Peak-less hypoglycemic effect of insulin glargine by complexation with maltosyl-ß-cyclodextrin.

Long-acting insulin products are desired that provide sustained blood glucose lowering without blood glucose level peaks. In the present study, to obtain the more desirable blood glucose lowering effect of long-acting insulin products, we investigated the effect of maltosyl-ß-cyclodextrin (G(2)-ß-CyD) on physicochemical properties and pharmacokinetics/pharmacodynamics of insulin glargine, which is the one of the most widely used insulin analog. G(2)-ß-CyD increased the solubility and suppressed the aggregation of insulin glargine in phosphate buffer at 9.5, probably due to the interaction of G(2)-ß-CyD with aromatic residues of the insulin glargine such as tyrosine. In addition, the dissolution rates of insulin glargine from its precipitates were increased by a complexation with G(2)-ß-CyD. Subcutaneous administration of an insulin glargine solution with G(2)-ß-CyD to rats gradually decreased blood glucose levels and provided a sustained blood glucose lowering effect without showing the glucose level peaks. These results suggest that G(2)-ß-CyD can be a useful excipient for sustained release and a truly peak-less formulation of insulin glargine.

Effects of Selected Anionic ß-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 ß-cyclodextrin sulfate (Sul-ß-CyD) and sulfobutylether ß-cyclodextrin (SBE7-ß-CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul-ß-CyD and SBE7-ß-CyD increased solubility of insulin glargine. SBE7-ß-CyD suppressed the formation of oligomer and enhanced the dissolution rate of insulin glargine from its precipitate, compared to that of Sul-ß-CyD. Additionally, we revealed that after subcutaneous administration of an insulin glargine solution, SBE7-ß-CyD, but not Sul-ß-CyD, increased bioavailability and sustained the blood-glucose lowering effect, possibly due to the inhibitory effects of SBE7-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE7-ß-CyD could be a useful excipient for sustained release of insulin glargine.

Effect of sulfobutyl ether-ß-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats.

Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-ß-cyclodextrin (SBE4-ß-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-ß-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-ß-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-ß-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-ß-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-ß-CyD can be a useful excipient for sustained release of insulin glargine.