Transdermal iontophoresis

O. Pillai, N. Kumar, C.S. Dey, S. Borkute, S. Nagalingam, and R. Panchagnula, Transdermal iontophoresis of insulin. Part 1 A study on the issues associated with the use of platinum electrodes on rat skin. J. Pharmacy Pharmacol. 55, 1505-1513 (2003). 

PUlai, O., V. Nair, R. Podnri, and R. Panchagnnla, Transdermal iontophoresis. Part IT. Peptide and protein delivery. Methods Find Exp Chn Pharmacol, 1999. 21(3) 229-40. 

Fang J, Hwang T, Huang Y, Tsai Y. Transdermal iontophoresis of sodium nonivamide acetate—V. Combined effect of physical enhancement methods. Int J Pharm 2002 235 95-105. 

Fang J, Hung C, Fang Y, Chan T. Transdermal iontophoresis of 5-fluorouracil combined with electroporation and laser treatment. Int J Pharm 2004 270 241-249. 

Pillai O, Nair V, Panchagnula R. Transdermal iontophoresis of insulin IV. Influence of chemical enhancers. Int J Pharm 2004 269 109-120. 

Transdermal iontophoresis involves the application of an electric field across the skin to facilitate (primarily) ionic transport across the membrane. Iontophoresis, it is important to point out, is differentiated from electroporation [14], another electrical approach to enhance transdermal transport, by the low fields employed. Whereas iontophoresis has achieved commercialization, there is (to our knowledge) no active development in progress of a transdermal delivery system employing electroporation. 

The development of the first transdermal patches in the 1980s generated considerable interest in this route of drug administration. Soon afterwards, iontophoresis was rediscovered and its potential to contribute to the new field of transdermal drug delivery was examined. This work provided the basic principles for modern iontophoretic devices [13,18-21]. Furthermore, and importantly, they demonstrated the existence of a (primarily) electroosmotic, convective solvent flux during transdermal iontophoresis [10,11,22-24], and it was shown that the permselective properties of the skin (a) could be exploited to enhance the transport of neutral, polar species and (b) have a clear impact on ionic transport. Subsequent research has better characterized skin permselectivity and the factors which determine the magnitude of electroosmosis [25-27],... 

In summary, there is evidence that the skin presents a weak cation permselectivity [25,76,77,80,93,125], which can be reversed by acidifying the pH of the solutions bathing the skin [10,23,76,77]. At pH>p/, the skin is negatively charged and electroosmotic flow proceeds in the anode-to-cathode direction. At pH < pi, the skin becomes positively charged and electroosmotic flow reverses to the cathode-to-anode direction. Under the application of an electric field, counterions (cations at physiological pH) are preferentially admitted into the skin. As a consequence, the sodium and chloride transport numbers are 0.6 and 0.4, respectively, during transdermal iontophoresis (in contrast to their values in a neutral membrane tNa = 0.45 rCi = 0.55) [126]. 

Pikal, M. J. 1992. The role of the electroosmotic flow in transdermal iontophoresis. Adv Drug Deliv Rev 9 201. 

Sieg, A., R.H. Guy, and M.B. Delgado-Charro. 2004. Electroosmosis in transdermal iontophoresis Implications for non-invasive and calibration-free glucose monitoring. Biophys J 87 3344. 

Pikal, M.J. 1990. Transport mechanisms in iontophoresis. I. A theoretical model for the effect of electroosmotic flow on flux enhancement in transdermal iontophoresis. Pharm Res 1 (2) 118. 

Yoshida, N.H., and M.S. Roberts. 1993. Solute molecular size and transdermal iontophoresis across excised human skin. J Control Release 25 177. 

Green, P.G., et al. 1992. Transdermal iontophoresis of amino acids and peptides in vitro. J Control Release 21 187. 

Santi, P., et al. 1997. Transdermal iontophoresis of salmon calcitonin can reproduce the hypocal-cemic effect of intravenous administration. Farmaco 52 (6) 445. 

Nicoli, S., et al. 2003. Characterization of the permselective properties of rabbit skin during transdermal iontophoresis. J Pharm Sci 92 (7) 1482. 

Fang, J.Y., et al. 1999. Evaluation of transdermal iontophoresis of enoxacin from polymer formulations In vitro skin permeation and in vivo microdialysis using Wistar rat as an animal model. Int J Pharm 180 137. 

Table 2 Solutes Used in In Vivo Transdermal Iontophoresis in Animal Studies...

Shed snake skin has been proposed as a relatively good model for human skin in transdermal permeation studies [66]. Hirvonen et al. [67] compared the transdermal iontophoresis of sotalol and salicylate in shed snake skin, Elaphe obsoleta, and human cadaver skin. They advised that snake skin should be used with caution as a model for human skin because snake skin has anion-selective properties while human skin has cation-selective properties. 

Hirvonen et al. [67] used dodecyl NA -dimethyl amino acetate (DDAA) and Azone as penetration enhancers in the transdermal iontophoresis of sotalol and salicylate. They compared the action of both enhancers in passive diffusion studies and iontophoretic studies and found no significant difference between the two, with the permeability of sotalol in the passive diffusion studies increasing to the order of magnitude found in the iontophoretic studies. The main mechanism of action of DDAA and Azone is the disordering of the lipids and the closing of iontophoretic penetration routes [123,124]. 

Hirvonen, J., Kontturi, K., Murtom i, L., Paronen, P., and Urtti, A. Transdermal iontophoresis of sotalol and salicylate The effect of skin charge and penetration enhancers. J. Controlled Rel. 26 109, 1993. 

Thysman, S., Tasset, C., and Preat, V. Transdermal iontophoresis of fentanyl ... 

Riviere, J. E., Monteiro-Riviere, N. A., and Inman. A. Determination of lidocaine concentrations in skin after transdermal iontophoresis Effects of vasoactive drugs. Pharm. Res. 9 211, 1992. 

Singh P, Anfiker M, Smith G, Zavortimk D, and Maibach H. Transdermal iontophoresis and solute penetration across excised human skin. J. Pharm. Sci. 1995 84 1342-1346. 

For current densities at or above 0.2mA/cm, the sensation associated with transdermal iontophoresis is determined by the type of ion being delivered into the skin. When human subjects compared the sensation experienced during iontophoresis of different salt solutions applied to the right and left forearms, delivery of calcium caused less sensation than delivery of phosphate, magnesium, and zinc, which caused less sensation than delivery of chloride, acetate, citrate, and sulfate, which in turn caused less sensation than delivery of lithium, potassium, and sodium. In general, multivalent ions were found to cause less sensation than monovalent ions. ... 

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