa活性、工艺杂质、降解杂质等。应用离子色谱、体积排阻色谱、反相色谱、气相色谱、核磁共振、原子吸收光谱法、微量生色底物法等多种物理、化学、生物学方法对低分子肝素进行质量标准研究。结果按生产工艺将国产低分子肝素产品分为3类:达肝素钠、依诺肝素钠、那屈肝素钙,拟定了原料和制剂共8个标准草案。拟定标准主要新增项目8个:结构式、制法要求、1,6-脱水衍生物含量测定、游离硫酸根、亚硝酸根、苯甲醇、依诺肝素钠紫外最大吸收及吸收系数测定,残留溶剂;修订项目15个:中文名、英文名、前言、性状、p H值、相对分子质量与相对分子质量分布、抗FⅩa效价、抗FⅩa/抗FⅡa、溶液颜色、钠、硫酸根与羧酸根比、干燥失重、装量、贮藏、制剂;删除项目1个:260、280 nm吸光度检查。结论与2005年低分子肝素新药标准转正时统一的国家标准比较,目前拟定的国家标准有大幅提高,将低分子肝素分类管理,项目设置更加完善,限度更为合理,与欧美等国际通用药典基本相当,在某些项目,如对降解产物游离硫酸根、残留溶剂等方面的控制更为严格,出于对检验经济学的考虑,目前欧美药典采用的核磁共振鉴别、硼、N-NO检查项目没有应用在拟定标准中。
OBJECTIVE To revise the national specification low molecular weight heparin for improving the quality and quality control level its domestic products as candidate new varieties Chinese Pharmacopoeia 2015 edition. METHODS Domestic and imported original products and related information were collected,including 27 batches raw material from 11 manufacturers and 49 batches injections from 13 manufacturers. Domestic low molecular weight heparin products were classified according to the production process.The analysis focused on the verification structure,molecular weight and activity,process impurities,and degradation impurities. Various physical,chemical and biological methods were used,such as ion chromatography,size exclusion chromatography,reversed phase chromatography,gas chromatography,NMR,atomic absorption spectrometry,micro-chromogenic substrate methods,and so on. RESULTS The domestic low molecular heparin products were divided into three categories： dalteparin sodium,enoxaparin sodium,and nadroparin calcium. Eight draft specifications the raw material and preparations have been made. In the draft specifications,eight items have been added： structure type,production,1,6-anhydro derivatives for enoxaparin sodium,free sulfate,nitrite,benzyl alcohol,ultraviolet absorption maximum specific absorption enoxaparin sodium,and residual solvent; 15 items have been revised： Chinese name,English name,definition,characters,p H value,molecular weight and molecular weight distribution,anti-FⅩ a activity,the ratio between anti-FⅩ a and anti-FⅡ a activity,the color the solution,sodium,sulfate and carboxylate ratio,loss on drying,volume injection,storage,preparation; one item has been deleted： light absorption at 260 and 280 nm. CONCLUSION The current draft specifications low molecular weight heparin have been greatly improved than the national specifications established in 2005. The products are divided into three categories. A lot items have been added and the limits are more reasonable. The draft specifications are roughly equal with the Europeand the United States Pharmacopoeia. The drafts are more stringent than the foreign Pharmacopoeias in some items,such as free sulfate and residual solvent. Due to economic consideration,NMR identification,boron,and N-NO examination,which are included in the Europe and the United States Pharmacopoeia,are not introduced in the draft specifications at present.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2014年第24期2210-2218,共9页
Chinese Pharmaceutical Journal
基金
国家质量监督检验检疫总局公益性行业专项"双打"中药品检验检测技术方法研究
子课题<低分子肝素标准提高研究>(2012104008-1-16)
关键词
低分子肝素
达肝素钠
依诺肝素钠
那屈肝素钙
国家标准
low molecular weight heparin
dalteparin sodium
enoxaparin sodium
nadroparin calcium
national specification
