pH Sensitive Complex Hydrogels for Protein Drug Release

聚甲基丙烯酸水凝胶(PMAA)接枝聚乙二醇水凝胶(PMAA)作为载体 口服(经粘膜)蛋白质输送。这些凝胶表现出可逆的、依赖于pH的膨胀行为，这是由于 酸性侧基与乙醚之间聚合物间络合物的形成或解离 一群群嫁接的链子。这些交付特征是由于网络网状结构的巨大变化造成的 在相对较窄的pH值范围内，这是由于形成了聚合物间的络合物。这个 聚合物间络合物的形成用于保护药物不与聚合物载体结合。 与其他设计相比，我们的系统具有优势，因为我们能够获得强大的、剂量- 依赖的降血糖作用。我们观察到基于胰岛素释放的生物利用度为12.8%。 我们的新假设是，胰岛素结合物(聚乙二醇胰岛素和转铁蛋白胰岛素)与 改进的蛋白质释放载体可以显著提高生物利用度。此外，生物利用度 也可以通过添加更多的提高我们网络结构的转变pH来增加 我们体系中的交联剂。当只有胰岛素从附着在表面的微粒中释放 粘液中，大多数被包裹的胰岛素在刷子边缘的微环境中释放。在……里面 这里提出的系统，被包裹的胰岛素-转铁蛋白结合物的一部分，被释放到 流明将得到进一步保护，不会被降解。这些系统的一个重要优势是 结合物通过跨细胞途径穿过肠道屏障。这些系统不会改变结构 并因此避免了与使用渗透相关的各种不良影响 增强剂或酶抑制剂。在目前的拨款中，我们将重点研究聚乙二醇的释放- 胰岛素和转铁蛋白-胰岛素从络合水凝胶中偶联。具体地说，我们将重点关注 动态pH条件下转铁蛋白分子在络合水凝胶中的释放规律研究 聚乙二醇-胰岛素和胰岛素-转铁蛋白偶联物的动态光谱分析 药物结合物从pH响应性络合物中释放的散射、完整分析 水凝胶.上述配方的共轭输送和输送的研究 通过HT29-MTX/Caco-2共培养和体内释放结合胰岛素的研究 络合水凝胶

Hydrogels of poly(methaerylie acid) (PMAA) grafted with poly(ethylene glycol) (PEG) are used as carriers for oral (transmucosal) protein delivery. These gels exhibit reversible, pH-dependent swelling behavior due to the formation or dissociation of interpolymer complexes between the acidic pendant groups and the ether groups of the grafted chains. These delivery characteristics are due to large changes in the network mesh over a relatively narrow range of pH values due to the formation of the interpolymer complexes. The formation of the interpolymer complexes serves to protect the drugs from binding with the polymeric carrier. Our systems are advantageous over other designs because we have been able to obtain strong, dose- dependent hypoglycemic effects. We have observed bioavailabilities of 12.8 %, based on insulin release. Our new hypothesis is that insulin conjugates (PEG-insulin and transferrin-insulin) in association with the improved protein release carriers can increase bioavailability significantly. Additionally, the bioavailability may also be increased by elevating the transition pH of our network structures by the addition of more crosslinking agent in our system. When only insulin is released from the microparticles adhering to the mucus, the majority of the entrapped insulin is released within the microenvironment of the brush border. In the systems proposed here, part of the entrapped insutin-transferrin conjugates that are released into the lumen will be further protected from degradation. One important advantage of these systems is that the conjugates cross the intestinal barrier via transcellular pathways. These systems do not change the structure of the paracellular junctions and hence avoid the various adverse effects associatedwith use of penetration enhancers or enzyme inhibitors. In the present grant we will focus on the investigation of release of PEG- insulin and transferrin-insulin conjugates from the complexation hydrogels. Specifically, we will focus on the investigation of the release profile of transferrin molecule from the complexation hydrogel under dynamic pH conditions, the structural analysis of PEG-insulin and insulin-transferrin conjugates by dynamic light scattering, complete analysis of release of the drug conjugate from the pH responsive complexation hydrogels, investigation of the conjugate delivery and transport from the formulations developed above through HT29-MTX/CaCo-2 cocultures, and in vivo studies of delivery of the conjugated insulin by the complexation hydrogels