(467b) Developing Thin, Drug-Eluting Topical Ocular Gels Formed By Administration of Low Concentration, Thermoreversible Polymer Solutions in Hypotonic Aqueous Vehicles

Problem: Eye drops are the most common ophthalmic pharmaceutical dosage form for treating and preventing ocular diseases. However, it is estimated that <5% of drugs dosed topically will be absorbed into the eye, while the rest is rapidly removed from the ocular surface. Therefore, many eye drops must be dosed multiple times per day to reach therapeutics levels, which unfortunately reduces patient compliance. Here, we engineered an in situ gelling hypotonic eye drop formulation that form a uniform, thin, and clear gel layer that resides longer on the ocular surface and delivers the drugs to the eye for a prolonged period of time.

Methods: Pluronic F127 (aka Poloxamer 407) was selected due to thermosensitive gelling properties and use in FDA-approved products. Multiple-particle tracking (MPT) was used to assess in vivo gelation properties. Fluorescently-labeled 200 nm PEGylated nanoparticles were added to eye drop formulations (0.0004% w/v) and dosed (5 µL) topically to Sprague Dawley rat eyes (n = 4-7 per group). An epifluorescence microscope were used to take time-lapse videos to calculate the ensemble-averaged mean square displacement (MSD). For the intraocular pressure (IOP) lowering efficacy study, the hypotonic gel-forming eye drop was formulated containing 0.15% w/v brimonidine tartrate (12% Hypo BT) and compared to both conventional thermogels formulated at the CGC (18% Iso BT) and commercially available Alphagan® P 0.15% eye drops. A single dose (50 µL) was topically administered to the eye of normotensive rabbits (n = 5-6 per group) and the IOP were measured with hand-held rebound tonometer (TonoVet) at various times up to 10 h. For posterior pharmacokinetics studies, the hypotonic gel-forming eye drop was formulated containing 0.4% w/v sunitinib malate (12% Hypo SM). Juvenile Yorkshire pigs (n = 4) were dosed daily with 12% Hypo SM for 5 days. The retina and choroid were collected 1 h after the last dose, and drug concentrations were measured by liquid chromatography–tandem mass spectrometry.

Results: We discovered that by formulating the polymer below the critical gel concentration (CGC) with ion content lower than physiological conditions, a thin, uniform gel layer could be formed over the ocular surface. The in vivo MPT study confirmed that the hypotonic 12% F127 solutions formed a gel structure on the ocular surface as evidenced by the low particle MSD, similar to the conventional 18% F127 gel. In the IOP lowering efficacy study, we demonstrated that 12% Hypo BT formulation provided the most significant and sustained decrease in IOP, which was still significant compared to the Alphagan® P (p < 0.0036) and 18% isotonic BT (p < 0.0012) at 10 h. Finally, we sought to test if the hypotonic gel-forming eye drop could deliver therapeutically relevant drug concentrations to the posterior segment in larger animals with eyes more similar in size to human eyes. The drug concentrations in the retina (140 ng/g) and choroid/retinal pigment epithelium (226 ng/g) were well above the Ki for SM inhibition of vascular endothelial growth factor receptor and platelet-derived growth factor receptor after topical dosing with 12% Hypo SM for 5 days.

Implications: Here we describe an innovative discovery for formulating thermosensitive in situ gelling polymers for enhanced topical ocular drug delivery. We characterized the 12% hypotonic gelling formulation properties and demonstrated more sustained IOP lowering compared with commercial Alphagan® P formulation. We further observed that the 12% hypotonic gelling formulation provided therapeutically relevant drug delivery to the posterior segment in large animals, demonstrating the potential for posterior segment delivery with an eye drop in a human-sized eye. Longer lasting and more sustained ocular drug delivery can reduce eye drop dosing frequency and improve patient quality of life.