人凝血酶原复合物的临床前药物安全性评价

Preclinical drug safety evaluation of human prothrombin complex

目的评价人凝血酶原复合物(human prothrombin complex,简称PCC)制品的临床前药物安全性。方法采用体外试管法进行兔红细胞体外溶血试验;采用同体自身对照法进行兔血管刺激性试验;按照《中国药典》三部(2010版)方法对PCC进行异常毒性试验、人凝血酶活性检查、肝素含量、活化的人凝血因子活性检查及磷酸三丁酯和聚山梨酯80残留量检测。结果体外溶血试验未观察到兔红细胞溶血,也未见红细胞聚集;人凝血酶原复合物静脉输注给予新西兰兔,给药局部未见与供试品相关的刺激性反应;小鼠和豚鼠经腹腔注射本品30 min后均无异常反应,观察期结束时,小鼠体重平均增加>50%,豚鼠体重平均增加>10%;肉眼观察供试品无凝块或纤维蛋白原析出;肝素含量和活化的人凝血因子活性检查均符合质量要求;聚山梨酯80残留量≤100μg/mL,磷酸三丁酯残留量≤10μg/mL。结论成都蓉生药业有限责任公司生产的PCC是安全的,可用于临床。

Objective To evaluate the preclinical drug safety of human prothrombin complex(PCC).Methods Hemolysis test in vitro of rabbit eryhocytes was performed by tube method in vitro,while rabbit irritation test by self-control method.According to the methods in Chinese Pharmacopoeia(Volume Ⅲ,2010 edition),PPC was tested for abnormal toxicity,human thrombin activity,heparin content,activated human coagulation factor activity as well as residual contents of tributyl phosphate and Tween 80.Results No hemolysis or aggregation of rabbit eryhocytes were observed in hemolysis test in vitro.No irritation reactions associated with test samples was found in the New Zealand rabbits injected i.v.with PCC.There was no abnormal reaction in mice and guinea pigs 30 min after intraperitoneal injection with PCC.At the end of the observation period,the average weight gain of mice was more than 50%,and that of guinea pigs was more than 10%.No clot or fibrinogen precipitation was observed in the test samples by naked eye.Both the heparin content and activated human coagulation factor activity met the quality requirements.The residual contents of Tween 80was not more than 100μg/mL,while that of tributyl phosphate was not more than 10μg/mL.Conclusion PCC manufactured by Chengdu Rongsheng Pharmaceuticals Co.,Ltd.is safe,which may be used for clinical trials.