注射用海参糖胺聚糖异常毒性和热原方法学研究  

Methodological research of abnormal toxicity and pyrogen on glycosaminoglycan from sea cucumber for injection

作　　者：王宗尉 肖佳音 王春雨 高海舒 姚尚辰[2] 许明哲[2] WANG Zongwei;XIAO Jiayin;WANG Chunyu;GAO Haishu;YAO Shangchen;XU Mingzhe(Institute of Biosafety Inspection,Heilongjiang Institute of Drug Inspection,Harbin Heilongjiang 150088,China;Institute for Drug Control,National Institutes for Food and Drug Control,Beijing 102629,China)

机构地区：[1]黑龙江省药品检验研究院生物安全检验研究所,黑龙江哈尔滨150088 [2]中国食品药品检定研究院,北京102629

出　　处：《中国药物警戒》2022年第11期1165-1169,共5页Chinese Journal of Pharmacovigilance

基　　金：国家重点研发计划(SQ2022YFC3400054)。

摘　　要：目的 建立注射用海参糖胺聚糖的异常毒性检查法和热原检查法。方法 参考《中华人民共和国药典》(2020年版)四部中《注射剂安全性检查法应用指导原则》,通过求得注射用海参糖胺聚糖静脉注射的半数致死量(LD50)及其95%可信限,确定异常毒性检查限值;对注射用海参糖胺聚糖进行热原检查的方法学研究。结果 本品静脉注射的LD50为189.4 mg·kg^(-1),95%可信限为239.0~139.8 mg·kg^(-1),取可信限下限(139.8 mg·kg^(-1))的1/4作为异常毒性检查限值,即小鼠尾静脉注射本品35 mg·kg^(-1)。取本品用氯化钠注射液配制成浓度为1.4 mg·mL^(-1)的溶液,按《中华人民共和国药典》(2020年版)四部通则1141异常毒性检查法依法检查,注射后全部小鼠状态正常,观察48 h无死亡;注射用海参糖胺聚糖用氯化钠注射液配制成1 mg·mL^(-1)的溶液,剂量按家兔体重注射2 mL·kg^(-1)(约为临床使用剂量的5倍),对细菌内毒素所致家兔体温升高无干扰作用。结论 可以采用35 mg·kg^(-1)剂量作为本品异常毒性检查限值对其进行检查;可以采用家兔法控制本品致热原,以2 mg·kg^(-1)剂量作为限值对其进行热原检查。Objective To establish abnormal toxicity test and pyrogen test of glycosaminoglycan from sea cucumber for injection. Methods The median ethal dose(LD50) and 95% confidence limit of glycosaminoglycan from sea cucumber for injection were obtained by referring to guiding Principles for Application of Injection Safety Test method in Pharmacopoeia of the people’s Republic of China, Volume IV, 2020 edition, and the limit of abnormal toxicity test was determined. A methodological study on pyrogen test of glycosaminoglycan from sea cucumber for injection was studied. Results The LD50 of this product was 189.4 mg·kg^(-1)for intravenous injection, and the 95% confidence limit was 239.0~139.8 mg·kg^(-1). 1/4of the lower confidence limit(139.8 mg·kg^(-1)) was taken as the limit of abnormal toxicity, that was, 35 mg·kg^(-1)was injected into the tail vein of mice. The product was prepared with sodium chloride injection into a solution with a concentration of 1.4mg·mL^(-1), and examined according to the abnormal toxicity test method 1141, Pharmacopoeia of the People’s Republic of China, Volume IV, 2020 Edition. As the results, all the mice were in normal state after injection, and no death was observed in 48 hours. Glycosaminoglycan from sea cucumber for injection was prepared with sodium chloride injection in a solution of 1 mg·mL^(-1)at a dose of 2 mg·kg^(-1)of rabbits body weight(about 5 times of the clinical dosage), which had no interference on the increase of rabbits’ body temperature caused by bacterial endotoxin. Conclusion 35 mg·kg^(-1)dose can be used as the limit of abnormal toxicity;the pyrogen of this product can be controlled by rabbits method, and 2 mg·kg^(-1)dose is used as the limit for pyrogen examination.

关 键 词：海参糖胺聚糖 注射剂 小鼠 异常毒性 兔 热原 

分 类 号：R917[医药卫生—药物分析学]