Unsurprisingly, with a calculated current density of 526 mA/cm2 for 10 min, small burns were observed in the retina and the choroid adjacent to the application of the probe. No electroretinographic changes and no histological (light and electron microscopy) lesions were observed elsewhere than at the application site. After 21 consecutive days of the same treatment, the site of burn was not increased compared to a single iontophoresis procedure (Yoshizumi et al. 1997). Iontophoresis could thus be an interesting alternative to repeated intravitreal injections.

15.4.3  Transscleral Iontophoresis of Anti-Inflammatory Drugs

15.4.3.1  Aspirin

CCI of aspirin (10 mg/mL) was performed in rabbits using 5 mA/cm2 and 10 min treatment. It was compared to topical and IV administration of aspirin. Levels of aspirin at 30 min after treatment were 1,614 mg/mg in the anterior uvea, 495.9 mg/mL in the aqueous humor, 443 mg/mg in the retina, 1,276 mg/mg in the choroid and 9.1 mg/mL in the vitreous. At 8 h, ocular aspirin concentrations were in the same range for CCI and IV administration. IV injection resulted in blood plasma levels up to 28 times higher than CCI and remained significantly elevated until 8 h after the treatments (Voigt et al. 2002a–c; Kralinger et al. 2003).

15.4.3.2  Glucocorticoids

Glucocorticoids are widely used in treating posterior ocular inflammation. In 1965, Lachaud demonstrated in a non-controlled trial that iontophoresis of hydrocortisone acetate was beneficial for uveitic patients. More than 20 years later, Lam et al. showed that transscleral iontophoresis of 30% dexamethasone, with a current density of 421 mA/cm2 and a 25 min treatment induce a peak concentration in the vitreous of 140 mg/mL compared to 0.2 mg/mL after sub-conjunctival injection. Chorioretinal and vitreal concentrations of dexamethasone were higher and lasted longer than either sub-conjunctival and retrobulbar injections (Lam et al. 1989). Efficiency of the iontophoresis of dexamethasone was compared to systemic administration in an ocular model of pan uveitis in the rat. Using a 2.6 mA/cm2 current density, a 400 mA current intensity for 4 min, iontophoresis was as efficient as intraperitoneal administration of dexamethasone in treating both the anterior and the posterior segment of the eye. There were no observed effects on the systemic production of cytokines. Iontophoresis of dexamethasone resulted in a reduced systemic effect of the corticotherapy, yet retained a strong ocular effect (Behar-Cohen et al. 1997).

In order to avoid pulsetherapy of methylprednisolone, such as in severe intraocular inflammation or the treatment of corneal graft rejection, we proposed to evaluate the effect of CCI on methylprednisolone (62.5 and 150 mg/mL) in the pigmented rabbits.

15.4.3.3  Transscleral Iontophoresis of Carboplatin

Pharmacological distribution of carboplatin was examined in New Zealand White Rabbits following a single intravenous infusion of carboplatin (18.7 mg/kg of body weight), single subconjunctival carboplatin injection (5.0 mg/400 mL) or single application of carboplatin delivered by Coulomb-controlled iontophoresis (CCI; 14 mg/mL carboplatin, 5.0 mA/cm2, 20 min). Significantly higher levels were achieved than those with intravenous administration. Carboplatin concentrations in the blood plasma were found to be significantly higher after intravenous delivery than after focal delivery by subconjunctival injection or CCI. No evidence of ocular toxicity was detected after focally delivered carboplatin (Hayden et al. 2004). On a mice model of retinoblastoma, mice received six serial iontophoretic treatments administered two times a week using a current density of 2.57 mA/cm2 for 5 min. A dose-dependent inhibition of intraocular tumor was observed after repetitive iontophoretic treatment. At carboplatin concentrations of 7 mg/mL, 50% of the treated eyes (4/8) exhibited tumor control. No corneal toxicity was observed in the eyes treated at carboplatin concentrations under 10 mg/mL (Hayden et al. 2006).

Using hydrogel iontophoresis, no effect of current was observed for carboplatin delivery in non-pigmented rabbits (Eljarrat-Binstock et al. 2008).

Because systemic carboplatin is associated with severe side effects in young children and because intravitreous injections are not recommended in retinoblastoma children for carcinologic reasons, iontophoresis of carboplatin could be an intriguing alternative. However, whether conjunctival and other loco-regional side effects could occur remains to be evaluated before clinical application.

15.4.3.4  Is Transscleral Iontophoresis Safe?

Table 15.4 summarizes reports of lesions observed after transscleral iontophoresis. Lesions that were observed were well circumscribed over the site of the direct current application. Furthermore, the size of the lesion was correlated to the time of treatment (Lam et al. 1991). According to Yoshizumi et al., repeated treatment did not increase the size and the importance of focal retinal and choroidal burns (Yoshizumi et al. 1997).

The mechanisms of injury for these lesions could be related to direct effect of high current density (capable of inducing cell membrane damage), heat insult, chemical burn due to hydrolysis or modification of the pH at the surface of the eye. However, it seems that efficient tissue concentrations of drugs were achieved without any induced lesions when the current density is controlled, and remains less than 100 mA/cm2 for 5 min (Hughes and Maurice 1984). When focal lesions are induced by iontophoretic application, the permeant drug may directly penetrate into the vitreous through disorganized tissues, following the kinetic of an intravitreal injection. In the case of iontophoresis without any observable lesion, the drug penetration should follow other mechanisms which could be better understood by systematic pharmacokinetic studies in all ocular tissues.

15.4.3.5  Transscleral Iontophoresis for High Molecular Weight Compounds and Proteins

One study was performed on excised human and porcine sclera to show that iontophoresis could significantly enhance the transscleral flow of dextran up to 120 kDa (Nicoli et al. 2009). However, these experiments cannot be extrapolated to in vivo situations. In our case, in vivo iontophoresis was not efficient for the delivery of proteins in ocular tissues at therapeutic concentrations. Enhanced formulations and/ or combinations of techniques may help achieve this purpose.

15.4.3.6  Clinical Application of Transscleral Iontophoresis

While a large number of pre-clinical studies not only in normal rabbits but also in some animal models of ocular diseases have shown that iontophoresis was efficient to deliver mostly antibacterial and corticosteroids into ocular tissues very limited clinical studies have been undertaken to evaluate the tolerance and potential of this drug delivery technique in humans.

In 2003, Iomed reported the ocular tolerance of a small surface applicator placed on the scleral surface in the cul de sac, with specific limitations in duration and intensity of the current to allow tolerance in patients (Parkinson et al. 2003a, b). In order to avoid irritation, not only the current and duration but also the probe placement and the pH of the drug during iontophoresis must be controlled. Moreover,

Fig. 15.8  Clinical tolerance of CCI on patients with severe intraocular inflammation. (a) Picture of the eye of a patient, before CCI, during CCI and immediately after CCI. (b) Subjective tolerance of CCI on 93 patients receiving 263 treatments

with the tissue resistance varying during the procedure, the delivered current must be adapted to these tissue changes.

In 2004, we published a portion of our results of a large clinical study evaluating the tolerance and efficacy of iontophoresis of methylprednisolone sodium succinate (Solumedrol) on patients with severe intraocular inflammation. Between April 1999 and October 2001, 93 patients were included in a study designed to evaluate the tolerance of transscleral iontophoresis. Patients with severe intraocular inflammation requiring systemic corticosteroids were included in the study and received instead of the systemic therapy, transscleral iontophoresis of sodium succinate methylprednisolone 62.5 mg/mL. Intensity of the current was 1.7 ± 0.18 mA for 3 min and the patients received 1–5 treatments, mean 2.7 ± 0.9.

As shown in Fig. 15.8, the treatment was well tolerated with 86% of the patients experiencing none to slight pain during the procedure. Seventeen patients were treated for acute graft rejection with iontophoresis of methylprednisolone in place of systemic pulsetherapy. As published in 2004, we showed that this local treatment allowed to reverse the rejection with an efficacy comparable to the known effects of pulse therapy in this indication (Halhal et al. 2004) (Fig. 15.9). Already at day 10, and after three iontophoresis, 88% demonstrated a complete reversal of the rejection processes. In two eyes, only a partial and temporary improvement was observed.