Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput–controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.

胰岛素已被用于治疗糖尿病近100年。但是，目前的速效胰岛素制剂尚没有足够快的药代动力学来维持进餐时严格的血糖控制。速溶制剂中胰岛素的主要缔合状态即胰岛素六聚体的解离是限速步骤，可导致起效延迟和作用时间延长。胰岛素单体的制剂将更紧密地模拟内源性餐后胰岛素的分泌，但是使用目前的制剂策略，单体胰岛素在溶液中是不稳定的并且迅速聚集为淀粉样蛋白原纤维。在这里，我们采用高通量控制的自由基聚合技术来生成旨在减少胰岛素聚集的大型丙烯酰胺载体/掺杂剂共聚物（AC / DC）赋形剂库。我们性能最佳的AC / DC赋形剂候选人使开发超快吸收的赖脯胰岛素（UFAL）制剂成为可能，该制剂在紧张的老化条件下可稳定保持25±1小时，而商用速效赖脯胰岛素制剂为5±2小时（Humalog）。在胰岛素缺乏型糖尿病的猪模型中，UFAL在9±4分钟时表现出峰值作用，而商业Humalog在25±10分钟时表现出峰值作用。这些超快的动力学特性使UFAL成为改善血糖控制和减轻糖尿病患者负担的有希望的候选者。在胰岛素缺乏型糖尿病的猪模型中，UFAL在9±4分钟时表现出峰值作用，而商业Humalog在25±10分钟时表现出峰值作用。这些超快的动力学特性使UFAL成为改善血糖控制和减轻糖尿病患者负担的有希望的候选者。在胰岛素缺乏型糖尿病的猪模型中，UFAL在9±4分钟时表现出峰值作用，而商业Humalog在25±10分钟时表现出峰值作用。这些超快的动力学特性使UFAL成为改善血糖控制和减轻糖尿病患者负担的有希望的候选者。