基于超细微粒制备技术的微粒成丸机理研究及其在微丸片中的应用

Controlled and sustained release dosage forms represent one of the most active trends in current pharmaceutical research, and among these dosage forms, pellet-containing tablet (PCT) has received numerous attentions since it combines the advantages of both single-unit and multi-unit dosage form. The challenges to prepare qualified PCT are achieving well-distributed tablets and maintaining the integrity of pellets after compaction. Ultra-fine particle processing system (UPPS), which was originally developed in our laboratory with intellectual property rights, was demonstrated to reliably manufacture drug-containing pellets with excellent properties such as uniformity, flowability, and compactibility for compaction. Combining the pellet-containing granules technique, this novel system induced a breakthrough for preparing pellets which are ready for manufacturing PCT. The preliminary studies indicated that in this new system liquid drop-chains were formed as the polymeric solution left from the spinning disk, and the liquid drop-chains formed individual liquid drops under their own surface tensions and the shearing of the air flow. Also, the subsequent drying efficiency of the liquid drops could influence the morphology, properties, and drug release behavior of the final pellets. However, the actual formation mechanism of pellets in UPPS is not clear. In this project, with the help of high-speed videography and laser inspection method, the pellet forming process was traced to explore the pellet formation mechanism. The outcomes of this study can provide a scientific support for improving the UPPS and a practical guiding for pellet preparation using UPPS.

缓控释制剂是药剂学研究的热点，而微丸片是缓控释制剂中优势最突出的一种剂型，兼具单单元制剂和多单元制剂的优点。微丸片的研发存在两个关键技术难点：微丸在片剂中分布的均匀性及微丸压片前后释药的一致性。.本研究拟采用课题组自主创新研制的超细微粒制备系统（UPPS），结合具有自主知识产权的粉体包合技术，突破微丸片研发的两大瓶颈。前期研究证实UPPS微丸的粒径小、可压性好，但UPPS系统的微粒成丸机理尚不明确。研究表明，高分子溶液在脱离旋碟瞬间以串珠状形式，在腔体中通过气流剪切作用和自身液体表面张力作用分散成独立的液滴，而液滴的干燥效率则会导致微丸的形态、性状、释药行为发生改变。本项目旨在前期工作的基础上，深入研究微粒成丸机理，采用高速摄像和激光检测信号法追踪微丸赋形的全过程，以UPPS成丸理论指导微丸的制备，结合粉体包合技术对理论加以验证，为确立UPPS系统制备适合压片的微丸提供充分的科学依据。

微丸片制剂兼具单单元制剂和多单元制剂的双重优点，且在专利保护方面意义巨大。但其制剂手段较为复杂，难以实现工业化生产，至今国际市场上仅有Beloc® ZOK、Antra® MUPS和Prevacid® SoluTabTM三种产品，均为阿斯利康公司垄断。微丸片的研发存在两个关键技术难点：微丸在片剂中分布的均匀度及微丸压片前后释药行为的一致性。本项目采用课题组创新研制的、拥有自主知识产权的超细微粒制备系统（UPPS）突破这些技术难点，并深入研究UPPS系统的成丸机理和各参数间的相互关系，为UPPS制备微丸体系提供更加完善的理论依据，也为微丸片的研制提供一种新的思路。项目执行以来，已发表论文5篇，获得授权专利1项，会议摘要3项，会议报告3个。