注射用海参糖胺聚糖异常毒性和热原方法学研究

doi:10.19803/j.1672-8629.20220397

摘要/Abstract

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。

关键词: 海参糖胺聚糖, 注射剂, 小鼠, 异常毒性, 兔, 热原

Abstract: 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. 1/4 of 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 1.4 mg·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.

Key words: glycosaminoglycan from sea cucumber, injection, mice, abnormal toxicity, rabbits, pyrogen

中图分类号:

R917

王宗尉, 肖佳音, 王春雨, 高海舒, 姚尚辰, 许明哲. 注射用海参糖胺聚糖异常毒性和热原方法学研究[J]. 中国药物警戒, 2022, 19(11): 1165-1169.

WANG Zongwei, XIAO Jiayin, WANG Chunyu, GAO Haishu, YAO Shangchen, XU Mingzhe. Methodological research of abnormal toxicity and pyrogen on glycosaminoglycan from sea cucumber for injection[J]. Chinese Journal of Pharmacovigilance, 2022, 19(11): 1165-1169.

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