Development of Microencapsulated Peptide Drugs with Specific Controlled Release Functions by Air Suspension Coating Process

本课题的目的是研制具有特定控释功能的多肽药物微囊。设计了三种不同释药方式的微囊，并采用空气悬浮包衣法制备了微囊。所提出的系统涉及用于经口结肠特异性肽递送的长期延迟释放、用于时辰性肽递送的周期性脉冲释放和用于外部温度激活肽递送的热敏性释放。1.以乳糖为芯材、药物层和新型丙烯酸酯为包衣的微囊，即使是分子量为20，000的大分子水溶性物质，也能实现非pH依赖性的缓释。发现该制剂的微囊化胰岛素以相同的方式释放，即使在注射后也保持稳定。 关于我们 在4℃下储存12个月。2.以聚N-异丙基丙烯酰胺接枝聚乙二醇（p（NIPAAm-g-EG））纳米粒和可生物降解的聚己内酯（PCL）为纳米组分，制备了周期性脉冲释药微囊。p（NIPAAm-g-EG）纳米球具有保护掺入的胰岛素免受高温和高剪切应力的能力，这使得该系统成为用于空气悬浮包衣技术的胰岛素载体的良好候选者。通过溶剂挥发法可以制备成膜性良好的PCL纳米粒，但需要进一步的处方研究来降低水的渗透性。3.通过在药物层芯上制备含有纳米级p（NIPAAm）水凝胶的乙基纤维素基质包衣，可以获得具有温敏控制药物释放能力的微囊。该微囊表现出正的温度敏感性药物释放，如预期的。本发明的微胶囊膜使得有可能获得“开-关”脉冲释放，其可以响应于37 ℃和42℃之间的逐步温度变化而在一分钟内改变释放速率。少

The aim of the present research project is to develop microcapsules with specific controlled release functions for peptide drug delivery. Three types of microcapsules with different drug-release mode were newly designed and their preparation was accomplished by the air suspension coating process. The proposed systems are directed to long-term delayed release for peroral colon-specific peptide delivery, periodically pulsatile release for chronophermacological peptide delivery and thermo-sensitive release for externally temperature-activated peptide delivery. The results obtained through this research project are summarized asfollows :1.The microcapsules composed of a lactose core, a drug-layer and a coat of newly synthesized acrylic terpolymer made it possible to achieve a pH-independent delayed-release even for a macromolecular water-soluble substance with MW of 20,000. The microencapsulated insulin with this formulation was found to be released in a same manner and stable even after t … More he storage at 4℃ for 12 months. In vivo oral administration studies of the microcapsules revealed a relatively good correlation between in vitro drug-release profiles and in vivo drug-absorption behaviors.2.Novel nano-sized components, i.e. poly(N-isbpropylacrylamide) with grafted poly(ethylene glycol)(p(NIPAAm-g-EG)) nanoparticles and biodegradable poly(e-caprolactone)(PCL), were prepared to fabricate the periodically pulsatile release microcapsules. The p(NIPAAm-g-EG) nanospheres had an ability to protect the incorporated insulin from high temperature and high shear stress that made the system a good candidate as a carrier for insulin for air suspension coating technology. The PCL nanoparticles showing a good film-formability could be prepared by a solvent-evaporation method, though further formulation studies are yet needed to reduce the water-permeability.3.The microcapsules having an ability to thermosensitively control drug-release could be achieved by fabricating an ethylcellulose matrix coat containing nano-sized p(NIPAAm) hydrogels onto a drug-layered core. The microcapsules demonstrated a positively thermosensitive drug-release as expected. The present microcapsule membrane made it possible to obtain an 'on-off' pulsatile release, which could alter the release rate in the order of a minute, in response to stepwise temperature changes between 37 and 42℃. Less