Taking into account that endothelial corneal cells do not regenerate and because corneal endothelial cell integrity is responsible for corneal transparency, corneal iontophoresis should only be performed in visually compromised cornea, due to infectious or severe inflammation.

15.4  Transscleral Iontophoresis

Transscleral iontophoresis has been used to achieve high drug concentrations of antibiotics, antiviral drugs, corticosteroids and fluorescein into the posterior segment of the eye. Many of the designed electrode arrangements for the earliest studies in this area were tubular with a reduced area of contact with the sclera over the pars plana, leading to a very high current density. Small burns over areas where the current was applied were, not unexpectedly, commonly described. Under these conditions, high drug concentrations in the vitreous were observed. However, the mechanism of penetration could be attributed at least in part to facilitated diffusion of the drug through ruptured tissue barriers. Very few of these studies reported complete pharmacokinetics of the target drugs after iontophoresis in the complete range of ocular tissues, which could have contributed to a increased understanding of this method of administration.

In the early 1990s, we began working on novel iontophoresis probes that had larger surfaces of application and were applied on an area that was thought at that time to have lower resistance: the pars plicata. We thought that drugs may penetrate through the sclera and follow anteroposterior and anterior migration and reach ocular tissues without inducing high vitreous levels (Fig. 15.1).

Many probe prototypes were successively made by J.M. Parel at the Bascom Palmer Eye Institute for experiments to be performed in different animal model and eye sizes by F. Behar-Cohen (Fig. 15.2). The optimized Coulomb controlled iontophoresis (CCI) is shown in Fig. 15.3. It is 14 mm in inner diameter and 17 mm in outer diameter and covers the whole circumference around the cornea (Fig. 15.3). This technology has been developed by Optis France and is now under clinical development by Eyegate Pharma (USA).

Other technology has been developed by Iomed to perform transscleral iontophoresis. The system is different because the semi-annular reservoir is placed in the cul de sac and covered by the eyelid (Fig. 15.4).

The advancement of MRI technology has provided new opportunities for noninvasive procedures and continuous monitoring of ocular drug-delivery systems with a contrast agent or a compound tagged with a contrast agent. MRI was therefore recently applied to study how drug penetrates an eye after transscleral iontophoresis. The delivery and distribution of the model permeants, manganese ion (Mn2+ and manganese ethylenediaminetetraacetic acid complex (MnEDTA2−) were studied. This method was implemented to study intraocular delivery by iontophoresis compared to subconjunctival injection and passive delivery. The total current and duration of application were 2 and 4 mA (current density 10 and 20 mA/cm2) and 20–60 min, respectively.

Fig. 15.1  Schematic representation of the potential routes of drug penetration in the ocular globe using an annular transscleral probe. The drug penetrates through the pars plana and migrates along the sclera and the suprachoroidal space. Direct penetration in the vitreous or in the aqueous humor does not seem to occur using low current densities (<10 mA/cm2)

Fig. 15.2  Representation of the different iontophoretic prototypes developed at the Bascom Palmer Eye Institute (J.M. Parel and F. Behar-Cohen and the team)

MRI studies showed that both anodal and cathodal iontophoresis provided significant enhancement in ocular delivery compared to passive transport in the in vitro and in vivo studies. Transscleral iontophoretic delivery was related to the position and duration of the iontophoresis application in vivo. Permeants were observed to be delivered primarily into the anterior segment of the eye when the pars plana was the application site. Extending the duration of iontophoresis at this site allowed the permeants to be delivered into the vitreous more deeply and to a greater extent than when the application site was at the back of the eye near the fornix.

This demonstrated that electrode placement was an important factor in transscleral iontophoresis, and the ciliary body (pars plana) was determined to be the pathway of least resistance for iontophoretic transport (Molokhia et al. 2007). Experiments involving constant current transscleral iontophoresis of 2 mA (current density 10 mA/cm2) and subconjunctival injection were conducted with rabbits in vivo and postmortem and with excised sclera in side-by-side diffusion cells in vitro. The postmortem and in vitro experiments were expected to be helpful in clarifying the importance of vascular clearance and other transport barriers in transscleral iontophoresis. Manganese ion (Mn2+) and manganese ethylenediaminetetraacetic acid complex (MnEDTA2−) were the model permeants. The results show that pretreatment of the eye with an electric field by iontophoresis enhanced subconjunctival delivery of the permeants to the anterior segment of the eye in vivo. This suggests that electric field induced barrier alterations can be an important absorption enhancing mechanism of ocular iontophoresis. Penetration enhancement was magnified in the postmortem experiments with larger amounts of the permeants delivered into the eye and to the back of the eye. The different results observed in the in vivo and postmortem studies can be attributed to ocular clearance in ocular delivery and suggest that pharmacokinetic studies performed ex vivo cannot be extrapolated to clinical situations (Molokhia et al. 2008).

15.4.1  Transscleral Iontophoresis of Antibiotics

Table 15.3 summarizes the principal studies on transscleral delivery of antibiotics. Barza et al. (1986) used a very small probe (1 mm in diameter) placed over the pars plana to deliver gentamycin, ticarcillin and cephazolin to the rabbit vitreous. High concentrations of those drugs were measured in the vitreous after iontophoresis of uninfected rabbits. However because of the high current densities used, burns were commonly observed at the site of iontophoresis. Therefore, the penetration of the drug directly to the vitreous could result, at least in part from direct penetration through disrupted tissues. Transscleral iontophoresis of gentamycin was found to be a useful supplement to intravitreal injection in an experimental endophthalmitis model caused by P. aeruginosa in the rabbit. Higher rates of sterilization were observed in eyes that received both transscleral iontophoresis of gentamycin and intravitreal injections of gentamycin compared to intravitreal injections alone (Barza et al. 1987a, b). In the monkey, therapeutic levels were obtained in the vitreous following transscleral iontophoresis of gentamycin. Electroretinograms were normal in all eyes after iontophoresis but indirect ophthalmoscopy showed localized area of retinal burns in the area of pars plana where the electrode had been placed (Barza et al. 1987a, b). Other studies reported lower antibiotic concentrations in the vitreous but used much lower current densities (Burstein et al. 1985). However, in this study tissue concentrations were not measured. It has been suggested that high and long-lasting concentrations of gentamycin could be obtained in the vitreous without any retinal lesion, by using 2% agar in the 10% gentamycin solution, and performing a transscleral iontophoresis with a 2 mm in diameter probe