硫辛酸注射液仿制药与原研药的制剂质量比较及其小鼠急性毒性实验研究

Comparison of the Quality of Generic and Original Preparations of Thioctic Acid Injection and Study on Its Acute Toxicity Test in Mice

目的:对硫辛酸注射液的原研药与国内2个厂家的仿制药进行制剂质量比较及小鼠急性毒性实验研究,探讨一致性评价方法的项目。方法:依据《中国药典》的相关质量标准,检测并比较3个厂家硫辛酸注射液样品的理化性质(性状、pH、渗透压等)、含量、有关物质及小鼠急性毒性实验(n=10)中的半数致死量(LD50)及以注射液原液注射给药后小鼠(n=30)死亡情况。结果:原研药与2个仿制药在理化性质和有关物质检查方面均符合质量标准,3个样品含量均为95%~105%;急性毒性试验结果显示2个仿制药的LD50值(LD50:247.911 mg/kg,95%置信区间222.209~277.999 mg/kg;LD50:215.291 mg/kg,95%置信区间196.637~235.053 mg/kg)明显低于原研药的LD50值(LD50:266.534 mg/kg,95%置信区间250.597~283.418 mg/kg),但差异无统计学意义(P>0.05)。取注射液原液直接单剂量注射时,3次重复实验结果显示2个仿制药引起的小鼠的死亡数(26、28只)与原研药(19只)比较差异有统计学意义(P均<0.05),且给药后原研药小鼠出现窜动和惊叫等兴奋性反应,而2个仿制药呈现抑制性反应。结论:硫辛酸注射液的2个仿制药与原研药在制剂质量标准方面均符合《中国药典》的有关规定,但是急性毒性实验结果差异较大,难以证明这2个仿制药与原研药的一致性;在注射液的一致性评价项目中建议纳入急性毒性实验。

OBJECTIVE:To compare the quality of original preparations of Thioctic acid injection and generic preparations from 2 domestic manufacturers,discuss the acute toxicity test of mice and to investigate the project of consistency evaluation methods. METHODS: According to the quality standard that stated in Chinese Pharmacopeia, physicochemical properties(characters,p H,osmotic pressure,etc.,contents and related substances of samples of Thioctic acid injection as well as LD50 in acute toxicity test(n=10),and mortality of mice after administration of injection solution(n=30) were compared among 3 manufacturers. RESULTS:The physicochemical properties as and related substances of the original drug and 2 generic drugs were all in line with the quality standard;the contents of 3 samples ranged 95%-105%. The acute toxicity test results showed that the LD50 values of 2 generic drugs(LD50:247.911 mg/kg,95% confidence interval:222.209-277.999 mg/kg;LD50:215.291 mg/kg,95% confidence interval:196.637-235.053 mg/kg)were smaller than that of original drug(LD50:266.534 mg/kg,95% confidence interval:250.597-283.418 mg/kg),but there was no statistical difference(P>0.05). The results of 3 repeated experiments showed that there was statistical significance in the number of animal death caused by the 2 generic drugs(26,28)was more than that of the original drug(19)(all P<0.05),when injection solution was injected into mice in a single dose. After administration of the original drug,mice showed excitatory reactions such as movement and squeal,while 2 generic drugs showed inhibitory reactions.CONCLUSIONS:2 generic drugs of Thioctic acid injection and the original drug all conform to the relevant regulations of Chinese Pharmacopoeia in terms of preparation quality standards,but the results of acute toxicity test are quite different,so it is difficult to prove the consistency between the 2 generic drugs and the original drug. Therefore,acute toxicity test is necessary for the consistency evaluation of injections.