目的 依照International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH)指导原则,采用化学反应动力学和热力学方法研究野黄芩苷及灯盏花素注射液水溶液在不同pH值、温度、离子强度及初始质量浓度等条件下的降解反应的动力学特征,以研究野黄芩苷降解机制,比较其制剂与单体稳定性的差异,并考察临床使用条件对制剂稳定性的影响。方法 采用HPLC法考察不同条件下野黄芩苷单体及灯盏花素注射液中其量随时间的变化,利用化学反应动力学的方法计算野黄芩苷在不同环境下的降解反应动力学参数,预测其半衰期(t_1/2)和活化能。同时考察灯盏花素注射液与5种常用输液剂(0.9%生理盐水溶液、5%葡萄糖注射液、10%葡萄糖注射液、乳酸钠林格注射液、复方电解质葡萄糖注射液)的配伍稳定性。结果 野黄芩苷单体及灯盏花素注射液在不同温度和酸碱条件下的降解反应均遵循一级动力学规律,25℃时其在中性水溶液环境中最稳定,单体t_1/2为203.87 h,活化能为97.9 kJ/mol。在各种条件下,灯盏花素注射液水溶液中野黄芩苷的稳定性均优于单体。Na⁺、Cl^-离子强度及溶液初始浓度对野黄芩苷降解速率无明显影响。灯盏花素注射液与5种输液剂配伍在30 d内均可观察到明显的质量浓度下降。结论 野黄芩苷在中性水溶液中较为稳定,受温度、酸碱环境影响较大,初始质量浓度和离子对野黄芩苷稳定性的影响不明显,而灯盏花素注射液与5种常用输液剂配伍均不稳定。为有效地预测含野黄芩苷的中药制剂的稳定性变化提供了合理准确的依据,为含野黄芩苷的中药制剂的安全应用提供技术支持。

Objective To investigate the stability of aqueous solution of scutellarin at different pH values, temperature, ionic strengths, and initial concentration under the condition of dynamic characteristics of the degradation reaction according to ICH guidelines. Methods The content of scutellarin change with time in different conditions was studied using HPLC method. Based on the chemical reaction kinetics, the parameters of degradation kinetics were calculated under different conditions. The activation energy and half-time (t_1/2) were evaluted. Results The degradation of scutellarin in different conditions followed the first-order kinetics process. The most stable enviroment was in aqueous solutions of pH 7 at 25℃, the half-life period was 203.87 h and the reaction activation energy was 97.9 kJ/mol. But with the temperature increased, the degradation reaction rate greatly accelerated. Under any condition, the stability is higher than the monomer. The initial concentration and ionic strength of Na⁺ and Cl^- had no influence for its degradation. Conclusion The degradation of scutellarin in different conditions follows the first-order kinetics process and is greatly influenced by the environment of high temperature, strong acid, and weak alkaline. The injection with five kinds of commonly used infusion compatibility is unstable.

国家自然科学基金面上基金项目资助(81473543);国家科技支撑计划(2014BAI05B01)