Development of concentrated and rapidly absorbed insulins for closed loop systems

开发用于闭环系统的浓缩且快速吸收的胰岛素

• 批准号: 8514596
• 负责人: Roderike Pohl
• 金额: $ 29.12万
• 依托单位: BIODEL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514596
• 关键词: Agitation; Algorithms; American; Area; Artificial Pancreas; Biological; Biological Assay; Blood Glucose; Body Temperature; Charge; Chemicals; Citrates; Citric Acid; Clinical Research; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Dose; Drug Formulations; Drug Kinetics; Edetic Acid; Ensure; Excipients; Exercise; Family suidae; Future; Gel; High Pressure Liquid Chromatography; Hour; Human; Individual; Infusion Pumps; Infusion procedures; Injectable; Injection of therapeutic agent; Insulin; Insulin Infusion Systems; Insulin Resistance; Laboratories; Lead; Light; Link; Marketing; Masks; Measures; Methods; Modeling; Molecular Weight; Patients; Pharmacodynamics; Pharmacopoeias; Phase; Plasma; Preparation; Property; Proteins; Pump; Qualifying; Recombinant DNA; Recombinants; Research; Sampling; Scientist; Solutions; Surface; Syringes; System; Testing; Time; Touch sensation; Zinc; absorption; analytical method; aqueous; base; design; diabetes control; diabetic; glucose sensor; glycemic control; improved; meetings; monomer; non-diabetic; particle; prospective; research study; response; success; therapeutic target; type I and type II diabetes

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.

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超过 200 单位。目前，U-500常规胰岛素经常用于治疗这些患者，然而，与该制剂相关的吸收缓慢和作用持续时间延长并不适合有效的闭环胰岛素泵治疗。在这种情况下，需要更快速吸收的浓缩胰岛素制剂，并且将提供比现有胰岛素制剂占用更少体积的额外益处。 Biodel 研究了专为进餐时超快速吸收而设计的重组人胰岛素配方。这些制剂使用 EDTA 螯合锌原子，从而破坏重组人胰岛素六聚体的稳定性。柠檬酸还用于掩盖胰岛素分子的表面电荷，抑制单体的重新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°C 下仍然可溶且稳定。在此应用中，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 制剂中已显示出超快速作用，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) 药典方法均适用于这些制剂，并将根据需要开发合适的方法。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售胰岛素泵系统兼容至少 14 天。