FIELD OF THE INVENTION

The present invention relates to stable aqueous pharmaceutical compositions of aflibercept, including compositions that are considered or intended to be a “biosimilar” of commercially available aflibercept products, methods of manufacture of the compositions, methods of their administration, and kits containing the same.

BACKGROUND OF THE INVENTION

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) regulates angiogenesis. Drugs that target VEGF-VEGFR interactions have demonstrated efficacy in treating ocular diseases. See Poz{dot over (a)}rowska et al. (2016) Cent Eur J Immunol 41(3): 311-316. A soluble VEGF-specific fusion protein antagonist, termed a “VEGF trap” was developed that interferes with binding of VEGF with its receptors. See, Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99:11393-8.

Aflibercept, developed by Regeneron Pharmaceuticals, Inc. is a 115 kDa recombinant fusion protein. It consists of an IgG backbone fused to extracellular Vascular Endothelial Growth Factor receptor sequences of the human VEGFR1 and VEGFR2 receptors. Aflibercept is a soluble decoy receptor that binds vascular endothelial growth factor-A (VEGF-A), VEGF-B, and placental growth factor (PIGF) with a greater affinity than the body's native receptors. Aflibercept's high affinity for VEGF prevents the subsequent binding and activation of native VEGF receptors. Reduced VEGF activity leads to decreased angiogenesis and vascular permeability. Inhibition of VEGF-B may also aid in the treatment of angiogenic conditions. VEGF-B overexpression has recently been connected with breakdown of the blood-retinal battier retinal angiogenesis. Aflibercept products have been approved by the FDA and are commercially available under the brand names of Eylea® and Zaltrap®.

Various formulations of aflibercept are known in the art. See, for example, Eylea®, Zaltrap®, U.S. Pat. Nos. 7,608,261; 7,807,164; 8,092, 803; 8,481,046; 8,802,107; 9,340,594; and 9,580,489. There is still need for stable liquid formulations of aflibercept suitable for ophthalmic administration.

BRIEF SUMMARY OF THE INVENTION

The invention provides stable aqueous formulations comprising aflibercept.

In general, the invention provides several types of aflibercept formulations: buffer-free formulations; formulations free of an organic co-solvent; and formulations that are free of both buffers and organic co-solvents.

In all embodiments of the invention, aflibercept can be present at concentrations of about 1 mg/mL to about 200 mg/mL, e.g., a concentration of about 1 mg/mL to about 190 mg/mL, about 1 mg/mL to about 180 mg/mL, about 1 mg/mL to about 170 mg/mL, about 1 mg/mL to about 160 mg/mL, about 1 mg/mL to about 150 mg/mL, about 1 mg/mL to about 140 mg/mL, about 1 mg/mL to about 130 mg/mL, about 1 mg/mL to about 120 mg/mL, about 1 mg/mL to about 110 mg/mL, about 1 mg/mL to about 100 mg/mL, about 1 mg/mL to about 90 mg/mL, about 1 mg/mL to about 80 mg/mL, about 1 mg/mL to about 70 mg/mL, about 1 mg/mL to about 60 mg/mL, about 1 mg/mL to about 50 mg/mL, about 1 mg/mL to about 45 mg/mL, about 1 mg/mL to about 40 mg/mL, about 1 mg/mL to about 35 mg/mL, about 1 mg/mL to about 30 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 20 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about 8 mg/mL, about 1 mg/mL to about 6 mg/mL, about 1 mg/mL to about 4 mg/mL, about 1 mg/mL to about 2 mg/mL, about 2 mg/mL to about 200 mg/mL, about 2 mg/mL to about 190 mg/mL, about 2 mg/mL to about 180 mg/mL, about 2 mg/mL to about 170 mg/mL, about 2 mg/mL to about 160 mg/mL, about 2 mg/mL to about 150 mg/mL, about 2 mg/mL to about 140 mg/mL, about 2 mg/mL to about 130 mg/mL, about 2 mg/mL to about 120 mg/mL, about 2 mg/mL to about 110 mg/mL, about 2 mg/mL to about 100 mg/mL, about 2 mg/mL to about 90 mg/mL, about 2 mg/mL to about 80 mg/mL, about 2 mg/mL to about 70 mg/mL, about 2 mg/mL to about 60 mg/mL, about 2 mg/mL to about 50 mg/mL, about 2 mg/mL to about 45 mg/mL, about 2 mg/mL to about 40 mg/mL, about 2 mg/mL to about 35 mg/mL, about 2 mg/mL to about 30 mg/mL, about 2 mg/mL to about 25 mg/mL, about 2 mg/mL to about 20 mg/mL, about 2 mg/mL to about 15 mg/mL, about 2 mg/mL to about 10 mg/mL, about 2 mg/mL to about 8 mg/mL, about 2 mg/mL to about 6 mg/mL, about 2 mg/mL to about 4 mg/mL, about 4 mg/mL to about 200 mg/mL, about 4 mg/mL to about 190 mg/mL, about 4 mg/mL to about 180 mg/mL, about 4 mg/mL to about 170 mg/mL, about 4 mg/mL to about 160 mg/mL, about 4 mg/mL to about 150 mg/mL, about 4 mg/mL to about 140 mg/mL, about 4 mg/mL to about 130 mg/mL, about 4 mg/mL to about 120 mg/mL, about 4 mg/mL to about 110 mg/mL, about 4 mg/mL to about 100 mg/mL, about 4 mg/mL to about 90 mg/mL, about 4 mg/mL to about 80 mg/mL, about 4 mg/mL to about 70 mg/mL, about 4 mg/mL to about 60 mg/mL, about 4 mg/mL to about 50 mg/mL, about 4 mg/mL to about 45 mg/mL, about 4 mg/mL to about 40 mg/mL, about 4 mg/mL to about 35 mg/mL, about 4 mg/mL to about 30 mg/mL, about 4 mg/mL to about 25 mg/mL, about 4 mg/mL to about 20 mg/mL, about 4 mg/mL to about 15 mg/mL, about 4 mg/mL to about 10 mg/mL, about 4 mg/mL to about 8 mg/mL, about 4 mg/mL to about 6 mg/mL, about 6 mg/mL to about 200 mg/mL, about 6 mg/mL to about 190 mg/mL, about 6 mg/mL to about 180 mg/mL, about 6 mg/mL to about 170 mg/mL, about 6 mg/mL to about 160 mg/mL, about 6 mg/mL to about 150 mg/mL, about 6 mg/mL to about 140 mg/mL, about 6 mg/mL to about 130 mg/mL, about 6 mg/mL to about 120 mg/mL, about 6 mg/mL to about 110 mg/mL, about 6 mg/mL to about 100 mg/mL, about 6 mg/mL to about 90 mg/mL, about 6 mg/mL to about 80 mg/mL, about 6 mg/mL to about 70 mg/mL, about 6 mg/mL to about 60 mg/mL, about 6 mg/mL to about 50 mg/mL, about 6 mg/mL to about 45 mg/mL, about 6 mg/mL to about 40 mg/mL, about 6 mg/mL to about 35 mg/mL, about 6 mg/mL to about 30 mg/mL, about 6 mg/mL to about 25 mg/mL, about 6 mg/mL to about 20 mg/mL, about 6 mg/mL to about 15 mg/mL, about 6 mg/mL to about 10 mg/mL, about 6 mg/mL to about 8 mg/mL, about 8 mg/mL to about 200 mg/mL, about 8 mg/mL to about 190 mg/mL, about 8 mg/mL to about 180 mg/mL, about 8 mg/mL to about 170 mg/mL, about 8 mg/mL to about 160 mg/mL, about 8 mg/mL to about 150 mg/mL, about 8 mg/mL to about 140 mg/mL, about 8 mg/mL to about 130 mg/mL, about 8 mg/mL to about 120 mg/mL, about 8 mg/mL to about 110 mg/mL, about 8 mg/mL to about 100 mg/mL, about 8 mg/mL to about 90 mg/mL, about 8 mg/mL to about 80 mg/mL, about 8 mg/mL to about 70 mg/mL, about 8 mg/mL to about 60 mg/mL, about 8 mg/mL to about 50 mg/mL, about 8 mg/mL to about 45 mg/mL, about 8 mg/mL to about 40 mg/mL, about 8 mg/mL to about 35 mg/mL, about 8 mg/mL to about 30 mg/mL, about 8 mg/mL to about 25 mg/mL, about 8 mg/mL to about 20 mg/mL, about 8 mg/mL to about 15 mg/mL, about 8 mg/mL to about 10 mg/mL, about 10 mg/mL to about 200 mg/mL, about 10 mg/mL to about 190 mg/mL, about 10 mg/mL to about 180 mg/mL, about 10 mg/mL to about 170 mg/mL, about 10 mg/mL to about 160 mg/mL, about 10 mg/mL to about 150 mg/mL, about 10 mg/mL to about 140 mg/mL, about 10 mg/mL to about 130 mg/mL, about 10 mg/mL to about 120 mg/mL, about 10 mg/mL to about 110 mg/mL, about 10 mg/mL to about 100 mg/mL, about 10 mg/mL to about 90 mg/mL, about 10 mg/mL to about 80 mg/mL, about 10 mg/mL to about 70 mg/mL, about 10 mg/mL to about 60 mg/mL, about 10 mg/mL to about 50 mg/mL, about 10 mg/mL to about 45 mg/mL, about 10 mg/mL to about 40 mg/mL, about 10 mg/mL to about 35 mg/mL, about 10 mg/mL to about 30 mg/mL, about 10 mg/mL to about 25 mg/mL, about 10 mg/mL to about 20 mg/mL, about 10 mg/mL to about 15 mg/mL, about 15 mg/mL to about 200 mg/mL, about 15 mg/mL to about 190 mg/mL, about 15 mg/mL to about 180 mg/mL, about 15 mg/mL to about 170 mg/mL, about 15 mg/mL to about 160 mg/mL, about 15 mg/mL to about 150 mg/mL, about 15 mg/mL to about 140 mg/mL, about 15 mg/mL to about 130 mg/mL, about 15 mg/mL to about 120 mg/mL, about 15 mg/mL to about 110 mg/mL, about 15 mg/mL to about 100 mg/mL, about 15 mg/mL to about 90 mg/mL, about 15 mg/mL to about 80 mg/mL, about 15 mg/mL to about 70 mg/mL, about 15 mg/mL to about 60 mg/mL, about 15 mg/mL to about 50 mg/mL, about 15 mg/mL to about 45 mg/mL, about 15 mg/mL to about 40 mg/mL, about 15 mg/mL to about 35 mg/mL, about 15 mg/mL to about 30 mg/mL, about 15 mg/mL to about 25 mg/mL, about 15 mg/mL to about 20 mg/mL, about 20 mg/mL to about 200 mg/mL, about 20 mg/mL to about 190 mg/mL, about 20 mg/mL to about 180 mg/mL, about 20 mg/mL to about 170 mg/mL, about 20 mg/mL to about 160 mg/mL, about 20 mg/mL to about 150 mg/mL, about 20 mg/mL to about 140 mg/mL, about 20 mg/mL to about 130 mg/mL, about 20 mg/mL to about 120 mg/mL, about 20 mg/mL to about 110 mg/mL, about 20 mg/mL to about 100 mg/mL, about 20 mg/mL to about 90 mg/mL, about 20 mg/mL to about 80 mg/mL, about 20 mg/mL to about 70 mg/mL, about 20 mg/mL to about 60 mg/mL, about 20 mg/mL to about 50 mg/mL, about 20 mg/mL to about 45 mg/mL, about 20 mg/mL to about 40 mg/mL, about 20 mg/mL to about 35 mg/mL, about 20 mg/mL to about 30 mg/mL, about 20 mg/mL to about 25 mg/mL, about 25 mg/mL to about 200 mg/mL, about 25 mg/mL to about 190 mg/mL, about 25 mg/mL to about 180 mg/mL, about 25 mg/mL to about 170 mg/mL, about 25 mg/mL to about 160 mg/mL, about 25 mg/mL to about 150 mg/mL, about 25 mg/mL to about 140 mg/mL, about 25 mg/mL to about 130 mg/mL, about 25 mg/mL to about 120 mg/mL, about 25 mg/mL to about 110 mg/mL, about 25 mg/mL to about 100 mg/mL, about 25 mg/mL to about 90 mg/mL, about 25 mg/mL to about 80 mg/mL, about 25 mg/mL to about 70 mg/mL, about 25 mg/mL to about 60 mg/mL, about 25 mg/mL to about 50 mg/mL, about 25 mg/mL to about 45 mg/mL, about 25 mg/mL to about 40 mg/mL, about 25 mg/mL to about 35 mg/mL, about 25 mg/mL to about 30 mg/mL, about 30 mg/mL to about 200 mg/mL, about 30 mg/mL to about 190 mg/mL, about 30 mg/mL to about 180 mg/mL, about 30 mg/mL to about 170 mg/mL, about 30 mg/mL to about 160 mg/mL, about 30 mg/mL to about 150 mg/mL, about 30 mg/mL to about 140 mg/mL, about 30 mg/mL to about 130 mg/mL, about 30 mg/mL to about 120 mg/mL, about 30 mg/mL to about 110 mg/mL, about 30 mg/mL to about 100 mg/mL, about 30 mg/mL to about 90 mg/mL, about 30 mg/mL to about 80 mg/mL, about 30 mg/mL to about 70 mg/mL, about 30 mg/mL to about 60 mg/mL, about 30 mg/mL to about 50 mg/mL, about 30 mg/mL to about 45 mg/mL, about 30 mg/mL to about 40 mg/mL, about 30 mg/mL to about 35 mg/mL, about 35 mg/mL to about 200 mg/mL, about 35 mg/mL to about 190 mg/mL, about 35 mg/mL to about 180 mg/mL, about 35 mg/mL to about 170 mg/mL, about 35 mg/mL to about 160 mg/mL, about 35 mg/mL to about 150 mg/mL, about 35 mg/mL to about 140 mg/mL, about 35 mg/mL to about 130 mg/mL, about 35 mg/mL to about 120 mg/mL, about 35 mg/mL to about 110 mg/mL, about 35 mg/mL to about 100 mg/mL, about 35 mg/mL to about 90 mg/mL, about 35 mg/mL to about 80 mg/mL, about 35 mg/mL to about 70 mg/mL, about 35 mg/mL to about 60 mg/mL, about 35 mg/mL to about 50 mg/mL, about 35 mg/mL to about 45 mg/mL, about 35 mg/mL to about 40 mg/mL, about 40 mg/mL to about 200 mg/mL, about 40 mg/mL to about 190 mg/mL, about 40 mg/mL to about 180 mg/mL, about 40 mg/mL to about 170 mg/mL, about 40 mg/mL to about 160 mg/mL, about 40 mg/mL to about 150 mg/mL, about 40 mg/mL to about 140 mg/mL, about 40 mg/mL to about 130 mg/mL, about 40 mg/mL to about 120 mg/mL, about 40 mg/mL to about 110 mg/mL, about 40 mg/mL to about 100 mg/mL, about 40 mg/mL to about 90 mg/mL, about 40 mg/mL to about 80 mg/mL, about 40 mg/mL to about 70 mg/mL, about 40 mg/mL to about 60 mg/mL, about 40 mg/mL to about 50 mg/mL, about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 200 mg/mL, about 45 mg/mL to about 190 mg/mL, about 45 mg/mL to about 180 mg/mL, about 45 mg/mL to about 170 mg/mL, about 45 mg/mL to about 160 mg/mL, about 45 mg/mL to about 150 mg/mL, about 45 mg/mL to about 140 mg/mL, about 45 mg/mL to about 130 mg/mL, about 45 mg/mL to about 120 mg/mL, about 45 mg/mL to about 110 mg/mL, about 45 mg/mL to about 100 mg/mL, about 45 mg/mL to about 90 mg/mL, about 45 mg/mL to about 80 mg/mL, about 45 mg/mL to about 70 mg/mL, about 45 mg/mL to about 60 mg/mL, about 45 mg/mL to about 50 mg/mL, about 50 mg/mL to about 200 mg/mL, about 50 mg/mL to about 190 mg/mL, about 50 mg/mL to about 180 mg/mL, about 50 mg/mL to about 170 mg/mL, about 50 mg/mL to about 160 mg/mL, about 50 mg/mL to about 150 mg/mL, about 50 mg/mL to about 140 mg/mL, about 50 mg/mL to about 130 mg/mL, about 50 mg/mL to about 120 mg/mL, about 50 mg/mL to about 110 mg/mL, about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to about 90 mg/mL, about 50 mg/mL to about 80 mg/mL, about 50 mg/mL to about 70 mg/mL, about 50 mg/mL to about 60 mg/mL, about 60 mg/mL to about 200 mg/mL, about 60 mg/mL to about 190 mg/mL, about 60 mg/mL to about 180 mg/mL, about 60 mg/mL to about 170 mg/mL, about 60 mg/mL to about 160 mg/mL, about 60 mg/mL to about 150 mg/mL, about 60 mg/mL to about 140 mg/mL, about 60 mg/mL to about 130 mg/mL, about 60 mg/mL to about 120 mg/mL, about 60 mg/mL to about 110 mg/mL, about 60 mg/mL to about 100 mg/mL, about 60 mg/mL to about 90 mg/mL, about 60 mg/mL to about 80 mg/mL, about 60 mg/mL to about 70 mg/mL, about 70 mg/mL to about 200 mg/mL, about 70 mg/mL to about 190 mg/mL, about 70 mg/mL to about 180 mg/mL, about 70 mg/mL to about 170 mg/mL, about 70 mg/mL to about 160 mg/mL, about 70 mg/mL to about 150 mg/mL, about 70 mg/mL to about 140 mg/mL, about 70 mg/mL to about 130 mg/mL, about 70 mg/mL to about 120 mg/mL, about 70 mg/mL to about 110 mg/mL, about 70 mg/mL to about 100 mg/mL, about 70 mg/mL to about 90 mg/mL, about 70 mg/mL to about 80 mg/mL, about 80 mg/mL to about 200 mg/mL, about 80 mg/mL to about 190 mg/mL, about 80 mg/mL to about 180 mg/mL, about 80 mg/mL to about 170 mg/mL, about 80 mg/mL to about 160 mg/mL, about 80 mg/mL to about 150 mg/mL, about 80 mg/mL to about 140 mg/mL, about 80 mg/mL to about 130 mg/mL, about 80 mg/mL to about 120 mg/mL, about 80 mg/mL to about 110 mg/mL, about 80 mg/mL to about 100 mg/mL, about 80 mg/mL to about 90 mg/mL, about 90 mg/mL to about 200 mg/mL, about 90 mg/mL to about 190 mg/mL, about 90 mg/mL to about 180 mg/mL, about 90 mg/mL to about 170 mg/mL, about 90 mg/mL to about 160 mg/mL, about 90 mg/mL to about 150 mg/mL, about 90 mg/mL to about 140 mg/mL, about 90 mg/mL to about 130 mg/mL, about 90 mg/mL to about 120 mg/mL, about 90 mg/mL to about 110 mg/mL, about 90 mg/mL to about 100 mg/mL, about 100 mg/mL to about 200 mg/mL, about 100 mg/mL to about 190 mg/mL, about 100 mg/mL to about 180 mg/mL, about 100 mg/mL to about 170 mg/mL, about 100 mg/mL to about 160 mg/mL, about 100 mg/mL to about 150 mg/mL, about 100 mg/mL to about 140 mg/mL, about 100 mg/mL to about 130 mg/mL, about 100 mg/mL to about 120 mg/mL, about 100 mg/mL to about 110 mg/mL, about 110 mg/mL to about 200 mg/mL, about 110 mg/mL to about 190 mg/mL, about 110 mg/mL to about 180 mg/mL, about 110 mg/mL to about 170 mg/mL, about 110 mg/mL to about 160 mg/mL, about 110 mg/mL to about 150 mg/mL, about 110 mg/mL to about 140 mg/mL, about 110 mg/mL to about 130 mg/mL, about 110 mg/mL to about 120 mg/mL, about 120 mg/mL to about 200 mg/mL, about 120 mg/mL to about 190 mg/mL, about 120 mg/mL to about 180 mg/mL, about 120 mg/mL to about 170 mg/mL, about 120 mg/mL to about 160 mg/mL, about 120 mg/mL to about 150 mg/mL, about 120 mg/mL to about 140 mg/mL, about 120 mg/mL to about 130 mg/mL, about 130 mg/mL to about 200 mg/mL, about 130 mg/mL to about 190 mg/mL, about 130 mg/mL to about 180 mg/mL, about 130 mg/mL to about 170 mg/mL, about 130 mg/mL to about 160 mg/mL, about 130 mg/mL to about 150 mg/mL, about 130 mg/mL to about 140 mg/mL, about 140 mg/mL to about 200 mg/mL, about 140 mg/mL to about 190 mg/mL, about 140 mg/mL to about 180 mg/mL, about 140 mg/mL to about 170 mg/mL, about 140 mg/mL to about 160 mg/mL, about 140 mg/mL to about 150 mg/mL, about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 190 mg/mL, about 150 mg/mL to about 180 mg/mL, about 150 mg/mL to about 170 mg/mL, about 150 mg/mL to about 160 mg/mL, about 160 mg/mL to about 200 mg/mL, about 160 mg/mL to about 190 mg/mL, about 160 mg/mL to about 180 mg/mL, about 160 mg/mL to about 170 mg/mL, about 170 mg/mL to about 200 mg/mL, about 170 mg/mL to about 190 mg/mL, about 170 mg/mL to about 180 mg/mL, about 180 mg/mL to about 200 mg/mL, about 180 mg/mL to about 190 mg/mL, or about 190 mg/mL to about 200 mg/mL, or a concentration of about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/m L, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 105 mg/mL, about 110 mg/mL, about 115 mg/mL, about 120 mg/mL, about 125 mg/mL, about 130 mg/mL, about 135 mg/m L, about 140 mg/mL, about 145 mg/mL, about 150 mg/mL, about 155 mg/mL, about 160 mg/mL, about 165 mg/mL, about 170 mg/mL, about 175 mg/mL, about 180 mg/mL, about 185 mg/mL, about 190 mg/mL, about 195 mg/mL, or 200 mg/mL.

Buffer-Free Formulations

In one embodiment, the invention provides an aqueous formulation comprising aflibercept, a stabilizer and an organic co-solvent, wherein the formulation is free of buffer.

In one embodiment, the formulation has a pH of about 5.5 to about 7.0 (e.g., about 5.5 to about 6.9, about 5.5 to about 6.8, about 5.5 to about 6.7, about 5.5 to about 6.6, about 5.5 to about 6.5, about 5.5 to about 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, about 5.5 to about 6.0, about 5.5 to about 5.9, about 5.5 to about 5.8, about 5.5 to about 5.7, about 5.6 to about 7.0, about 5.6 to about 6.9, about 5.6 to about 6.8, about 5.6 to about 6.7, about 5.6 to about 6.6, about 5.6 to about 6.5, about 5.6 to about 6.4, about 5.6 to about 6.3, about 5.6 to about 6.2, about 5.6 to about 6.1, about 5.6 to about 6.0, about 5.6 to about 5.9, about 5.6 to about 5.8, about 5.7 to about 7.0, about 5.7 to about 6.9, about 5.7 to about 6.8, about 5.7 to about 6.7, about 5.7 to about 6.6, about 5.7 to about 6.5, about 5.7 to about 6.4, about 5.7 to about 6.3, about 5.7 to about 6.2, about 5.7 to about 6.1, about 5.7 to about 6.0, about 5.7 to about 5.9, about 5.8 to about 7.0, about 5.8 to about 6.9, about 5.8 to about 6.8, about 5.8 to about 6.7, about 5.8 to about 6.6, about 5.8 to about 6.5, about 5.8 to about 6.4, about 5.8 to about 6.3, about 5.8 to about 6.2, about 5.8 to about 6.1, about 5.8 to about 6.0, about 5.9 to about 7.0, about 5.9 to about 6.9, about 5.9 to about 6.8, about 5.9 to about 6.7, about 5.9 to about 6.6, about 5.9 to about 6.5, about 5.9 to about 6.4, about 5.9 to about 6.3, about 5.9 to about 6.2, about 5.9 to about 6.1, about 6.0 to about 7.0, about 6.0 to about 6.9, about 6.0 to about 6.8, about 6.0 to about 6.7, about 6.0 to about 6.6, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about 6.3, about 6.0 to about 6.2, about 6.1 to about 7.0, about 6.1 to about 6.9, about 6.1 to about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to about 6.3, about 6.2 to about 7.0, about 6.2 to about 6.9, about 6.2 to about 6.8, about 6.2 to about 6.7, about 6.2 to about 6.6, about 6.2 to about 6.5, about 6.2 to about 6.4, about 6.3 to about 7.0, about 6.3 to about 6.9, about 6.3 to about 6.8, about 6.3 to about 6.7, about 6.3 to about 6.6, about 6.3 to about 6.5, about 6.4 to about 7.0, about 6.4 to about 6.9, about 6.4 to about 6.8, about 6.4 to about 6.7, about 6.4 to about 6.6, about 6.5 to about 7.0, about 6.5 to about 6.9, about 6.5 to about 6.8, about 6.5 to about 6.7, about 6.6 to about 7.0, about 6.6 to about 6.9, about 6.6 to about 6.8, about 6.7 to about 7.0, about 6.7 to about 6.9, or about 6.8 to about 7.0).

In another embodiment, the pH is about 6.0 to about 6.5. In yet another embodiment, the pH is about 6.2. In another embodiment, the pH is about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.0.

In one embodiment, the stabilizer is selected from the group consisting of amino acids, sugars, polyols, polymers, and combinations thereof.

In one embodiment, the organic co-solvent is selected from the group consisting of a surfactant, polyethylene glycol (PEG), propylene glycol, a block copolymer, an alkyl saccharide (e.g., a ProTek alkyl saccharide, octyl glucoside, N-decyl-pyranoside, N-octyl-glucopyranoside, Intravail®, and those described in U.S. Pat. Nos. 9,446,134; 8,846,044, 8,226,949; 7,998,927; 8,084,022; 7,425,542; and 10,046,025), and FM1000.

In one embodiment, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, sodium dodecyl sulfate (SDS), n-Dodecyl-β-D-maltoside (DDM) and poloxamer 188 (Pluronic F-68).

In another embodiment, the buffer-free formulations of the invention further comprise one or more salt(s). In one embodiment, the salt is selected from the group consisting of sodium chloride, magnesium chloride, calcium chloride, and potassium chloride. Each of the one or more salt(s) may be present at a concentration of about 0.1 mM-100 mM (e.g., about 0.1 mM to about 90 mM, about 0.1 mM to about 80 mM, about 0.1 mM to about 70 mM, about 0.1 mM to about 65 mM, about 0.1 mM to about 60 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 10 mM, about 0.1 mM to about 5 mM, about 1 mM to about 100 mM, about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 70 mM, about 1 mM to about 60 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 mM to about 10 mM, about 10 mM to about 95 mM, about 10 mM to about 90 mM, about 10 mM to about 85 mM, about 10 mM to about 80 mM, about 10 mM to about 75 mM, about 10 mM to about 70 mM, about 10 mM to about 65 mM, about 10 mM to about 60 mM, about 10 mM to about 55 mM, about 10 mM to about 50 mM, about 10 mM to about 45 mM, about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 10 mM to about 20 mM, about 10 mM to about 18 mM, about 10 mM to about 16 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, about 12 mM to about 100 mM, about 12 mM to about 95 mM, about 12 mM to about 90 mM, about 12 mM to about 85 mM, about 12 mM to about 80 mM, about 12 mM to about 75 mM, about 12 mM to about 70 mM, about 12 mM to about 65 mM, about 12 mM to about 60 mM, about 12 mM to about 55 mM, about 12 mM to about 50 mM, about 12 mM to about 45 mM, about 12 mM to about 40 mM, about 12 mM to about 35 mM, about 12 mM to about 30 mM, about 12 mM to about 25 mM, about 12 mM to about 20 mM, about 12 mM to about 18 mM, about 12 mM to about 16 mM, about 12 mM to about 14 mM, about 14 mM to about 100 mM, about 14 mM to about 95 mM, about 14 mM to about 90 mM, about 14 mM to about 85 mM, about 14 mM to about 80 mM, about 14 mM to about 75 mM, about 14 mM to about 70 mM, about 14 mM to about 65 mM, about 14 mM to about 60 mM, about 14 mM to about 55 mM, about 14 mM to about 50 mM, about 14 mM to about 45 mM, about 14 mM to about 40 mM, about 14 mM to about 35 mM, about 14 mM to about 30 mM, about 14 mM to about 25 mM, about 14 mM to about 20 mM, about 14 mM to about 18 mM, about 14 mM to about 16 mM, about 16 mM to about 100 mM, about 16 mM to about 95 mM, about 16 mM to about 90 mM, about 16 mM to about 85 mM, about 16 mM to about 80 mM, about 16 mM to about 75 mM, about 16 mM to about 70 mM, about 16 mM to about 65 mM, about 16 mM to about 60 mM, about 16 mM to about 55 mM, about 16 mM to about 50 mM, about 16 mM to about 45 mM, about 16 mM to about 40 mM, about 16 mM to about 35 mM, about 16 mM to about 30 mM, about 16 mM to about 25 mM, about 16 mM to about 20 mM, about 16 mM to about 18 mM, about 18 mM to about 100 mM, about 18 mM to about 95 mM, about 18 mM to about 90 mM, about 18 mM to about 85 mM, about 18 mM to about 80 mM, about 18 mM to about 75 mM, about 18 mM to about 70 mM, about 18 mM to about 65 mM, about 18 mM to about 60 mM, about 18 mM to about 55 mM, about 18 mM to about 50 mM, about 18 mM to about 45 mM, about 18 mM to about 40 mM, about 18 mM to about 35 mM, about 18 mM to about 30 mM, about 18 mM to about 25 mM, about 18 mM to about 20 mM, about 20 mM to about 100 mM, about 20 mM to about 95 mM, about 20 mM to about 90 mM, about 20 mM to about 85 mM, about 20 mM to about 80 mM, about 20 mM to about 75 mM, about 20 mM to about 70 mM, about 20 mM to about 65 mM, about 20 mM to about 60 mM, about 20 mM to about 55 mM, about 20 mM to about 50 mM, about 20 mM to about 45 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, about 25 mM to about 100 mM, about 25 mM to about 95 mM, about 25 mM to about 90 mM, about 25 mM to about 85 mM, about 25 mM to about 80 mM, about 25 mM to about 75 mM, about 25 mM to about 70 mM, about 25 mM to about 65 mM, about 25 mM to about 60 mM, about 25 mM to about 55 mM, about 25 mM to about 50 mM, about 25 mM to about 45 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, about 25 mM to about 30 mM, about 30 mM to about 100 mM, about 30 mM to about 95 mM, about 30 mM to about 90 mM, about 30 mM to about 85 mM, about 30 mM to about 80 mM, about 30 mM to about 75 mM, about 30 mM to about 70 mM, about 30 mM to about 65 mM, about 30 mM to about 60 mM, about 30 mM to about 55 mM, about 30 mM to about 50 mM, about 30 mM to about 45 mM, about 30 mM to about 40 mM, about 30 mM to about 35 mM, about 35 mM to about 100 mM, about 35 mM to about 95 mM, about 35 mM to about 90 mM, about 35 mM to about 85 mM, about 35 mM to about 80 mM, about 35 mM to about 75 mM, about 35 mM to about 70 mM, about 35 mM to about 65 mM, about 35 mM to about 60 mM, about 35 mM to about 55 mM, about 35 mM to about 50 mM, about 35 mM to about 45 mM, about 35 mM to about 40 mM, about 40 mM to about 100 mM, about 40 mM to about 95 mM, about 40 mM to about 90 mM, about 40 mM to about 85 mM, about 40 mM to about 80 mM, about 40 mM to about 75 mM, about 40 mM to about 70 mM, about 40 mM to about 65 mM, about 40 mM to about 60 mM, about 40 mM to about 55 mM, about 40 mM to about 50 mM, about 40 mM to about 45 mM, about 45 mM to about 100 mM, about 45 mM to about 95 mM, about 45 mM to about 90 mM, about 45 mM to about 85 mM, about 45 mM to about 80 mM, about 45 mM to about 75 mM, about 45 mM to about 70 mM, about 45 mM to about 65 mM, about 45 mM to about 60 mM, about 45 mM to about 55 mM, about 45 mM to about 50 mM, about 50 mM to about 100 mM, about 50 mM to about 95 mM, about 50 mM to about 90 mM, about 50 mM to about 85 mM, about 50 mM to about 80 mM, about 50 mM to about 75 mM, about 50 mM to about 70 mM, about 50 mM to about 65 mM, about 50 mM to about 60 mM, about 50 mM to about 55 mM, about 55 mM to about 100 mM, about 55 mM to about 95 mM, about 55 mM to about 90 mM, about 55 mM to about 85 mM, about 55 mM to about 80 mM, about 55 mM to about 75 mM, about 55 mM to about 70 mM, about 55 mM to about 65 mM, about 55 mM to about 60 mM, about 60 mM to about 100 mM, about 60 mM to about 95 mM, about 60 mM to about 90 mM, about 60 mM to about 85 mM, about 60 mM to about 80 mM, about 60 mM to about 75 mM, about 60 mM to about 70 mM, about 60 mM to about 65 mM, about 65 mM to about 100 mM, about 65 mM to about 95 mM, about 65 mM to about 90 mM, about 65 mM to about 85 mM, about 65 mM to about 80 mM, about 65 mM to about 75 mM, about 65 mM to about 70 mM, about 70 mM to about 100 mM, about 70 mM to about 95 mM, about 70 mM to about 90 mM, about 70 mM to about 85 mM, about 70 mM to about 80 mM, about 70 mM to about 75 mM, about 75 mM to about 100 mM, about 75 mM to about 95 mM, about 75 mM to about 90 mM, about 75 mM to about 85 mM, about 75 mM to about 80 mM, about 80 mM to about 100 mM, about 80 mM to about 95 mM, about 80 mM to about 90 mM, about 80 mM to about 85 mM, about 85 mM to about 100 mM, about 85 mM to about 95 mM, about 85 mM to about 90 mM, about 90 mM to about 100 mM, about 90 mM to about 95 mM, or about 95 mM to about 100 mM).

In one embodiment, the stabilizer is a sugar. In another embodiment, the stabilizer is a sugar (e.g., sucrose). In some embodiments, the stabilizer is trehalose. In some embodiments, the stabilizer is human serum albumin or Recombumin®. In some embodiments, the stabilizer is betaine. In some embodiments of any of the aqueous formulations described herein, a stabilizer (e.g., any of the exemplary stabilizers described herein) can be present at a final concentration of about 0.01% w/v to about 8.0% w/v (e.g., about 0.01% w/v to about 7.5% w/v, about 0.01% w/v to about 7.0% w/v, about 0.01% w/v to about 6.5% w/v, about 0.01% w/v to about 6.0% w/v, about 0.01% w/v to about 5.5% w/v, about 0.01% w/v to about 5.0% w/v, about 0.01% w/v to about 4.5% w/v, about 0.01% w/v to about 4.0% w/v, about 0.01% w/v to about 3.5% w/v, about 0.01% w/v to about 3.0% w/v, about 0.01% w/v to about 2.5% w/v, about 0.01% w/v to about 2.0% w/v, about 0.01% w/v to about 1.5% w/v, about 0.01% w/v, to about 1.0% w/v, about 0.01% w/v to about 0.5% w/v, about 0.1% w/v to about 8.0% w/v, about 0.1% w/v to about 7.5% w/v, about 0.1% w/v to about 7.0% w/v, about 0.1% w/v to about 6.5% w/v, about 0.1% w/v to about 6.0% w/v, about 0.1% w/v to about 5.5% w/v, about 0.1% w/v to about 5.0% w/v, about 0.1% w/v to about 4.5% w/v, about 0.1% w/v to about 4.0% w/v, about 0.1% w/v to about 3.5% w/v, about 0.1% w/v to about 3.0% w/v, about 0.1% w/v to about 2.5% w/v, about 0.1% w/v to about 2.0% w/v, about 0.1% w/v to about 1.5% w/v, about 0.1% w/v, to about 1.0% w/v, about 0.1% w/v to about 0.5% w/v, about 0.5% w/v to about 8.0% w/v, about 0.5% w/v to about 7.5% w/v, about 0.5% w/v to about 7.0% w/v, about 0.5% w/v to about 6.5% w/v, about 0.5% w/v to about 6.0% w/v, about 0.5% w/v to about 5.5% w/v, about 0.5% w/v to about 5.0% w/v, about 0.5% w/v to about 4.5% w/v, about 0.5% w/v to about 4.0% w/v, about 0.5% w/v to about 3.5% w/v, about 0.5% w/v to about 3.0% w/v, about 0.5% w/v to about 2.5% w/v, about 0.5% w/v to about 2.0% w/v, about 0.5% w/v to about 1.5% w/v, about 0.5% w/v to about 1.0% w/v, about 1.0% w/v to about 8.0% w/v, about 1.0% w/v to about 7.5% w/v, about 1.0% w/v to about 7.0% w/v, about 1.0% w/v to about 6.5% w/v, about 1.0% w/v to about 6.0% w/v, about 1.0% w/v to about 5.5% w/v, about 1.0% w/v to about 5.0% w/v, about 1.0% w/v to about 4.5% w/v, about 1.0% w/v to about 4.0% w/v, about 1.0% w/v to about 3.5% w/v, about 1.0% w/v to about 3.0% w/v, about 1.0% w/v to about 2.5% w/v, about 1.0% w/v to about 2.0% w/v, about 1.0% w/v to about 1.5% w/v, about 1.5% w/v to about 8.0% w/v, about 1.5% w/v to about 7.5% w/v, about 1.5% w/v to about 7.0% w/v, about 1.5% w/v to about 6.5% w/v, about 1.5% w/v to about 6.0% w/v, about 1.5% w/v to about 5.5% w/v, about 1.5% w/v to about 5.0% w/v, about 1.5% w/v to about 4.5% w/v, about 1.5% w/v to about 4.0% w/v, about 1.5% w/v to about 3.5% w/v, about 1.5% w/v to about 3.0% w/v, about 1.5% w/v to about 2.5% w/v, about 1.5% w/v to about 2.0% w/v, about 2.0% w/v to about 8.0% w/v, about 2.0% w/v to about 7.5% w/v, about 2.0% w/v to about 7.0% w/v, about 2.0% w/v to about 6.5% w/v, about 2.0% w/v to about 6.0% w/v, about 2.0% w/v to about 5.5% w/v, about 2.0% w/v to about 5.0% w/v, about 2.0 w/v to about 4.5% w/v, about 2.0% w/v to about 4.0% w/v, about 2.0% w/v to about 3.5% w/v, about 2.0% w/v to about 3.0% w/v, about 2.0% w/v to about 2.5% w/v, about 2.5% w/v to about 8.0% w/v, about 2.5% w/v to about 7.5% w/v, about 2.5% w/v to about 7.0% w/v, about 2.5% w/v to about 6.5% w/v, about 2.5% w/v to about 6.0% w/v, about 2.5% w/v to about 5.5% w/v, about 2.5% w/v to about 5.0% w/v, about 2.5% w/v to about 4.5% w/v, about 2.5% w/v to about 4.0% w/v, about 2.5% w/v to about 3.5% w/v, about 2.5% w/v to about 3.0% w/v, about 3.0% w/v to about 8.0% w/v, about 3.0% w/v to about 7.5% w/v, about 3.0% w/v to about 7.0% w/v, about 3.0% w/v to about 6.5% w/v, about 3.0% w/v to about 6.0% w/v, about 3.0% w/v to about 5.5% w/v, about 3.0% w/v to about 5.0% w/v, about 3.0% w/v to about 4.5% w/v, about 3.0% w/v to about 4.0% w/v, about 3.0% w/v to about 3.5% w/v, about 3.5% w/v to about 8.0% w/v, about 3.5% w/v to about 7.5% w/v, about 3.5% w/v to about 7.0% w/v, about 3.5% w/v to about 6.5% w/v, about 3.5% w/v to about 6.0% w/v, about 3.5% w/v to about 5.5% w/v, about 3.5% w/v to about 5.0% w/v, about 3.5% w/v to about 4.5% w/v, about 3.5% w/v to about 4.0% w/v, about 4.0% w/v to about 8.0% w/v, about 4.0% w/v to about 7.5% w/v, about 4.0% w/v to about 7.0% w/v, about 4.0% w/v to about 6.5% w/v, about 4.0% w/v to about 6.0% w/v, about 4.0% w/v to about 5.5% w/v, about 4.0% w/v to about 5.0% w/v, about 4.0% w/v to about 4.5% w/v, about 4.5% w/v to about 8.0% w/v, about 4.5% w/v to about 7.5% w/v, about 4.5% w/v to about 7.0% w/v, about 4.5% w/v to about 6.5% w/v, about 4.5% w/v to about 6.0% w/v, about 4.5% w/v to about 5.5% w/v, about 4.5% w/v to about 5.0% w/v, about 5.0% w/v to about 8.0% w/v, about 5.0% w/v to about 7.5% w/v, about 5.0% w/v to about 7.0% w/v, about 5.0% w/v to about 6.5% w/v, about 5.0% w/v to about 6.0% w/v, about 5.0% w/v to about 5.5% w/v, about 5.5% w/v to about 8.0% w/v, about 5.5% w/v to about 7.5% w/v, about 5.5% w/v to about 7.0% w/v, about 5.5% w/v to about 6.5% w/v, about 5.5% w/v to about 6.0% w/v, about 6.0% w/v to about 8.0% w/v, about 6.0% w/v to about 7.5% w/v, about 6.0% w/v to about 7.0% w/v, about 6.0% w/v to about 6.5% w/v, about 6.5% w/v to about 8.0% w/v, about 6.5% w/v to about 7.5% w/v, about 6.5% w/v to about 7.0% w/v, about 7.0% w/v to about 8.0% w/v, about 7.0% w/v to about 7.5% w/v, or about 7.5% w/v to about 8.0% w/v).

In one embodiment, the stabilizer is an amino acid (e.g., an aromatic amino acid, e.g., tyrosine, phenylalanine, and tryptophan). In another embodiment, the amino acid is selected from the group consisting of glycine, arginine, and proline or combinations thereof. The amino acids may be present at a concentration of about 5-300 mM (e.g., about 5 mM to about 280 mM, about 5 mM to about 260 mM, about 5 mM to about 240 mM, about 5 mM to about 220 mM, about 5 mM to about 200 mM, about 5 mM to about 180 mM, about 5 mM to about 160 mM, about 5 mM to about 140 mM, about 5 mM to about 120 mM, about 5 mM to about 100 mM, about 5 mM to about 80 mM, about 5 mM to about 60 mM, about 5 mM to about 40 mM, about 5 mM to about 20 mM, about 5 mM to about 10 mM, about 10 mM to about 300 mM, about 10 mM to about 280 mM, about 10 mM to about 260 mM, about 10 mM to about 240 mM, about 10 mM to about 220 mM, about 10 mM to about 200 mM, about 10 mM to about 180 mM, about 10 mM to about 160 mM, about 10 mM to about 140 mM, about 10 mM to about 120 mM, about 10 mM to about 100 mM, about 10 mM to about 80 mM, about 10 mM to about 60 mM, about 10 mM to about 40 mM, about 10 mM to about 20 mM, about 20 mM to about 300 mM, about 20 mM to about 280 mM, about 20 mM to about 260 mM, about 20 mM to about 240 mM, about 20 mM to about 220 mM, about 20 mM to about 200 mM, about 20 mM to about 180 mM, about 20 mM to about 160 mM, about 20 mM to about 140 mM, about 20 mM to about 120 mM, about 20 mM to about 100 mM, about 20 mM to about 80 mM, about 20 mM to about 60 mM, about 20 mM to about 40 mM, about 40 mM to about 300 mM, about 40 mM to about 280 mM, about 40 mM to about 260 mM, about 40 mM to about 240 mM, about 40 mM to about 220 mM, about 40 mM to about 200 mM, about 40 mM to about 180 mM, about 40 mM to about 160 mM, about 40 mM to about 140 mM, about 40 mM to about 120 mM, about 40 mM to about 100 mM, about 40 mM to about 80 mM, about 40 mM to about 60 mM, about 40 mM to about 40 mM, about 60 mM to about 300 mM, about 60 mM to about 280 mM, about 60 mM to about 260 mM, about 60 mM to about 240 mM, about 60 mM to about 220 mM, about 60 mM to about 200 mM, about 60 mM to about 180 mM, about 60 mM to about 160 mM, about 60 mM to about 140 mM, about 60 mM to about 120 mM, about 60 mM to about 100 mM, about 60 mM to about 80 mM, about 80 mM to about 300 mM, about 80 mM to about 250 mM, about 80 mM to about 200 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM, about 100 mM to about 200 mM, about 100 mM to about 150 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 150 mM to about 200 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, or about 250 mM to about 300 mM).

In some embodiments, the stabilizer is sucrose, the organic co-solvent is polysorbate 20 and the pH of the formulation is about 5.5-7.0 (e.g., about 5.5 to about 6.9, about 5.5 to about 6.8, about 5.5 to about 6.7, about 5.5 to about 6.6, about 5.5 to about 6.5, about 5.5 to about 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, about 5.5 to about 6.0, about 5.5 to about 5.9, about 5.5 to about 5.8, about 5.5 to about 5.7, about 5.6 to about 7.0, about 5.6 to about 6.9, about 5.6 to about 6.8, about 5.6 to about 6.7, about 5.6 to about 6.6, about 5.6 to about 6.5, about 5.6 to about 6.4, about 5.6 to about 6.3, about 5.6 to about 6.2, about 5.6 to about 6.1, about 5.6 to about 6.0, about 5.6 to about 5.9, about 5.6 to about 5.8, about 5.7 to about 7.0, about 5.7 to about 6.9, about 5.7 to about 6.8, about 5.7 to about 6.7, about 5.7 to about 6.6, about 5.7 to about 6.5, about 5.7 to about 6.4, about 5.7 to about 6.3, about 5.7 to about 6.2, about 5.7 to about 6.1, about 5.7 to about 6.0, about 5.7 to about 5.9, about 5.8 to about 7.0, about 5.8 to about 6.9, about 5.8 to about 6.8, about 5.8 to about 6.7, about 5.8 to about 6.6, about 5.8 to about 6.5, about 5.8 to about 6.4, about 5.8 to about 6.3, about 5.8 to about 6.2, about 5.8 to about 6.1, about 5.8 to about 6.0, about 5.9 to about 7.0, about 5.9 to about 6.9, about 5.9 to about 6.8, about 5.9 to about 6.7, about 5.9 to about 6.6, about 5.9 to about 6.5, about 5.9 to about 6.4, about 5.9 to about 6.3, about 5.9 to about 6.2, about 5.9 to about 6.1, about 6.0 to about 7.0, about 6.0 to about 6.9, about 6.0 to about 6.8, about 6.0 to about 6.7, about 6.0 to about 6.6, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about 6.3, about 6.0 to about 6.2, about 6.1 to about 7.0, about 6.1 to about 6.9, about 6.1 to about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to about 6.3, about 6.2 to about 7.0, about 6.2 to about 6.9, about 6.2 to about 6.8, about 6.2 to about 6.7, about 6.2 to about 6.6, about 6.2 to about 6.5, about 6.2 to about 6.4, about 6.3 to about 7.0, about 6.3 to about 6.9, about 6.3 to about 6.8, about 6.3 to about 6.7, about 6.3 to about 6.6, about 6.3 to about 6.5, about 6.4 to about 7.0, about 6.4 to about 6.9, about 6.4 to about 6.8, about 6.4 to about 6.7, about 6.4 to about 6.6, about 6.5 to about 7.0, about 6.5 to about 6.9, about 6.5 to about 6.8, about 6.5 to about 6.7, about 6.6 to about 7.0, about 6.6 to about 6.9, about 6.6 to about 6.8, about 6.7 to about 7.0, about 6.7 to about 6.9, or about 6.8 to about 7.0, or about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.0).

In some embodiments of any of the formulations described herein, the formulation is about 5.5-7.0 (e.g., about 5.5 to about 6.9, about 5.5 to about 6.8, about 5.5 to about 6.7, about 5.5 to about 6.6, about 5.5 to about 6.5, about 5.5 to about 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, about 5.5 to about 6.0, about 5.5 to about 5.9, about 5.5 to about 5.8, about 5.5 to about 5.7, about 5.6 to about 7.0, about 5.6 to about 6.9, about 5.6 to about 6.8, about 5.6 to about 6.7, about 5.6 to about 6.6, about 5.6 to about 6.5, about 5.6 to about 6.4, about 5.6 to about 6.3, about 5.6 to about 6.2, about 5.6 to about 6.1, about 5.6 to about 6.0, about 5.6 to about 5.9, about 5.6 to about 5.8, about 5.7 to about 7.0, about 5.7 to about 6.9, about 5.7 to about 6.8, about 5.7 to about 6.7, about 5.7 to about 6.6, about 5.7 to about 6.5, about 5.7 to about 6.4, about 5.7 to about 6.3, about 5.7 to about 6.2, about 5.7 to about 6.1, about 5.7 to about 6.0, about 5.7 to about 5.9, about 5.8 to about 7.0, about 5.8 to about 6.9, about 5.8 to about 6.8, about 5.8 to about 6.7, about 5.8 to about 6.6, about 5.8 to about 6.5, about 5.8 to about 6.4, about 5.8 to about 6.3, about 5.8 to about 6.2, about 5.8 to about 6.1, about 5.8 to about 6.0, about 5.9 to about 7.0, about 5.9 to about 6.9, about 5.9 to about 6.8, about 5.9 to about 6.7, about 5.9 to about 6.6, about 5.9 to about 6.5, about 5.9 to about 6.4, about 5.9 to about 6.3, about 5.9 to about 6.2, about 5.9 to about 6.1, about 6.0 to about 7.0, about 6.0 to about 6.9, about 6.0 to about 6.8, about 6.0 to about 6.7, about 6.0 to about 6.6, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about 6.3, about 6.0 to about 6.2, about 6.1 to about 7.0, about 6.1 to about 6.9, about 6.1 to about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to about 6.3, about 6.2 to about 7.0, about 6.2 to about 6.9, about 6.2 to about 6.8, about 6.2 to about 6.7, about 6.2 to about 6.6, about 6.2 to about 6.5, about 6.2 to about 6.4, about 6.3 to about 7.0, about 6.3 to about 6.9, about 6.3 to about 6.8, about 6.3 to about 6.7, about 6.3 to about 6.6, about 6.3 to about 6.5, about 6.4 to about 7.0, about 6.4 to about 6.9, about 6.4 to about 6.8, about 6.4 to about 6.7, about 6.4 to about 6.6, about 6.5 to about 7.0, about 6.5 to about 6.9, about 6.5 to about 6.8, about 6.5 to about 6.7, about 6.6 to about 7.0, about 6.6 to about 6.9, about 6.6 to about 6.8, about 6.7 to about 7.0, about 6.7 to about 6.9, or about 6.8 to about 7.0, or about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.0).

In some embodiments of any of the formulations described herein, the formulation can include one or more of: sodium ion at a final concentration of about 100 mM to about 200 mM (e.g., about 100 mM to about 180 mM, about 100 mM to about 160 mM, about 100 mM to about 140 mM, about 100 mM to about 120 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 160 mM, about 120 mM to about 140 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, or about 180 mM to about 200 mM); potassium ion at a final concentration of about 1 mM to about 20 mM (e.g., about 1 mM to about 18 mM, about 1 mM to about 16 mM, about 1 mM to about 14 mM, about 1 mM to about 12 mM, about 1 mM to about 10 mM, about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 20 mM, about 2 mM to about 18 mM, about 2 mM to about 16 mM, about 2 mM to about 14 mM, about 2 mM to about 12 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 20 mM, about 4 mM to about 18 mM, about 4 mM to about 16 mM, about 4 mM to about 14 mM, about 4 mM to about 12 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 20 mM, about 6 mM to about 18 mM, about 6 mM to about 16 mM, about 6 mM to about 14 mM, about 6 mM to about 12 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, about 8 mM to about 20 mM, about 8 mM to about 18 mM, about 8 mM to about 16 mM, about 8 mM to about 14 mM, about 8 mM to about 12 mM, about 8 mM to about 10 mM, about 10 mM to about 20 mM, about 10 mM to about 18 mM, about 10 mM to about 16 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, about 12 mM to about 20 mM, about 12 mM to about 18 mM, about 12 mM to about 16 mM, about 12 mM to about 14 mM, about 14 mM to about 20 mM, about 14 mM to about 18 mM, about 14 mM to about 16 mM, about 16 mM to about 20 mM, about 16 mM to about 18 mM, or about 18 mM to about 20 mM); chloride ion at a final concentration of about 10 mM to about 200 mM (e.g., about 10 mM to about 180 mM, about 10 mM to about 160 mM, about 10 mM to about 140 mM, about 10 mM to about 120 mM, about 10 mM to about 100 mM, about 10 mM to about 80 mM, about 10 mM to about 60 mM, about 10 mM to about 40 mM, about 10 mM to about 20 mM, about 50 mM to about 200 mM, 50 mM to about 180 mM, about 50 mM to about 160 mM, about 50 mM to about 140 mM, about 50 mM to about 120 mM, about 50 mM to about 100 mM, about 50 mM to about 80 mM, about 100 mM to about 200 mM, about 100 mM to about 180 mM, about 100 mM to about 160 mM, about 100 mM to about 140 mM, about 100 mM to about 120 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 160 mM, about 120 mM to about 140 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, or about 180 mM to about 200 mM); calcium ion at a final concentration of about 0.1 mM to about 5 mM (e.g., about 0.1 mM to about 4 mM, about 0.1 mM to about 3 mM, about 0.1 mM to about 2 mM, about 0.1 mM to about 1 mM, about 0.1 mM to about 0.5 mM, about 0.5 mM to about 5 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1 mM, about 1 mM to about 5 mM, about 1 mM to about 4 mM, about 1 mM to about 3 mM, about 1 mM to about 2 mM, about 2 mM to about 5 mM, about 2 mM to about 4 mM, about 2 mM to about 3 mM, about 3 mM to about 5 mM, about 3 mM to about 4 mM, or about 4 mM to about 5 mM); magnesium ion at a final concentration of about 0.1 mM to about 3 mM (e.g., about 0.1 mM to about 2.5 mM, about 0.1 mM to about 2.0 mM, about 0.1 mM to about 1.5 mM, about 0.1 mM to about 1.0 mM, about 0.1 mM to about 0.5 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2.5 mM, about 0.5 mM to about 2.0 mM, about 0.5 mM to about 1.5 mM, about 0.5 mM to about 1.0 mM, about 1.0 mM to about 3.0 mM, about 1.0 mM to about 2.5 mM, about 1.0 mM to about 2.0 mM, about 1.0 mM to about 1.5 mM, about 1.5 mM to about 3.0 mM, about 1.5 mM to about 2.5 mM, about 1.5 mM to about 2.0 mM, about 2.0 mM to about 3.0 mM, about 2.0 mM to about 2.5 mM, or about 2.5 mM to about 3.0 mM); sugar (e.g., glucose) at a final concentration of about 0.5 mM to about 10 mM (e.g., about 0.5 mM to about 8 mM, about 0.5 mM to about 6 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1 mM, about 1 mM to about 10 mM, about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, or about 8 mM to about 10 mM); lactate at a final concentration of about 1 mM to about 10 mM (e.g., about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, or about 8 mM to about 10 mM); beta-hyrdoxybutyrate at a final concentration of about 0.01 mM to about 0.3 mM (e.g., about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.1 mM, about 0.01 mM to about 0.05 mM, about 0.05 mM to about 3 mM, about 0.05 mM to about 0.2 mM, about 0.05 mM to about 0.1 mM, about 0.1 mM to about 3 mM, about 0.1 mM to about 0.2 mM, or about 0.2 mM to about 0.3 mM); copper ion at a concentration of about 0.1 μM to about 1.0 μM (e.g., about 0.1 μM to about 0.8 μM, about 0.1 μM to about 0.6 μM, about 0.1 μM to about 0.4 μM, or about 0.1 μM to about 0.2 μM), zinc ion at a final concentration of about 0.1 μM to about 10 μM (e.g., about 0.1 μM to about 8 μM, about 0.1 μM to about 6 μM, about 0.1 μM to about 4 μM, or about 0.1 μM to about 2 μM); selenium ion at a final concentration of about 0.01 μM to about 0.2 μM (e.g., about 0.01 μM to about 0.15 μM, about 0.01 μM to about 0.10 μM, or about 0.01 μM to about 0.5 μM), iron ion at a final concentration of about 0.01 μM to about 8 μM (e.g., about 0.01 μM to about 6 μM, about 0.01 μM to about 4 μM, about 0.01 μM to about 2 μM, about 0.01 μM to about 1 μM, about 0.01 μM to about 0.05 μM), ferritin at a final concentration of about 0.1 μM to about 50 μM (e.g., 0.1 μM to about 40 μM, about 0.1 μM to about 30 μM, about 0.1 μM to about 20 μM, about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.1 μM to about 1 μM); and transferrin at final concentration of about 0.01 μM to about 0.2 μM (e.g., about 0.01 μM to about 0.15 μM, about 0.01 μM to about 0.10 μM, about 0.01 μM to about 0.05 μM).

In one embodiment, the formulation is iso-osmolar relative to the vitreous.

Formulations Free of Organic Co-Solvent

In one embodiment, the invention provides an aqueous formulation comprising aflibercept, a stabilizer and a buffer, wherein the formulation is free of an organic co-solvent.

In one embodiment, the formulation has a pH of about 5.5 to about 7.0 (e.g., any of the subranges of described herein or about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.0). In another embodiment, the pH is about 6.0 to about 6.5. In yet another embodiment, the pH is about 6.2.

In one embodiment, the stabilizer is selected from the group consisting of amino acids, sugars (e.g., sucrose), polyols, polymers, block copolymers, alkyl saccharides (e.g., a ProTek alkyl saccharides, octyl glucoside, N-decyl-pyranoside, N-octyl-glucopyranoside, Intravail®, and those described in U.S. Pat. Nos. 9,446,134; 8,846,044, 8,226,949; 7,998,927; 8,084,022; 7,425,542; and 10,046,025), and FM1000, or any combination thereof.

In some embodiments, the stabilizer is trehalose. In some embodiments, the stabilizer is human serum albumin or Recombumin®. In some embodiments, the stabilizer is betaine. In some embodiments of any of the aqueous formulations described herein, a stabilizer (e.g., any of the exemplary stabilizers described herein) can be present at a final concentration of about 0.01% w/v to about 8.0% w/v (e.g., about 0.01% w/v to about 7.5% w/v, about 0.01% w/v to about 7.0% w/v, about 0.01% w/v to about 6.5% w/v, about 0.01% w/v to about 6.0% w/v, about 0.01% w/v to about 5.5% w/v, about 0.01% w/v to about 5.0% w/v, about 0.01% w/v to about 4.5% w/v, about 0.01% w/v to about 4.0% w/v, about 0.01% w/v to about 3.5% w/v, about 0.01% w/v to about 3.0% w/v, about 0.01% w/v to about 2.5% w/v, about 0.01% w/v to about 2.0% w/v, about 0.01% w/v to about 1.5% w/v, about 0.01% w/v, to about 1.0% w/v, about 0.01% w/v to about 0.5% w/v, about 0.1% w/v to about 8.0% w/v, about 0.1% w/v to about 7.5% w/v, about 0.1% w/v to about 7.0% w/v, about 0.1% w/v to about 6.5% w/v, about 0.1% w/v to about 6.0% w/v, about 0.1% w/v to about 5.5% w/v, about 0.1% w/v to about 5.0% w/v, about 0.1% w/v to about 4.5% w/v, about 0.1% w/v to about 4.0% w/v, about 0.1% w/v to about 3.5% w/v, about 0.1% w/v to about 3.0% w/v, about 0.1% w/v to about 2.5% w/v, about 0.1% w/v to about 2.0% w/v, about 0.1% w/v to about 1.5% w/v, about 0.1% w/v, to about 1.0% w/v, about 0.1% w/v to about 0.5% w/v, about 0.5% w/v to about 8.0% w/v, about 0.5% w/v to about 7.5% w/v, about 0.5% w/v to about 7.0% w/v, about 0.5% w/v to about 6.5% w/v, about 0.5% w/v to about 6.0% w/v, about 0.5% w/v to about 5.5% w/v, about 0.5% w/v to about 5.0% w/v, about 0.5% w/v to about 4.5% w/v, about 0.5% w/v to about 4.0% w/v, about 0.5% w/v to about 3.5% w/v, about 0.5% w/v to about 3.0% w/v, about 0.5% w/v to about 2.5% w/v, about 0.5% w/v to about 2.0% w/v, about 0.5% w/v to about 1.5% w/v, about 0.5% w/v to about 1.0% w/v, about 1.0% w/v to about 8.0% w/v, about 1.0% w/v to about 7.5% w/v, about 1.0% w/v to about 7.0% w/v, about 1.0% w/v to about 6.5% w/v, about 1.0% w/v to about 6.0% w/v, about 1.0% w/v to about 5.5% w/v, about 1.0% w/v to about 5.0% w/v, about 1.0% w/v to about 4.5% w/v, about 1.0% w/v to about 4.0% w/v, about 1.0% w/v to about 3.5% w/v, about 1.0% w/v to about 3.0% w/v, about 1.0% w/v to about 2.5% w/v, about 1.0% w/v to about 2.0% w/v, about 1.0% w/v to about 1.5% w/v, about 1.5% w/v to about 8.0% w/v, about 1.5% w/v to about 7.5% w/v, about 1.5% w/v to about 7.0% w/v, about 1.5% w/v to about 6.5% w/v, about 1.5% w/v to about 6.0% w/v, about 1.5% w/v to about 5.5% w/v, about 1.5% w/v to about 5.0% w/v, about 1.5% w/v to about 4.5% w/v, about 1.5% w/v to about 4.0% w/v, about 1.5% w/v to about 3.5% w/v, about 1.5% w/v to about 3.0% w/v, about 1.5% w/v to about 2.5% w/v, about 1.5% w/v to about 2.0% w/v, about 2.0% w/v to about 8.0% w/v, about 2.0% w/v to about 7.5% w/v, about 2.0% w/v to about 7.0% w/v, about 2.0% w/v to about 6.5% w/v, about 2.0% w/v to about 6.0% w/v, about 2.0% w/v to about 5.5% w/v, about 2.0% w/v to about 5.0% w/v, about 2.0 w/v to about 4.5% w/v, about 2.0% w/v to about 4.0% w/v, about 2.0% w/v to about 3.5% w/v, about 2.0% w/v to about 3.0% w/v, about 2.0% w/v to about 2.5% w/v, about 2.5% w/v to about 8.0% w/v, about 2.5% w/v to about 7.5% w/v, about 2.5% w/v to about 7.0% w/v, about 2.5% w/v to about 6.5% w/v, about 2.5% w/v to about 6.0% w/v, about 2.5% w/v to about 5.5% w/v, about 2.5% w/v to about 5.0% w/v, about 2.5% w/v to about 4.5% w/v, about 2.5% w/v to about 4.0% w/v, about 2.5% w/v to about 3.5% w/v, about 2.5% w/v to about 3.0% w/v, about 3.0% w/v to about 8.0% w/v, about 3.0% w/v to about 7.5% w/v, about 3.0% w/v to about 7.0% w/v, about 3.0% w/v to about 6.5% w/v, about 3.0% w/v to about 6.0% w/v, about 3.0% w/v to about 5.5% w/v, about 3.0% w/v to about 5.0% w/v, about 3.0% w/v to about 4.5% w/v, about 3.0% w/v to about 4.0% w/v, about 3.0% w/v to about 3.5% w/v, about 3.5% w/v to about 8.0% w/v, about 3.5% w/v to about 7.5% w/v, about 3.5% w/v to about 7.0% w/v, about 3.5% w/v to about 6.5% w/v, about 3.5% w/v to about 6.0% w/v, about 3.5% w/v to about 5.5% w/v, about 3.5% w/v to about 5.0% w/v, about 3.5% w/v to about 4.5% w/v, about 3.5% w/v to about 4.0% w/v, about 4.0% w/v to about 8.0% w/v, about 4.0% w/v to about 7.5% w/v, about 4.0% w/v to about 7.0% w/v, about 4.0% w/v to about 6.5% w/v, about 4.0% w/v to about 6.0% w/v, about 4.0% w/v to about 5.5% w/v, about 4.0% w/v to about 5.0% w/v, about 4.0% w/v to about 4.5% w/v, about 4.5% w/v to about 8.0% w/v, about 4.5% w/v to about 7.5% w/v, about 4.5% w/v to about 7.0% w/v, about 4.5% w/v to about 6.5% w/v, about 4.5% w/v to about 6.0% w/v, about 4.5% w/v to about 5.5% w/v, about 4.5% w/v to about 5.0% w/v, about 5.0% w/v to about 8.0% w/v, about 5.0% w/v to about 7.5% w/v, about 5.0% w/v to about 7.0% w/v, about 5.0% w/v to about 6.5% w/v, about 5.0% w/v to about 6.0% w/v, about 5.0% w/v to about 5.5% w/v, about 5.5% w/v to about 8.0% w/v, about 5.5% w/v to about 7.5% w/v, about 5.5% w/v to about 7.0% w/v, about 5.5% w/v to about 6.5% w/v, about 5.5% w/v to about 6.0% w/v, about 6.0% w/v to about 8.0% w/v, about 6.0% w/v to about 7.5% w/v, about 6.0% w/v to about 7.0% w/v, about 6.0% w/v to about 6.5% w/v, about 6.5% w/v to about 8.0% w/v, about 6.5% w/v to about 7.5% w/v, about 6.5% w/v to about 7.0% w/v, about 7.0% w/v to about 8.0% w/v, about 7.0% w/v to about 7.5% w/v, or about 7.5% w/v to about 8.0% w/v).

In one embodiment, the buffer is selected from the group consisting of acetate, histidine, phosphate, citrate, succinate, tartrate, imidazole, and maleate, and any combination thereof. In another embodiment, the buffer is present at a concentration of about 1 mM to 150 mM (e.g., about 1 mM to about 140 mM, about 1 mM to about 130 mM, about 1 mM to about 120 mM, about 1 mM to about 110 mM, about 1 mM to about 100 mM, about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 70 mM, about 1 mM to about 60 mM, about 1 mM to about 50 mM, about 1 mM to about 45 mM, about 1 mM to about 40 mM, about 1 mM to about 35 mM, about 1 mM to about 30 mM, about 1 mM to about 25 mM, about 1 mM to about 20 mM, about 1 mM to about 18 mM, about 1 mM to about 16 mM, about 1 mM to about 14 mM, about 1 mM to about 12 mM, about 1 mM to about 10 mM, about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 150 mM, about 2 mM to about 140 mM, about 2 mM to about 130 mM, about 2 mM to about 120 mM, about 2 mM to about 110 mM, about 2 mM to about 100 mM, about 2 mM to about 90 mM, about 2 mM to about 80 mM, about 2 mM to about 70 mM, about 2 mM to about 60 mM, about 2 mM to about 50 mM, about 2 mM to about 45 mM, about 2 mM to about 40 mM, about 2 mM to about 35 mM, about 2 mM to about 30 mM, about 2 mM to about 25 mM, about 2 mM to about 20 mM, about 2 mM to about 18 mM, about 2 mM to about 16 mM, about 2 mM to about 14 mM, about 2 mM to about 12 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 150 mM, about 4 mM to about 140 mM, about 4 mM to about 130 mM, about 4 mM to about 120 mM, about 4 mM to about 110 mM, about 4 mM to about 100 mM, about 4 mM to about 90 mM, about 4 mM to about 80 mM, about 4 mM to about 70 mM, about 4 mM to about 60 mM, about 4 mM to about 50 mM, about 4 mM to about 45 mM, about 4 mM to about 40 mM, about 4 mM to about 35 mM, about 4 mM to about 30 mM, about 4 mM to about 25 mM, about 4 mM to about 20 mM, about 4 mM to about 18 mM, about 4 mM to about 16 mM, about 4 mM to about 14 mM, about 4 mM to about 12 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 150 mM, about 6 mM to about 140 mM, about 6 mM to about 130 mM, about 6 mM to about 120 mM, about 6 mM to about 110 mM, about 6 mM to about 100 mM, about 6 mM to about 90 mM, about 6 mM to about 80 mM, about 6 mM to about 70 mM, about 6 mM to about 60 mM, about 6 mM to about 50 mM, about 6 mM to about 45 mM, about 6 mM to about 40 mM, about 6 mM to about 35 mM, about 6 mM to about 30 mM, about 6 mM to about 25 mM, about 6 mM to about 20 mM, about 6 mM to about 18 mM, about 6 mM to about 16 mM, about 6 mM to about 14 mM, about 6 mM to about 12 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, about 8 mM to about 150 mM, about 8 mM to about 140 mM, about 8 mM to about 130 mM, about 8 mM to about 120 mM, about 8 mM to about 110 mM, about 8 mM to about 100 mM, about 8 mM to about 90 mM, about 8 mM to about 80 mM, about 8 mM to about 70 mM, about 8 mM to about 60 mM, about 8 mM to about 50 mM, about 8 mM to about 45 mM, about 8 mM to about 40 mM, about 8 mM to about 35 mM, about 8 mM to about 30 mM, about 8 mM to about 25 mM, about 8 mM to about 20 mM, about 8 mM to about 18 mM, about 8 mM to about 16 mM, about 8 mM to about 14 mM, about 8 mM to about 12 mM, about 8 mM to about 10 mM, about 10 mM to about 150 mM, about 10 mM to about 140 mM, about 10 mM to about 130 mM, about 10 mM to about 120 mM, about 10 mM to about 110 mM, about 10 mM to about 100 mM, about 10 mM to about 90 mM, about 10 mM to about 80 mM, about 10 mM to about 70 mM, about 10 mM to about 60 mM, about 10 mM to about 50 mM, about 10 mM to about 45 mM, about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 10 mM to about 20 mM, about 10 mM to about 18 mM, about 10 mM to about 16 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, about 12 mM to about 150 mM, about 12 mM to about 140 mM, about 12 mM to about 130 mM, about 12 mM to about 120 mM, about 12 mM to about 110 mM, about 12 mM to about 100 mM, about 12 mM to about 90 mM, about 12 mM to about 80 mM, about 12 mM to about 70 mM, about 12 mM to about 60 mM, about 12 mM to about 50 mM, about 12 mM to about 45 mM, about 12 mM to about 40 mM, about 12 mM to about 35 mM, about 12 mM to about 30 mM, about 12 mM to about 25 mM, about 12 mM to about 20 mM, about 12 mM to about 18 mM, about 12 mM to about 16 mM, about 12 mM to about 14 mM, about 14 mM to about 150 mM, about 14 mM to about 140 mM, about 14 mM to about 130 mM, about 14 mM to about 120 mM, about 14 mM to about 110 mM, about 14 mM to about 100 mM, about 14 mM to about 90 mM, about 14 mM to about 80 mM, about 14 mM to about 70 mM, about 14 mM to about 60 mM, about 14 mM to about 50 mM, about 14 mM to about 45 mM, about 14 mM to about 40 mM, about 14 mM to about 35 mM, about 14 mM to about 30 mM, about 14 mM to about 25 mM, about 14 mM to about 20 mM, about 14 mM to about 18 mM, about 14 mM to about 16 mM, about 16 mM to about 150 mM, about 16 mM to about 140 mM, about 16 mM to about 130 mM, about 16 mM to about 120 mM, about 16 mM to about 110 mM, about 16 mM to about 100 mM, about 16 mM to about 90 mM, about 16 mM to about 80 mM, about 16 mM to about 70 mM, about 16 mM to about 60 mM, about 16 mM to about 50 mM, about 16 mM to about 45 mM, about 16 mM to about 40 mM, about 16 mM to about 35 mM, about 16 mM to about 30 mM, about 16 mM to about 25 mM, about 16 mM to about 20 mM, about 16 mM to about 18 mM, about 18 mM to about 150 mM, about 18 mM to about 140 mM, about 18 mM to about 130 mM, about 18 mM to about 120 mM, about 18 mM to about 110 mM, about 18 mM to about 100 mM, about 18 mM to about 90 mM, about 18 mM to about 80 mM, about 18 mM to about 70 mM, about 18 mM to about 60 mM, about 18 mM to about 50 mM, about 18 mM to about 45 mM, about 18 mM to about 40 mM, about 18 mM to about 35 mM, about 18 mM to about 30 mM, about 18 mM to about 25 mM, about 18 mM to about 20 mM, about 20 mM to about 150 mM, about 20 mM to about 140 mM, about 20 mM to about 130 mM, about 20 mM to about 120 mM, about 20 mM to about 110 mM, about 20 mM to about 100 mM, about 20 mM to about 90 mM, about 20 mM to about 80 mM, about 20 mM to about 70 mM, about 20 mM to about 60 mM, about 20 mM to about 50 mM, about 20 mM to about 45 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, about 25 mM to about 150 mM, about 25 mM to about 140 mM, about 25 mM to about 130 mM, about 25 mM to about 120 mM, about 25 mM to about 110 mM, about 25 mM to about 100 mM, about 25 mM to about 90 mM, about 25 mM to about 80 mM, about 25 mM to about 70 mM, about 25 mM to about 60 mM, about 25 mM to about 50 mM, about 25 mM to about 45 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, about 25 mM to about 30 mM, about 30 mM to about 150 mM, about 30 mM to about 140 mM, about 30 mM to about 130 mM, about 30 mM to about 120 mM, about 30 mM to about 110 mM, about 30 mM to about 100 mM, about 30 mM to about 90 mM, about 30 mM to about 80 mM, about 30 mM to about 70 mM, about 30 mM to about 60 mM, about 30 mM to about 50 mM, about 30 mM to about 45 mM, about 30 mM to about 40 mM, about 30 mM to about 35 mM, about 35 mM to about 150 mM, about 35 mM to about 140 mM, about 35 mM to about 130 mM, about 35 mM to about 120 mM, about 35 mM to about 110 mM, about 35 mM to about 100 mM, about 35 mM to about 90 mM, about 35 mM to about 80 mM, about 35 mM to about 70 mM, about 35 mM to about 60 mM, about 35 mM to about 50 mM, about 35 mM to about 45 mM, about 35 mM to about 40 mM, about 40 mM to about 150 mM, about 40 mM to about 140 mM, about 40 mM to about 130 mM, about 40 mM to about 120 mM, about 40 mM to about 110 mM, about 40 mM to about 100 mM, about 40 mM to about 90 mM, about 40 mM to about 80 mM, about 40 mM to about 70 mM, about 40 mM to about 60 mM, about 40 mM to about 50 mM, about 40 mM to about 45 mM, about 45 mM to about 150 mM, about 45 mM to about 140 mM, about 45 mM to about 130 mM, about 45 mM to about 120 mM, about 45 mM to about 110 mM, about 45 mM to about 100 mM, about 45 mM to about 90 mM, about 45 mM to about 80 mM, about 45 mM to about 70 mM, about 45 mM to about 60 mM, about 45 mM to about 50 mM, about 50 mM to about 150 mM, about 50 mM to about 140 mM, about 50 mM to about 130 mM, about 50 mM to about 120 mM, about 50 mM to about 110 mM, about 50 mM to about 100 mM, about 50 mM to about 90 mM, about 50 mM to about 80 mM, about 50 mM to about 70 mM, about 50 mM to about 60 mM, about 60 mM to about 150 mM, about 60 mM to about 140 mM, about 60 mM to about 130 mM, about 60 mM to about 120 mM, about 60 mM to about 110 mM, about 60 mM to about 100 mM, about 60 mM to about 90 mM, about 60 mM to about 80 mM, about 60 mM to about 70 mM, about 70 mM to about 150 mM, about 70 mM to about 140 mM, about 70 mM to about 130 mM, about 70 mM to about 120 mM, about 70 mM to about 110 mM, about 70 mM to about 100 mM, about 70 mM to about 90 mM, about 70 mM to about 80 mM, about 80 mM to about 150 mM, about 80 mM to about 140 mM, about 80 mM to about 130 mM, about 80 mM to about 120 mM, about 80 mM to about 110 mM, about 80 mM to about 100 mM, about 80 mM to about 90 mM, about 90 mM to about 150 mM, about 90 mM to about 140 mM, about 90 mM to about 130 mM, about 90 mM to about 120 mM, about 90 mM to about 110 mM, about 90 mM to about 100 mM, about 100 mM to about 150 mM, about 100 mM to about 140 mM, about 100 mM to about 130 mM, about 100 mM to about 120 mM, about 100 mM to about 110 mM, about 110 mM to about 150 mM, about 110 mM to about 140 mM, about 110 mM to about 130 mM, about 110 mM to about 120 mM, about 120 mM to about 150 mM, about 120 mM to about 140 mM, about 120 mM to about 130 mM, about 130 mM to about 150 mM, about 130 mM to about 140 mM, or about 140 mM to about 150 mM). In still another embodiment, the buffer concentration is about 5 mM to 20 mM. In yet another embodiment, the buffer concentration is about 10 mM.

In one embodiment, the stabilizer is a sugar. In another embodiment, the stabilizer is sucrose. In some embodiments, the stabilizer is trehalose. In some embodiments, the stabilizer is human serum albumin or Recombumin®. In some embodiments, the stabilizer is betaine. In some embodiments of any of the aqueous formulations described herein, a stabilizer (e.g., any of the exemplary stabilizers described herein) can be present at a final concentration of about 0.01% w/v to about 8.0% w/v (e.g., about 0.01% w/v to about 7.5% w/v, about 0.01% w/v to about 7.0% w/v, about 0.01% w/v to about 6.5% w/v, about 0.01% w/v to about 6.0% w/v, about 0.01% w/v to about 5.5% w/v, about 0.01% w/v to about 5.0% w/v, about 0.01% w/v to about 4.5% w/v, about 0.01% w/v to about 4.0% w/v, about 0.01% w/v to about 3.5% w/v, about 0.01% w/v to about 3.0% w/v, about 0.01% w/v to about 2.5% w/v, about 0.01% w/v to about 2.0% w/v, about 0.01% w/v to about 1.5% w/v, about 0.01% w/v, to about 1.0% w/v, about 0.01% w/v to about 0.5% w/v, about 0.1% w/v to about 8.0% w/v, about 0.1% w/v to about 7.5% w/v, about 0.1% w/v to about 7.0% w/v, about 0.1% w/v to about 6.5% w/v, about 0.1% w/v to about 6.0% w/v, about 0.1% w/v to about 5.5% w/v, about 0.1% w/v to about 5.0% w/v, about 0.1% w/v to about 4.5% w/v, about 0.1% w/v to about 4.0% w/v, about 0.1% w/v to about 3.5% w/v, about 0.1% w/v to about 3.0% w/v, about 0.1% w/v to about 2.5% w/v, about 0.1% w/v to about 2.0% w/v, about 0.1% w/v to about 1.5% w/v, about 0.1% w/v, to about 1.0% w/v, about 0.1% w/v to about 0.5% w/v, about 0.5% w/v to about 8.0% w/v, about 0.5% w/v to about 7.5% w/v, about 0.5% w/v to about 7.0% w/v, about 0.5% w/v to about 6.5% w/v, about 0.5% w/v to about 6.0% w/v, about 0.5% w/v to about 5.5% w/v, about 0.5% w/v to about 5.0% w/v, about 0.5% w/v to about 4.5% w/v, about 0.5% w/v to about 4.0% w/v, about 0.5% w/v to about 3.5% w/v, about 0.5% w/v to about 3.0% w/v, about 0.5% w/v to about 2.5% w/v, about 0.5% w/v to about 2.0% w/v, about 0.5% w/v to about 1.5% w/v, about 0.5% w/v to about 1.0% w/v, about 1.0% w/v to about 8.0% w/v, about 1.0% w/v to about 7.5% w/v, about 1.0% w/v to about 7.0% w/v, about 1.0% w/v to about 6.5% w/v, about 1.0% w/v to about 6.0% w/v, about 1.0% w/v to about 5.5% w/v, about 1.0% w/v to about 5.0% w/v, about 1.0% w/v to about 4.5% w/v, about 1.0% w/v to about 4.0% w/v, about 1.0% w/v to about 3.5% w/v, about 1.0% w/v to about 3.0% w/v, about 1.0% w/v to about 2.5% w/v, about 1.0% w/v to about 2.0% w/v, about 1.0% w/v to about 1.5% w/v, about 1.5% w/v to about 8.0% w/v, about 1.5% w/v to about 7.5% w/v, about 1.5% w/v to about 7.0% w/v, about 1.5% w/v to about 6.5% w/v, about 1.5% w/v to about 6.0% w/v, about 1.5% w/v to about 5.5% w/v, about 1.5% w/v to about 5.0% w/v, about 1.5% w/v to about 4.5% w/v, about 1.5% w/v to about 4.0% w/v, about 1.5% w/v to about 3.5% w/v, about 1.5% w/v to about 3.0% w/v, about 1.5% w/v to about 2.5% w/v, about 1.5% w/v to about 2.0% w/v, about 2.0% w/v to about 8.0% w/v, about 2.0% w/v to about 7.5% w/v, about 2.0% w/v to about 7.0% w/v, about 2.0% w/v to about 6.5% w/v, about 2.0% w/v to about 6.0% w/v, about 2.0% w/v to about 5.5% w/v, about 2.0% w/v to about 5.0% w/v, about 2.0 w/v to about 4.5% w/v, about 2.0% w/v to about 4.0% w/v, about 2.0% w/v to about 3.5% w/v, about 2.0% w/v to about 3.0% w/v, about 2.0% w/v to about 2.5% w/v, about 2.5% w/v to about 8.0% w/v, about 2.5% w/v to about 7.5% w/v, about 2.5% w/v to about 7.0% w/v, about 2.5% w/v to about 6.5% w/v, about 2.5% w/v to about 6.0% w/v, about 2.5% w/v to about 5.5% w/v, about 2.5% w/v to about 5.0% w/v, about 2.5% w/v to about 4.5% w/v, about 2.5% w/v to about 4.0% w/v, about 2.5% w/v to about 3.5% w/v, about 2.5% w/v to about 3.0% w/v, about 3.0% w/v to about 8.0% w/v, about 3.0% w/v to about 7.5% w/v, about 3.0% w/v to about 7.0% w/v, about 3.0% w/v to about 6.5% w/v, about 3.0% w/v to about 6.0% w/v, about 3.0% w/v to about 5.5% w/v, about 3.0% w/v to about 5.0% w/v, about 3.0% w/v to about 4.5% w/v, about 3.0% w/v to about 4.0% w/v, about 3.0% w/v to about 3.5% w/v, about 3.5% w/v to about 8.0% w/v, about 3.5% w/v to about 7.5% w/v, about 3.5% w/v to about 7.0% w/v, about 3.5% w/v to about 6.5% w/v, about 3.5% w/v to about 6.0% w/v, about 3.5% w/v to about 5.5% w/v, about 3.5% w/v to about 5.0% w/v, about 3.5% w/v to about 4.5% w/v, about 3.5% w/v to about 4.0% w/v, about 4.0% w/v to about 8.0% w/v, about 4.0% w/v to about 7.5% w/v, about 4.0% w/v to about 7.0% w/v, about 4.0% w/v to about 6.5% w/v, about 4.0% w/v to about 6.0% w/v, about 4.0% w/v to about 5.5% w/v, about 4.0% w/v to about 5.0% w/v, about 4.0% w/v to about 4.5% w/v, about 4.5% w/v to about 8.0% w/v, about 4.5% w/v to about 7.5% w/v, about 4.5% w/v to about 7.0% w/v, about 4.5% w/v to about 6.5% w/v, about 4.5% w/v to about 6.0% w/v, about 4.5% w/v to about 5.5% w/v, about 4.5% w/v to about 5.0% w/v, about 5.0% w/v to about 8.0% w/v, about 5.0% w/v to about 7.5% w/v, about 5.0% w/v to about 7.0% w/v, about 5.0% w/v to about 6.5% w/v, about 5.0% w/v to about 6.0% w/v, about 5.0% w/v to about 5.5% w/v, about 5.5% w/v to about 8.0% w/v, about 5.5% w/v to about 7.5% w/v, about 5.5% w/v to about 7.0% w/v, about 5.5% w/v to about 6.5% w/v, about 5.5% w/v to about 6.0% w/v, about 6.0% w/v to about 8.0% w/v, about 6.0% w/v to about 7.5% w/v, about 6.0% w/v to about 7.0% w/v, about 6.0% w/v to about 6.5% w/v, about 6.5% w/v to about 8.0% w/v, about 6.5% w/v to about 7.5% w/v, about 6.5% w/v to about 7.0% w/v, about 7.0% w/v to about 8.0% w/v, about 7.0% w/v to about 7.5% w/v, or about 7.5% w/v to about 8.0% w/v).

In one embodiment, the stabilizer is an amino acid (e.g., an aromatic amino acid, e.g., tyrosine, phenylalanine, and tryptophan). In another embodiment, the amino acid is selected from the group consisting of glycine, arginine, and proline or combinations thereof. The amino acids may be present at a concentration of about 5-300 mM (e.g., about 5 mM to about 280 mM, about 5 mM to about 260 mM, about 5 mM to about 240 mM, about 5 mM to about 220 mM, about 5 mM to about 200 mM, about 5 mM to about 180 mM, about 5 mM to about 160 mM, about 5 mM to about 140 mM, about 5 mM to about 120 mM, about 5 mM to about 100 mM, about 5 mM to about 80 mM, about 5 mM to about 60 mM, about 5 mM to about 40 mM, about 5 mM to about 20 mM, about 5 mM to about 10 mM, about 10 mM to about 300 mM, about 10 mM to about 280 mM, about 10 mM to about 260 mM, about 10 mM to about 240 mM, about 10 mM to about 220 mM, about 10 mM to about 200 mM, about 10 mM to about 180 mM, about 10 mM to about 160 mM, about 10 mM to about 140 mM, about 10 mM to about 120 mM, about 10 mM to about 100 mM, about 10 mM to about 80 mM, about 10 mM to about 60 mM, about 10 mM to about 40 mM, about 10 mM to about 20 mM, about 20 mM to about 300 mM, about 20 mM to about 280 mM, about 20 mM to about 260 mM, about 20 mM to about 240 mM, about 20 mM to about 220 mM, about 20 mM to about 200 mM, about 20 mM to about 180 mM, about 20 mM to about 160 mM, about 20 mM to about 140 mM, about 20 mM to about 120 mM, about 20 mM to about 100 mM, about 20 mM to about 80 mM, about 20 mM to about 60 mM, about 20 mM to about 40 mM, about 40 mM to about 300 mM, about 40 mM to about 280 mM, about 40 mM to about 260 mM, about 40 mM to about 240 mM, about 40 mM to about 220 mM, about 40 mM to about 200 mM, about 40 mM to about 180 mM, about 40 mM to about 160 mM, about 40 mM to about 140 mM, about 40 mM to about 120 mM, about 40 mM to about 100 mM, about 40 mM to about 80 mM, about 40 mM to about 60 mM, about 40 mM to about 40 mM, about 60 mM to about 300 mM, about 60 mM to about 280 mM, about 60 mM to about 260 mM, about 60 mM to about 240 mM, about 60 mM to about 220 mM, about 60 mM to about 200 mM, about 60 mM to about 180 mM, about 60 mM to about 160 mM, about 60 mM to about 140 mM, about 60 mM to about 120 mM, about 60 mM to about 100 mM, about 60 mM to about 80 mM, about 80 mM to about 300 mM, about 80 mM to about 250 mM, about 80 mM to about 200 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM, about 100 mM to about 200 mM, about 100 mM to about 150 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 150 mM to about 200 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, or about 250 mM to about 300 mM).

In another embodiment, the co-solvent-free formulations of the invention further comprise one or more salt(s). In one embodiment, the one or more salt(s) can be selected from the group consisting of sodium chloride, magnesium chloride, calcium chloride, and potassium chloride. Each of the one or more salt(s) may be present at a concentration of about 10 mM-100 mM (e.g., about 0.1 mM to about 90 mM, about 0.1 mM to about 80 mM, about 0.1 mM to about 70 mM, about 0.1 mM to about 65 mM, about 0.1 mM to about 60 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 10 mM, about 0.1 mM to about 5 mM, about 1 mM to about 100 mM, about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 70 mM, about 1 mM to about 60 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 mM to about 10 mM, about 10 mM to about 95 mM, about 10 mM to about 90 mM, about 10 mM to about 85 mM, about 10 mM to about 80 mM, about 10 mM to about 75 mM, about 10 mM to about 70 mM, about 10 mM to about 65 mM, about 10 mM to about 60 mM, about 10 mM to about 55 mM, about 10 mM to about 50 mM, about 10 mM to about 45 mM, about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 10 mM to about 20 mM, about 10 mM to about 18 mM, about 10 mM to about 16 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, about 12 mM to about 100 mM, about 12 mM to about 95 mM, about 12 mM to about 90 mM, about 12 mM to about 85 mM, about 12 mM to about 80 mM, about 12 mM to about 75 mM, about 12 mM to about 70 mM, about 12 mM to about 65 mM, about 12 mM to about 60 mM, about 12 mM to about 55 mM, about 12 mM to about 50 mM, about 12 mM to about 45 mM, about 12 mM to about 40 mM, about 12 mM to about 35 mM, about 12 mM to about 30 mM, about 12 mM to about 25 mM, about 12 mM to about 20 mM, about 12 mM to about 18 mM, about 12 mM to about 16 mM, about 12 mM to about 14 mM, about 14 mM to about 100 mM, about 14 mM to about 95 mM, about 14 mM to about 90 mM, about 14 mM to about 85 mM, about 14 mM to about 80 mM, about 14 mM to about 75 mM, about 14 mM to about 70 mM, about 14 mM to about 65 mM, about 14 mM to about 60 mM, about 14 mM to about 55 mM, about 14 mM to about 50 mM, about 14 mM to about 45 mM, about 14 mM to about 40 mM, about 14 mM to about 35 mM, about 14 mM to about 30 mM, about 14 mM to about 25 mM, about 14 mM to about 20 mM, about 14 mM to about 18 mM, about 14 mM to about 16 mM, about 16 mM to about 100 mM, about 16 mM to about 95 mM, about 16 mM to about 90 mM, about 16 mM to about 85 mM, about 16 mM to about 80 mM, about 16 mM to about 75 mM, about 16 mM to about 70 mM, about 16 mM to about 65 mM, about 16 mM to about 60 mM, about 16 mM to about 55 mM, about 16 mM to about 50 mM, about 16 mM to about 45 mM, about 16 mM to about 40 mM, about 16 mM to about 35 mM, about 16 mM to about 30 mM, about 16 mM to about 25 mM, about 16 mM to about 20 mM, about 16 mM to about 18 mM, about 18 mM to about 100 mM, about 18 mM to about 95 mM, about 18 mM to about 90 mM, about 18 mM to about 85 mM, about 18 mM to about 80 mM, about 18 mM to about 75 mM, about 18 mM to about 70 mM, about 18 mM to about 65 mM, about 18 mM to about 60 mM, about 18 mM to about 55 mM, about 18 mM to about 50 mM, about 18 mM to about 45 mM, about 18 mM to about 40 mM, about 18 mM to about 35 mM, about 18 mM to about 30 mM, about 18 mM to about 25 mM, about 18 mM to about 20 mM, about 20 mM to about 100 mM, about 20 mM to about 95 mM, about 20 mM to about 90 mM, about 20 mM to about 85 mM, about 20 mM to about 80 mM, about 20 mM to about 75 mM, about 20 mM to about 70 mM, about 20 mM to about 65 mM, about 20 mM to about 60 mM, about 20 mM to about 55 mM, about 20 mM to about 50 mM, about 20 mM to about 45 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, about 25 mM to about 100 mM, about 25 mM to about 95 mM, about 25 mM to about 90 mM, about 25 mM to about 85 mM, about 25 mM to about 80 mM, about 25 mM to about 75 mM, about 25 mM to about 70 mM, about 25 mM to about 65 mM, about 25 mM to about 60 mM, about 25 mM to about 55 mM, about 25 mM to about 50 mM, about 25 mM to about 45 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, about 25 mM to about 30 mM, about 30 mM to about 100 mM, about 30 mM to about 95 mM, about 30 mM to about 90 mM, about 30 mM to about 85 mM, about 30 mM to about 80 mM, about 30 mM to about 75 mM, about 30 mM to about 70 mM, about 30 mM to about 65 mM, about 30 mM to about 60 mM, about 30 mM to about 55 mM, about 30 mM to about 50 mM, about 30 mM to about 45 mM, about 30 mM to about 40 mM, about 30 mM to about 35 mM, about 35 mM to about 100 mM, about 35 mM to about 95 mM, about 35 mM to about 90 mM, about 35 mM to about 85 mM, about 35 mM to about 80 mM, about 35 mM to about 75 mM, about 35 mM to about 70 mM, about 35 mM to about 65 mM, about 35 mM to about 60 mM, about 35 mM to about 55 mM, about 35 mM to about 50 mM, about 35 mM to about 45 mM, about 35 mM to about 40 mM, about 40 mM to about 100 mM, about 40 mM to about 95 mM, about 40 mM to about 90 mM, about 40 mM to about 85 mM, about 40 mM to about 80 mM, about 40 mM to about 75 mM, about 40 mM to about 70 mM, about 40 mM to about 65 mM, about 40 mM to about 60 mM, about 40 mM to about 55 mM, about 40 mM to about 50 mM, about 40 mM to about 45 mM, about 45 mM to about 100 mM, about 45 mM to about 95 mM, about 45 mM to about 90 mM, about 45 mM to about 85 mM, about 45 mM to about 80 mM, about 45 mM to about 75 mM, about 45 mM to about 70 mM, about 45 mM to about 65 mM, about 45 mM to about 60 mM, about 45 mM to about 55 mM, about 45 mM to about 50 mM, about 50 mM to about 100 mM, about 50 mM to about 95 mM, about 50 mM to about 90 mM, about 50 mM to about 85 mM, about 50 mM to about 80 mM, about 50 mM to about 75 mM, about 50 mM to about 70 mM, about 50 mM to about 65 mM, about 50 mM to about 60 mM, about 50 mM to about 55 mM, about 55 mM to about 100 mM, about 55 mM to about 95 mM, about 55 mM to about 90 mM, about 55 mM to about 85 mM, about 55 mM to about 80 mM, about 55 mM to about 75 mM, about 55 mM to about 70 mM, about 55 mM to about 65 mM, about 55 mM to about 60 mM, about 60 mM to about 100 mM, about 60 mM to about 95 mM, about 60 mM to about 90 mM, about 60 mM to about 85 mM, about 60 mM to about 80 mM, about 60 mM to about 75 mM, about 60 mM to about 70 mM, about 60 mM to about 65 mM, about 65 mM to about 100 mM, about 65 mM to about 95 mM, about 65 mM to about 90 mM, about 65 mM to about 85 mM, about 65 mM to about 80 mM, about 65 mM to about 75 mM, about 65 mM to about 70 mM, about 70 mM to about 100 mM, about 70 mM to about 95 mM, about 70 mM to about 90 mM, about 70 mM to about 85 mM, about 70 mM to about 80 mM, about 70 mM to about 75 mM, about 75 mM to about 100 mM, about 75 mM to about 95 mM, about 75 mM to about 90 mM, about 75 mM to about 85 mM, about 75 mM to about 80 mM, about 80 mM to about 100 mM, about 80 mM to about 95 mM, about 80 mM to about 90 mM, about 80 mM to about 85 mM, about 85 mM to about 100 mM, about 85 mM to about 95 mM, about 85 mM to about 90 mM, about 90 mM to about 100 mM, about 90 mM to about 95 mM, or about 95 mM to about 100 mM, or about 10 mM, about 12 mM, about 14 mM, about 16 mM, about 18 mM, about 20 mM, about 22 mM, about 24 mM, about 26 mM, about 28 mM, about 30 mM, about 32 mM, about 34 mM, about 36 mM, about 38 mM, about 40 mM, about 42 mM, about 44 mM, about 46 mM, about 48 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM about 95 mM, or about 100 mM).

In some embodiments of any of the formulations described herein, the formulation can include one or more of: sodium ion at a final concentration of about 100 mM to about 200 mM (e.g., about 100 mM to about 180 mM, about 100 mM to about 160 mM, about 100 mM to about 140 mM, about 100 mM to about 120 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 160 mM, about 120 mM to about 140 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, or about 180 mM to about 200 mM); potassium ion at a final concentration of about 1 mM to about 20 mM (e.g., about 1 mM to about 18 mM, about 1 mM to about 16 mM, about 1 mM to about 14 mM, about 1 mM to about 12 mM, about 1 mM to about 10 mM, about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 20 mM, about 2 mM to about 18 mM, about 2 mM to about 16 mM, about 2 mM to about 14 mM, about 2 mM to about 12 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 20 mM, about 4 mM to about 18 mM, about 4 mM to about 16 mM, about 4 mM to about 14 mM, about 4 mM to about 12 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 20 mM, about 6 mM to about 18 mM, about 6 mM to about 16 mM, about 6 mM to about 14 mM, about 6 mM to about 12 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, about 8 mM to about 20 mM, about 8 mM to about 18 mM, about 8 mM to about 16 mM, about 8 mM to about 14 mM, about 8 mM to about 12 mM, about 8 mM to about 10 mM, about 10 mM to about 20 mM, about 10 mM to about 18 mM, about 10 mM to about 16 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, about 12 mM to about 20 mM, about 12 mM to about 18 mM, about 12 mM to about 16 mM, about 12 mM to about 14 mM, about 14 mM to about 20 mM, about 14 mM to about 18 mM, about 14 mM to about 16 mM, about 16 mM to about 20 mM, about 16 mM to about 18 mM, or about 18 mM to about 20 mM); chloride ion at a final concentration of about 10 mM to about 200 mM (e.g., about 10 mM to about 180 mM, about 10 mM to about 160 mM, about 10 mM to about 140 mM, about 10 mM to about 120 mM, about 10 mM to about 100 mM, about 10 mM to about 80 mM, about 10 mM to about 60 mM, about 10 mM to about 40 mM, about 10 mM to about 20 mM, about 50 mM to about 200 mM, 50 mM to about 180 mM, about 50 mM to about 160 mM, about 50 mM to about 140 mM, about 50 mM to about 120 mM, about 50 mM to about 100 mM, about 50 mM to about 80 mM, about 100 mM to about 200 mM, about 100 mM to about 180 mM, about 100 mM to about 160 mM, about 100 mM to about 140 mM, about 100 mM to about 120 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 160 mM, about 120 mM to about 140 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, or about 180 mM to about 200 mM); calcium ion at a final concentration of about 0.1 mM to about 5 mM (e.g., about 0.1 mM to about 4 mM, about 0.1 mM to about 3 mM, about 0.1 mM to about 2 mM, about 0.1 mM to about 1 mM, about 0.1 mM to about 0.5 mM, about 0.5 mM to about 5 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1 mM, about 1 mM to about 5 mM, about 1 mM to about 4 mM, about 1 mM to about 3 mM, about 1 mM to about 2 mM, about 2 mM to about 5 mM, about 2 mM to about 4 mM, about 2 mM to about 3 mM, about 3 mM to about 5 mM, about 3 mM to about 4 mM, or about 4 mM to about 5 mM); magnesium ion at a final concentration of about 0.1 mM to about 3 mM (e.g., about 0.1 mM to about 2.5 mM, about 0.1 mM to about 2.0 mM, about 0.1 mM to about 1.5 mM, about 0.1 mM to about 1.0 mM, about 0.1 mM to about 0.5 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2.5 mM, about 0.5 mM to about 2.0 mM, about 0.5 mM to about 1.5 mM, about 0.5 mM to about 1.0 mM, about 1.0 mM to about 3.0 mM, about 1.0 mM to about 2.5 mM, about 1.0 mM to about 2.0 mM, about 1.0 mM to about 1.5 mM, about 1.5 mM to about 3.0 mM, about 1.5 mM to about 2.5 mM, about 1.5 mM to about 2.0 mM, about 2.0 mM to about 3.0 mM, about 2.0 mM to about 2.5 mM, or about 2.5 mM to about 3.0 mM); sugar (e.g., glucose) at a final concentration of about 0.5 mM to about 10 mM (e.g., about 0.5 mM to about 8 mM, about 0.5 mM to about 6 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1 mM, about 1 mM to about 10 mM, about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, or about 8 mM to about 10 mM); lactate at a final concentration of about 1 mM to about 10 mM (e.g., about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, or about 8 mM to about 10 mM); beta-hyrdoxybutyrate at a final concentration of about 0.01 mM to about 0.3 mM (e.g., about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.1 mM, about 0.01 mM to about 0.05 mM, about 0.05 mM to about 3 mM, about 0.05 mM to about 0.2 mM, about 0.05 mM to about 0.1 mM, about 0.1 mM to about 3 mM, about 0.1 mM to about 0.2 mM, or about 0.2 mM to about 0.3 mM); copper ion at a concentration of about 0.1 μM to about 1.0 μM (e.g., about 0.1 μM to about 0.8 μM, about 0.1 μM to about 0.6 μM, about 0.1 μM to about 0.4 μM, or about 0.1 μM to about 0.2 μM), zinc ion at a final concentration of about 0.1 μM to about 10 μM (e.g., about 0.1 μM to about 8 μM, about 0.1 μM to about 6 μM, about 0.1 μM to about 4 μM, or about 0.1 μM to about 2 μM); selenium ion at a final concentration of about 0.01 μM to about 0.2 μM (e.g., about 0.01 μM to about 0.15 μM, about 0.01 μM to about 0.10 μM, or about 0.01 μM to about 0.5 μM), iron ion at a final concentration of about 0.01 μM to about 8 μM (e.g., about 0.01 μM to about 6 μM, about 0.01 μM to about 4 μM, about 0.01 μM to about 2 μM, about 0.01 μM to about 1 μM, about 0.01 μM to about 0.05 μM), ferritin at a final concentration of about 0.1 μM to about 50 μM (e.g., 0.1 μM to about 40 μM, about 0.1 μM to about 30 μM, about 0.1 μM to about 20 μM, about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.1 μM to about 1 μM); and transferrin at final concentration of about 0.01 μM to about 0.2 μM (e.g., about 0.01 μM to about 0.15 μM, about 0.01 μM to about 0.10 μM, about 0.01 μM to about 0.05 μM).

In one embodiment, the formulation is iso-osmolar relative to the vitreous.

Formulations Free of Buffer and Organic Co-Solvent

In another embodiment, the invention provides an aqueous formulation comprising aflibercept and a stabilizer, wherein the formulation is free of both an organic co-solvent and a buffer.

In one embodiment, the formulation has a pH of about 5.5 to about 7.0 (e.g., or any of the subranges of this range described herein, e.g., about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.0). In another embodiment, the pH is about 6.0 to about 6.5. In yet another embodiment, the pH is about 6.2.

In one embodiment, the stabilizer is selected from the group consisting of amino acids, sugars (e.g., sucrose), polyols, polymers, block copolymers, alkyl saccharides (e.g., a ProTek alkyl saccharides, octyl glucoside, N-decyl-pyranoside, N-octyl-glucopyranoside, Intravail®, and those described in U.S. Pat. Nos. 9,446,134; 8,846,044, 8,226,949; 7,998,927; 8,084,022; 7,425,542; and 10,046,025), and FM1000, or any combination thereof.

In one embodiment, the stabilizer is a block copolymer. In another embodiment, the block copolymer is poloxamer (a water-soluble nonionic A-B-A and B-A-B triblock copolymers, where A is poly(ethylene oxide) (PEO) and B is poly(propylene oxide) (PPO)). In a further embodiment, the poloxamer is one described in Bodratti A M, Alexandridis P. Formulation of Poloxamers for Drug Delivery.J Funct Biomater.2018; 9(1):11.

In one embodiment, the stabilizer is a sugar. In another embodiment, the stabilizer is sucrose.

In one embodiment, the stabilizer is an amino acid (e.g., an aromatic amino acid, e.g., tyrosine, phenylalanine, and tryptophan). In another embodiment, the amino acid is selected from the group consisting of glycine, arginine, and proline or combinations thereof. The amino acids may be present at a concentration of about 5-300 mM (e.g., about 25 mM to about 280 mM, about 25 mM to about 260 mM, about 25 mM to about 240 mM, about 25 mM to about 220 mM, about 25 mM to about 200 mM, about 25 mM to about 180 mM, about 25 mM to about 160 mM, about 25 mM to about 140 mM, about 25 mM to about 120 mM, about 25 mM to about 100 mM, about 25 mM to about 95 mM, about 25 mM to about 90 mM, about 25 mM to about 85 mM, about 25 mM to about 80 mM, about 25 mM to about 75 mM, about 25 mM to about 70 mM, about 25 mM to about 65 mM, about 25 mM to about 60 mM, about 25 mM to about 55 mM, about 25 mM to about 50 mM, about 25 mM to about 45 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, about 25 mM to about 30 mM, about 30 mM to about 300 mM, about 30 mM to about 280 mM, about 30 mM to about 260 mM, about 30 mM to about 240 mM, about 30 mM to about 220 mM, about 30 mM to about 200 mM, about 30 mM to about 180 mM, about 30 mM to about 160 mM, about 30 mM to about 140 mM, about 30 mM to about 120 mM, about 30 mM to about 100 mM, about 30 mM to about 95 mM, about 30 mM to about 90 mM, about 30 mM to about 85 mM, about 30 mM to about 80 mM, about 30 mM to about 75 mM, about 30 mM to about 70 mM, about 30 mM to about 65 mM, about 30 mM to about 60 mM, about 30 mM to about 55 mM, about 30 mM to about 50 mM, about 30 mM to about 45 mM, about 30 mM to about 40 mM, about 30 mM to about 35 mM, about 35 mM to about 300 mM, about 35 mM to about 280 mM, about 35 mM to about 260 mM, about 35 mM to about 240 mM, about 35 mM to about 220 mM, about 35 mM to about 200 mM, about 35 mM to about 180 mM, about 35 mM to about 160 mM, about 35 mM to about 140 mM, about 35 mM to about 120 mM, about 35 mM to about 100 mM, about 35 mM to about 95 mM, about 35 mM to about 90 mM, about 35 mM to about 85 mM, about 35 mM to about 80 mM, about 35 mM to about 75 mM, about 35 mM to about 70 mM, about 35 mM to about 65 mM, about 35 mM to about 60 mM, about 35 mM to about 55 mM, about 35 mM to about 50 mM, about 35 mM to about 45 mM, about 35 mM to about 40 mM, about 40 mM to about 300 mM, about 40 mM to about 280 mM, about 40 mM to about 260 mM, about 40 mM to about 240 mM, about 40 mM to about 220 mM, about 40 mM to about 200 mM, about 40 mM to about 180 mM, about 40 mM to about 160 mM, about 40 mM to about 140 mM, about 40 mM to about 120 mM, about 40 mM to about 100 mM, about 40 mM to about 95 mM, about 40 mM to about 90 mM, about 40 mM to about 85 mM, about 40 mM to about 80 mM, about 40 mM to about 75 mM, about 40 mM to about 70 mM, about 40 mM to about 65 mM, about 40 mM to about 60 mM, about 40 mM to about 55 mM, about 40 mM to about 50 mM, about 40 mM to about 45 mM, about 45 mM to about 300 mM, about 45 mM to about 280 mM, about 45 mM to about 260 mM, about 45 mM to about 240 mM, about 45 mM to about 220 mM, about 45 mM to about 200 mM, about 45 mM to about 180 mM, about 45 mM to about 160 mM, about 45 mM to about 140 mM, about 45 mM to about 120 mM, about 45 mM to about 100 mM, about 45 mM to about 95 mM, about 45 mM to about 90 mM, about 45 mM to about 85 mM, about 45 mM to about 80 mM, about 45 mM to about 75 mM, about 45 mM to about 70 mM, about 45 mM to about 65 mM, about 45 mM to about 60 mM, about 45 mM to about 55 mM, about 45 mM to about 50 mM, about 50 mM to about 300 mM, about 50 mM to about 280 mM, about 50 mM to about 260 mM, about 50 mM to about 240 mM, about 50 mM to about 220 mM, about 50 mM to about 200 mM, about 50 mM to about 180 mM, about 50 mM to about 160 mM, about 50 mM to about 140 mM, about 50 mM to about 120 mM, about 50 mM to about 100 mM, about 50 mM to about 95 mM, about 50 mM to about 90 mM, about 50 mM to about 85 mM, about 50 mM to about 80 mM, about 50 mM to about 75 mM, about 50 mM to about 70 mM, about 50 mM to about 65 mM, about 50 mM to about 60 mM, about 50 mM to about 55 mM, about 55 mM to about 300 mM, about 55 mM to about 280 mM, about 55 mM to about 260 mM, about 55 mM to about 240 mM, about 55 mM to about 220 mM, about 55 mM to about 200 mM, about 55 mM to about 180 mM, about 55 mM to about 160 mM, about 55 mM to about 140 mM, about 55 mM to about 120 mM, about 55 mM to about 100 mM, about 55 mM to about 95 mM, about 55 mM to about 90 mM, about 55 mM to about 85 mM, about 55 mM to about 80 mM, about 55 mM to about 75 mM, about 55 mM to about 70 mM, about 55 mM to about 65 mM, about 55 mM to about 60 mM, about 60 mM to about 300 mM, about 60 mM to about 280 mM, about 60 mM to about 260 mM, about 60 mM to about 240 mM, about 60 mM to about 220 mM, about 60 mM to about 200 mM, about 60 mM to about 180 mM, about 60 mM to about 160 mM, about 60 mM to about 140 mM, about 60 mM to about 120 mM, about 60 mM to about 100 mM, about 60 mM to about 95 mM, about 60 mM to about 90 mM, about 60 mM to about 85 mM, about 60 mM to about 80 mM, about 60 mM to about 75 mM, about 60 mM to about 70 mM, about 60 mM to about 65 mM, about 65 mM to about 300 mM, about 65 mM to about 280 mM, about 65 mM to about 260 mM, about 65 mM to about 240 mM, about 65 mM to about 220 mM, about 65 mM to about 200 mM, about 65 mM to about 180 mM, about 65 mM to about 160 mM, about 65 mM to about 140 mM, about 65 mM to about 120 mM, about 65 mM to about 100 mM, about 65 mM to about 95 mM, about 65 mM to about 90 mM, about 65 mM to about 85 mM, about 65 mM to about 80 mM, about 65 mM to about 75 mM, about 65 mM to about 70 mM, about 70 mM to about 300 mM, about 70 mM to about 280 mM, about 70 mM to about 260 mM, about 70 mM to about 240 mM, about 70 mM to about 220 mM, about 70 mM to about 200 mM, about 70 mM to about 180 mM, about 70 mM to about 160 mM, about 70 mM to about 140 mM, about 70 mM to about 120 mM, about 70 mM to about 100 mM, about 70 mM to about 95 mM, about 70 mM to about 90 mM, about 70 mM to about 85 mM, about 70 mM to about 80 mM, about 70 mM to about 75 mM, about 75 mM to about 300 mM, about 75 mM to about 280 mM, about 75 mM to about 260 mM, about 75 mM to about 240 mM, about 75 mM to about 220 mM, about 75 mM to about 200 mM, about 75 mM to about 180 mM, about 75 mM to about 160 mM, about 75 mM to about 140 mM, about 75 mM to about 120 mM, about 75 mM to about 100 mM, about 75 mM to about 95 mM, about 75 mM to about 90 mM, about 75 mM to about 85 mM, about 75 mM to about 80 mM, about 80 mM to about 300 mM, about 80 mM to about 280 mM, about 80 mM to about 260 mM, about 80 mM to about 240 mM, about 80 mM to about 220 mM, about 80 mM to about 200 mM, about 80 mM to about 180 mM, about 80 mM to about 160 mM, about 80 mM to about 140 mM, about 80 mM to about 120 mM, about 80 mM to about 100 mM, about 80 mM to about 95 mM, about 80 mM to about 90 mM, about 80 mM to about 85 mM, about 85 mM to about 300 mM, about 85 mM to about 280 mM, about 85 mM to about 260 mM, about 85 mM to about 240 mM, about 85 mM to about 220 mM, about 85 mM to about 200 mM, about 85 mM to about 180 mM, about 85 mM to about 160 mM, about 85 mM to about 140 mM, about 85 mM to about 120 mM, about 85 mM to about 100 mM, about 85 mM to about 95 mM, about 85 mM to about 90 mM, about 90 mM to about 300 mM, about 90 mM to about 280 mM, about 90 mM to about 260 mM, about 90 mM to about 240 mM, about 90 mM to about 220 mM, about 90 mM to about 200 mM, about 90 mM to about 180 mM, about 90 mM to about 160 mM, about 90 mM to about 140 mM, about 90 mM to about 120 mM, about 90 mM to about 100 mM, about 90 mM to about 95 mM, about 95 mM to about 300 mM, about 95 mM to about 280 mM, about 95 mM to about 260 mM, about 95 mM to about 240 mM, about 95 mM to about 220 mM, about 95 mM to about 200 mM, about 95 mM to about 180 mM, about 95 mM to about 160 mM, about 95 mM to about 140 mM, about 95 mM to about 120 mM, about 95 mM to about 100 mM, about 100 mM to about 300 mM, about 100 mM to about 280 mM, about 100 mM to about 260 mM, about 100 mM to about 240 mM, about 100 mM to about 220 mM, about 100 mM to about 200 mM, about 100 mM to about 180 mM, about 100 mM to about 160 mM, about 100 mM to about 140 mM, about 100 mM to about 120 mM, about 120 mM to about 300 mM, about 120 mM to about 280 mM, about 120 mM to about 260 mM, about 120 mM to about 240 mM, about 120 mM to about 220 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 160 mM, about 120 mM to about 140 mM, about 140 mM to about 300 mM, about 140 mM to about 280 mM, about 140 mM to about 260 mM, about 140 mM to about 240 mM, about 140 mM to about 220 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 300 mM, about 160 mM to about 280 mM, about 160 mM to about 260 mM, about 160 mM to about 240 mM, about 160 mM to about 220 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, about 180 mM to about 300 mM, about 180 mM to about 280 mM, about 180 mM to about 260 mM, about 180 mM to about 240 mM, about 180 mM to about 220 mM, about 180 mM to about 200 mM, about 200 mM to about 300 mM, about 200 mM to about 280 mM, about 200 mM to about 260 mM, about 200 mM to about 240 mM, about 200 mM to about 220 mM, about 220 mM to about 300 mM, about 220 mM to about 280 mM, about 220 mM to about 260 mM, about 220 mM to about 240 mM, about 240 mM to about 300 mM, about 240 mM to about 280 mM, about 240 mM to about 260 mM, about 260 mM to about 300 mM, about 260 mM to about 280 mM, or about 280 mM to about 300 mM, or about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, about 250 mM, about 260 mM, about 270 mM, about 280 mM, about 290 mM, or about 300 mM). In another embodiment, the co-solvent-free and buffer-free formulations of the invention further comprise a salt. In one embodiment, the salt is selected from the group consisting of sodium chloride, magnesium chloride and calcium chloride. The salts may be present at a concentration of about 10 mM-100 mM (e.g., or any of the subranges of this range described herein or about 10 mM, about 12 mM, about 14 mM, about 16 mM, about 18 mM, about 20 mM, about 22 mM, about 24 mM, about 26 mM, about 28 mM, about 30 mM, about 32 mM, about 34 mM, about 36 mM, about 38 mM, about 40 mM, about 42 mM, about 44 mM, about 46 mM, about 48 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM about 95 mM, or about 100 mM).

In another embodiment, the co-solvent-free formulations of the invention further comprise one or more salt(s). In one embodiment, the one or more salt(s) can be selected from the group consisting of sodium chloride, magnesium chloride, calcium chloride, and potassium chloride. Each of the one or more salt(s) may be present at a concentration of about 10 mM-100 mM (e.g., about 0.1 mM to about 90 mM, about 0.1 mM to about 80 mM, about 0.1 mM to about 70 mM, about 0.1 mM to about 65 mM, about 0.1 mM to about 60 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 10 mM, about 0.1 mM to about 5 mM, about 1 mM to about 100 mM, about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 70 mM, about 1 mM to about 60 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 mM to about 10 mM, about 10 mM to about 95 mM, about 10 mM to about 90 mM, about 10 mM to about 85 mM, about 10 mM to about 80 mM, about 10 mM to about 75 mM, about 10 mM to about 70 mM, about 10 mM to about 65 mM, about 10 mM to about 60 mM, about 10 mM to about 55 mM, about 10 mM to about 50 mM, about 10 mM to about 45 mM, about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 10 mM to about 20 mM, about 10 mM to about 18 mM, about 10 mM to about 16 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, about 12 mM to about 100 mM, about 12 mM to about 95 mM, about 12 mM to about 90 mM, about 12 mM to about 85 mM, about 12 mM to about 80 mM, about 12 mM to about 75 mM, about 12 mM to about 70 mM, about 12 mM to about 65 mM, about 12 mM to about 60 mM, about 12 mM to about 55 mM, about 12 mM to about 50 mM, about 12 mM to about 45 mM, about 12 mM to about 40 mM, about 12 mM to about 35 mM, about 12 mM to about 30 mM, about 12 mM to about 25 mM, about 12 mM to about 20 mM, about 12 mM to about 18 mM, about 12 mM to about 16 mM, about 12 mM to about 14 mM, about 14 mM to about 100 mM, about 14 mM to about 95 mM, about 14 mM to about 90 mM, about 14 mM to about 85 mM, about 14 mM to about 80 mM, about 14 mM to about 75 mM, about 14 mM to about 70 mM, about 14 mM to about 65 mM, about 14 mM to about 60 mM, about 14 mM to about 55 mM, about 14 mM to about 50 mM, about 14 mM to about 45 mM, about 14 mM to about 40 mM, about 14 mM to about 35 mM, about 14 mM to about 30 mM, about 14 mM to about 25 mM, about 14 mM to about 20 mM, about 14 mM to about 18 mM, about 14 mM to about 16 mM, about 16 mM to about 100 mM, about 16 mM to about 95 mM, about 16 mM to about 90 mM, about 16 mM to about 85 mM, about 16 mM to about 80 mM, about 16 mM to about 75 mM, about 16 mM to about 70 mM, about 16 mM to about 65 mM, about 16 mM to about 60 mM, about 16 mM to about 55 mM, about 16 mM to about 50 mM, about 16 mM to about 45 mM, about 16 mM to about 40 mM, about 16 mM to about 35 mM, about 16 mM to about 30 mM, about 16 mM to about 25 mM, about 16 mM to about 20 mM, about 16 mM to about 18 mM, about 18 mM to about 100 mM, about 18 mM to about 95 mM, about 18 mM to about 90 mM, about 18 mM to about 85 mM, about 18 mM to about 80 mM, about 18 mM to about 75 mM, about 18 mM to about 70 mM, about 18 mM to about 65 mM, about 18 mM to about 60 mM, about 18 mM to about 55 mM, about 18 mM to about 50 mM, about 18 mM to about 45 mM, about 18 mM to about 40 mM, about 18 mM to about 35 mM, about 18 mM to about 30 mM, about 18 mM to about 25 mM, about 18 mM to about 20 mM, about 20 mM to about 100 mM, about 20 mM to about 95 mM, about 20 mM to about 90 mM, about 20 mM to about 85 mM, about 20 mM to about 80 mM, about 20 mM to about 75 mM, about 20 mM to about 70 mM, about 20 mM to about 65 mM, about 20 mM to about 60 mM, about 20 mM to about 55 mM, about 20 mM to about 50 mM, about 20 mM to about 45 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, about 25 mM to about 100 mM, about 25 mM to about 95 mM, about 25 mM to about 90 mM, about 25 mM to about 85 mM, about 25 mM to about 80 mM, about 25 mM to about 75 mM, about 25 mM to about 70 mM, about 25 mM to about 65 mM, about 25 mM to about 60 mM, about 25 mM to about 55 mM, about 25 mM to about 50 mM, about 25 mM to about 45 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, about 25 mM to about 30 mM, about 30 mM to about 100 mM, about 30 mM to about 95 mM, about 30 mM to about 90 mM, about 30 mM to about 85 mM, about 30 mM to about 80 mM, about 30 mM to about 75 mM, about 30 mM to about 70 mM, about 30 mM to about 65 mM, about 30 mM to about 60 mM, about 30 mM to about 55 mM, about 30 mM to about 50 mM, about 30 mM to about 45 mM, about 30 mM to about 40 mM, about 30 mM to about 35 mM, about 35 mM to about 100 mM, about 35 mM to about 95 mM, about 35 mM to about 90 mM, about 35 mM to about 85 mM, about 35 mM to about 80 mM, about 35 mM to about 75 mM, about 35 mM to about 70 mM, about 35 mM to about 65 mM, about 35 mM to about 60 mM, about 35 mM to about 55 mM, about 35 mM to about 50 mM, about 35 mM to about 45 mM, about 35 mM to about 40 mM, about 40 mM to about 100 mM, about 40 mM to about 95 mM, about 40 mM to about 90 mM, about 40 mM to about 85 mM, about 40 mM to about 80 mM, about 40 mM to about 75 mM, about 40 mM to about 70 mM, about 40 mM to about 65 mM, about 40 mM to about 60 mM, about 40 mM to about 55 mM, about 40 mM to about 50 mM, about 40 mM to about 45 mM, about 45 mM to about 100 mM, about 45 mM to about 95 mM, about 45 mM to about 90 mM, about 45 mM to about 85 mM, about 45 mM to about 80 mM, about 45 mM to about 75 mM, about 45 mM to about 70 mM, about 45 mM to about 65 mM, about 45 mM to about 60 mM, about 45 mM to about 55 mM, about 45 mM to about 50 mM, about 50 mM to about 100 mM, about 50 mM to about 95 mM, about 50 mM to about 90 mM, about 50 mM to about 85 mM, about 50 mM to about 80 mM, about 50 mM to about 75 mM, about 50 mM to about 70 mM, about 50 mM to about 65 mM, about 50 mM to about 60 mM, about 50 mM to about 55 mM, about 55 mM to about 100 mM, about 55 mM to about 95 mM, about 55 mM to about 90 mM, about 55 mM to about 85 mM, about 55 mM to about 80 mM, about 55 mM to about 75 mM, about 55 mM to about 70 mM, about 55 mM to about 65 mM, about 55 mM to about 60 mM, about 60 mM to about 100 mM, about 60 mM to about 95 mM, about 60 mM to about 90 mM, about 60 mM to about 85 mM, about 60 mM to about 80 mM, about 60 mM to about 75 mM, about 60 mM to about 70 mM, about 60 mM to about 65 mM, about 65 mM to about 100 mM, about 65 mM to about 95 mM, about 65 mM to about 90 mM, about 65 mM to about 85 mM, about 65 mM to about 80 mM, about 65 mM to about 75 mM, about 65 mM to about 70 mM, about 70 mM to about 100 mM, about 70 mM to about 95 mM, about 70 mM to about 90 mM, about 70 mM to about 85 mM, about 70 mM to about 80 mM, about 70 mM to about 75 mM, about 75 mM to about 100 mM, about 75 mM to about 95 mM, about 75 mM to about 90 mM, about 75 mM to about 85 mM, about 75 mM to about 80 mM, about 80 mM to about 100 mM, about 80 mM to about 95 mM, about 80 mM to about 90 mM, about 80 mM to about 85 mM, about 85 mM to about 100 mM, about 85 mM to about 95 mM, about 85 mM to about 90 mM, about 90 mM to about 100 mM, about 90 mM to about 95 mM, or about 95 mM to about 100 mM, or about 10 mM, about 12 mM, about 14 mM, about 16 mM, about 18 mM, about 20 mM, about 22 mM, about 24 mM, about 26 mM, about 28 mM, about 30 mM, about 32 mM, about 34 mM, about 36 mM, about 38 mM, about 40 mM, about 42 mM, about 44 mM, about 46 mM, about 48 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM about 95 mM, or about 100 mM).

In some embodiments of any of the formulations described herein, the formulation can include one or more of: sodium ion at a final concentration of about 100 mM to about 200 mM (e.g., about 100 mM to about 180 mM, about 100 mM to about 160 mM, about 100 mM to about 140 mM, about 100 mM to about 120 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 160 mM, about 120 mM to about 140 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, or about 180 mM to about 200 mM); potassium ion at a final concentration of about 1 mM to about 20 mM (e.g., about 1 mM to about 18 mM, about 1 mM to about 16 mM, about 1 mM to about 14 mM, about 1 mM to about 12 mM, about 1 mM to about 10 mM, about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 20 mM, about 2 mM to about 18 mM, about 2 mM to about 16 mM, about 2 mM to about 14 mM, about 2 mM to about 12 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 20 mM, about 4 mM to about 18 mM, about 4 mM to about 16 mM, about 4 mM to about 14 mM, about 4 mM to about 12 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 20 mM, about 6 mM to about 18 mM, about 6 mM to about 16 mM, about 6 mM to about 14 mM, about 6 mM to about 12 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, about 8 mM to about 20 mM, about 8 mM to about 18 mM, about 8 mM to about 16 mM, about 8 mM to about 14 mM, about 8 mM to about 12 mM, about 8 mM to about 10 mM, about 10 mM to about 20 mM, about 10 mM to about 18 mM, about 10 mM to about 16 mM, about 10 mM to about 14 mM, about 10 mM to about 12 mM, about 12 mM to about 20 mM, about 12 mM to about 18 mM, about 12 mM to about 16 mM, about 12 mM to about 14 mM, about 14 mM to about 20 mM, about 14 mM to about 18 mM, about 14 mM to about 16 mM, about 16 mM to about 20 mM, about 16 mM to about 18 mM, or about 18 mM to about 20 mM); chloride ion at a final concentration of about 10 mM to about 200 mM (e.g., about 10 mM to about 180 mM, about 10 mM to about 160 mM, about 10 mM to about 140 mM, about 10 mM to about 120 mM, about 10 mM to about 100 mM, about 10 mM to about 80 mM, about 10 mM to about 60 mM, about 10 mM to about 40 mM, about 10 mM to about 20 mM, about 50 mM to about 200 mM, 50 mM to about 180 mM, about 50 mM to about 160 mM, about 50 mM to about 140 mM, about 50 mM to about 120 mM, about 50 mM to about 100 mM, about 50 mM to about 80 mM, about 100 mM to about 200 mM, about 100 mM to about 180 mM, about 100 mM to about 160 mM, about 100 mM to about 140 mM, about 100 mM to about 120 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 160 mM, about 120 mM to about 140 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, or about 180 mM to about 200 mM); calcium ion at a final concentration of about 0.1 mM to about 5 mM (e.g., about 0.1 mM to about 4 mM, about 0.1 mM to about 3 mM, about 0.1 mM to about 2 mM, about 0.1 mM to about 1 mM, about 0.1 mM to about 0.5 mM, about 0.5 mM to about 5 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1 mM, about 1 mM to about 5 mM, about 1 mM to about 4 mM, about 1 mM to about 3 mM, about 1 mM to about 2 mM, about 2 mM to about 5 mM, about 2 mM to about 4 mM, about 2 mM to about 3 mM, about 3 mM to about 5 mM, about 3 mM to about 4 mM, or about 4 mM to about 5 mM); magnesium ion at a final concentration of about 0.1 mM to about 3 mM (e.g., about 0.1 mM to about 2.5 mM, about 0.1 mM to about 2.0 mM, about 0.1 mM to about 1.5 mM, about 0.1 mM to about 1.0 mM, about 0.1 mM to about 0.5 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2.5 mM, about 0.5 mM to about 2.0 mM, about 0.5 mM to about 1.5 mM, about 0.5 mM to about 1.0 mM, about 1.0 mM to about 3.0 mM, about 1.0 mM to about 2.5 mM, about 1.0 mM to about 2.0 mM, about 1.0 mM to about 1.5 mM, about 1.5 mM to about 3.0 mM, about 1.5 mM to about 2.5 mM, about 1.5 mM to about 2.0 mM, about 2.0 mM to about 3.0 mM, about 2.0 mM to about 2.5 mM, or about 2.5 mM to about 3.0 mM); sugar (e.g., glucose) at a final concentration of about 0.5 mM to about 10 mM (e.g., about 0.5 mM to about 8 mM, about 0.5 mM to about 6 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1 mM, about 1 mM to about 10 mM, about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, or about 8 mM to about 10 mM); lactate at a final concentration of about 1 mM to about 10 mM (e.g., about 1 mM to about 8 mM, about 1 mM to about 6 mM, about 1 mM to about 4 mM, about 1 mM to about 2 mM, about 2 mM to about 10 mM, about 2 mM to about 8 mM, about 2 mM to about 6 mM, about 2 mM to about 4 mM, about 4 mM to about 10 mM, about 4 mM to about 8 mM, about 4 mM to about 6 mM, about 6 mM to about 10 mM, about 6 mM to about 8 mM, or about 8 mM to about 10 mM); beta-hyrdoxybutyrate at a final concentration of about 0.01 mM to about 0.3 mM (e.g., about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.1 mM, about 0.01 mM to about 0.05 mM, about 0.05 mM to about 3 mM, about 0.05 mM to about 0.2 mM, about 0.05 mM to about 0.1 mM, about 0.1 mM to about 3 mM, about 0.1 mM to about 0.2 mM, or about 0.2 mM to about 0.3 mM); copper ion at a concentration of about 0.1 μM to about 1.0 μM (e.g., about 0.1 μM to about 0.8 μM, about 0.1 μM to about 0.6 μM, about 0.1 μM to about 0.4 μM, or about 0.1 μM to about 0.2 μM), zinc ion at a final concentration of about 0.1 μM to about 10 μM (e.g., about 0.1 μM to about 8 μM, about 0.1 μM to about 6 μM, about 0.1 μM to about 4 μM, or about 0.1 μM to about 2 μM); selenium ion at a final concentration of about 0.01 μM to about 0.2 μM (e.g., about 0.01 μM to about 0.15 μM, about 0.01 μM to about 0.10 μM, or about 0.01 μM to about 0.5 μM), iron ion at a final concentration of about 0.01 μM to about 8 μM (e.g., about 0.01 μM to about 6 μM, about 0.01 μM to about 4 μM, about 0.01 μM to about 2 μM, about 0.01 μM to about 1 μM, about 0.01 μM to about 0.05 μM), ferritin at a final concentration of about 0.1 μM to about 50 μM (e.g., 0.1 μM to about 40 μM, about 0.1 μM to about 30 μM, about 0.1 μM to about 20 μM, about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.1 μM to about 1 μM); and transferrin at final concentration of about 0.01 μM to about 0.2 μM (e.g., about 0.01 μM to about 0.15 μM, about 0.01 μM to about 0.10 μM, about 0.01 μM to about 0.05 μM).

In one embodiment, the formulation is iso-osmolar relative to the vitreous.

These and other aspects will become apparent from the following description of the various embodiments, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

