ISSN:
1573-904X
Keywords:
monomeric insulin analogs
;
analytical ultracentrifugation
;
peptide formulation
;
insulin association
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. The purpose of the current study was to investigate the effects of two important excipients, zinc and m-cresol, on the self-association properties of a series of monomeric insulin analogs. In this way, the effects on formulation behavior of individual amino acid substitutions in the C-terminal region of the insulin B-chain could be compared. Methods. The self-association of ten insulin analogs was monitored by equilibrium and velocity analytical ultracentrifugation under three different conditions: (i) in neutral buffer alone; (ii) in neutral buffer containing zinc ion; and (iii) in neutral buffer containing both zinc ion and phenolic preservative (a typical condition for insulin formulations). The self-association properties of these analogs were compared to those of human insulin and the rapid-acting insulin analog LysB28ProB29-human insulin. Results. The analogs in the current study exhibited a wide range of association properties when examined in neutral buffer alone or in neutral buffer containing zinc ion. However, all of these analogs had association properties similar to human insulin in the presence of both zinc and m-cresol. Under these formulation conditions each analog had an apparent sedimentation coefficient of s* = 2.9−3.1 S, which corresponds to the insulin hexamer. Conclusions. Analogs with changes in the B27−B29 region of human insulin form soluble hexamers in the presence of both zinc and m-cresol, and m-cresol binding overrides the otherwise destabilizing effects of these mutations on self assembly.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1011961923870
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