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

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 mug; 0.1 mA cm(-2)) showed current-responsive increases in serum hPTH(1-34) levels in all the animals. In SID rats, the area under the curve s of serum hPTH(1-34) levels (AUCs) were proportional to the doses (40, 120 , 200, 400 and 1000 mug) and current densities (0.05, 0.1 and 0.15 mA cm(-2 )) applied. The absorption rates per 200-mug dose, calculated by a deconvol ution method, were 6.7, 2.4 and 3.7 mug h(-1) for SID rats, hairless rats a nd beagle dogs, respectively. These values correlated well with the ratios of the skin porosity to the dermal thickness reported for these animals, wh ich are believed to represent the reciprocal of the electrical resistance o f the aqueous channels formed by the hair follicles. From this correlation, we suggested that absorption of hPTH(1-34) occurs mainly via the hair-foll icle route, and that the absorption rate in man might be intermediate betwe en those in hairless rats and beagle dogs. Three-fold repetitions of 30 min current with various rest intervals produced current-responsive triple pul ses in serum hPTH(1-34) levels in SID rats. Seven-fold repetitions of curre nt also produced similar current-responsive pulsatile serum hPTH(1-34) leve ls. However, peak serum hPTH(1-34) levels tended to decrease gradually afte r the fourth current application, possibly due to consumption of the electr odes, suggesting that three-fold repetitions of cur-rent 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 o steoporosis with hPTH(1-34).