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Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats

Dual‐hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogen...

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Autores principales: Maikawa, Caitlin L., Chen, Peyton C., Vuong, Eric T., Nguyen, Leslee T., Mann, Joseph L., d'Aquino, Andrea I., Lal, Rayhan A., Maahs, David M., Buckingham, Bruce A., Appel, Eric A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564421/
https://www.ncbi.nlm.nih.gov/pubmed/34499434
http://dx.doi.org/10.1002/advs.202101575
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author Maikawa, Caitlin L.
Chen, Peyton C.
Vuong, Eric T.
Nguyen, Leslee T.
Mann, Joseph L.
d'Aquino, Andrea I.
Lal, Rayhan A.
Maahs, David M.
Buckingham, Bruce A.
Appel, Eric A.
author_facet Maikawa, Caitlin L.
Chen, Peyton C.
Vuong, Eric T.
Nguyen, Leslee T.
Mann, Joseph L.
d'Aquino, Andrea I.
Lal, Rayhan A.
Maahs, David M.
Buckingham, Bruce A.
Appel, Eric A.
author_sort Maikawa, Caitlin L.
collection PubMed
description Dual‐hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co‐secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co‐formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra‐rapid action. The co‐formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co‐formulation result in increased insulin–pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co‐formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co‐formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co‐formulation will be well preserved in future translation to humans. Together these results suggest that the co‐formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.
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spelling pubmed-85644212021-11-09 Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats Maikawa, Caitlin L. Chen, Peyton C. Vuong, Eric T. Nguyen, Leslee T. Mann, Joseph L. d'Aquino, Andrea I. Lal, Rayhan A. Maahs, David M. Buckingham, Bruce A. Appel, Eric A. Adv Sci (Weinh) Research Articles Dual‐hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co‐secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co‐formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra‐rapid action. The co‐formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co‐formulation result in increased insulin–pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co‐formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co‐formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co‐formulation will be well preserved in future translation to humans. Together these results suggest that the co‐formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes. John Wiley and Sons Inc. 2021-09-09 /pmc/articles/PMC8564421/ /pubmed/34499434 http://dx.doi.org/10.1002/advs.202101575 Text en © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Maikawa, Caitlin L.
Chen, Peyton C.
Vuong, Eric T.
Nguyen, Leslee T.
Mann, Joseph L.
d'Aquino, Andrea I.
Lal, Rayhan A.
Maahs, David M.
Buckingham, Bruce A.
Appel, Eric A.
Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats
title Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats
title_full Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats
title_fullStr Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats
title_full_unstemmed Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats
title_short Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats
title_sort ultra‐fast insulin–pramlintide co‐formulation for improved glucose management in diabetic rats
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564421/
https://www.ncbi.nlm.nih.gov/pubmed/34499434
http://dx.doi.org/10.1002/advs.202101575
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