肝素质量评价与研究

Quality Evaluation and specification Research of Heparin

目的考察国产肝素的质量现状及存在问题,对现行质量标准的科学性及检验方法进行研究,完善质量标准。方法采用现行标准对抽验样品进行法定检验;查阅国内外标准及文献,赴生产企业实地调研,建立并完善了多个检验方法,包括离子色谱法、毛细管电泳法、激光光散射法、反相色谱法、体积排阻色谱法、微量生色底物法等。结果 2009年和2010年连续两年的全国评价性抽验结果表明绝大多数样品符合2005年版《中国药典》标准规定,但该标准缺乏对杂质的控制,部分检验项目限度较低;个别样品中含有类肝素杂质;防腐剂苯酚的添加有一定随意性;抗Ⅹa因子和抗Ⅱa因子活性测定专属性高,有利于控制肝素效价;原料中个别样品乙醇残留超标;核酸及蛋白杂质控制情况较好;旋光度、渗透压等项目的检测反映出一些问题;通过本次研究,对2010年版《中国药典》中收载的肝素标准做了大幅提高和修订。结论目前国产肝素质量较好,2010年版《中国药典》肝素原料及制剂的标准较为完善,与欧美等国际通用药典基本相当。我国肝素类产品的检验检测水平日益提高,多次参与国际协作研究,在肝素类产品质量控制方面赢得了国际话语权。

OBJECTIVE To understand the quality status and problems of domestic heparin products and evaluate the suitability of statutory standard and test methods. METHODS The statutory methods were adopted to test the samples. Many testing methods were established or improved on the basis of domestic and international standards and literature review and field research, including ion chromatography, capillary electrophoresis, mutiangle laser fight scatter （MALLS）, reverse phase chromatography, size exclusion chro- matography, micro-chromogenic substrate methods, etc. RESULTS The national evaluation test in two consecutive years of 2009 and 2010 showed that the majority of the samples complied with the 2005 edition of Chinese Pharmacopoeia. But this standard lacked control of impurities, and the limits of some items were not suitable. A few samples contained heparin-like impurities; phenol was added as preservatives arbitrarily. The assay method of anti-factor X a and anti-factor 11 a activity had high specificity, which was better to control the potency of heparin. Ethanol residues in the raw material of some samples exceeded the standard limit. The control of nucleic acid and protein was good. The determination of polarimetry and osmolality reflected some problems. Through this study, the quality specification of heparin in the 2010 edition of Ch. P had been improved a lot. CONCLUSION Domestic heparin products have better quality at present. The quality specification of the raw material and injection of heparin in the 2010 edition of Chinese Pharmacopoeia is relatively perfect and close to European Pharmacopoeia and the United States Pharmacopoeia. Our capability of quality test of heparin has been substantially improved, Consequently, we have taken part in several international collaborative studies and won international voice in the quality control of heparin products.