Enhancement of skin permeation of fluorescein isothiocyanate-dextran 4 kDa (FD4) and insulin by thermalporation.

Thermalporation has gained attention as a physical means to enhance skin permeation by creating micropores in the primary skin barrier, stratum corneum, which allows much higher permeation of middle and high molecular weight biopharmaceuticals. In the present study, a PassPort® system (PS) was used as a thermalporation device, and the obtained change in permeation resistance of drugs was evaluated using a parallel skin permeation-resistance model. In addition, the blood concentration-time profile after topical application of insulin was also investigated with the PS treatment. Fluorescein isothiocyanate-dextran (FD-4) and insulin were used as model middle molecular weight drugs. Micropores created by the PS treatment were measured using an optical microscope. An in vitro skin permeation and an in vivo pharmacokinetics experiments were done with FD-4 and insulin, respectively. Barrier function recovery after the PS treatment was evaluated with changes in the electrical skin resistance. About 960-fold higher skin permeation of FD-4 was observed by PSs treatment (4 milliseconds (ms), 200 micropores/cm2). A gradually increased blood concentration of insulin was observed by the PSs treatment, and the relative bioavailability of insulin was 21.1% compared with subcutaneous injection. Skin resistance value was dramatically decreased immediately after the PS treatment, but its value was turned into the initial one by 12 h. The thermalporation is effective for improving skin permeation of FD-4 and transdermal absorption of insulin. These results suggested that the PS treatment may be utilized to increase the skin permeation of topically applied FD-4 and insulin.

Prevention of bone loss in ovariectomized rats by pulsatile transdermal iontophoretic administration of human PTH(1-34).

Serum human parathyroid hormone (1-34)[hPTH(1-34)] levels and the anabolic effect of hPTH(1-34) were compared after administration using multiple pulses of iontophoresis or subcutaneous (sc) intermittent injections to ovariectomized (OVX) Sprague Dawley rats. Triple-pulse iontophoretic administration of hPTH(1-34) (doses: 40-400 microg/patch), achieved by repeated 30-min applications of a 0.1 mA/cm(2) current separated by 45-min rest intervals, produced three sharp peaks in the serum hPTH(1-34) level in response to application of the current. Each peak appeared at the end of the 30-min current application period and was proportional to the hPTH(1-34) dose. Compared with once-daily sc injections (7 pulses/week), triple-pulses iontophoretic administered 3 times/week (9 pulses/week) for 4 weeks produced dose-related increases in the bone mineral density (BMD) of the distal 1/3 femur. For the sc administration, the relative BMD values using the vehicle injection as a reference standard for 1, 5, and 25 microg/kg/day were 104, 114, and 121%, respectively. For iontophoretic administration, the relative BMD values using the placebo patch as a reference standard for 40, 120, and 400 microg/patch were 104, 110, and 116%, respectively. The increase in the BMD plotted against the area under the hPTH(1-34) serum level-time curve (AUC) over 1 week resulted in similar straight lines in the 9 pulses/week iontophoretic administration and the 7 pulses/week sc administration groups. The estimated iontophoretic dose giving an equivalent BMD to once-daily sc administration at 5 microg/kg/day was 120 microg/patch. These findings strongly suggest that three iontophoretic pulses administered on alternate days will exert an anabolic effect equivalent to that of daily sc administration at doses giving the same weekly AUC. Furthermore, this method of administering hPTH(1-34) might enable self-medication, a useful advance in the treatment of osteoporosis.