Co-Formulations of Amylin Analogues with Insulin Analogues for Treatment of Diabetes

项目总结 这项拟议工作的最终目标是开发一种新的胰岛素类似物的联合配方(例如Lispro. 与胰淀素类似物(例如，普拉林肽)，以实现糖尿病的变革性新疗法 构成了真正的替代疗法。1.25最优血糖控制的最具挑战性的方面 美国有100万1型糖尿病患者正在限制餐后血糖的大幅上升。 1型糖尿病患者不会产生身体处理葡萄糖所需的胰岛素，所以胰岛素 必须由每日注射取代。胰淀素是一种与胰岛素一起分泌的小肽激素，由 胰腺β胰岛细胞起中枢作用，减缓胃排空，抑制餐后胰高血糖素分泌， 并减少食物摄入量，从而补充胰岛素调节血糖水平的作用。类似于 1型糖尿病患者由于缺乏胰岛素和胰淀素，因此胰岛素和胰淀素的产生完全缺失。 胰腺β细胞。在餐中联合应用胰岛素和胰淀素类似物治疗糖尿病 TIMES已被证明比单独使用胰岛素更有效，繁重的胰岛素和 胰淀素类似物作为两个单独的注射，因为这些蛋白质不能被共同配制。塞姆林(Pramlintie； 阿斯利康(AstraZeneca)，唯一商业化的淀粉素类似物制剂，在pH~4下配制，而Novolog(Aspart； 诺维诺德)和Humalog(利斯普罗；礼来公司)，胰岛素类似物，通常在pH~7.4的条件下配制。 我们已经开发了一种蛋白质的非共价聚乙二醇化的方法，使其能够稳定地共同形成 这两种药物是第一次fi，从而它们的最佳治疗比例是在配方中fiNed。这部小说 联合治疗将产生前所未有的餐后血糖控制，并催化发展 糖尿病管理的有力工具，提供了迄今尚未实现的治疗效果。

PROJECT SUMMARY The ultimate goal of the proposed work is to develop a novel co-formulation of insulin analogues (e.g. lispro and aspart) with an amylin analogue (e.g. pramlintide) to enable a transformational new treatment for diabetes constituting a true replacement therapy. The most challenging aspect of optimal glycemic control for the 1.25 million people with type 1 diabetes in the United States is limiting large increases in blood glucose after a meal. People with type 1 diabetes do not produce the insulin required for the body to process glucose, so insulin must be replaced by daily injections. Amylin is a small peptide hormone excreted alongside insulin by pancreatic β islet cells that acts centrally to slow gastric emptying, suppress postprandial glucagon secretion, and decrease food intake, thus complementing the action of insulin to regulate blood glucose levels. Similar to insulin, amylin production is completely absent in individuals with type 1 diabetes on account of their lack of pancreatic β cells. While treatment of diabetes with a combination of insulin and amylin analogues at meal times has been shown to be more effective than insulin alone, the burdensome administration of insulin and amylin analogues as two separate injections since these proteins can't be co-formulated. Symlin (Pramlintide; AstraZeneca), the only commercial amylin analogue formulation, is formulated at pH~4 while Novolog (Aspart; Novonordisk) and Humalog (Lispro; Eli Lilly), insulin analogue formulations, are typically formulated at pH~7.4. We have developed an approach to non-covalent PEGylation of proteins enabling stable co-formulation of these two drugs for the first time whereby their optimal therapeutic ratio is defined in the formulation. This novel combination therapy will yield unprecedented postprandial glycemic control and catalyze the development of a powerful tool for the management of diabetes affording thus far unrealized therapeutic impact.