Chapter 15

Ocular Iontophoresis

Francine F. Behar-Cohen, Peter Milne, Jean-Marie Parel,

and Indu Persaud

15.1  Introduction

15.1.1  General Mechanisms of Iontophoretic Drug Delivery

Iontophoresis is a process that increases the penetration of ionized substances into or through a tissue by application of an electrical field. Despite the general concept of using an electric field to enhance the penetration of charged molecules through the skin having been suggested nearly a century ago by Leduc and MacKenna (1908), a clear and complete understanding of the biophysical and biochemical consequences of the technique has continued to remain elusive. Over recent decades ophthalmological uses of the technique has been subject to several enthusiastic rediscoveries or reformulations on the part of proponents interested in its clinical possibilities in general (Banga and Chien 1988) as well as several more sobering accounts of its clinical practice on the part of its detractors. From the perspective of ocular drug delivery it should also be remembered that much of the systematic study of the mechanistic aspects of iontophoresis derive from its application as a drug delivery modality across skin barriers. This spurred from the therapeutic and commercial interests of transdermal drug delivery patches. Systematic and especially optimized accounts of its use in clinically relevant ophthalmological settings remain to be fully reexamined, in part due to earlier critical and unfavorable instances of its usage.

For the utilization of iontophoresis for drug delivery, optimal drug candidates are low molecular weight, positively charged molecules. In the presence of a weak electric field, a positively charged molecule will be driven from the anode of an electrode pair, and if negatively charged it will be driven from the cathode. An electrode pair

F.F. Behar-Cohen (*)

Université Paris Descartes, Inserm UMRS 872, Hôtel-Dieu de Paris, Assistance Publique Hôpitaux de Paris, Paris, France

e-mail: francine.behar@gmail.com

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 361 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_15,

© American Association of Pharmaceutical Scientists, 2011

placed across an otherwise permeable resistant membrane or tissue barrier provides an additional force to the one presented by an opposing concentration gradient preventing drug and equalization of the permeability of the intervening tissues. Although iontophoretic delivery could reasonably be expected to be inversely dependent upon the molecular weight of the permeating molecule or species (Turner et al. 1997), it has been shown that delivery of neutral molecules and even high molecular weight molecules such as proteins can also be delivered across the skin by means of iontophoresis (Bhatia et al. 1997; Chien et al. 1987). Moreover, the molecular size of target drugs is an important consideration for iontophoretic delivery. It has been demonstrated that steady-state permeability through the skin is dependent on the base pair, and not solely on the oligonucleotide base composition. In other words, the molecular shape can also influence iontophoretic transport (Brand et al. 1998).

Several aspects of the physical and biological principles of enhanced drug penetration by iontophoresis, especially in vivo, currently remain unclear. A useful distinction is the differences between iontophoresis and electroporation. Both are bioelectric phenomena of interest in understanding the electric field mediated transport of drugs and various molecules across cell and tissue barriers. Electroporation is reserved for the use of short electrical pulses (t » 100 ms to 20 ms) that lead to transmembrane voltages of the fluid lipid bilayer of individual or groups of cells reaching values (Vm » 0.7–1.0 V) high enough to create new aqueous (hydrophilic) membrane pores. Molecules which are not easily transported through intact membranes become exchangeable between the inside and the outside of the cell. The application of higher field strength and greater pulse length further increases the permeability of the cell’s lipid bilayer membrane. However, too high a field strength and/or pulse lengths will lead to cell lysis and death, essentially overpowering the cell’s ability to repair its compromised lipid bilayer structure. This alteration of the microscopic pore structure of cell membranes is typically achieved (Weaver 2000) by the application of short (~milliseconds) electrical pulses at field strengths considerably higher (~100 V and currents of several amps) and of short pulse lengths than used in iontophoresis. Iontophoresis, in contrast, employs low voltages (<10 V) and low currents (~few mA) typically over much longer periods (minutes to tens of minutes or greater) to provide a sustained and regulated driving force. Enhanced iontophoretic permeability is based on the classical laws of electrochemical diffusion, repulsion and migration of charged and polar species. This diffusion takes place in the complex multilayered and often non-cellular matrices of the dermis or tissues such as those characteristically found in ocular structures. Iontophoresis depends on pre-existing pathways, conduits or entry points through otherwise impermeable tissue barriers. These barriers must be amenable to increased permeability in the presence of the externally applied electrical driving force. In the skin, these appendage pathways include hair follicles, sweat glands, pores, holes and other imperfections in the dermal layers. In this sense iontophoresis and electroporation act upon separate and distinct biophysical scales, and employ separate and distinct mechanisms to achieve different therapeutic goals. Both happen to use the same physical principle of the application of an external electric field to biological systems. Furthermore, electroporation and iontophoresis are not mutually exclusive