多角度表面解吸常压化学电离源质谱对口服类抗生素缓释剂体外释放度原位检测研究

Oral sustained-release antibiotics have become increasingly important in medicine due to their convenience, reducing the times of taking medicine, lower degradation and offering patient compliance comparing to traditional antibiotics preparations. Considering that any unanticipated change in product performance of such systems may result intoxicity, antibiotic resistance and/or change in vivo efficacy, it is essential to develop suitable in vitro release testing methods to ensure product quality and performance, and to assist in product development. This study build a novel analysis device for in vitro release with surface desorption atmospheric pressure chemical ionization(SDAPCI), mass spectrometry(MS)with adjutable inlet and dissolution device of sustained release preparations, optimize detection signal of MS, and assess in vitro drug release from sustained-release antibiotics in situ based on the built device. A kinetic model was proposed and used to correct for the drug degradation in dissolve condition to obtain the actual release profiles. The study couples high sensitivity with high speed and stability including continous measurements in real time, which is suitable for reliable detection of in vitro release for all antibiotics, offer the theory and experimental platform for all oral sustained-release antibiotics's quality control and development especially in preliminary stages. And the method seems to provide highly useful initial guidelines in the development process of relevant field.

相比传统抗生素制剂，口服抗生素缓释制剂由于其便利性、给药次数少、降解程度低和患者依从性提高而在药界占据着越来越重要的地位。但该制剂释药行为的变化可能导致药物中毒、细菌抗药性或体内有效性的改变，因此有必要发展有效的体外释放度检测方法以确保缓释剂的质量，促进缓释剂的发展。本研究以先进的表面解吸常压化学电离源质谱（SDAPCI-MS）为基础，设计多角度可调质谱入口，构建SDAPCI、MS与缓释剂溶出装置的检测接口，优化接口设计，并以此接口为检测平台，建立抗生素缓释剂体外释放度质谱原位定量检测新方法。针对抗生素从缓释基质溶出过程中产生的降解，建立动力学模型校正降解造成的体外释放度曲线偏差。该方法具灵敏度高、快速和稳定性强，可实时连续监测，适用于所有抗生素缓释剂体外释放度的准确检测，为缓释剂质量控制及设计提供理论基础和实验研究平台。项目在研究方法上的探索对开展相关领域的研究具有启发和借鉴意义。

口服类抗生素缓释剂相比传统口服类抗生素制剂，减少了给药次数，降低了药物毒副作用，但抗生素缓释剂的突释易造成药物中毒，抗生素药物释放的速度不合格易引起细菌的抗药性，而药物释放的不完全易造成环境污染及用药成本增加。为提高抗生素用药安全，本研究采用先进的表面解吸常压化学电离源质谱（SDAPCI-MS）为原位检测技术，开展了以下几方面的工作：. 1）开发设计多角度可调质谱入口，构建SDAPCI、MS与缓释剂溶出装置的检测接口，优化接口设计，并以此接口为检测平台，建立头孢及大环内酯类抗生素缓释剂体外释放度质谱原位定量检测新方法。. 2）考察了头孢克洛处于不同酸度及温度下的稳定性及溶出度，结果表明，头孢克洛在pH 1.2和pH 4.5的环境中较为稳定，其溶出规律符合国家标准；针对头孢克洛处于pH 6.8时的环境较不稳定，易降解，建立校正方程，经校正后，溶出度可达99%左右，可用于指示头孢克洛的最大溶出量。此外，还进一步探讨了模拟体内变pH条件下，头孢克洛缓释剂的溶出状况，为药物的安全使用提供了参考。. 3）考察了克拉霉素缓释剂在不同酸度下的溶出度，建立了加速在线检测及变pH在线检测，建立加速与常规溶出时间相关性线性方程，相关性均达0.99以上，极大的提高了克拉霉素缓释剂的检测速度，并对其在模拟体内的释放情况作了进一步的研究。. 4）对SDAPCI-MS原位检测技术及常规取样检测法进行了比较，数据相似度高。