Effects of Selected Anionic β-Cyclodextrins on Persistence of Blood Glucose Lowering by Insulin Glargine after Subcutaneous Injection to Rats

Insulin glargine is a synthetic long-acting insulin product used for patients with diabetes mellitus. In this study, to obtain the further desirable blood-glucose lowering profile of insulin glargine, we investigated the effects of β -cyclodextrin sulfate (Sul- β -CyD) and sulfobutylether β -cyclodextrin (SBE7- β -CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul- β -CyD and SBE7- β -CyD increased solubility of insulin glargine. SBE7- β -CyD suppressed the formation of oligomer and enhanced the dissolution rate of insulin glargine from its precipitate, compared to that of Sul- β -CyD. Additionally, we revealed that after subcutaneous administration of an insulin glargine solution, SBE7- β -CyD, but not Sul- β -CyD, increased bioavailability and sustained the blood-glucose lowering effect, possibly due to the inhibitory effects of SBE7- β -CyD on the enzymatic degradation at the injection site. These results suggest that SBE7- β -CyD could be a useful excipient for sustained release of insulin glargine.