Intraocular delivery of crystalline sorafenib provides sustained, potent inhibition of wet age-related macular degeneration.

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness worldwide. Anti-VEGF agents are very beneficial for nAMD, with intravitreal (IVT) delivery becoming the gold standard for treatment of nAMD and other retinal conditions. Incomplete response remains a major challenge, as does the requirement for high-frequency, repeat IVT injections, which pose a significant burden on patients. Many potential drug candidates have attractive pharmacodynamic profiles but are limited by their insolubility, precluding IVT administration. These include tyrosine kinase inhibitors (TKIs), which target multiple receptors regulating angiogenesis, including the VEGF receptors. Thus, there is a great need for alternative treatment approaches. To this end, we developed a crystallization formulation approach for sorafenib (SFB), a very hydrophobic anti-angiogenic, multi-receptor TKI, for sustained intraocular release. We evaluated the efficacy of this formulation in two mouse models of nAMD: laser-induced choroidal neovascularization (LI-CNV) and Vldlr knockout (Vldlr-/-). Crystalline sorafenib ("Crystal SFB") exhibited controlled, prolonged drug release across both an accelerated release assay in vitro and in C57BL/6 mice, with ∼13% remaining in the eye after 28 days in vivo. Further, a single IVT injection effectively suppressed both neovascularization and vascular leakage, two critical clinical parameters in nAMD, for at least 28 days. IVT administration of Crystal SFB did not have discernible adverse effects on intraocular pressure, retinal morphology assessed by OCT, or neuroretinal function as measured by ERG. These results suggest that Crystal SFB offers a promising alternative for long-term nAMD management and a proof-of-concept for ocular utilization of other crystallized drugs.