CYCLODEXTRINS AS MUCOSAL ABSORPTION PROMOTERS OF INSULIN .2. EFFECTS OF BETA-CYCLODEXTRIN DERIVATIVES ON ALPHA-CHYMOTRYPTIC DEGRADATION ANDENTERAL ABSORPTION OF INSULIN IN RATS

The relative effectiveness of two beta-cyclodextrin derivatives, i.e., dimethyl-beta-cyclodextrin (DM beta CD) and hydroxypropyl-beta-cyclod extrin (HP beta CD), in enhancing enteral absorption of insulin was ev aluated 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 be ta CD to a 0.5 mg/ml porcine-zinc insulin solution dramatically increa sed insulin bioavailability from a negligible value (similar to 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 uptak e significantly with a bioavailability of only 0.07%. Similarly, the p harmacodynamic relative efficacy values obtained after the enteral adm inistration of 20 U/kg insulin, 20 U/kg insulin with 10% HP beta CD, a nd 20 U/kg insulin with 10% DM beta CD were 0.24%, 0.26%, and 1.75%, r espectively. Biodegradation studies of 0.5 mg/ml insulin hexamers by 0 .5 mu M alpha-chymotrypsin revealed no inhibitory effect on the enzyma tic activity by the two cyclodextrins. On the contrary, the apparent f irst-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 de tect tissue damage following enteral administration of the beta-cyclod extrin derivatives. Light microscopic inspection indicated no observab le tissue damage, thereby arguing direct membrane fluidization as the primary mechanism for enhanced insulin uptake. This study indicates th e feasibility of using cyclodextrins as mucosal absorption promoters o f proteins and peptide drugs.