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

本研究项目的目的是开发具有适当控制释放功能的纳米和微颗粒系统，用于肽药物的递送。该系统用于经口结肠特异性肽递送的长期延迟释放，用于时间药理学肽递送的外部温度激活周期性脉冲释放，以及用于口服肽递送的使用温度和ph敏感纳米凝胶的ph依赖性延迟释放。所得结果总结如下：1。该微胶囊由乳糖核心、胰岛素层和新合成的丙烯酸三元共聚物涂层组成，可以实现不依赖ph的延迟释放，其特征是胰岛素的滞后和随后的快速释放。微囊化胰岛素在4℃下保存24个月后仍保持稳定。体内口服研究表明，微胶囊具有明显的降血糖作用，延迟6小时，表明通过结肠吸收胰岛素更多。药理学利用度达5.1%。这种具有热敏控制药物释放能力的微胶囊可以通过在药物层状核心上制造含有纳米级p（NIPAAm）水凝胶的乙基纤维素基质涂层来实现。在p（NIPAAm）纳米凝胶中引入聚（□-己内酯）大分子或使用羟丙基纤维素作为替代的热敏成分，有助于实现不同的热敏周期性脉冲释放。研究了由热敏p（NIPAAm）核和pH敏（MAA-g-EG）壳（csnp）组成的口服肽递送纳米凝胶的载药能力和粘接性能。新建立的载药方法可显著提高药物含量（20 wt%）。利用胶体探针CSNPs的原子力显微镜（AFM）分析颗粒-粘蛋白层的相互作用也可以建立起来：观察到CSNPs与粘蛋白层之间的相互作用力随ph的变化。干粉涂层技术是一种无溶剂的制备工艺。该技术有望在无菌条件下稳定地加工湿敏肽药。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