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

本研究的目的是开发具有特定控释功能的微胶囊，用于多肽药物的递送。设计了3种不同释药方式的微胶囊，采用空气悬浮包衣法制备。所提出的系统针对经口结肠特异性肽递送的长期延迟释放，时间药物学肽递送的周期性脉冲释放和外部温度激活肽递送的热敏释放。本课题的研究成果总结如下：1。该微胶囊由乳糖核心、药物层和新合成的丙烯酸三元共聚物涂层组成，即使对分子量为20,000的大分子水溶性物质也可以实现不受ph影响的延迟释放。用该配方制备的微囊化胰岛素在4℃下贮存12个月后仍能保持相同的释放方式和稳定性。该微胶囊的体内口服给药研究表明，其体外药物释放谱与体内药物吸收行为具有较好的相关性。制备了接枝聚乙二醇（p(NIPAAm-g-EG)）纳米粒子的聚（n -异丙基丙烯酰胺）和可生物降解的聚（e-己内酯）（PCL）等新型纳米组分，制备了周期脉冲释放微胶囊。p（NIPAAm-g-EG）纳米球具有保护胰岛素免受高温和高剪切应力影响的能力，是胰岛素空气悬浮包覆技术的理想载体。采用溶剂蒸发法制备出具有良好成膜性的PCL纳米颗粒，但还需要进一步的配方研究来降低其透水性。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。微胶囊表现出预期的正热敏药物释放。目前的微胶囊膜可以实现“开-关”脉冲释放，可以在一分钟内改变释放速度，以响应37至42℃之间的逐步温度变化。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