August 2010

 

OPHTHALMOLOGY NEWS

 

Beyond the physics of drug delivery


by Matt Young EyeWorld Contributing Editor

   

While age-related macular degeneration (AMD) has been treated with intravitreal injections in the past, a new method using electric current to deliver drugs could offer a futuristic exception to the needle rule. "The drug-delivery technology uses a series of optimally tuned AC signals applied with a custom-designed combination of successive electrodes that induces temporary polarisation, preconcentrates and enhances mobility in AMD drugs, thus making them candidates for active transcleral drug delivery," reported lead study author Rishi P. Singh, M.D., Cole Eye Institute, Cleveland. "This unique pattern of specifically tuned frequencies determined individually for each drug works to first align the drug for delivery inside the electro-chemical-based drug delivery system, and then drive the drug through the sclera."

The method, called Macroesis (Buckeye Pharmaceuticals, Beachwood, Ohio), is interesting beyond just the physics. "Intravitreal injections have been associated with significant side effects such as pain, infection, bleeding and retinal detachment," Dr. Singh noted. "Beyond the socio-economic impact of monthly patient visits, intravitreal injections must be administered by an ophthalmologist and place significant demands on ophthalmic practices given the growth of the number of patients with AMD." Macroesis, alternatively, offers advantages including increased patient safety and the ability for patients to administer drug doses at home on their own or with the help of a nurse in an office setting. Dr. Singh put macroesis to the test in two preclinical models of drug delivery, with promising results published in the February issue of the British Journal of Ophthalmology.

New drug delivery in the making

Dr. Singh analyzed two models of drug delivery involving ranibizumab (Lucentis, Genentech, South San Francisco, Calif.) and triamcinolone acetonide to ocular tissue. "In the first model, full-thickness sections of rabbit ocular tissue (conjunctiva to retina) were placed on an interdigitated electrode platform, and the drug was placed on the surface of the tissue," Dr. Singh reported. "A non-uniform electrical field was applied to the ocular tissue, and electrical conductivity, a measurement of drug delivery, was monitored during the course of the experiment."

The second model was called the simulated vitreous model. "The same full-thickness sections of rabbit ocular tissue were mounted below the electrode device, and the test compounds were placed on the electrodes," Dr. Singh reported. "The fluid below the tissue, which simulated the vitreous cavity, was analysed using UV spectroscopy at the end of the study for the presence of drug."

It was clear in both models that the drug moved to the target areas. "In the electrical conductivity studies, the electric characteristics of the tissue-drug system clearly showed movement of the drug through the tissue to the dielectric sensor based on changes in the electrical conductivity of the tissue sample with triamcinolone," Dr. Singh reported. "No change in tissue conductivity was observed when no drug was placed."

In the simulated vitreous model, research using triamcinolone resulted in concentrations ranging from 0.280 to 0.970 mg/ml. Variations in concentration were dependant on the voltage, frequency, and time applied. "In as little as 6.7 min, clinically efficacious doses could be obtained in the preclinical system," Dr. Singh reported. Attained concentrations of ranibizumab, meanwhile, ranged from 0.070 to 0.171 mg/ml. "In as little at 6.7 min, 92.8% throughput could be achieved," Dr. Singh reported. Notably, no heat generation occurred during the study, and there was no gross tissue destruction either. "Similar technologies using AC current have been used for delivery of steroids in dermal applications and in the delivery of antifungal drugs to human nail beds," Dr. Singh reported. John D. Sheppard, M.D., professor of ophthalmology, microbiology, and immunology, Eastern Medical School, Norfolk, Va., said Macroesis could prove to be a useful application of technology. "The ability of molecules to migrate based on charge or polarity is well established and beginning to be used in medicinal delivery," Dr. Sheppard said. "A negatively or positively charged molecule can be driven into the eye. Enhancing drug delivery through very small electrical charges is both safe and effective." Still, it may be difficult to get a large moleculelike ranibizumabinto the eye with such a method. Smaller molecules such as steroids may penetrate into the eye more easily, he said. "Nevertheless, more difficult drug delivery problems have been solved in the past," Dr. Sheppard said. Already, drug delivery methods are varied and increasingly ingenious, according to Dr. Sheppard. He cited Retisert (fluocinolone acetonide intravitreal implant, Bausch + Lomb, Rochester, N.Y.) as a smart sustained-release intravitreal drug implant for treating chronic non-infectious uveitis affecting the posterior segment.

He also mentioned Ozurdex (dexamethasone intravitreal implant, Allergan, Irvine, Calif.), a biodegradable implant administered via intravitreal injection delivering extended release dexamethasone. Ozurdex is placed in the vitreous cavity in the back of the eye to treat the macular edema associated with retinal vein occlusion. "These are pioneers in the field of delivery systems," Dr. Sheppard said.

Editors' note: Dr. Singh reported no financial interests related to this study. Dr. Sheppard has financial interests with Bausch + Lomb (Rochester, N.Y.).

Contact information

Sheppard: 757-622-2200, docshep@hotmail.com
Singh: singhr@ccf.org

Beyond the physics of drug delivery Beyond the physics of drug delivery
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