An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients

Monomeric insulin stabilized with polymeric excipient exhibits increased stability and faster pharmacokinetics than current rapid-acting insulins. Faster formulations People with type 1 diabetes require exogenous insulin to regulate blood glucose, but controlling glycemic excursions at mealtimes is difficult using current insulin formulations. Mann et al. developed polymeric excipients to reduce insulin aggregation and improve pharmacokinetics. When formulated with insulin lispro, the top-performing acrylamide carrier/dopant copolymer excipient enabled fast insulin absorption upon subcutaneous delivery in diabetic pigs and improved stability in response to stressed aging conditions as compared to commercial fast-acting insulin lispro. This rapidly absorbed insulin formulation could improve glucose control for diabetes. 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.