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

Abstract

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.

Sulfobutylether-β-Cyclodextrin for Inhibition and Rupture of Amyloid Fibrils

“…Uehata et al have reported that the presence of SBE 7 β-CD increased the solubility and bioavailability of a synthetic long-acting insulin product i.e. insulin glargine and sustained the blood-glucose lowering effect by inhibiting the enzymatic degradation . The derivatives of β-CD, such as hydroxypropyl β-CD, glucosyl β-CD, and β-CD dimer inhibit the fibrillation process of insulin/insulin analogues and Aβ(1–40) to some extent through the encapsulation of hydrophobic amino acids in the hydrophobic β-CD cavity. − In a recent study we have demonstrated that CB7 macrocycle forms nanoassembly with proteins such as bovine serum albumin, human serum albumin, and lysozyme and stabilizes their native form …”