超临界流体技术制备葡萄糖响应型药物载体及其对胰岛素释放调控作用的研究

Glucose-responsive drug carrier can control the release of the drug according to the glucose concentration in the blood, and have extensive applications in intelligent insulin drug delivery system. However, the conventional preparation process of the glucose-responsive drug carrier has some deficiencies, and it is essential to develop a green preparation method of glucose-responsive drug carrier. The present work will focus on the green preparation of glucose-responsive drug carrier with well controlled structure and biocompatibility using supercritical fluid drying and reaction in supercritical carbon dioxide. In the study, chitosan is used as carrier matrix, acetylaminophenylboronic acid and acrylamide are used as monomers to control insulin release. The influences of operation conditions on the structure, drug loading capacity and the glucose-responsive behavior of the glucose-responsive drug carrier will be elucidated, and the impacts of the specific structure and glucose-responsive behavior of the drug carrier on the drug release profile will be investigated. Meanwhile, the mechanisms of the drying during the preparation of the glucose-responsive drug carrier will be discussed. This multidisciplinary work will serve to expand the application of supercritical fluid based technologies to fabrication of drug carriers, and will be meaningful to design of drug delivery system and scaling up of this green process.

葡萄糖响应型药物载体可根据环境中葡萄糖浓度变化控制药物释放，在胰岛素智能给药领域具有广阔的应用前景。针对现有葡萄糖响应型药物载体制备方法的不足，结合给药系统应用中对葡萄糖响应型药物载体的要求，本研究以壳聚糖为载体基质材料，3-丙烯酰胺基苯硼酸和丙烯酰胺为葡萄糖响应功能单体，胰岛素为药物，在超临界流体中进行载体基质水凝胶的干燥，随后结合超临界流体中的反应在载体基质中进行功能单体的聚合，制备具有特定形貌结构及生物相容性的葡萄糖响应型药物载体，从而达到胰岛素葡萄糖响应性释放的目的。考察制备条件对载体形貌结构、药物负载量以及葡萄糖响应行为的影响；对葡萄糖响应型药物载体生物相容性进行表征；研究药物载体结构和葡萄糖响应行为对药物释放过程的影响；探讨葡萄糖响应型药物载体制备过程中的干燥机理。该研究将拓展超临界流体技术在药物载体制备中的应用，对给药系统的超临界流体绿色化制备工艺设计和工业化具有重要意义。

按照计划书的研究内容，首先构建了超临界流体中干燥及反应过程的实验装置和流程，选取壳聚糖作为载体基质材料，胰岛素为模型药物，研究了壳聚糖水凝胶在超临界流体环境中的干燥过程，考察了壳聚糖水凝胶制备过程及超临界流体干燥过程对壳聚糖载体基质形貌的影响。随后，以3-丙烯酰胺基苯硼酸及丙烯酰胺为单体，偶氮二异丁腈为引发剂，在超临界流体环境中，于壳聚糖载体基质上合成具有葡萄糖响应性的聚（3-丙烯酰胺基苯硼酸-丙烯酰胺），研究了药物载体的葡萄糖响应性能以及药物载体中胰岛素释放行为随葡萄糖浓度变化的规律。此外，将超临界流体中制备功能性复合材料过程应用于包装材料领域，制备了负载丁香酚、肉桂醛的壳聚糖膜用于抑菌包装，结果表明，超临界流体环境下制备的复合材料具有抑菌作用。研究结果对药物载体绿色化制备技术的进一步研究及新剂型的开发提供了参考。