OCULAR DRUG DELIVERY

Iontophoresis offers many opportunities for non-invasive delivery of drugs in a large number of ophthalmic applications, Joseph Frucht-Pery MD told a session of the 7th International Conference on Ocular Infections in Barcelona, Spain.

“Iontophoresis is a non-invasive technique in which a small electric current is applied in order to enhance penetration of ionized drug into tissue. When applied transcorneally, it can deliver a high drug concentration to the cornea, aqueous humour, ciliary body, iris and lens. This has the potential to treat corneal ulcers, keratitis, glaucoma, dry eyes and ocular inflammation,” said Dr Frucht-Pery.

The limitations of the current modalities of ophthalmic drug delivery are well known. Topical solutions are diluted by tears and washed away within minutes. Suspensions provide longer contact with the ocular surface, but the drug particles can cause irritation.

Ointments and emulsions can blur vision and do not offer controlled drug release. And gels, although comfortable, also do not allow for a controlled rate of diffusion. Regarding more invasive treatments, intravitreal injections carry risks of infection and retinal detachment, while subconjunctival drug application can in rare instances lead to scleral perforation.

Iontophoresis has several advantages over traditional topical medications. Retention of the drug at the administration site, forming a depot that allows for prolonged drug release, increases bioavailability.

The absence of preservatives helps avoid topical toxicity. This combination might lead to increased compliance, in part due to a reduction in the number of required administrations. Also, because the drug is delivered locally and enters the ocular tissue immediately, the chances of systemic side effects are diminished.

SAME CHARGE

“In iontophoresis, the drug and the electrode carry the same charge, while the ground electrode, which in the case of ocular administration is attached to the ear, is of the opposite charge. It works best when the drug in question is a small, charged molecule such as an antibiotic,” said Dr Frucht-Pery, of Hadassah University Hospital, Jerusalem, Israel.

Two types of devices are the eye cup and the gel probe. Dr Frucht-Pery helped design an iontophoresis device with a disposable hydrogel probe. The hydrogel, 5mm in diameter, is soft and flexible and is first placed in a drug solution, where it becomes saturated with the treatment drug. This is then pressed against the cornea, for anterior segment disease, or against the sclera for posterior segment pathology.

“The possibility of targeting internal ocular tissue through non-corneal routes is intriguing,” noted Dr Frucht-Pery.

SUCCESSFUL PENETRATION

Experiments in rabbits demonstrated successful penetration of antibiotics into the cornea and anterior chamber. Gentamicin, applied via transcorneal iontophoresis, was detected at therapeutic levels in the cornea more than eight hours after treatment. This allows less frequent administration than hourly drops now used for severe keratitis.

“In experimental keratitis in rabbit eyes by intrastromal injection of pseudomonas aeruginosa, transcorneal iontophoresis of gentamicin, tobramycin and ciprofloxacin resulted in significantly fewer bacterial colony-forming units in the cornea, as compared with frequent instillation of eye drops,” said Dr Frucht-Pery. The difference was three log units, or a factor of one thousand fewer units after iontophoresis.

Drugs delivered transcorneally cannot reach the posterior segment, due to the lens barrier. However, transscleral iontophoresis can also deliver drugs directly into the vitreous and retina.

“The iontophoretic device is placed on the conjunctiva. This must be located over the pars plana, to avoid electrical toxicity to the retina,” said Dr Frucht-Pery. The goal is to avoid the complications of intravitreal injection, and studies have demonstrated successful delivery of antibiotics to the vitreous of rabbit eyes.

But what about the potential for toxicity using this technique? In toxicity studies in rabbit corneas, toxicity was related to the strength of the current and the duration of the procedure. Aberrations included epithelial defects and mild stromal oedema. However, transscleral iontophoresis showed no damage on light microscopy.

Transscleral iontophoresis with low current densities can provide effective concentration of antibiotics for hours in the cornea, aqueous humour, vitreous and retina, he said.

Joseph Frucht-Pery: josefr@hadassah.org.il