Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues

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DOI

  • Caitlin L. Maikawa, Stanford Univ, Stanford University, Dept Bioengn
  • ,
  • Anton A. A. Smith
  • Lei Zou, University of Notre Dame
  • ,
  • Catherine M. Meis, Stanford Univ, Stanford University, Dept Mat Sci & Engn
  • ,
  • Joseph L. Mann, Stanford Univ, Stanford University, Dept Mat Sci & Engn
  • ,
  • Matthew J. Webber, University of Notre Dame
  • ,
  • Eric A. Appel, Stanford Univ, Stanford University, Dept Pediat Endocrinol

Current "fast-acting" insulin analogues contain amino acid modifications meant to inhibit dimer formation and shift the equilibrium of association states toward the monomeric state. However, the insulin monomer is highly unstable and current formulation techniques require insulin to primarily exist as hexamers to prevent aggregation into inactive and immunogenic amyloids. Insulin formulation excipients have thus been traditionally selected to promote insulin association into the hexameric form to enhance formulation stability. This study exploits a novel excipient for the supramolecular PEGylation of insulin analogues, including aspart and lispro, to enhance the stability and maximize the prevalence of insulin monomers in formulation. Using multiple techniques, it is demonstrated that judicious choice of formulation excipients (tonicity agents and parenteral preservatives) enables insulin analogue formulations with 70-80% monomer and supramolecular PEGylation imbued stability under stressed aging for over 100 h without altering the insulin association state. Comparatively, commercial "fast-acting" formulations contain less than 1% monomer and remain stable for only 10 h under the same stressed aging conditions. This simple and effective formulation approach shows promise for next-generation ultrafast insulin formulations with a short duration of action that can reduce the risk of post-prandial hypoglycemia in the treatment of diabetes.

OriginalsprogEngelsk
Artikelnummer1900094
TidsskriftAdvanced Therapeutics
Vol/bind3
Sider (fra-til)1900094 1-9
Antal sider9
ISSN2366-3987
DOI
StatusUdgivet - 2020

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