Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co-formulation result in increased insulin–pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co-formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co-formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.

中文翻译：

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超快速胰岛素-普兰林肽复合制剂可改善糖尿病大鼠的血糖管理

1 型糖尿病患者使用胰岛素和胰淀素双激素替代疗法有可能改善血糖管理。不幸的是，目前可用的制剂需要在进餐时进行繁琐的单独注射，并且具有不同的药代动力学，不能模拟内源性共同分泌。在这里，两亲性丙烯酰胺共聚物用于创建单体胰岛素和胰淀素类似物（赖脯胰岛素和普兰林肽）的稳定复合制剂，具有同步药代动力学和超快速作用。该复合制剂在应激老化条件下可稳定超过 16 小时，而商业赖脯胰岛素 (Humalog) 在 8 小时内即可聚集。该复合制剂中单体胰岛素的药代动力学更快，导致胰岛素-普兰林肽重叠增加 75 ± 6%，而单独注射的重叠仅为 47 ± 7%。与单独递送的普兰林肽相比，复合制剂导致类似的胃排空延迟。在大鼠的葡萄糖挑战中，与单独施用胰岛素或单独施用胰岛素和普兰林肽相比，复合制剂减少了与基线血糖的偏差。此外，单体普兰林肽的种间药代动力学比较表明，在复合制剂中观察到的药代动力学在未来应用于人类时将得到很好的保留。这些结果共同表明，复合制剂有可能改善进餐时血糖管理并减轻糖尿病治疗中的患者负担。