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Drew Wassel, Rafal Farjo, Fadee Mondalek; Development of Fenofibrate Eyedrop Emulsions for Targeted Delivery Into the Eye. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4617.
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Peroxisome proliferator-activated receptor alpha (PPARα) activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis. Oral delivery of Fenofibrate, a small molecule agonist of PPARα, has conferred a significant reduction in the progression and severity of diabetic retinopathy in two large clinical trials, The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. Due to its low aqueous solubility, it is difficult to formulate as a classic eye drop, so we sought to develop an emulsion based eye drop that can deliver therapeutic concentrations of fenofibrate into the eye. We also assessed whether fenofibrate could be converted to the active metabolite, fenofibric acid, following topical installation.
Four different emulsions were prepared and evaluated for ocular penetration in C57Bl/6 mice. The size of the oil droplets in the emulsions were approximately 150 nm in diameter. All formulations were made up of oils and surfactants that are commonly used in ophthalmic formulations and take from the FDA’s inactive ingredients list. The study was conducted for 5 days with Q.I.D. topical instillation of 7 ul of three 3.0% fenofibrate emulsions and one 0.5% emulsion. At study termination, the eyes were enucleated, homogenized to a concentration of 125 mg/ml in PBS, and the amounts of fenofibrate and fenofibric acid in the entire eye was quantified using LC-MS/MS.
Following topical administration of the various eye drop formulations, it was observed that all three 3% emulsions delivered 51.9 ± 39.0, 20.8 ± 12.5, 19.0 ± 14.4 ng of fenofibrate per gram of eye tissue and 40.3 ± 7.6, 35.2 ± 6.2, 36.5 ±14.2 ng of fenofibric acid per gram of eye tissue. The concentration of fenofibrate in the 0.5% formulation was below the LLOQ (7.84 ng/g) however fenofibric acid was detected at a concentration of 9.1 ±1.1 ng/g.
Fenofibrate can be formulated into emulsion eye drops which can deliver significant amounts into the eye. Furthermore, fenofibrate can be metabolized into its active form, fenofibric acid, inside of the eye, even at low drug loadings of 0.5% w/w.
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