Iontophoretic pulsatile transdermal delivery of human parathyroid hormone (1-34)

Abstract

Iontophoretic pulsatile transdermal delivery of hPTH(1-34) was examined in Sprague-Dawley (SD) rats, hairless rats and beagle dogs. Application for 60 min (200 microg; 0.1 mA cm(-2)) showed current-responsive increases in serum hPTH(1-34) levels in all the animals. In SD rats, the area under the curves of serum hPTH(1-34) levels (AUCs) were proportional to the doses (40, 120, 200, 400 and 1000 microg) and current densities (0.05, 0.1 and 0.15mA cm(-2)) applied. The absorption rates per 200-microg dose, calculated by a deconvolution method, were 6.7, 2.4 and 3.7 microg h(-1) for SD rats, hairless rats and beagle dogs, respectively. These values correlated well with the ratios of the skin porosity to the dermal thickness reported for these animals, which are believed to represent the reciprocal of the electrical resistance of the aqueous channels formed by the hair follicles. From this correlation, we suggested that absorption of hPTH(1-34) occurs mainly via the hair-follicle route, and that the absorption rate in man might be intermediate between those in hairless rats and beagle dogs. Three-fold repetitions of 30 min current with various rest intervals produced current-responsive triple pulses in serum hPTH(1-34) levels in SD rats. Seven-fold repetitions of current also produced similar current-responsive pulsatile serum hPTH(1-34) levels. However, peak serum hPTH(1-34) levels tended to decrease gradually after the fourth current application, possibly due to consumption of the electrodes, suggesting that three-fold repetitions of current might be optimal. These findings suggest that this iontophoretic administration system could create a repeated-pulsatile pattern of serum hPTH(1-34) levels without the necessity for frequent injections, and may be useful for the treatment of osteoporosis with hPTH(1-34).