Development of concentrated and rapidly absorbed insulins for closed loop systems

描述（由申请人提供）：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，这种配方吸收缓慢，作用时间长，不适合有效的闭环胰岛素泵治疗。在这种情况下，需要一种吸收更快的浓缩胰岛素制剂，并且比目前的胰岛素制剂占用更少的体积。Biodel研究了重组人胰岛素的配方，设计用于在用餐时间超快速吸收。这些配方使用EDTA螯合锌原子，破坏重组人胰岛素六聚体的稳定。柠檬酸也被用来掩盖胰岛素分子的表面电荷，抑制单体的重新聚集，直接促进吸收。迄今为止的实验表明，EDTA/柠檬酸盐为基础的配方在高达400单位/毫升的浓度下仍可在5℃下保持溶解和稳定。在此应用中，Biodel建议优化多种pH为7的浓缩重组人胰岛素水溶液配方，以及U-100配方中的赋形剂，这些赋形剂已被证明具有超快速作用，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。我们将在糖尿病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兼容至少14天。

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.