Cyclodextrins as mucosal absorption promoters of insulin. II. Effects of beta-cyclodextrin derivatives on alpha-chymotryptic degradation and enteral absorption of insulin in rats.

The relative effectiveness of two beta-cyclodextrin derivatives, i.e., dimethyl-beta-cyclodextrin (DM beta CD) and hydroxypropyl-beta-cyclodextrin (HP beta CD), 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) DM beta CD to a 0.5 mg/ml porcine-zinc insulin solution dramatically increased insulin bioavailability from a negligible value (approximately 0.06%) to 5.63%, when administered enterally at a dose of 20 U/kg. However, addition of 10% (w/v) HP beta CD 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% HP beta CD, and 20 U/kg insulin with 10% DM beta CD were 0.24%, 0.26%, and 1.75%, respectively. Biodegradation studies of 0.5 mg/ml insulin hexamers by 0.5 microM alpha-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% DM beta CD, suggesting insulin oligomer dissociation by DM beta CD. Histopathological examination of the rat intestine was performed to detect tissue damage following enteral administration of the beta-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.