Development of novel and stable glucagon formulations for closed loop systems

描述(申请人提供)：一种设备系统，它通过对连续检测到的血糖浓度数据做出反应，通过给药胰岛素来自动将血糖浓度维持在正常范围内，这代表了一种现代尝试，即机械模拟正常的β细胞生理，并解决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。通过算法将连续的血糖传感器与胰岛素输注泵连接起来，开发这样的“闭环”人工胰腺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，需要碳水化合物注射的低血糖并未通过多种实验算法被消除。仅使用胰岛素的人工胰腺方法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到来的低血糖。这种只有胰岛素的AP系统对葡萄糖浓度下降做出反应的唯一方法是减少或停止皮下注射胰岛素。这并不能保证胰岛素效应的迅速终止，部分原因是皮下腔内残留的胰岛素。在正常生理条件下，胰腺阿尔法细胞会分泌高血糖素来对抗胰岛素的降糖作用。其中一种逆调节激素是胰高血糖素，它是一种由29个氨基酸组成的多肽，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表明，血糖控制良好，低血糖发生率很低。在这些研究中，胰升糖素也被用于算法预防低血糖。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科学家已经制备了在pH为7的情况下保持溶液稳定的含水胰高血糖素的实验室配方。在这一应用中，Biodel建议优化多个pH为7的胰高血糖素水溶液配方，以便在冷藏和室温(如果可能的话)条件下提供至少18个月的稳定性，以满足长期储存要求。我们将评估是否所有当前的美国药典(USP)药典方法都适用于这些制剂，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，并将证明我们的配方与市场上销售的胰岛素泵系统在高温下至少9天是兼容的。

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.