2. Academic Validation
  3. An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients

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

  • Sci Transl Med. 2020 Jul 1;12(550):eaba6676. doi: 10.1126/scitranslmed.aba6676.
Joseph L Mann 1,  Caitlin L Maikawa 2,  Anton A A Smith 1 3,  Abigail K Grosskopf 4,  Sam W Baker 5,  Gillie A Roth 2,  Catherine M Meis 1,  Emily C Gale 6,  Celine S Liong 2,  Santiago Correa 1,  Doreen Chan 7,  Lyndsay M Stapleton 2,  Anthony C Yu 1,  Ben Muir 8,  Shaun Howard 8,  Almar Postma 8,  Eric A Appel 9 2 10 11
Affiliations

Affiliations

  • 1 Department of Materials Science and Engineering, Stanford University, Stanford, CA 94025, USA.
  • 2 Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • 3 Department of Science and Technology, Aarhus University, 8000 Aarhus, Denmark.
  • 4 Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
  • 5 Department of Comparative Medicine, Stanford University, Palo Alto, CA 94305, USA.
  • 6 Department of Biochemistry, Stanford University, Palo Alto, CA 94305, USA.
  • 7 Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
  • 8 CSIRO Manufacturing, Clayton, VIC 3168, Australia.
  • 9 Department of Materials Science and Engineering, Stanford University, Stanford, CA 94025, USA. eappel@stanford.edu.
  • 10 ChEM-H Institute, Stanford University, Stanford, CA 94305, USA.
  • 11 Department of Pediatrics (Endocrinology), Stanford University, Stanford, CA 94305, USA.
PMID: 32611683 DOI: 10.1126/scitranslmed.aba6676
Abstract

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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