Improvement of subcutaneous bioavailability of insulin by sulphobutyl ether beta-cyclodextrin in rats

The objective of this study was to examine and compare how hydrophilic beta -cyclodextrin derivatives (beta-CyDs) improve the bioavailability of insuli n following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of beta-CyDs were injected into the d orsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximate ly 50%, When maltosyl-beta-cyclo-dextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with thos e of the insulin-alone solution. Dimethyl-beta-cyclodextrin decreased the b ioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothioc yanate-dextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-beta-cyclodextrin with a degree of substituti on of the sulphobutyl group of 3.9 (SBE4-beta-CyD) were injected, the IRI l evel rapidly increased and maintained higher IRI levels for at least 8 h, T he bioavailability of the insulin/SBE4-beta-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-beta-Cy D may be in part due to the inhibitory effects of SBE4-beta-CyDs on the enz ymatic degradation and/or the adsorption of insulin onto the subcutaneous t issue at the injection site, although this does not apparently facilitate c apillary permeability. These results suggest that SBE4-beta-CyD in aqueous insulin injection for s ubcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.