超快速同步辐射动态断层扫描成像技术解析缓控释制剂的释放机理

The structure of dosage forms is the important primary property which determines the releasing process and therapeutic efficacy. Investigating the dynamic changing structures of Sustained/Controlled release preparations during release is one of the premises for the research of release mechanism. Synchrotron radiation computed micro-tomography is the most powerful available technique which can satisfy the demands of quantitative structure analysis, whereas the common microscope and electron microscope can’t provide multi-dimensional and multi-scale quantitative micro-structure from nanometer to millimeter. The applicants have firstly worked on the quantitative analysis of pharmaceutical structures by using Shanghai Synchrotron Radiation Facility (SSRF), and realized the great-leap-forward development for the pharmaceutical fine structure research from 2D imaging to micro-CT. Meanwhile, we carry out a series of explorative researches of pharmaceutics structures in competition with other leading countries, and have preliminarily established the theory and method of pharmaceutics structures based on synchrotron radiation imaging. Based on the above, this project is to optimize and develop new techniques and methods of pharmaceutics structure study, including ultra-fast high-resolution X-ray dynamic CT and protocols for the analysis of huge four dimensional structural data. Being mainly focused on the typical Sustained/Controlled release systems, we are to systematically investigate the hydro-gel matrix tablet and osmotic pump tablet based on synchrotron radiation micro-CT, to utilize the unique advantages of synchrotron radiation imaging technique on revealing the releasing mechanism of dosage forms, to demonstrate the multi-dimensional and multi-scale dynamic pharmaceutics structures and the rules of the influences on drug release, and to provide theoretical and methodological supporting for development of innovative drug delivery systems, which can greatly deepen the fundamental researches on theories of pharmaceutics.

结构是缓控释给药系统的核心与灵魂，是其发挥良好临床疗效的关键，研究缓控释制剂释放过程中的动态变化是解析其释放机理的前提。限于常规方法仅能给出二维和表面的特征，纳米~微米~毫米尺度的制剂三维结构尤其是动态结构的研究几乎是被忽略的领域。近年来，本团队依托上海光源强大的结构解析能力，与先进国家同步开展制剂结构的探索性研究，初步建立基于同步辐射光源成像的制剂结构研究方法，为考察制剂的静态内部结构、物质空间分布，处方、工艺因素及药剂学性质之间的关系提供了一种全新的研究手段。本课题将专注于基于同步辐射的超快速高分辨动态显微CT成像技术的方法学研究，实现凝胶骨架片、渗透泵释放过程中动态结构的原位实时高精度的测定，同时发展大规模四维结构数据分析的新方法，将结构药剂学理论扩展至更高的维度，关注缓控释制剂研究的核心基本问题即释放动力学的驱动机制，揭示决定释药速率的关键结构因素，明确缓控释制剂的控释机理。

本课题执行期间按照任务书的年度研究计划有序开展，针对拟解决的关键科学问题发展关键技术。首先，发展和优化基于同步辐射显微CT成像技术的原位测定方法，充分利用同步辐射光源的优点，进一步提高SR-μCT技术的时间分辨率，优化不同材料之间的对比度，实现药物制剂低Z物质的内部精细三维结构信息无损、精确、定量成像；然后，基于SR-μCT技术原位、实时、高分辨观测以渗透泵、凝胶骨架片和缓释微丸为代表的典型高端缓控释制剂释放过程中的动态结构；最后，通过动态结构可视化及高精度定量表征，识别其关键的功能结构特征，阐明缓控释制剂的多维多尺度动态结构及其对药物释放影响的规律。.系统研究推拉型双室渗透泵中助推剂晶体由推动层向药物层的移动模式、空隙和药物层通道等3D微观结构变化，当推动层触发片剂外围区域的推动力时，药物层通过相同的路线朝孔口移动以产生可控的药物释放，定义“地下河模型”来阐释药物释放机制；通过采集埃索美拉唑镁肠溶微丸（ESO）和奥美拉唑镁肠溶微丸（OME）在人工介质和大鼠消化道内的三维动态结构信息，并对微丸的结构进行重构和定量，揭示了以微丸为代表的口服固体制剂在体内体外溶出过程中结构变化的差异，并且通过优化体外溶出条件成功地将肠溶微丸在体内、体外的三维结构桥接起来，对体外更好地模拟体内药物释放环境，具有指导意义，药物制剂的质量控制提供新的思路；通过对琥珀酸美托洛尔片剂及其中的微丸单微丸在溶出过程的动态变化进行准确的结构表征，为微丸缓释片的内在质量研究和逆向工程提供了指导；研究了离子型亲水聚合物骨架缓释片的水化动力学结构特征，首次系统阐明凝胶骨架缓释片剂的水化动力学微观结构特征，依据不同的水化程度区分侵蚀前沿、膨胀前沿和溶剂渗透前沿，并首次实现交联膜的识别和可视化。.通过本课题的顺利执行，进一步体现了同步辐射光源成像技术揭示制剂释药机理的独特优势，完善和丰富了基于同步辐射光源显微CT的制剂结构研究理论和方法。