Structural Design of Micro-and Nano-gel Particles for Appropriate Controlled Release of Peptide Drugs

本研究的目的是开发具有适当控释功能的纳米和微球系统，用于多肽药物的释放。所建议的系统针对经口结肠特异性多肽的长期延迟释放，用于时辰药理多肽的外部温度激活的周期性脉动释放，以及用于口服多肽的温度和pH敏感的纳米凝胶的pH依赖的延长释放。主要研究结果如下：1.由乳糖核、胰岛素层和新合成的丙烯酸三元共聚物组成的微胶囊实现了胰岛素的pH非依赖性延迟释放，其特征是具有滞后和随后快速释放的特点。微囊化胰岛素在4℃保存24个月后仍保持稳定。体内口服滞留时间为6h的微囊的研究表明，该微囊具有显著的降血糖作用，指示剂…通过结肠吸收更多的胰岛素。药理利用度为5.1%。通过将含有纳米p(NIPAAm)水凝胶的乙基纤维素基质包衣在药物层状核心上，可以获得具有温敏控制药物释放能力的微胶囊。在p(NIPAAm)纳米凝胶中引入聚己内酯大分子单体或使用羟丙基纤维素作为替代温敏成分，有利于实现明显的温敏周期性脉动释放。研究了由温敏型p(NIPAAm)核和pH敏感型(MAA-g-EG)壳(CSNPs)组成的口服多肽纳米凝胶的载药量和粘附性。新建立的载药方法有利于显著提高药物含量(20wt%)。利用CSNPs胶体探针的原子力显微镜(AFM)分析了CSNPs与粘蛋白层之间的相互作用，发现CSNPs与粘蛋白层之间的相互作用力随pH的变化。作为一种无溶剂的制备工艺，干粉包衣技术是可以建立的。这项技术有望在无菌条件下稳定地加工湿敏多肽药物。较少

The aim of the present research project is to develop nano-and micro-particulate systems with appropriate controlled release functions for peptide drug delivery. The proposed systems are directed to long-term delayed release for peroral colon-specific peptide delivery, externally temperature-activated periodically pulsatile release for chronopharmacological peptide delivery, and pH-dependent prolonged release using thermo-and pH-sensitive nanogels for oral peptide delivery. The results obtained are summarized as follows :1. The microcapsules composed of a lactose core, an insulin-layer and a coat of newly synthesized acrylic terpolymer made it possible to achieve a pH-independent delayed-release characterized by a lag-time and subsequent rapid insulin release. The microencapsulated insulin was found to be stable even after the storage at 4℃ for 24 months. In vivo oral administration studies of the microcapsules with a lag-time of 6h revealed a significant hypoglycemic effect, indicatin … More g insulin absorption through the colon. The pharmacological availability reached 5.1%.2. The microcapsules having an ability to thermosensitively control the drug-release could be achieved by fabricating an ethylcellulose matrix coat containing nano-sized p(NIPAAm) hydrogels onto a drug-layered core. Introduction of poly(□-caprolactone) macromer into p(NIPAAm) nanogels or use of hydroxypropylcellulose as an alternative thermosensitively component was useful to achieve distinct thermosensitive periodical pulsatile release.3. The nanogels composed of thermosensitive p(NIPAAm) core and pH sensitive (MAA-g-EG) shells (CSNPs) for oral peptide delivery were characterized in terms of drug loading capacity and muco-adhesive properties. Newly established drug-loading method was useful to significantly increase drug content (20 wt%). Atomic force microscopy (AFM) using colloidal probe of CSNPs for analyzing particle-mucin layer interaction could also be established : pH-dependent changes of interaction force were observed between CSNPs and mucin layer.4. As a solvent-free preparation process, dry-powder coating technique could be established. This technology is expected to process moisture-sensitive peptide-drug stably in an aseptic condition. Less