Cyclodextrins as Mucosal Absorption Promoters of Insulin. II. Effects of β-Cyclodextrin Derivatives on α-Chymotryptic Degradation and Enteral Absorption of Insulin in Rats

Abstract

The relative effectiveness of two β-cyclodextrin derivatives, i.e., dimethyl-β-cyclodextrin (DMβCD) and hydroxypropyl-β-cyclodextrin (HPβCD), in enhancing enteral absorption of insulin was evaluated in the lower jejunal/upper ileal segments of the rat by means of an in situ closed loop method. The incorporation of 10% (w/v) DMβCD to a 0.5 mg/ml porcine-zinc insulin solution dramatically increased insulin bioavailability from a negligible value (~0.06%) to 5.63%, when administered enterally at a dose of 20 U/kg. However, addition of 10% (w/v) HPβCD did not improve enteral insulin uptake significantly with a bioavailability of only 0.07%. Similarly, the pharmacodynamic relative efficacy values obtained after the enteral administration of 20 U/kg insulin, 20 U/kg insulin with 10% HPβCD, and 20 U/kg insulin with 10% DMβCD were 0.24%, 0.26%, and 1.75%, respectively. Biodegradation studies of 0.5 mg/ml insulin hexamers by 0.5 µM α-chymotrypsin revealed no inhibitory effect on the enzymatic activity by the two cyclodextrins. On the contrary, the apparent first-order rate constant increased significantly in the presence of 10% DMβCD, suggesting insulin oligomer dissociation by DMβCD. Histopathological examination of the rat intestine was performed to detect tissue damage following enteral administration of the β-cyclodextrin derivatives. Light microscopic inspection indicated no observable tissue damage, thereby arguing direct membrane fluidization as the primary mechanism for enhanced insulin uptake. This study indicates the feasibility of using cyclodextrins as mucosal absorption promoters of proteins and peptide drugs.