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Small-molecule drugs are being developed for topical application via the transconjunctival/transscleral route. The topical drugs that are under development have shown good posterior segment penetrance, safety, and efficacy in animal models. Clinical studies are now under way.
Irvine, CA-Topical therapy to treat posterior segment disease is possible despite the limitations of the blood-retinal barrier. Transcorneal or transconjunctival/transscleral routes of drug penetrance of topical therapy are effective.
A few such drugs are under development, and the hope is that they will eliminate the complications associated with intravitreal injections of drugs, said Baruch Kuppermann, MD, PhD, chief of the retina service, Department of Ophthalmology, University of California, Irvine.
"Topical ocular drops are the most commonly used delivery route for ocular drug treatment," Dr. Kuppermann said.
"The transcorneal route has many features. The cornea allows passage of drugs that are both hydrophobic and hydrophilic, but if the drug is purely polar or purely nonpolar, the drug will not penetrate the cornea as well," Dr. Kuppermann said. "Regarding the transconjunctival route, if the corneal surface is mechanically blocked, there seems to be little effect on drug penetration into the posterior tissues. This supports the notion of the effectiveness of the transscleral pathway. The sclera has a large and accessible surface area and a high degree of hydration that renders it conductive to water-soluble substances. The sclera is relatively devoid of cells, and the sclera has few proteolytic enzymes or protein-binding sites that can degrade or sequester drugs."
An important factor is that patient age does not affect the permeability of the scleral tissue, he added.
Several new topically administered drugs are being developed to treat choroidal neovascularization (CNV), Dr. Kuppermann said.
One, TG100801 kinase inhibitor (TargeGen), has activity against vascular endothelial growth factor (VEGF) receptor/PDGF receptor/Src family kinases and stops leakage, angiogenesis, and inflammation. In animal studies, the drug has been shown to have high concentrations in the anterior segment, lower effective concentrations in the posterior segment, very low concentrations in the aqueous and vitreous, and extremely low concentrations in the plasma.
The results of preclinical studies indicated that the drug decreases VEGF-induced leakage response by about 60% after one topical application; increased dosing reduced the leak response even further. Topical application of the drug reduced retinal edema 26% to 47%. Application of eye drops three times a day prevented laser-induced CNV by about 47% compared with controls.
ATG003 (mecamylamine) (CoMentis) is a powerful nonselective nAChR antagonist that has reduced angiogenesis in animal models and inhibits VEGF synthesis and release and responses. Topical mecamylamine, a small molecule with a molecular weight of 167, was seen to penetrate the retina-choroid in mice, probably by the transconjunctival/transscleral route.
OC-10X (OcuCure Therapeutics) is a nontoxic vascular targeting agent with selective tubulin inhibition that also is a small molecule with a molecular weight of about 300. The agent is lipid-soluble and crosses the human cornea; it achieves therapeutic concentrations at the retina-choroid. In rats, the drug, when given once every hour for 4 hours, achieved a corneal level of 100%, a lens/vitreous level of 11%, and a retina-choroid-sclera level of 83%. This drug is not yet in clinical trials.