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 insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of beta-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-beta-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-beta-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-beta-cyclodextrin with a degree of substitution of the sulphobutyl group of 3.9 (SBE4-beta-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8 h. The bioavailability of the insulin/SBE4-beta-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-beta-CyD may be in part due to the inhibitory effects of SBE4-beta-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-beta-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.
Tokihiro
K
K
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Arima
H
H
Tajiri
S
S
Irie
T
T
Hirayama
F
F
Uekama
K
K
D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D003505:Cyclodextrins / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D006207:Half-Life; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption / Q000187:drug effects; D047392:beta-Cyclodextrins
D001786:Blood Glucose; D003505:Cyclodextrins; D007328:Insulin; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D016650:Fluorescein-5-isothiocyanate