从葛根素异常毒性实验看药用辅料重要性.docVIP

从葛根素异常毒性实验看药用辅料重要性[摘要] 目的:探讨葛根素注射剂出现毒性反应的原因。方法:参照《中国药典》2005年版,附录Ⅺ C异常毒性检查法,按照尾静脉注射给药法试验,平行检测不同厂家和剂型的葛根素注射剂和不同浓度的丙二醇溶液的毒性反应。结果:葛根素注射剂的毒性反应和其中所含丙二醇的量呈正相关。结论:丙二醇对于葛根素注射剂的毒性反应有很大影响。改进制剂工艺,加强对制剂辅料的监管非常必要。 [关键词] 葛根素;丙二醇;药物制剂;辅料;安全评价;质量标准 [中图分类号] R944.9[文献标识码]A [文章编号]1673-7210(2010)05(a)-047-02 The importance of pharmaceutical excipients according to the abnormal toxicity of Puerarin ZHOU Yongbiao, PAN Weisong (Institute for Drug Control of Guangzhou, Guangzhou 510160, China) [Abstract] Objective: To study the reasons of Puerarin Injection occuring toxicity. Methods: According to the Chinese Pharmacopoeia 2005 edition, Appendix Ⅺ C test for abnormal toxicity, in accordance with tail intravenous injection test, parallel detect different manufacturers and dosage forms of Puerarin Injection and different concentrations of propylene glycol solution toxicity. Results: Puerarin Injection of toxic reactions and the amount of propylene glycol contained in them showed positive correlation. Conclusion: Propylene glycol has great influence on Puerarin Injection toxicity. Improving preparation process, strengthening the supervision and management of pharmaceutical excipients are very necessary. [Key words] Puerarin; Propylene glycol; Pharmaceutical preparation; Excipients; Safety evaluation; Quality standard 传统上认为辅料应是非活性的,所以出现药物不良反应时,人们往往归之于活性成分。事实上,辅料并非惰性,药用辅料所引发的药物不良反应屡见报道[1]。葛根素是一有效的β-肾上腺受体阻滞剂。临床验证有肯定的抗急性心肌梗死,抗高肾素型高血压、抗心律失常疗效。葛根素注射液临床使用较为广泛,主要用于辅助治疗冠心病、心绞痛、心肌梗死、视网膜动、静脉阻塞、突发性耳聋及缺血性脑血管病、小儿病毒性心肌炎、糖尿病等。传统医学认为葛根无毒。已有报道小鼠的静脉注射葛根素的LD50为738.1 mg/kg,95%的可信限为604.0～901.8 mg/kg[2-3]。 目前国内生产的葛根素注射液在生产工艺中通常系以50%丙二醇作为增溶剂。丙二醇(1,2-二羟丙烷,propylene glycol,1,2-dihydroxy propan)广泛用于制药、食品和化妆品工业中,在药品中常用作增溶剂、润湿剂、保湿剂、防腐剂等。人体对于丙二醇的安全范围并无明确界定,丙二醇对小鼠静脉注射的LD50为66 301 mg/kg[4]。笔者在进行注射剂标准提高的研究中,发现葛根素注射剂的毒性反应与丙二醇的含量存在相关性。为了证实丙二醇的含量影响葛根素注射剂的毒性反应,特进行了如下实验研究。 1 仪器与试药 1,2-丙二醇[批号1,分析纯,密度(g/ml,20℃):1.036~1.039,广州化学试剂厂];灭菌注射用水(批号:0701090202,广东神州制药有限公司);氯化钠注射液(批号:D061224,湖南科伦制药有限