Amphiphilic Polyacrylamide Excipients Lead to a Record-Breaking Fast-Acting Insulin

Fast-acting insulins are central to the regulation of prandial glucose in diabetic patients. Current fast-acting insulins require 20–30 min for the onset and longer for the peak blood concentrations. The recent work by Mann et al. used high-throughput synthesis and screening of polyacrylamide-based excipients to yield a formulation with pharmacokinetics that is faster than the currently available fast-acting insulins.

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See also the related recent work: An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients from Mann et al.:

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.

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Joseph L. Mann, Caitlin L. Maikawa, Anton A. A. Smith, Abigail K. Grosskopf, Sam W. Baker, Gillie A. Roth, Catherine M. Meis, Emily C. Gale, Celine S. Liong, Santiago Correa, Doreen Chan, Lyndsay M. Stapleton, Anthony C. Yu, Ben Muir, Shaun Howard, Almar Postma and Eric A. Appel
Science Translational Medicine 01 Jul 2020, Vol. 12, Issue 550, eaba6676
DOI: 10.1126/scitranslmed.aba6676