A few ocular iontophoresis systems have been investigated recently: Ocuphor1 (Iomed Inc., USA) (Parkinson et al. 2003a, b), Eyegate II Delivery System1 (EyeGate Pharma, USA) (Halhal et al. 2004) and Visulex1 (Aciont Inc., USA) (Higuchi et al. 2006). These devices avoid adverse effects that were frequently observed in the past studies with higher electrical current densities [58, 59]. These devices are also easier to use than the older iontophoretic systems. Eyegate II Delivery System (Halhal et al. 2004) is the first and only device used in the patients to date. On the basis of the first experiences it is effective, easy to use and well tolerated.

15.3  Ophthalmic Applications of Iontophoresis

15.3.1  Transconjunctival Iontophoresis

15.3.1.1  Transconjunctival Iontophoresis of Antimitotics

Transconjunctival iontophoresis of 5-fluorouracil (5-FU) was investigated (Kondo and Araie 1989) in a rabbit for the inhibition of sub-conjunctival and scleral fibroblast proliferation. Using low (0.32 mA/cm2) current density for times as short as 30 s, the acute 5-FU concentration in the conjunctiva was 480 and 168 mg/mL in the sclera. At post treatment times of 10 h it was 0.6 and 1.2 mg/mL, respectively, still above ID50 levels for cultured conjunctival fibroblasts. The amount of 5-FU introduced by iontophoresis was approximately 0.1% of the dose given to patients by subconjunctival injections.

15.3.1.2  Transconjunctival Iontophoresis of Anesthetics

Sisler (1978) reported that iontophoresis of lidocaine could be used for palpebral surgery. Iontophoresis of lidocaine to tarsal conjunctiva from a cotton pad was performed in 27 patients prior to surgical excision of intraand sub-conjunctival lesions. The excision was painless for 24 patients, while three others required a local injection of the anesthetic.

15.3.2  Transcorneal Iontophoresis

Transcorneal iontophoresis has been used to deliver fluorescein, antibiotics and antiviral drugs into the cornea and the aqueous humor. This delivery results in high and sustained drug concentrations in the cornea and the aqueous humor, but in low drug concentrations in the posterior segment of phakic eyes.

15.3.2.1  Transcorneal of Fluorescein Iontophoresis for Aqueous Humor Dynamic Studies

In 1966, Jones and Maurice used iontophoresis using fluorescein and a slit lamp fluorophotometer to measure the rate of flow of aqueous humor in patients. Iontophoresis was performed with a 10% fluorescein solution, 2% agar and 0.1 solution of methylhydroxybenzoate as a preservative (Jones and Maurice 1966). No corneal lesions were observed on numerous patients who received iontophoresis with a 0.2 mA current intensity for 10–15 s. Similar results were obtained by Starr (1966) with a 1 min treatment. Tonjum and Green (1971) assayed the effect of current intensity and duration of treatment on rabbit eyes in vitro and demonstrated that fluorescein penetration in aqueous humor was optimal with a 0.5 mA current intensity for 10 s. In 1982, Brubaker used iontophoresis of fluorescein with a central 5 mm gel containing 2% agar and 10% fluorescein, with currents of 0.2 mA for 5–7 min in more than 1,000 patients without any lesions except for some epithelial defects (Brubaker 1982). This abrasion was caused by part of the apparatus that contained the agar and did not result from direct consequence of the iontophoresis. These studies demonstrated that under specific conditions, iontophoresis can be used safely on patients.

15.3.2.2  Transcorneal Iontophoresis of Antibiotics

The efficacy of transcorneal iontophoresis of antibiotics has been assayed both on pharmacokinetic studies and on corneal abscess models. Table 15.1 gives a summary of the main studies using transcorneal iontophoresis.

Hughes and Maurice (1984) reported on iontophoresis of gentamycin to uninfected rabbit eyes and showed rapid and sustained attainment of efficacious concentrations of drug in the cornea and aqueous humor. Fishman et al. (1984) iontophoresed gentamycin into aphakic rabbit eyes. Peak corneal and aqueous humor concentrations were obtained 30 min after iontophoresis (Table 15.1) while a peak vitreous concentration (10.4 mg/mL) was obtained 16 h after treatment. This demonstrates transcorneal iontophoresis could potentially deliver therapeutic antibiotic concentrations for the treatment of endophthalmitis in aphakic eyes (Fishman et al. 1984). Grossman et al. (1990) demonstrated that the concentration of gentamycin after iontophoresis resulted in higher and sustained gentamycin levels compared to subconjunctival injections. In addition, the combination of a 2% agar solution to the 10% gentamycin was found to lead to high drug concentrations in the cornea and the aqueous humor.

Iontophoresis of tobramycin has been demonstrated to be efficient in the treatment of experimental Pseudomonas aeruginosa keratitis in the rabbit (Rootman et al. 1988a, b). Transcorneal iontophoresis performed after 22 and 27 h inoculation resulted in “sterile” corneas in over half of the animals 1 h after the treatment. Tobramycin iontophoresis allowed a 106 average reduction in colony-forming units (CFUs) in the cornea relative to untreated corneas. Safety of tobramycin iontophoresis was demonstrated by Rootman et al. (1988a, b). Iontophoresis of tobramycin

delivered high concentrations to uninfected and pseudomonas-infected corneas, 20 times higher than fortified tobramycin (1.36%) drops (Hobden et al. 1988). Moreover, iontophoresis of 2.5% tobramycin resulted in a 103 reduction in the number of a tobramycin-resistant strain of Pseudomonas, demonstrating the potential of this method to deliver effective concentrations of pharmaceuticals (Hobden et al. 1989). In addition, Quinolone iontophoresis is an efficient way to treat Pseudomonas keratitis (Hobden et al. 1990). Interestingly, transcorneal iontophoresis of vancomycin was as efficient as subconjunctival injection. The peak concentration was 122.4 mg/mL after 2 h of iontophoresis and 14.7 mg/mL 4 h after 2.5 mg subconjunctival injection. This was the first report which demonstrated that a high molecular weight glycopeptide (1,448 Da) could be delivered by iontophoresis into the cornea and aqueous humor (Choi and Lee 1988).

More recently, iontophoresis using a hydrogel probe containing gentamicin was evaluated for the treatment of Pseudomonas keratitis in rabbit corneas. After iontophoretic treatment of gentamicin with a current of 0.5 mA, the logarithmic value of Pseudomonas CFUs was 2.96 ± 0.45 as compared to 7.62 ± 0.28 in the non-treated group. This demonstrated that corneal iontophoresis of gentamicin efficiently reduced Pseudomonas proliferation in the rabbit cornea (Frucht-Pery et al. 2006).

Studies were also carried out utilizing transcorneal iontophoresis for delivery of ciprofloxacin hydrochloride to the anterior chamber of the eye. Effect of current density (0.75–6.25 mA/cm2 applied for 5 min) on drug permeation and load through the cornea was investigated in vitro as well as ex vivo in a porcine cornea model. The drug loaded in the cornea increased with current density. After 5 min iontophoresis, the drug concentration in the fluid receiver compartment (in vitro) or in aqueous humor (ex vivo) was not significantly higher than control (in which electric current was not applied). Waiting for 6–12 h after a treatment of 5 min of iontophoresis, the concentrations of drug in aqueous humor in ex vivo studies were approximately 6–5-fold higher than control (130.12 ± 78.99 ng/mL). Cytotoxicity studies demonstrated the safety of the technique. The application of 6.25 mA/cm2 for 5 min was well tolerated. This study demonstrated that iontophoresis rapidly delivers ciprofloxacin into the cornea where a drug reservoir is formed, which eventually releases slowly into aqueous humor, eliciting sustained therapeutic effect (Vaka et al. 2008).

We used transcorneal iontophoresis to treat a fungal keratitis in a 51-year-old male patient who was referred with an existing diagnosis of fungal keratitis (Paecilomyces) in his left eye for 7 weeks. He was initially treated with fluoroquinolones and mild steroids, which worsened his condition. After the cultures were positive for Paecilomyces microorganism, he was started on miconazole 1% topical drops every hour and 400 mg ketoconazole orally. The patient responded to topical treatment and in 3 days his hypopyon regressed, but the central corneal infiltrate and the inflammation persisted. Over a 40-day follow-up period, the visual acuity gradually deteriorated (4/200 “E”), the infiltrate remained the same, anterior chamber inflammation increased, and a 0.5-mm hypopyon recurred. The patient was re-evaluated for an iontophoretic delivery of miconazole. A transcorneal iontophoretic applicator