pH Sensitive Complex Hydrogels for Protein Drug Release

聚（甲基丙烯酸）（PMAA）接枝聚（乙二醇）（PEG）的水凝胶用作载体， 口服（经粘膜）蛋白质递送。这些凝胶表现出可逆的pH依赖性溶胀行为， 酸性侧基和醚之间的共聚体复合物的形成或解离 接枝链的基团。这些传递特性是由于网络网格中的大的变化 在相对窄的pH值范围内，由于形成互聚物络合物。的 共聚体复合物的形成起到保护药物不与聚合物载体结合的作用。 我们的系统优于其他设计，因为我们已经能够获得强大的，剂量- 依赖性降糖作用。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，与胰岛素结合的胰岛素缀合物（PEG-胰岛素和转铁蛋白-胰岛素）， 改进的蛋白质释放载体可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 交联剂在我们的系统中。当仅胰岛素从粘附于膜的微粒释放时， 在粘液中，大部分截留的胰岛素在刷状缘的微环境内释放。在 这里提出的系统，部分包埋的胰岛素-转铁蛋白缀合物被释放到 将进一步保护流明免于降解。这些系统的一个重要优点是， 缀合物通过跨细胞途径穿过肠屏障。这些系统不会改变结构 因此避免了与使用穿透相关的各种不良反应 增强剂或酶抑制剂。在本补助金中，我们将重点关注PEG释放的调查- 胰岛素和转铁蛋白-胰岛素缀合物。具体而言，我们将重点关注 动态pH条件下转铁蛋白分子从复合水凝胶中释放的研究 条件下，PEG-胰岛素和胰岛素-转铁蛋白缀合物的结构分析，通过动态光 散射，药物偶联物从pH响应性络合物中释放的完整分析 水凝胶，研究从上述开发的制剂的缀合物递送和转运 通过HT 29-MTX/CaCo-2共培养物，以及通过HT 29-MTX/CaCo-2共培养物递送缀合胰岛素的体内研究。 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