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Rapid-acting and human insulins

  • Purpose: Comparison of the dissociation kinetics of rapid-acting insulins lispro, aspart, glulisine and human insulin under physiologically relevant conditions. Methods: Dissociation kinetics after dilution were monitored directly in terms of the average molecular mass using combined static and dynamic light scattering. Changes in tertiary structure were detected by near-UV circular dichroism. Results: Glulisine forms compact hexamers in formulation even in the absence of Zn2+. Upon severe dilution, these rapidly dissociate into monomers in less than 10 s. In contrast, in formulations of lispro and aspart, the presence of Zn2+ and phenolic compounds is essential for formation of compact R6 hexamers. These slowly dissociate in times ranging from seconds to one hour depending on the concentration of phenolic additives. The disadvantage of the long dissociation times of lispro and aspart can be diminished by a rapid depletion of the concentration of phenolic additives independent of the insulin dilution. This is especiallyPurpose: Comparison of the dissociation kinetics of rapid-acting insulins lispro, aspart, glulisine and human insulin under physiologically relevant conditions. Methods: Dissociation kinetics after dilution were monitored directly in terms of the average molecular mass using combined static and dynamic light scattering. Changes in tertiary structure were detected by near-UV circular dichroism. Results: Glulisine forms compact hexamers in formulation even in the absence of Zn2+. Upon severe dilution, these rapidly dissociate into monomers in less than 10 s. In contrast, in formulations of lispro and aspart, the presence of Zn2+ and phenolic compounds is essential for formation of compact R6 hexamers. These slowly dissociate in times ranging from seconds to one hour depending on the concentration of phenolic additives. The disadvantage of the long dissociation times of lispro and aspart can be diminished by a rapid depletion of the concentration of phenolic additives independent of the insulin dilution. This is especially important in conditions similar to those after subcutaneous injection, where only minor dilution of the insulins occurs. Conclusion: Knowledge of the diverging dissociation mechanisms of lispro and aspart compared to glulisine will be helpful for optimizing formulation conditions of rapid-acting insulins.show moreshow less

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Metadaten
Author:Klaus Gast, Anja SchülerGND, Martin Wolff, Anja Thalhammer, Harald Berchtold, Norbert NagelGND, Gudrun Lenherr, Gerrit Hauck, Robert SecklerORCiDGND
URN:urn:nbn:de:kobv:517-opus4-431572
DOI:https://doi.org/10.25932/publishup-43157
ISSN:1866-8372
Parent Title (German):Postprints der Universität Potsdam Mathematisch-Naturwissenschaftliche Reihe
Subtitle (English):hexamer dissociation kinetics upon dilution of the pharmaceutical formulation
Series (Serial Number):Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe (795)
Document Type:Postprint
Language:English
Date of first Publication:2019/12/16
Year of Completion:2017
Publishing Institution:Universität Potsdam
Release Date:2019/12/16
Tag:circular dichroism; dissociation kinetics; insulin analog; light scattering; rapid-acting
Issue:795
Pagenumber:17
First Page:2270
Last Page:2286
Source:Pharmaceutical Research 34 (2017) 11, S. 2270–2286 DOI: 10.1007/s11095-017-2233-0
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Peer Review:Referiert
Publication Way:Open Access
Licence (German):License LogoCreative Commons - Namensnennung, 4.0 International