DISSOCIATION OF INSULIN OLIGOMERS AND ENHANCEMENT OF PERCUTANEOUS-ABSORPTION OF INSULIN

This study was designed to evaluate the percutaneous absorption of ins ulin in an attempt to develop an efficient transdermal therapeutic sys tem (system) for the treatment of diabetes. First, the dissociation of porcine insulin existing mainly as hexamers was examined. Next, enhan cement of the percutaneous absorption of the hormone was studied by th e combined use of two or more kinds of enhancers which exert their enh ancement effects by different mechanisms, or by preparing the liposoma l formulation of insulin. Porcine insulin dissociated in 0.1 M glycine -HCl buffer (pH 4.0), probably to a dimer, this being demonstrated by the notable attenuation of the maxima at 221 and 274 nm of the circula r dichroism (CD) spectra. Thus, 0.1 M (or partly 1 M) glycine-HCl buff er (pH 4.0) was selected for the preparation of all gel formulations. The in vivo absorption of insulin through Wistar rat skin was estimate d by blood glucose level. System 3 containing liposomal insulin, D-lim onen and taurocholate gave the greatest hypoglycemic response, out of the formulations used, with its response persisting over a 10 h period and resulting in the highest pharmacological availability (20.7 +/- 4 .6%). The combination of n-octyl-beta-D-thioglucoside (OTG), cineol an d deoxycholate (system 6) or D-limonen and OTG (system 5) also produce d a high hypoglycemic effect. The in vitro penetration of insulin was investigated using system 5 and 6. The percutaneous penetration of ins ulin was demonstrated by an in vitro experiment, but was small in quan tity. Our data present unambiguous evidence that this hydrophilic macr omolecule was absorbed through the stratum corneum of rat skin under s elected conditions.