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

用于治疗糖尿病的胰淀素类似物与胰岛素类似物的复合制剂

基本信息

批准号：
10713360
负责人：
Eric Andrew Appel
金额：
$ 12.1万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10713360
关键词：
Address Amyloid Fibrils Animal Model Artificial Pancreas Biological Products Blindness Blood Glucose Combined Modality Therapy Complement Crystallization Data Development Devices Diabetes Mellitus Drug Kinetics Eating Excipients Excretory function Formulation Gastric Emptying Glucagon Glucose Goals Heart Diseases Hormone secretion Hormones Hour Individual Injections Insulin Insulin, Lispro, Human Insulin-Dependent Diabetes Mellitus Islet Cell NovoLog Obesity Outcome Pancreas Patients Performance Persons Pharmaceutical Preparations Physiological Population Pramlintide Process Production Proteins Pump Rattus Replacement Therapy Research Rodent Model Science Structure of beta Cell of islet Subcutaneous Injections Subcutaneous Tissue Testing Therapeutic Time Toxic effect Translating United States Validation Work analog blood glucose regulation clinically relevant diabetes management diabetic diabetic rat effective therapy glycemic control innovation islet amyloid polypeptide limb loss next generation novel novel strategies peptide hormone prevent response side effect tool

项目摘要

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.

项目摘要拟议工作的最终目标是开发一种新型的胰岛素类似物的共同制定（例如Lispro 和Aspart）具有淀粉蛋白类似物（例如现象inintide），以实现糖尿病的转化新治疗方法构成真正的替代疗法。 1.25的最佳血糖控制的最挑战方面在美国，有百万人患有1型糖尿病的人限制了一顿饭后的血糖增加。患有1型糖尿病的人不会产生人体处理葡萄糖所需的胰岛素，因此胰岛素必须用每日注射替换。氨基蛋白是一种小胡椒激素独家，伴随着胰岛素胰腺β胰岛细胞集中在缓慢的胃排空中，抑制餐后胰高血糖素的分泌，并减少食物摄入量，从而完成胰岛素对调节血糖水平的作用。类似于胰岛素，1型糖尿病患者完全不存在氨基链淀粉蛋白，因为他们缺乏胰腺β细胞。饮食中胰岛素和淀粉蛋白类似物的糖尿病治疗显示时代比单独胰岛素，胰岛素给药和胰岛素更有效淀粉蛋白类似物作为两种单独的注射，因为这些蛋白质无法共同成型。 Symlin（Pramlintide; 阿斯利康（Astrazeneca）是唯一的商业Amylin模拟配方，在Novolog（Aspart; Aspart; Novonordisk）和HumanLog（Lispro; Eli Lilly），胰岛素模拟配方，通常在pH〜7.4处配制。我们已经开发了一种非共价蛋白质的方法这两种药物是在公式中定义其最佳治疗比率的第一次药物。这本小说联合疗法将产生前所未有的餐后血糖控制，并促进A的发展迄今为止，迄今为止无法实现的治疗影响，是管理糖尿病的强大工具。