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

基本信息

批准号：
8388786
负责人：
Robert Hauser
金额：
$ 29.12万
依托单位：
BIODEL, INC.
依托单位国家：
美国
项目类别：
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/8388786
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

项目摘要

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.

描述（由适用提供）：糖尿病患者的极端胰岛素抵抗定义为每天大于200单位的胰岛素剂量需求。目前，U-500常规胰岛素经常用于治疗这些患者，但是，与该配方相关的损失缓慢且作用持续时间延长并不能使其自身用于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式，并且将提供比当前胰岛素制剂更少的额外好处。 Biodel研究了重组人类胰岛素的配方，旨在在膳食时吸收超增生。这些公式使用EDTA来樱桃锌原子，破坏了重组人类胰岛素六聚物的稳定。柠檬酸还用于掩盖抑制单体重新聚集并直接促进抽象的胰岛素分子上的表面电荷。 Experiments to date have shown that EDTA/citrate based formulas at concentrations of up to 400 units/ml remain solid and stable at 5¿ C. In this application, Biodel proposals to optimize multiple pH 7 aqueous formulas of concentrated recombinant human insulin together with excipients which in U-100 formulas have been shown to be ultra-rapid acting, to provide a minimum of 18 months stability under refrigerated conditions.我们将确保所有当前的美国药物（USP）汇编方法适用于这些公式，并在需要时开发合适的方法。我们将在糖尿病猪模型中展示生物学活性，并将证明我们的配方至少与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定义为每天超过200个单位的胰岛素剂量需求。这通常是用U-500常规胰岛素治疗的，自2008年以来的使用几乎翻了一番。U-500与长期峰值效应和延长的作用持续时间有关，这两者都不希望在泵中使用，尤其是在闭合Loop胰岛素系统的情况下。在这种情况下，需要更快速吸收的浓缩胰岛素式，并提供比当前胰岛素制剂更少的空间的额外好处。在此应用中，Biodel提出了一种策略，以开发具有更快吸收特性的浓缩胰岛素以用于胰岛素泵。