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目的:考察国内盐酸氯胺酮注射液的整体质量状况,并对现行质量标准进行评价与完善。方法:按照中国药典2010年版二部现行质量标准对样品进行检验,并针对现行标准在对特定杂质的控制、含量限度等方面存在的问题以及国内外药典标准的差异,开展多项探索性研究以完善现行标准,包括对现行标准有关物质检查项色谱方法的优化、盐酸氯胺酮原料与注射液中有关物质的研究及其主要杂质的结构确证、特定已知杂质羟亚胺与盐酸氯胺酮的体外细胞毒性和斑马鱼胚胎毒性的比较研究以及对现行标准含量测定方法的优化。结果:优化有关物质检查色谱条件,提高了杂质的检出率;样品中检出2个未知杂质,经分析与氯胺酮的热破坏降解物有关,其中一主要杂质与USP杂质B具有相同的结构,这与羟亚胺在酸性溶液中降解相关;盐酸氯胺酮和羟亚胺对小鼠成纤维细胞L929和人神经母细胞瘤SH-SY5Y 2种试验细胞株增殖的抑制作用无显著差异,但羟亚胺对斑马鱼胚胎发育的毒性和对幼体运动系统的损伤作用均要强于盐酸氯胺酮;建议提高含量测定的限度要求,由中国药典现行版的90.0%~110.0%提高至95.0%~105.0%。结论:盐酸氯胺酮注射液的质量基本能够符合中国药典的质量标准要求;但其质量标准尚有亟待修订和完善之处,建议在盐酸氯胺酮原料现行标准中增加对已知杂质羟亚胺的控制,在盐酸氯胺酮注射液标准中增加对降解杂质的控制,并提高盐酸氯胺酮注射液含量测定现行UV法的限度要求。
OBJECTIVE: To investigate the overall quality of ketamine hydrochloride injection in China and to evaluate and improve the current quality standards. Methods: According to the current Chinese Pharmacopoeia 2010 edition of the two current quality standards for testing the sample, and for the current standards in the control of specific impurities, content limits and other aspects of the problems and standards at home and abroad Pharmacopoeia differences, to carry out a number of exploratory research to Improve the current standards, including the optimization of the chromatographic methods of the relevant substances of the current standards, the study of related substances in ketamine hydrochloride raw materials and injections and the structural verification of the major impurities, the known in vitro cytotoxicity of hydroxyl amine and ketamine hydrochloride And zebrafish embryo toxicity of the comparative study and the determination of the current standard method of optimization. Results: Chromatographic conditions were optimized and the detection rate of impurities was improved. Two unknown impurities were detected in the sample, which were related to the thermal destruction of ketamine. One of the major impurities had the same structure as USP impurity B, This is related to the degradation of hydroxyimine in acidic solution. The inhibitory effect of ketamine hydrochloride and hydroxyimine on the proliferation of mouse fibroblast L929 and human neuroblastoma SH-SY5Y were not significantly different, The toxicity of amines to embryonic development of zebrafish and the injury to larval motor system were stronger than that of ketamine hydrochloride. The proposed limit to increase the content of amines was increased from 90.0% to 110.0% of the current edition of Chinese Pharmacopoeia to 95.0% to 105.0%. Conclusion: The quality of ketamine hydrochloride injection can basically meet the quality standard of Chinese Pharmacopoeia. However, its quality standard still needs to be revised and perfected. It is suggested to increase the control of known impurity hydroxyl imine in the current standard of ketamine hydrochloride, Ketamine hydrochloride injection standards to increase the control of degradation of impurities, and increase the content of ketamine hydrochloride injection to determine the current requirements of the UV method.