基于等温滴定量热技术表征的中药注射剂临床联合用药相容性评价

Compatibility evaluation of Chinese medicines injections based on isothermal titration calorimetry

为建立一种快速评价中药注射剂临床联合用药相容性的方法,采用等温滴定量热法(isothermal titration calorimetry,ITC),考察模式药益气复脉冻干粉针(YQFM)与常用联合用药维生素C注射液(Vc)及5%葡萄糖注射液(5%GS)的相容性,以热力学参数吉布斯自由能(ΔG)、焓变(ΔH)、熵变(ΔS)判断溶合反应类型,以反应活性谱判断反应热量变化,辅以化学特征色谱法进行佐证。结果显示,YQFM与Vc溶合过程中│ΔH│>T│ΔS│,为焓驱动反应,且反应活性谱显示两者溶合放出大量热,即溶合过程中化学反应起主导作用,活性成分发生质变;与5%GS溶合过程│ΔH│<T│ΔS│,为熵驱动反应,且反应活性谱显示两者溶合放出较小热量,即物理反应起主导作用,活性成分被稀释,未发生质变。化学特征色谱中特征成分的变化印证这一观点。借助ITC快速、灵敏、实时在线、差热功率补偿系统的技术优势,及其结果参数多元化、量热变化易读取的特点,该方法可作为中药注射剂临床联合用药相容性评价方法。

The paper is to report the establishment of a method for quickly evaluating compatibility of Chinese medicines injections.Isothermal titration calorimetry（ITC） was used to evaluate compatibility of Yiqifumai（YQFM） and vitamin C injection（Vc） / 5% glucose injection（5% GS）.The diversification of Gibbs free energy（ΔG）,enthalpy（ΔH） and entropy（ΔS） were used to decide reaction types of colliquefaction procedures of different injections.The reactive profiles were used to determine signs and quantity of heat.And high performance liquid chromatography（HPLC） was used as a supportive method for ITC.Then,feasible binding sites were analyzed based on the information of spatial structures of major compositions.During the colliquefaction procedure of YQFM and Vc,│ΔH│ T│ΔS│,so,the reaction is enthalpy-driving.And the reactive profile showed that a big deal of heat was given out during the procedure.Obviously,chemical reactions happened and the major compositions changed.On the other side,the reaction of YQFM mixed with 5% GS was entropy-driving,because │ΔH│ T│ΔS│.The reactive profile showed there was a little heat gave out.So,non-chemical reactions happened,and the major compositions did not change.The conformity existed between the results of ITC and HPLC.ITC could be used to evaluate the compatibility of Chinese medicines injections because of the advantages of ITC,such as real time,fast,sensitive and having more parameters.