Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues

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Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues. / Maikawa, Caitlin L.; Smith, Anton A. A.; Zou, Lei; Meis, Catherine M.; Mann, Joseph L.; Webber, Matthew J.; Appel, Eric A.

I: Advanced Therapeutics, Bind 3, Nr. 1, 1900094, 2020.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Maikawa, CL, Smith, AAA, Zou, L, Meis, CM, Mann, JL, Webber, MJ & Appel, EA 2020, 'Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues', Advanced Therapeutics, bind 3, nr. 1, 1900094. https://doi.org/10.1002/adtp.201900094

APA

Maikawa, C. L., Smith, A. A. A., Zou, L., Meis, C. M., Mann, J. L., Webber, M. J., & Appel, E. A. (2020). Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues. Advanced Therapeutics, 3(1), [1900094]. https://doi.org/10.1002/adtp.201900094

CBE

Maikawa CL, Smith AAA, Zou L, Meis CM, Mann JL, Webber MJ, Appel EA. 2020. Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues. Advanced Therapeutics. 3(1):Article 1900094. https://doi.org/10.1002/adtp.201900094

MLA

Vancouver

Maikawa CL, Smith AAA, Zou L, Meis CM, Mann JL, Webber MJ o.a. Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues. Advanced Therapeutics. 2020;3(1). 1900094. https://doi.org/10.1002/adtp.201900094

Author

Maikawa, Caitlin L. ; Smith, Anton A. A. ; Zou, Lei ; Meis, Catherine M. ; Mann, Joseph L. ; Webber, Matthew J. ; Appel, Eric A. / Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues. I: Advanced Therapeutics. 2020 ; Bind 3, Nr. 1.

Bibtex

@article{c8596c88fb324056aaa91a4faf20edd5,
title = "Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues",
abstract = "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.",
keywords = "diabetes, drug delivery, insulin, PEGylation, polymers, supramolecular, SELF-ASSOCIATION, AQUEOUS-SOLUTION, PRAMLINTIDE, TYPE-1, RECOGNITION, FIBRILLATION, THERAPIES, STABILITY, MECHANISM, PEPTIDES",
author = "Maikawa, {Caitlin L.} and Smith, {Anton A. A.} and Lei Zou and Meis, {Catherine M.} and Mann, {Joseph L.} and Webber, {Matthew J.} and Appel, {Eric A.}",
year = "2020",
doi = "10.1002/adtp.201900094",
language = "English",
volume = "3",
journal = "Advanced Therapeutics",
issn = "2366-3987",
publisher = "Wiley",
number = "1",

}

RIS

TY - JOUR

T1 - Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues

AU - Maikawa, Caitlin L.

AU - Smith, Anton A. A.

AU - Zou, Lei

AU - Meis, Catherine M.

AU - Mann, Joseph L.

AU - Webber, Matthew J.

AU - Appel, Eric A.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - diabetes

KW - drug delivery

KW - insulin

KW - PEGylation

KW - polymers

KW - supramolecular

KW - SELF-ASSOCIATION

KW - AQUEOUS-SOLUTION

KW - PRAMLINTIDE

KW - TYPE-1

KW - RECOGNITION

KW - FIBRILLATION

KW - THERAPIES

KW - STABILITY

KW - MECHANISM

KW - PEPTIDES

U2 - 10.1002/adtp.201900094

DO - 10.1002/adtp.201900094

M3 - Journal article

C2 - 32190729

VL - 3

JO - Advanced Therapeutics

JF - Advanced Therapeutics

SN - 2366-3987

IS - 1

M1 - 1900094

ER -