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Background: Commercially available insulin products used for continuous subcutaneous insulin infusion have been compared with respect to resistance towards isoelectric insulin precipitation.

Methods: The degree of isoelectric insulin precipitation of insulin aspart injection (IAsp), insulin lispro injection (ILis), and buffered human regular insulin injection (BHR) was examined while reducing pH through addition of diluted HCl or exposure to CO₂.

Results: The pH at which defined fractions of the insulins precipitated differed among the three products; 10% and 90% precipitation, respectively, was observed at pH 6.41 and pH 6.30 for ILis, pH 6.18 and pH 5.95 for BHR, and pH 5.90 and pH 5.67 for IAsp, in accordance with the isoelectric points of these insulin species. The amount of H⁺-equivalents per microliter of product to reach 10% precipitation was found to be highest for IAsp (5.49 nmol of H⁺-equivalents), with ILis and BHR almost equivalent to each other (4.46 and 4.32 nmol of H⁺-equivalents, respectively). Exposure to a CO₂-enriched environment resulted in the same order of insulin precipitation of the three products as tested with HCl.

Conclusions: Resistance towards isoelectric precipitation is highest for IAsp, lowest for ILis, and intermediate for BHR. Isoelectric precipitation will alter the pharmacokinetic properties of the insulin and could lead to occlusion of the infusion catheter, causing elevated blood glucose and ultimately causing diabetic ketoacidosis if no intervention is made. Causal relationships between the observed differences in resistance towards isoelectric precipitation of the insulin products, the mechanism behind catheter occlusion, and the clinical relevance of the observations require further studies.