难溶性药物缓控释制剂三维立体释药机制研究

Much attention has been paid to the mechanism governing the transport of highly soluble drugs from the controlled drug release systems. However, few investigations have been reported for release mechanism of poorly water-soluble drugs, which is more complex and challenge. .The microstructure is obviously the primary physical character of the controlled drug delivery systems and the internal steric structure of the dosage form is changing correspondingly during drug release process. Water uptake of the semi-membrane, swelling of the polymeric matrix, pores and channels occurring, hydration of the tablet core are all have significant effects on the intrinsic quality of the pharmaceutical products. However, the release profiles measured by conventional methods do not provide information of the internal structure..In our previous study, 3D steric drug mechanism of felodipine monolith osmotic pump tablets and felodipine HPMC matrix tablets have been investigated using synchrotron radiation X-ray microtomography (SR-μCT) technique. In this project, 3D steric release mechanism of poorly water-soluble drug (nifedipine) from two-layer osmotic pump tablets and pH-dependent hydrophilic matrix tablets are planned to be researched using SR-μCT combining with magnetic resonance imaging technique under real-time and dynamic conditions. .The primary objectives are (i) to visualize changes in surface morphology, internal 3D structure and the hydration layer of the tablet at different stages of drug release process; (ii) to quantify the dynamic changes of the microstructure with 3D parameters and fractal dimension values; (iii) to establish quantitative relationships between 3D parameters, fractal dimension values and drug release kinetics through single parameter correlation and multiple linear regression analysis; (iv) to elucidate the release mechanism of poorly water-soluble drugs from controlled release systems with internal 3D steric data and to propose novel theory for the design and quality of the controlled drug delivery systems. .In summary, modern in-vitro tomography techniques are efficient tools which can directly reveal the internal structure and dynamic characteristics of the tablet core at different stages of the drug release process.

难溶性缓控释制剂研发难度大，现有缓控释制剂释药理论主要集中于水溶性药物，较少研究难溶性药物的释药机理。剂型内部的立体结构在释药过程中发生着动态变化，外层半透膜或聚合物基质的溶胀与孔隙生成、内部含药片芯的水化、片芯体积和表面积的变化等均与药物释放机制（渗透、扩散、溶胀和溶蚀）、制剂内在质量（释药速率、血药浓度的波动小）紧密相关。本课题在前期难溶性药物非洛地平单室渗透泵片和骨架缓释片的同步辐射光源立体重构研究基础上，结合核磁共振成像技术，以硝苯地平为代表性药物，同步、实时、动态地研究双室渗透泵和pH依赖型亲水凝胶骨架片的三维立体释药机制及其调控方法，获取制剂释药连续动态立体画面和三维结构，计算释药过程中片芯、半透膜、水化层的立体特征结构参数及剂型的三维空间分形维数，求证其与制剂释药动力学的相关性，揭示控制难溶性药物释药速率的关键立体结构因素，为该类药物新型缓控释制剂的设计、质量控制提供新理论。

本项目按研究计划将大科学装置与药物输送系统的评价需求相结合，建立了难溶性药物缓控释制剂的定量化模型和三维立体释药机制的评价方法以及释药动力学理论，深入研究了多单元给药系统等具有特殊结构的缓控释制剂，为设计具有独特结构特征的难溶性药物缓控释制剂提供了基础。本项目成功建立了渗透泵片和骨架缓释片的三维立体定量评价方法并提出了难溶性药物缓控释制剂的立体释药动力学理论；基于对缓控释制剂结构的研究，进行了具有新型结构的渗透泵给药系统研发，实现了在渗透泵内部精细结构、宏观双层结构、渗透压活性剂/推动剂和仿生结构上的创新；基于成像技术对制剂结构的探索发现和新认识，研发了具有特殊新型结构的制剂，为具有创新结构的制剂设计提供了新的选择。动态表征了难溶性药物亲水凝胶骨架片的立体结构研究，与制剂释放动力学定量关联，揭示控制缓控释制剂恒速释药的关键立体因素。发展了用于表征缓控释制剂物质分布的同步辐射红外显微成像技术和基于图像分析技术的非均相制剂沉降动力学表征方法等。本项目研究过程中，共发表相关论文17篇，其中9篇被SCI收录，申请中国专利共7项，已经获得授权4项，其中关于新驱动机制的渗透泵剂型申请PCT国际专利，在日本获得授权。本项目的科研成果为难溶性药物的新型缓控释制剂的设计、质量控制提供了新的方法，推进了缓控释制剂三维立体释药动力学理论与方法完整体系的建立。

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