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

项目摘要 拟议工作的最终目标是开发胰岛素类似物（例如赖脯胰岛素）的新型联合制剂 和门冬胰岛素）与胰淀素类似物（例如普兰林肽）的组合，以实现糖尿病的变革性新治疗 这是真正的替代疗法。最具挑战性的方面的最佳血糖控制为1.25 在美国，100万1型糖尿病患者正在限制餐后血糖的大幅增加。 1型糖尿病患者不能产生身体处理葡萄糖所需的胰岛素，因此胰岛素 必须用每日注射来代替。胰淀素是一种与胰岛素一起分泌的小肽激素， 胰岛β细胞，其中枢作用以减慢胃排空，抑制餐后胰高血糖素分泌， 并减少食物摄入，从而补充胰岛素调节血糖水平的作用。类似于 胰岛素、胰淀素的产生在患有1型糖尿病的个体中完全不存在，这是由于他们缺乏胰岛素， 胰腺β细胞在餐时联合使用胰岛素和胰淀素类似物治疗糖尿病的同时， 倍已被证明比单独的胰岛素更有效，胰岛素的繁重施用和 胰淀素类似物作为两个单独的注射剂，因为这些蛋白质不能共同配制。Symlin（普兰林肽; AstraZeneca），唯一的商业胰淀素类似物制剂，在pH~4下配制，而Novolog（Aspart; 胰岛素类似物制剂（例如，Novonordisk）和Humaldehyde（Lispro; Eli Lilly）通常在pH约7.4下配制。 我们已经开发了一种蛋白质的非共价聚乙二醇化方法，使得能够稳定地共配制 这两种药物首次在配方中确定了最佳治疗比例。这本小说 联合治疗将产生前所未有的餐后血糖控制，并促进 糖尿病管理的有力工具，提供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.