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Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues
Author(s) -
Maikawa Caitlin L.,
Smith Anton A. A.,
Zou Lei,
Meis Catherine M.,
Mann Joseph L.,
Webber Matthew J.,
Appel Eric A.
Publication year - 2020
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.201900094
Subject(s) - pegylation , insulin , monomer , chemistry , insulin lispro , supramolecular chemistry , excipient , insulin aspart , combinatorial chemistry , biochemistry , organic chemistry , medicine , hypoglycemia , polymer , chromatography , molecule , polyethylene glycol
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.