Esther Eljarrat-Binstock

New techniques for drug delivery to the posterior eye segment.

ABSTRACTOcular drug delivery has become an increasingly important field of research especially when treating posterior segment diseases of the eye, such as age-related macular degeneration, diabetic retinopathy, posterior uveitis and retinitis. These diseases are the leading causes of vision loss in developed countries which require repeated long-term administration of therapeutic agents. New drugs for the medication of the posterior ocular segment have emerged, but most drugs are delivered by repeated intravitreal injections associated with ocular complications. Advances in ocular drug delivery system research are expected to provide new tools for the treatment of the posterior segment diseases, providing improved drug penetration, prolonged action, higher efficacy, improved safety and less invasive administration, resulting in higher patient compliance. This review provides an insight into the recent progress and trends in ocular drug delivery systems for treating posterior eye segment diseases, with an emphasis on transscleral iontophoresis.

Charged nanoparticles delivery to the eye using hydrogel iontophoresis.

Ocular iontophoresis has been investigated for many years as a non-invasive technique for enhancing ionized drug penetration through ocular tissues. In this study we assessed the penetration of charged fluorescent nanoparticles into rabbit eyes using hydrogel iontophoresis. Particle distribution into ocular tissues and penetration efficiency of negative nanoparticles compared with positive nanoparticles was also evaluated. Cathodal and anodal iontophoretic administrations were performed using polyacrylic hydrogels loaded with charged nanoparticle suspension (20-45 nm), applying a current intensity of 1.5 mA for 5 min onto the cornea and sclera. At pre-set time points post treatment, eyes were dissected and tissues were evaluated for fluorescence intensity. Strong fluorescence evidence was observed at anterior and posterior ocular tissues. Negative particle distribution profile revealed fast uptake into the outer ocular tissues, within 30 min post treatment, followed by particle migration into the inner tissues up to 12 h post treatment. The positively charged particles demonstrated better penetration abilities into inner ocular tissues compared to the negatively charge particles. This work provides an opening for the development of a new ocular therapeutic pathway using iontophoresis of extended release drug-loaded charged nanoparticles.

Hydrogel probe for iontophoresis drug delivery to the eye.

The aim of this study was to evaluate the use of a solid hydrogel loaded with a drug solution as a probe for ejecting drugs to the eye upon application of low current iontophoresis. Hydroxyethyl methacrylate (HEMA), cross-linked with ethylene glycol dimethacrylate (EGDMA), and cross-linked arabinogalactan or dextran were prepared to form solid hydrogels. The hydrogels were examined for their mechanical suitability, absorption of drug solution and in vitro release properties when applying an iontophoretic current through the drug-loaded hydrogel into a solid-agar surface. Transconjunctival and transscleral iontophoresis of gentamicin sulfate was studied in healthy rabbits using drug-loaded disposable HEMA hydrogel disc probes. Gentamicin concentrations in different eye segments were assayed using a fluorescence polarization immunoassay. Preliminary corneal toxicity was examined in rabbits using a current intensity of 2.5 and 5.1 mA/cm2 for 60 and 120 s. The most appropriate hydrogel is composed of HEMA, 2% EGDMA and 75% water. Iontophoresis onto agar gel was found indicative for the evaluation of iontophoretic activity of a hydrogel. Transscleral iontophoretic treatment resulted in high concentrations of drugs in the posterior segments of the eye. Application of iontophoresis onto the rabbit eye caused a reversible swelling of the cornea which lasted a few hours after application. Low current iontophoresis using drug-loaded hydrogel has a potential clinical value in obtaining high drug concentration at posterior segments of the eye.

Methylprednisolone delivery to the back of the eye using hydrogel iontophoresis.

AIM The aim of this study was to evaluate methylprednisolone penetration into ocular structures after low-current trans-scleral hydrogel iontophoresis, as compared with the common intravenous (i.v.) treatment. METHODS Methylprednisolone hemisuccinate (MPH) iontophoresis was studied in rabbits, using drug-loaded hydrogels mounted on a portable iontophoretic device. Cathodal iontophoresis of 2.6 mA/cm(2) was applied for 5 min at two opposite sites on the sclera or for 10 min at the same site. Ocular drug levels were determined 2 h after iontophoretic treatment, then compared to mock iontophoresis and i.v. infusion of 10 mg/kg methylprednisolone. RESULTS Significantly higher methylprednisolone levels were found in ocular tissues after iontophoresis, compared with the control groups, except for the sclera concentrations, which were similar to the concentrations achieved after mock iontophoresis. Two (2) h after the trans-scleral iontophoretic treatment, 178.59 +/- 21.63 microg/g, 6.74 +/- 2.38 microg/ml, and 2.71 +/- 0.57 microg/mL were found in the retina, aqueous humor, and vitreous, respectively. No significant differences were found between one or two site treatments of trans-scleral iontophoresis. Nondetectable concentrations were found 2 h after the i.v. infusion of 10 mg/kg of methylprednisolone in all evaluated ocular tissues and fluids. CONCLUSIONS A short, low-current noninvasive iontophoretic treatment, using methylprednisolone-loaded hydrogels, has potential clinical value in treating ocular inflammatory diseases.

Iontophoretic treatment of experimental pseudomonas keratitis in rabbit eyes using gentamicin-loaded hydrogels.

Purpose: To evaluate the efficacy of iontophoresis using a hydrogel probe containing gentamicin for the treatment of Pseudomonas keratitis in the rabbit cornea. Methods: Five groups (Groups 1-5) of 8 rabbits each were infected by injecting Pseudomonas aeruginosa into their corneas. Three dosings of corneal iontophoresis were performed, at intervals of 3.5 hours, using soft disposable gentamicin-loaded hydroxyethyl methacrylate hydrogel discs mounted on a portable iontophoretic device. Groups 1 and 2 were treated with corneal iontophoresis for 60 seconds and a current of 0.5 and 0.2 mA. Groups 3 and 4 were treated with hydrogel loaded with 0.9% NaCl solution, using a current of 0.2 mA and mock iontophoresis. Group 5 was treated with eye drops of 1.4% gentamicin every hour for 8 hours. One and a half hours after the last treatment, the animals were killed, and the corneas were excised and cultured for P. aeruginosa count after 24-hour incubation. Results: After iontophoretic treatment of gentamicin with a current of 0.5 mA (Group 1), the logarithmic value of Pseudomonas colony-forming units (CFUs) was 2.96 ± 0.45. After lower current iontophoretic treatment (Group 2), the logarithmic Pseudomonas count was 5.25 ± 0.54 CFUs. At the control groups (Groups 3-5), the Pseudomonas counts were found to be much higher, 7.62 ± 0.28, 7.22 ± 0.29, and 6.29 ± 0.45 CFUs, respectively. Conclusion: A short iontophoretic treatment using gentamicin-loaded hydrogels has potential clinical value in treating corneal infections.

In Vitro and In Vivo Evaluation of Carboplatin Delivery to the Eye Using Hydrogel-Iontophoresis

Purpose: To investigate in vitro and in vivo hydrogel-iontophoresis delivery of carboplatin to the eye. Methods: Iontophoresis was applied on agar gels resembling the eye using different current intensities and durations. Transscleral iontophoresis was performed on healthy rabbits, applying 0, 1, and 3 mA current for 10 min. Results: Similar drug concentrations were obtained in all experimental groups, in in vitro and in vivo studies, regardless of the iontophoretic current applied. A 20-mm penetration depth was found for carboplatin at the agar model. High drug levels were found at the sclera and retina, while lower levels were found at ocular fluids. Conclusion: Carboplatin-iontophoretic application at the above conditions does not have an obvious advantage over passive penetration due to high diffusion properties and insufficient molecular charge. Passive carboplatin diffusion from loaded hydrogels inserted in the lower cul-de-sac should be further investigated as a potential clinical treatment for intraocular retinoblastoma.

Hydrogel iontophoresis for gentamicin administration to the rabbit eye

Iontophoresis (IONT) is a non-invasive technique in which a low electric current is used to enhance the penetration of charged molecules into tissue. This technique has been used in various fields of medicine, mostly in transdermal drug delivery. This study was aimed to evaluate the efficacy and the distribution profile of gentamicin using corneal IONT on infected and healthy rabbit eyes. Corneal iontophoresis of gentamicin sulfate was studied using drug-loaded disposable hydrogel probes mounted on a portable iontophoretic device, applying a low current for 60 seconds. This study confirmed that a triple iontophoretic treatment of gentamicin for only 60 seconds (0.5mA) significantly reduces the count of pseudomonas in the infected cornea to a non-infectious level. Peak gentamicin concentrations at the healthy corneas (363.1 ± 127.3 μg/g) and at the aqueous humor (29.4 ± 17.4 μg/ml) were reached immediately and two hours after a single iontophoretic treatment, respectively. The concentration versus time profile of gentamicin following iontophoresis revealed a gentamicin half life of 2.07 h in the anterior chamber, and a clearance of 1.73 μl/min from the anterior chamber to the posterior segments of the eye. This study indicates that a short iontophoretic treatment using gentamicin-loaded hydrogels has a potential clinical value in treating corneal infections, by increasing drug penetration to the eye and maintaining therapeutic levels for more than eight hours.