Development of concentrated and rapidly absorbed insulins for closed loop systems

描述（由申请方提供）：糖尿病患者的极端胰岛素抵抗定义为每日胰岛素剂量需求大于200单位。目前，U-500常规胰岛素经常用于治疗这些患者，然而，与该制剂相关的缓慢吸收和延长的作用持续时间并不适用于有效的闭环胰岛素泵治疗。在这种情况下，更快速吸收的浓缩胰岛素制剂将是期望的，并且将提供比当前胰岛素制剂占据更少体积的额外益处。Biodel研究了重组人胰岛素的配方，设计用于在进餐时间超快速吸收。这些制剂使用EDTA螯合锌原子，使重组人胰岛素六聚体不稳定。柠檬酸还用于掩蔽胰岛素分子上的表面电荷，抑制单体的再聚集并直接促进吸收。迄今为止的实验表明，浓度高达400单位/ml的EDTA/柠檬酸盐基制剂在5 ℃下保持可溶和稳定。在本申请中，Biodel建议优化浓缩重组人胰岛素与赋形剂的多种pH 7水性制剂，在U-100制剂中，赋形剂已被证明具有超快速作用，以在冷藏条件下提供至少18个月的稳定性。我们将确保所有现行美国药典（USP）药典方法适用于这些制剂，并将在需要时开发合适的方法。我们将在糖尿病猪模型中证明生物活性，并将证明我们的制剂与市售胰岛素泵系统相容至少14天。 公共卫生相关性：糖尿病患者的重度胰岛素抵抗定义为每日胰岛素剂量需求大于200单位。通常使用U-500常规胰岛素治疗，自2008年以来，其使用量几乎翻了一番。U-500与长时间达到峰值效应和延长的作用持续时间相关，这两者都使得其不适合用于泵，特别是在闭环胰岛素系统的设置中。在这种情况下，更快速吸收的浓缩胰岛素制剂将是理想的，并且将提供比目前的胰岛素制剂占用更少空间的额外益处。在该应用中，Biodel提出了一种策略，以开发用于胰岛素泵的具有更快吸收特性的浓缩胰岛素。

DESCRIPTION (provided by applicant): Extreme insulin resistance in patients with diabetes is defined as insulin dose requirement of greater than 200 units daily. Currently, U-500 regular insulin is frequently used to treat these patients, however, the slow absorption and prolonged duration of action associated with this formulation does not lend itself to effective closed loop insulin pump therapy. A more rapidly absorbed formulation of concentrated insulin would be desirable in this scenario and would provide the additional benefit of taking up less volume than current insulin preparations. Biodel has studied formulations of recombinant human insulin designed for ultra-rapid absorption at meal time. These formulations use EDTA to chelate zinc atoms, destabilizing recombinant human insulin hexamers. Citric acid is also used to mask surface charges on the insulin molecules inhibiting re-aggregation of monomers and directly facilitating absorption. Experiments to date have shown that EDTA/citrate based formulations at concentrations of up to 400 units/ml remain soluble and stable at 5¿C. In this application, Biodel proposes to optimize multiple pH 7 aqueous formulations of concentrated recombinant human insulin together with excipients which in U-100 formulations have been shown to be ultra-rapid acting, to provide a minimum of 18 month stability under refrigerated conditions. We will ensure that all current US Pharmacopeia (USP) compendia methods are applicable to these formulations and will develop suitable methods if required. We will demonstrate biological activity in a diabetic swine model and will demonstrate that our formulation is compatible with a marketed insulin pump system for at least 14 days. PUBLIC HEALTH RELEVANCE: Severe insulin resistance in patients with diabetes is defined as insulin dose requirement of greater than 200 units daily. This is usually treated with U-500 regular insulin, the use of which has nearly doubled since 2008. U-500 is associated with long period to peak effect and a prolonged duration of action, both of which make it not desirable for use in pumps, particularly in the setting of closed loop insulin systems. A more rapidly absorbed formulation of concentrated insulin would be desirable in this setting and would provide the additional benefit of taking up less space than current insulin preparations. In this application, Biodel proposes a strategy to develop concentrated insulin with more rapid absorption properties for use in insulin pumps.