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Development of novel and stable glucagon formulations for closed loop systems

开发用于闭环系统的新颖且稳定的胰高血糖素制剂

基本信息

批准号：
8547068
负责人：
Roderike Pohl
金额：
$ 29.35万
依托单位：
BIODEL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547068
关键词：
Address Algorithms Alpha Cell Amino Acids Area Artificial Pancreas Beta Cell Biological Biological Assay Blood Glucose Body Temperature Carbohydrates Cell physiology Chemicals Clinical Clinical Research Continuous Infusion Data Development Devices Diabetes Mellitus Dose Drug Formulations Emergency Situation Excipients Exercise Family suidae Gel Glucagon Glucose Glycogen High Pressure Liquid Chromatography High temperature of physical object Hormonal Hormones Hour Hypoglycemia Infusion Pumps Infusion procedures Injectable Injection of therapeutic agent Insulin Insulin Infusion Systems Intramuscular Injections Laboratories Lead Light Link Liver Marketing Measures Methods Miniature Swine Modeling Molecular Weight Normal Range Patients Peptides Pharmacopoeias Phase Physiology Plasma Powder dose form Proteins Pump Qualifying Quality of life Research Residual state Sampling Scientist Simulate Solutions Structure of alpha Cell of islet Structure of beta Cell of islet Subcutaneous Injections Syringes System Technology Temperature Testing Time Touch sensation Vial device analytical method aqueous blood glucose regulation comparative depot-insulin design diabetic glucagon (rDNA)glucose sensor glycogenolysis improved novel particle prevent reconstitution research study response subcutaneous

项目摘要

DESCRIPTION (provided by applicant): A device system which automatically maintain blood glucose concentrations in the normal range by dosing insulin in response to continuously sensed glucose concentration data represents a modern attempt to mechanically simulate normal beta cell physiology and solve many of the problems associated with intensive insulin therapy today, including improving the quality of life for patients with diabetes and improving glucose control. The development of such a "closed loop" artificial pancreas algorithmically linking continuous glucose sensors with insulin infusion pumps is an active area of research. Most studies with experimental artificial pancreas (AP) systems which have used insulin only have shown that hypoglycemia requiring carbohydrate administrations has not been eliminated using multiple experimental algorithms. The insulin- only approach to the artificial pancreas does not fully mimic normal physiology in that there is no ability to abort impending hypoglycemia through the use of counter-regulatory hormones. The only way for such insulin only AP system to react to declining glucose concentrations is to reduce or stop infusing subcutaneous insulin. This will not guarantee prompt termination of insulin effect in part because of residual depots of insulin in the subcutaneous space. In normal physiology, pancreatic alpha cells secrete glucagon to counter the glucose lowering effect of insulin. One of these counter-regulatory hormones is glucagon, a 29 amino acid peptide which stimulates the conversion of glycogen stored in the liver into glucose (glycogenolysis). Recent closed loop insulin studies in which glucagon is also used algorithmically to prevent impeding hypoglycemia have shown excellent glucose control with very low rates of hypoglycemia. Glucagon in its currently marketed form however is chemically and physically unstable in solution and therefore not practical for clinical development in bi-hormonal artificial pancreas systems. Biodel scientist have prepared lab formulations of aqueous glucagon at pH 7 that remain stable in solution. In this application, Biodel proposes to optimize multiple pH 7 aqueous formulations of glucagon to provide a minimum of 18 month stability under refrigerated and if possible, room temperature (25C) conditions for long-term storage requirements. We will assess whether all current US Pharmacopeia (USP) compendia methods are applicable to these formulations and we will develop suitable methods if required. We will demonstrate biological activity in a swine model and we will demonstrate that our formulation is compatible with a marketed insulin pump system at elevated temperatures for at least 9 days.

描述（由申请人提供）：一种设备系统，根据连续感知的葡萄糖浓度数据，通过给药胰岛素自动将血糖浓度维持在正常范围内，代表了机械模拟正常β细胞生理的现代尝试，并解决了当今与强化胰岛素治疗相关的许多问题，包括改善糖尿病患者的生活质量和改善血糖控制。这种通过算法将连续葡萄糖传感器与胰岛素输注泵连接起来的“闭环”人工胰腺的开发是一个活跃的研究领域。大多数仅使用胰岛素的实验性人工胰腺（AP）系统的研究表明，使用多种实验算法并不能消除需要碳水化合物治疗的低血糖。仅使用胰岛素的人工胰腺不能完全模拟正常生理，因为没有能力通过使用反调节激素来中止即将发生的低血糖。这种仅限胰岛素的AP系统对葡萄糖浓度下降作出反应的唯一途径是减少或停止皮下注射胰岛素。这并不能保证胰岛素作用的迅速终止，部分原因是皮下空间中存在残留的胰岛素。在正常生理中，胰腺细胞分泌胰高血糖素来对抗胰岛素的降血糖作用。其中一种反调节激素是胰高血糖素，它是一种由29个氨基酸组成的肽，能刺激储存在肝脏中的糖原转化为葡萄糖（糖原分解）。最近的闭环胰岛素研究中，胰高血糖素也被算法地用于预防阻碍性低血糖，结果显示血糖控制良好，低血糖率极低。然而，目前上市的胰高血糖素在溶液中化学和物理上都不稳定，因此不适用于双激素人工胰腺系统的临床开发。Biodel科学家已经制备了pH值为7的水型胰高血糖素的实验室配方，在溶液中保持稳定。在本应用中，Biodel建议优化多种pH值为7的胰高血糖素水溶液配方，以在冷藏条件下提供至少18个月的稳定性，如果可能的话，在室温（25℃）条件下长期储存。我们将评估是否所有现行的美国药典（USP）药典方法适用于这些制剂，如果需要，我们将开发合适的方法。我们将在猪模型中展示生物活性，我们将证明我们的配方在高温下与市场上销售的胰岛素泵系统兼容至少9天。