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
- 来源:
- 关键词:AdolescentAdrenal Cortex HormonesBindingBiochemicalBiological AssayBlood capillariesBreast Cancer CellBudgetsCancer cell lineCell Culture TechniquesCharacteristicsChargeClinicalClinical ResearchCrystallizationDiabetes MellitusDisadvantagedDiscriminationDoseDrug FormulationsDrug KineticsElectrostaticsEngineeringEuglycemic ClampingExhibitsFamily suidaeFutureGlucose ClampGlycosylated hemoglobin AGray unit of radiation doseHealthHealth systemHourHumanHyperinsulinismHypoglycemiaInjection of therapeutic agentInsulinInsulin Infusion SystemsInsulin ReceptorInsulin ResistanceInsulin, Lispro, HumanInsulin-Dependent Diabetes MellitusInsulin-Like Growth Factor ReceptorIsophane InsulinKineticsLantusLasersLeadLeftLicensingLifeLipodystrophyMCF7 cellMediatingMembrane ProteinsMiniaturizationMinorityMitochondriaModelingMutagenesisNational Institute of Diabetes and Digestive and Kidney DiseasesNon-Insulin-Dependent Diabetes MellitusNude MiceObesityOctreotidePainPatientsPeer ReviewPharmacodynamicsPhasePhysical condensationPositioning AttributePreparationPreventionPropertyProteinsPumpRelative (related person)ResistanceSafetySecondary toShapesSignal TransductionSmall Business Innovation Research GrantSolubilitySolutionsSpeedSurfaceSyndromeTestingThermodynamicsTimeLineTrypsinUniversitiesZincabsorptionanalogbasecapillarycarcinogenesiscarcinogenicitycareercompliance behaviordesignexperienceglargineglycemic controlimprovedin vivoinnovationinsulin secretionlight scatteringmouse modelnovelpreventprogramsreceptorreceptor bindingsubcutaneousward
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(由申请人提供):我们寻求开发一种用于2型和1型糖尿病(T2DM和T1DM)患者的速效U-500胰岛素类似物制剂。这种新产品将改善两种情况下的治疗:(i)对于具有明显胰岛素抵抗的2型糖尿病患者(与“糖尿病”相关,继发于皮质类固醇治疗,线粒体糖尿病综合征MIDD或脂肪营养不良),速效U-500配方将增强餐或泵治疗的安全性,便利性和有效性,并且可以通过减少注射量相关的疼痛,提高患者的依从性;(ii)无胰岛素抵抗的患者(即大多数T1DM患者)或T2DM患者
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Bruce Hill Frank其他文献
Bruce Hill Frank的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
8511621 - 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:
8395099 - 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:














{{item.name}}会员




