Intrinsic Fibrillation of Fast-Acting Insulin Analogs

BD Technologies, Durham, North Carolina 27709, USA.
Journal of diabetes science and technology 03/2012; 6(2):265-76. DOI: 10.1177/193229681200600209
Source: PubMed


Background: Aggregation of insulin into insoluble fibrils (fibrillation) may lead to complications for diabetes patients such as reduced insulin potency, occlusion of insulin delivery devices, or potentially increased immunological potential. Even after extensive investigation of fibril formation in regular human insulin, there are little published data about the intrinsic fibrillation of fast-acting analogs. This article investigates and compares the intrinsic fibrillation of three fast-acting insulin analogs—lispro, aspart, and glulisine—as a function of their primary protein structure and exclusive of the stabilizing excipients that are added to their respective commercial formulations.

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    ABSTRACT: We review and summarize the literature on the safety and stability of rapid-acting insulin analogs used for continuous subcutaneous insulin infusion (CSII) in patients with diabetes. Two predefined search strategies were systematically implemented to search Medline and the Cochrane Register of Clinical Trials for publications between 1996 and 2012. Twenty studies were included in the review: 13 in vitro studies and 7 clinical studies. In vitro studies investigated the effects of extreme CSII conditions (high temperature and mechanical agitation) on the risk of catheter occlusions and insulin stability factors, such as potency, purity, high molecular weight protein content, pH stability, and preservative content (m-cresol, phenol). Under these conditions, the overall stability of rapid-acting insulin analogs was similar for insulin lispro, insulin aspart, and insulin glulisine, although insulin glulisine showed greater susceptibility to insulin precipitation and catheter occlusions. A limited number of clinical trials were identified; this evidence-based information suggests that the rate of catheter occlusions in patients with type 1 diabetes using CSII treatment may vary depending on the rapid-acting analog used. Based on a limited amount of available data, the safety, stability, and performance of the three available rapid-acting insulin analogs available for use with CSII were similar. However, there is limited evidence suggesting that the risk of occlusion may vary with the insulin preparation under certain circumstances.
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    ABSTRACT: Lag period is an inherent characteristic of the kinetic curves registered for protein aggregation. The appearance of a lag period is connected with the nucleation stage and the stages of the formation of folding or unfolding intermediates prone to aggregation (for example, the stage of protein unfolding under stress conditions). Discovering the kinetic regularities essential for elucidation of the protein aggregation mechanism comprises deducing the relationship between the lag period and aggregation rate. Frändrich proposed the following equation connecting the duration of the lag phase (tlag) and the aggregate growth rate (kg) in the amyloid fibrillation: kg=const/tlag. To establish the relationship between the initial rate of protein aggregation (v) and the lag period (t0) in the case of amorphous aggregation, the kinetics of dithithreitol-induced aggregation of holo-α-lactalbumin from bovine milk was studied (0.1M Na-phosphate buffer, pH 6.8; 37°C). The order of aggregation with respect to protein (n) was calculated from the dependence of the initial rate of protein aggregation on the α-lactalbumin concentration (n=5.3). The following equation connecting v and t0 has been proposed: v(1/n)=const/(t0 - t0,lim), where t0,lim is the limiting value of t0 at high concentrations of the protein.
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    ABSTRACT: The stability of three commercial "fast-acting" insulin analogs, insulin lispro, insulin aspart, and insulin glulisine, was studied at various concentrations of phenolic preservatives (phenol and/or meta-cresol) during 9 days of incubation at 37°C. The analysis by both size-exclusion and reversed-phase chromatography showed degradation of lispro and aspart that was inversely dependent on the concentration of phenolic preservatives. Insulin glulisine was much more stable than the other analogs and showed minimal degradation even in the absence of phenolic preservatives. With sedimentation velocity ultracentrifugation, we determined the preservatives' effect on the insulins' self-assembly. When depleted of preservatives, insulin glulisine dissociates from higher molecular weight species into a number of intermediate molecular weight species, in between monomer and hexamer, whereas insulin aspart and insulin lispro dissociate into monomers and dimers. Decreased stability of insulin lispro and insulin aspart seems to be because of the extent of dissociation when depleted of preservative. Insulin glulisine's dissociation to intermediate molecular weight species appears to help minimize its degradation during incubation at 37°C. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
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