Transdermal electroporation

Edwards [105] has extended the macrotransport method, originally developed by Brenner [48] and based upon a generalization of Taylor-Aris dispersion theory, to the analysis of electrokinetic transport in spatially periodic porons media. Edwards and Langer [106] applied this methodology to transdermal dmg delivery by iontophoresis and electroporation. 

Denet A, Vanbever R, Preat V. Skin electroporation for transdermal and topical delivery. Adv Drug Delivery Rev 2004 56 659-674. 

Denet A, Preat V. Transdermal delivery of timolol by electroporation through human skin. J Control Release 2003 88 253-262. 

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. 

Zewert T, Pliquett U, Vanbever R, Langer R, Weaver J. Creation of transdermal pathways for macromolecule transport by skin electroporation and a low toxicity, pathway-enlarging molecule. Bioelectrochem Bioenerg 1999 49 11-20. 

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. 

As electroporation is still largely in the experimental stage and may possibly be never used clinically, many workers have employed model nontherapeutic molecules to demonstrate the feasibility of its use, such as sulforhodamine, calcein, and caffeine. However, more therapeutic and biotechnologically derived molecules have now been investigated for transdermal delivery, including, for example, fentanyl [22], metoprolol [21], timolol [36], flurbiprofen [37], cyclosporin [38], heparin [39], oligonucleotides [40], and genes [41]. 

In contrast to low-current iontophoresis, which utilizes an electrical driving force to push permeants into and across the skin, electroporation increases transdermal transport primarily... 

Iontophoresis by definition is the process of transport of ions into or through a tissue by the use of an applied potential difference across the tissue [52], Depending on the physicochemical characteristics of a molecular species, electrorepulsion is usually the primary mechanism of transdermal transport for ions, whereas electroosmosis and increased passive diffusion (as a result of the reduced barrier properties) are more prominent for neutral species [53]. In contrast, enhancement in flux for neutral or weakly charged species during electroporation arises predominantly from the reduced barrier properties of the membrane, whereas direct electrorepulsion is usually of secondary importance [25],... 

Jadoul and Preat [56] have also proposed a similar explanation for the lack of synergistic effects on transdermal delivery of domperidone with combined electroporation (1 pulse of 1000 V with a time constant of 4 ms) and iontophoresis (0.4 mA/cm2) despite the fact that iontophoresis was switched on within a few seconds after electroporation. Combined pulsing and iontophoresis also did not improve penetration of sodium nonivamide acetate through nude mouse skin [51], Therefore, when combing the two protocols, it should be more efficient to use a system that delivers current during or immediately after pulsing without delay. 

Several reports in the literature have indicated that transdermal delivery may be further increased by combining chemical excipients with electroporation. These investigations included macromolecules like dextrans [58], cyclodextrins [59] and even simple salts such as calcium chloride [60]. Other workers have, however, looked at encapsulation of compounds within lipid vesicles (liposomes) as potential candidates for electroporation-mediated delivery [61,62]. A fuller treatment of this combination is described in Chapter 17. 

Prausnitz, M.R., et al. 1996. Transdermal transport efficiency during skin electroporation and iontophoresis. J Control Release 38 205. 

Vanbever, R., E. Le Boulenge, and V. Preat. 1996. Transdermal delivery of fentanyl by electroporation. I. Influence of electrical factors. Pharm Res 13 559. 

Vanbever, R., M. Leroy, and V. Preat. 1998. Transdermal penetration of neutral molecules by skin electroporation. J Control Release 54 243. 

Prausnitz, M.R. 1999. A practical assessment of transdermal drug delivery by skin electroporation. 

Pliquett, U. 1999. Mechanistic studies of molecular transdermal transport due to skin electroporation. Adv Drug Deliv Rev 35 41. 

Bommannan, D.B., et al. 1994. Effect of electroporation on transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro. Pharm Res 11 1809. 

Riviere, J.E., et al. 1995. Pulsatile transdermal delivery of LHRH using electroporation Drug delivery and skin toxicology. J Control Release 40 229. 

Chang, S.L., et al. 2000. The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. J Control Release 66 127. 

Murthy, S.N., et al. 2004. Cyclodextrin enhanced transdermal delivery of piroxicam and carboxy-fluorescein by electroporation. J Control Release 99 393. 

Badkar, A.V., et al. 1999. Enhancement of transdermal iontophoretic delivery of a liposomal formulation of colchicine by electroporation. Drug Deliv 6 111. 

Ultrasound also exhibited a synergistic effect with electroporation [72], Ultrasound reduced the threshold voltage for electroporation as well as increased transdermal transport at a given electroporation voltage. The enhancement of transdermal transport induced by the combination of ultrasound and electroporation was higher than the sum of the enhancement induced by each enhancer alone. 

Vanbever et al. [4] hypothesized that administration of macromolecules during electroporation would, in some fashion, stabilize aqueous pores produced by high-voltage pulsing. This group studied mannitol transdermal transport under electroporation with coadministered... 

Sen, A., M.E. Daly, and S.W. Hui. 2002. Transdermal insulin delivery using lipid enhanced electroporation. Biochim Biophys Acta 1564 (1) 5. 

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