Hexalog: A Rapid-Acting Ultra-Concentrated Insulin Formulation

Hexalog:速效超浓缩胰岛素制剂

基本信息

  • 批准号:
    8592724
  • 负责人:
  • 金额:
    $ 16.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-01 至 2016-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): We seek to develop a rapid-acting U-500 insulin analog formulation for patients with Type 2 and Type 1 diabetes mellitus (T2DM and T1DM). Such a novel product would improve treatment in two contexts: (i) for T2DM patients with marked insulin resistance (as associated with "diabesity," secondary to corticosteroid treatment, the mitochondrial diabetes syndrome MIDD, or lipodystrophies), a rapid-acting U-500 formulation would enhance safety, convenience, and efficacy of prandial or pump therapy and could, by reducing injection volume- associated pain, improve patient compliance; (ii) for patients without insulin resistance (i.e., the majority of patients with T1DM) or for T2DM patients who want the convenience of a patch-pump, a rapid acting U-500 formulation would extend by fivefold the reservoir life of current disposable pumps and/or would enable miniaturization of these disposable pumps without decreasing reservoir life. An innovative structural approach is proposed based on "electrostatic engineering." Only a single U-500 product is currently available (Lilly Humulin R U-500, containing wild-type human insulin); its pharmacokinetic and pharmacodynamic (PK/PD) properties are so prolonged that they resemble U- 100 NPH insulin. Experimental U-500 versions of Humalog likewise exhibit prolonged PK/PD and so are suboptimal for prandial or pump use. The key barrier to design of a rapid-acting U-500 formulation is posed by concentration-dependent hexamer-hexamer interactions. Such interactions retard disassembly of insulin hexamers in the subcutaneous depot and so block capillary absorption. The insulin hexamer is doughnut-shaped. Linear stacking of successive hexamers (the predominant mode of crystal packing) is mediated by trimer-related protein surfaces at the top and bottom of the doughnut. We have discovered that a rapid-acting U-500 formulation (designated Hexalog-1) is made possible by combining the "lispro" substitutions of Humalog? with a two-residue acidic extension of the B-chain: residues GluB31 and GluB32. Compatible with native potency, these negative charges are positioned to cause electrostatic repulsion between opposing hexamer surfaces. As a further potential benefit, the acidic extension (opposite in charge from the ArgB31-ArgB32 extension in the reportedly mitogenic basal analog insulin glargine; Lantus?) reduces cross-binding to the mitogenic IGF receptor. Speed of disassembly may be further enhanced by an optional chloro-aromatic substitution at the para position of PheB24 (Hexalog-Cl). Dr. B. Frank (PI) was co-inventor of Humalog? during his prior career at Eli Lilly. Thermalin Diabetes, LLC has an exclusive license to U500- related IP, which is owned by CWRU. Project Description
描述(由申请方提供):我们寻求开发一种用于2型和1型糖尿病(T2 DM和T1 DM)患者的速效U-500胰岛素类似物制剂。这种新产品将在两种情况下改善治疗:(i)对于具有显著胰岛素抵抗的T2 DM患者,(与继发于皮质类固醇治疗的“糖尿病”、线粒体糖尿病综合征MIDD或脂肪营养不良相关),速效U-500制剂将增强膳食或泵疗法的安全性、便利性和功效,并且可以通过减少注射体积相关的疼痛,改善患者依从性;(ii)对于没有胰岛素抵抗的患者(即,大多数T1 DM患者)或T2 DM患者 想要贴片泵的便利性的人,快速作用U-500制剂将使当前一次性泵的贮存器寿命延长五倍和/或将使这些一次性泵能够小型化而不降低贮存器寿命。提出了一种基于“静电工程学”的结构设计方法。“目前只有一种U-500产品可用(礼来优泌林R U-500,含有野生型人胰岛素);其药代动力学和药效学(PK/PD)特性如此之长,以至于它们类似于U- 100 NPH胰岛素。实验性U-500版本的Humanoid同样表现出延长的PK/PD,因此对于餐时或泵使用而言是次优的。设计速效U-500制剂的关键障碍是浓度依赖性六聚体-六聚体相互作用。这种相互作用延缓了皮下贮库中胰岛素六聚体的分解,从而阻断了毛细血管的吸收。胰岛素六聚体呈甜甜圈状。连续六聚体的线性堆积(晶体堆积的主要模式)是由甜甜圈顶部和底部的三聚体相关蛋白质表面介导的。我们已经发现,一种快速作用的U-500制剂(命名为Hexadectin-1)是可能的,通过结合“赖脯氨酸”取代Humadectin?具有B链的两个残基酸性延伸:残基GluB 31和GluB 32。与天然效力相容,这些负电荷被定位以在相对的六聚体表面之间引起静电排斥。作为进一步的潜在获益,酸性延伸(与报告的促有丝分裂基础类似物甘精胰岛素;来得时?中ArgB 31-ArgB 32延伸的电荷相反)减少与促有丝分裂IGF受体的交叉结合。通过在PheB 24的帕拉(Hexalog-Cl)处任选的氯代芳族取代可以进一步提高分解速度。B医生。弗兰克(PI)是Humanitarian的共同发明者。他在礼来公司的职业生涯。Thermalin Diabetes,LLC拥有U 500相关知识产权的独家许可,该知识产权归CWRU所有。项目描述

项目成果

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Bruce Hill Frank其他文献

Bruce Hill Frank的其他文献

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{{ truncateString('Bruce Hill Frank', 18)}}的其他基金

Enabling implantable artificial pancreas pumps with heat-stable, ultra-rapid insulin
使用热稳定、超快速胰岛素实现植入式人工胰腺泵
  • 批准号:
    9185181
  • 财政年份:
    2016
  • 资助金额:
    $ 16.48万
  • 项目类别:
Optimizing diabetes therapy: re-engineering insulin as a biased agonist
优化糖尿病治疗:将胰岛素重新设计为偏向激动剂
  • 批准号:
    8981741
  • 财政年份:
    2015
  • 资助金额:
    $ 16.48万
  • 项目类别:
Optimizing diabetes therapy: re-engineering insulin as a biased agonist
优化糖尿病治疗:将胰岛素重新设计为偏向激动剂
  • 批准号:
    9464064
  • 财政年份:
    2015
  • 资助金额:
    $ 16.48万
  • 项目类别:
An Ultra-Stable Insulin Analog with Intrinsic Basal-Bolus Action
具有内在基础推注作用的超稳定胰岛素类似物
  • 批准号:
    8780579
  • 财政年份:
    2014
  • 资助金额:
    $ 16.48万
  • 项目类别:
Novel Design of a Fast-On/Fast-Off Insulin Analog for Closed-Loop Systems
用于闭环系统的快速启动/快速关闭胰岛素模拟物的新颖设计
  • 批准号:
    8592770
  • 财政年份:
    2013
  • 资助金额:
    $ 16.48万
  • 项目类别:
Manipulating Aromaticity: characterization of an ultra-rapid insulin analog
控制芳香度:超快速胰岛素类似物的表征
  • 批准号:
    8395099
  • 财政年份:
    2012
  • 资助金额:
    $ 16.48万
  • 项目类别:
Manipulating Aromaticity: characterization of an ultra-rapid insulin analog
控制芳香度:超快速胰岛素类似物的表征
  • 批准号:
    8511621
  • 财政年份:
    2012
  • 资助金额:
    $ 16.48万
  • 项目类别:
Fluorolog: A Rapid-Acting Ultra-Concentrated Insulin Formulation
Fluorolog:一种速效超浓缩胰岛素制剂
  • 批准号:
    8645450
  • 财政年份:
    2011
  • 资助金额:
    $ 16.48万
  • 项目类别:
Optimized Receptor Binding Profile in an Ultra-Stable, Ultra-Rapid-Acting Insulin
超稳定、超速效胰岛素中优化的受体结合特性
  • 批准号:
    8124625
  • 财政年份:
    2011
  • 资助金额:
    $ 16.48万
  • 项目类别:
Chlorolog: Production Scaling and Testing of a Fast-Acting, Ultra-stable Insulin
Chlorolog:速效、超稳定胰岛素的生产规模和测试
  • 批准号:
    8640167
  • 财政年份:
    2010
  • 资助金额:
    $ 16.48万
  • 项目类别:
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