Halogenated Insulin: a fast-acting, ultra stable analog.

描述（由申请人提供）：提出了一种用于治疗糖尿病的新型速效胰岛素类似物的临床前开发1期SBIR项目。我们的产品被命名为胰岛素- cl，是胰岛素lispro （HumalogTM的活性成分）的衍生物，在b链上保守的苯丙氨酸（PheB24）的芳香环上含有一个单氯取代。胰岛素- cl保留残基B28和B29的交换（替换为ProB28）。lyss和LysB29。Pro)赋予HumalogTM在皮下注射后的快速吸收。胰岛素- cl为患者提供了以下潜在优势：(1)更长的保质期和在室温以上的温度下降解的稳定性；和（ii）可能的配方作为无锌溶液，以提供超快速吸收。目前的餐时胰岛素类似物，如HumalogTM和NovalogTM不如人胰岛素稳定，必须配制成锌胰岛素六聚体；因此，吸收原则上不如无锌配方提供的吸收速度快。在与葡萄糖传感器耦合的闭环“智能泵”中，胰岛素- cl的超快速吸收可能为患者提供额外的便利，并增强了安全性。我们试图测试胰岛素- cl的候选配方，并在动物模型中评估其体内效力和药代动力学。胰岛素- cl是凯斯西储大学发明的，目前正在Thermalin糖尿病公司的许可下进行开发。首席研究员是胰岛素lispro的共同发明人，他在胰岛素配方的药物研究方面有40年的经验。

DESCRIPTION (provided by applicant): A Phase 1 SBIR program of pre-clinical development is proposed focusing on a novel rapid-acting insulin analog for the treatment of diabetes mellitus. Designated Insulin-Cl, our product is a derivative of insulin lispro (the active component of HumalogTM) containing a single chloro-substitution within the aromatic ring of a conserved phenylalanine in the B-chain (PheB24). Insulin-Cl retains the interchange of residues B28 and B29 (substitutions ProB28 .Lys and LysB29.Pro) that confers upon HumalogTM its rapid absorption following subcutaneous injection. Insulin-Cl offers to patients the potential advantages of (i) greater shelf life and stability to degradation at temperatures above room temperature; and (ii) possible formulation as a zinc-free solution to provide ultra- rapid absorption. Current meal-time insulin analogs such as HumalogTM and NovalogTM are less stable than human insulin and must be formulated as zinc insulin hexamers; as a consequence, absorption is in principle not as rapid as could be provided by a zinc-free formulation. Ultra-rapid absorption of Insulin-Cl may offer added patient convenience and also enhanced safety in closed-loop "smart pumps" coupled to glucose sensors. We seek to test candidate formulations of Insulin-Cl and to assess its in vivo potency and pharmacokinetics in animal models. Insulin-Cl was invented at Case Western Reserve University and is being developed under license to Thermalin Diabetes, Inc. The principal investigator, who brings to this application four decades of experience in pharmacetical studies of insulin formulations, was co-inventor of insulin lispro. PUBLIC HEALTH RELEVANCE: Diabetes is an increasingly prevalent disease in the developed and developing worlds; patients seek greater convenience, improved glycemic control, and fewer adverse side-effects, all of which result in greater compliance and lower healthcare costs. This project will complete pre- clinical development of Insulin-Cl, a potentially ultra-stable and ultra-rapid acting insulin analog which could conveniently be stored without refrigeration and taken closer to meal time and could cause less post-meal glucose deficiency.