modification­ of extracellular space, pro-inflammatory and immune response, blood flow modification, alterations to morphology of retinal layers, hemorrhage, necrosis/apoptosis/paraptosis of tissue, fibrosis, and RPE hyperplasia all have been reported in conjunction with too much current or voltage, or too long a duration of application (Butterwick et al. 2007).

6. Pain: Electrostimulation of pain receptors occurs when the current is applied rapidly. For iontophoresis, slowly changing the current up or down prevents this sensation.

16.3.2.7  Possible Strategies to Improve Electric Field-Mediated Drug Delivery

1. Pretreatment of the targeted tissues with hyaluronidase increases the ratio of electrotransferred cells while reducing the need for high electric voltage, hence decreasing the risk of tissue damage.

2. In general, bigger electrodes offer a lower current density: There is a need for novel electrodes for ocular treatment depending on cell to be treated.

16.3.3  Experiences with Iontophoresis

Animal studies demonstrated how current and ions flow through the eye. An illuminating set of studies was the use of MRI to monitor iontophoresis in real time (Li et al. 2004, 2008; Molokhia et al. 2009). Manganese ions are detected by nuclear magnetic resonance, showing where the current is flowing within the eye in an electric field, and this analysis can be performed on live animals in real time while iontophoresis is in progress. In transscleral iontophoresis, manganese ions moved macroscopic distances within the eye of a living anesthetized rabbit. These ions penetrated the sclera. Via a transcorneal route, the manganese ions became fully distributed in the anterior chamber.

16.3.3.1  Examples of Iontophoresis

Iontophoresis to deliver drugs into the cornea has been used extensively in Europe (Hughes and Maurice 1984). Examples include: Iodide iontophoresis was used to treat dry eye symptoms in patients with ocular surface disease. Numerous classes of drugs have been delivered including antibiotics, antifungals, antivirals, antiinflammatories, and analgesics (Eljarrat-Binstock and Domb 2006). A 0.2 mA current level or 1.6 mA/cm2 density does not appear to cause damage (Hughes and Maurice 1984). No unpleasant sensation was described with a 0.2-mA current applied to the anesthetized human cornea. However, currents over 2 mA cause pain (Hughes and

Maurice 1984). These current levels caused muscular contractions in rabbits that were under general anesthesia. Also, switching a current of about 1 mA on and off caused a shock. Current should be applied and reduced gradually. Parel and colleagues (Behar-Cohen et al. 1997, 2002) developed a “coulomb-controlled” device that adjusts voltage and current if tissue resistance charges during iontophoresis. With this device, iontophoresis is safe up to 50 mA/cm2 for 5 min. Tissue properties change during and after iontophoresis. Present hypotheses are that barriers within or surrounding tissues are altered by exposure to the electric field. These alterations may increase permeability of the tissue to the flow or diffusion of a drug after iontophoresis.

In addition to current flow, proper electrode placement is important in transscleral iontophoresis. Placement of one electrode at the pars plana provides maximal delivery of a drug into the vitreous. Ongoing experiments will test whether the par plana exhibits the lowest electrical resistance or whether the pars plana is most vulnerable to barrier breakdown during iontophoresis (Molokhia et al. 2008).

Li and colleagues discovered that iontophoresis could be used to create a drug depot in the sclera that subsequently undergoes sustained drug release. This strategy reduces the number and frequency of iontophoretic treatments. Triamcinolone acetonide phosphate was delivered into the eye from one electrode, and calcium ions were supplied from the other electrode simultaneously. Calcium ions and the phosphate moiety on the triamcinolone acetonide analog precipitate when they come into contact, forming a reservoir of drug in the sclera. The precipitate dissolved slowly, providing a slow-release formulation of drug that could be used to treat uveitis in an animal model. The slow release formulation was effective over long periods of time and prevented symptoms (Higuchi et al. 2007).

16.3.3.2  Summary of the Strengths and Weaknesses of Iontophoresis

Strengths – Over short distances, high concentrations of drugs can be delivered in a short period of time. These treatments are clinically useful and are in common practice in Europe. Iontophoresis is a method of choice for charged drugs, which pose difficulties in crossing membranes and hydrophobic barriers. Iontophoretic pretreatment increases delivery into the eye in vivo, suggesting that electric fields increase the permeability of biological matrices or membranes.

Weaknesses – It is impractical to transport drugs macroscopic distances (~1–2 cm) from the anterior surface of the cornea to the posterior segment of the eye by iontophoresis due to the weak electric field applied across the eye, the low mobility of drugs, and short duration of treatment. Anterior segment structures may be sensitive to electric field strength, and it appears necessary and advantageous to avoid current flow through or near these structures. For delivery to the posterior segment, the transscleral, not transcorneal, route appears to be the better approach. As with all new drug delivery approaches, careful consideration and evaluation of collateral tissue damage, both intraocular and extraocular, is needed.