Development of concentrated and rapidly absorbed insulins for closed loop systems

描述(申请人提供)：糖尿病患者的极端胰岛素抵抗定义为每天需要超过200个单位的胰岛素剂量。目前，U-500常规胰岛素经常用于治疗这些患者，然而，与该制剂相关的吸收缓慢和持续时间长的特点不利于有效的闭环式胰岛素泵疗法。在这种情况下，较快吸收的浓缩胰岛素制剂将是可取的，并且将提供比目前的胰岛素制剂占用的体积更少的额外好处。Biodel研究了用于在进餐时超快速吸收的重组人胰岛素的配方。这些制剂使用EDTA来螯合锌原子，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表面的电荷，抑制单体的重新聚集，并直接促进吸收。到目前为止的实验表明，EDTA/柠檬酸盐配方在浓度高达400个单位/毫升时仍保持溶解并在5℃下稳定。在这一应用中，Biodel建议优化多个pH为7的浓缩重组人胰岛素水溶液配方以及已被证明在U-100配方中具有超快速作用的赋形剂，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的美国药典(USP)药典方法都适用于这些制剂，并将在必要时开发合适的方法。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。 公共卫生相关性：糖尿病患者的严重胰岛素抵抗被定义为每天需要超过200单位的胰岛素剂量。这通常是用U-500常规胰岛素治疗的，自2008年以来，U-500的使用量几乎翻了一番。U-500具有较长的峰值效应周期和较长的作用持续时间，这两种情况都使其不适合用于泵，特别是在设置闭合环路胰岛素系统时。在这种情况下，更快吸收的浓缩胰岛素制剂将是可取的，并将提供比目前的胰岛素制剂占用更少空间的额外好处。在这项申请中，Biodel提出了一种策略，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.