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多肽类药物微囊。设计了三种不同释药方式的微囊，并采用空气悬浮包衣工艺完成了微囊的制备。建议的系统针对口服结肠特异性多肽释放的长期延迟释放，用于时药学多肽传递的周期性脉冲式释放，以及用于外部温度激活多肽传递的温度敏感释放。研究结果如下：1.由乳糖核、药层和新合成的丙烯酸三元共聚物包衣而成的微胶囊，即使对于相对分子质量为20000的大分子水溶性物质，也可以实现pH非依赖性的延迟释放。含有该制剂的微囊化胰岛素被发现以相同的方式释放，即使在t…之后也是稳定的。在4℃条件下贮藏12个月。体内口服给药研究表明，微囊的体外释药曲线与体内的药物吸收行为具有较好的相关性。2.制备了新型纳米组分，即聚(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(e-己内酯)(PCL)，以制备周期性脉动释放微囊。P(NIPAAm-g-EG)纳米球具有保护胰岛素免受高温和高剪应力影响的能力，这使该系统成为空气悬浮涂层技术中胰岛素的良好候选载体。通过溶剂挥发法制备了具有良好成膜性的聚己内酯纳米粒子，但还需要进一步的配方研究来降低其透水性。3.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。微囊显示出了预期的正温度敏感药物释放。本发明的微胶囊膜能够在37到42℃之间响应温度的阶跃变化而获得可以在一分钟量级上改变释放速率的“开-关”脉冲释放。较少

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