Transdermal iontophoretic delivery of insulin using a photoetched microdevice

Abstract

In order to develop practical iontophoretic devices for insulin delivery, five types of device, a square type, a square anode with a U-shaped inset cathode-type device (2 divided type), and three types with a square anode, with, respectively, 4, 9 and 16 small square inset cathodes (4, 9 and 16 divided types), were fabricated by a photoetching technique, and their effectiveness was examined in vitro by measuring the permeability of 6-carboxyfluorescein (6-CF) through the excised abdominal skin of a nude mouse. All four divided types enhanced the penetration rate of 6-CF more than 16-fold compared with passive diffusion. To test the transdermal iontophoretic delivery of insulin in normoglycemic control and diabetic rats, we selected the 2 divided type device, since this pattern was the easiest to fabricate. A significant reduction in blood glucose level (BGL) of 33% after 90 min of treatment, and a corresponding increase in immunoreactive insulin (IRI) concentration were observed in diabetic rats during cathodic direct current (DC) iontophoresis (IP) at a constant voltage of 1.5 V. The effectiveness of pulsed IP was also studied, but there was no significant difference between DC and pulsed IP in the decrease of BGL. The level of current during the initial 10 min was closely related to the hypoglycemic effect. These findings suggest that some cathodic reaction products may change the function of the stratum corneum or that these products may develop a shunt pathway and enhance the transdermal delivery of aggregated insulin molecules. Iontophoresis-induced skin damage was also evaluated by measuring impedance changes. It was shown that at constant-voltage IP of 1.5 V, IP could be carried out for up to 60 min without any marked effects on the skin.