Aug. 6, 2020  38  US 2020/0246423 Al  400 mM, about 80 mM to about 350 mM, about 80 mM to  about 300 mM, about 80 mM to about 250 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 100 mM to about 500 mM, about 100 mM  to about 450 mM, about 100 mM to about 400 mM, about  100 mM to about 350 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 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 500 mM,  about 120 mM to about 450 mM, about 120 mM to about  400 mM, about 120 mM to about 350 mM, about 120 mM  to about 300 mM, about 120 mM to about 250 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 500 mM, about 140 mM  to about 450 mM, about 140 mM to about 400 mM, about  140 mM to about 350 mM, about 140 mM to about 300 mM,  about 140 mM to about 250 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 500 mM, about  160 mM to about 450 mM, about 160 mM to about 400 mM,  about 160 mM to about 350 mM, about 160 mM to about  300 mM, about 160 mM to about 250 mM, about 160 mM  to about 200 mM, about 160 mM to about 180 mM, about  180 mM to about 500 mM, about 180 mM to about 450 mM,  about 180 mM to about 400 mM, about 180 mM to about  350 mM, about 180 mM to about 300 mM, about 180 mM  to about 250 mM, about 180 mM to about 200 mM, about  200 mM to about 500 mM, about 200 mM to about 450 mM,  about 200 mM to about 400 mM, about 200 mM to about  350 mM, about 200 mM to about 300 mM, about 200 mM  to about 250 mM, about 250 mM to about 500 mM, about  250 mM to about 450 mM, about 250 mM to about 400 mM,  about 250 mM to about 350 mM, about 250 mM to about  300 mM, about 300 mM to about 500 mM, about 300 mM  to about 450 mM, about 300 mM to about 400 mM, about  300 mM to about 350 mM, about 350 mM to about 500 mM,  about 350 mM to about 450 mM, about 350 mM to about  400 mM, about 400 mM to about 500 mM, about 400 mM  to about 450 mM, or about 450 mM to about 500 mM).  [0159]  c. Aflibercept Stabilized with Amino Acids  [0160]  Amino acids, e.g., praline, serine, sodium glutamic  acid, glutamate, alanine, histidine, tryptophan, tyrosine,  arginine, glycine, lysine, methionine, threonine, glutamic  acid, aspartic acid, sarcosine, glycine betaine, and mixtures  of the foregoing may be employed as stabilizers in certain  aflibercept formulations.  [0161]  These compositions may use the free base form of  the amino acid or any conjugate acid form such as a  hydrochloride salt. Such amino acids are readily available  from commercial suppliers. For example, in one embodi› ment, the invention provides a stable aqueous pharmaceu› tical composition comprising aflibercept and one or more  amino acids, wherein the amino acid(s) is selected from the  group consisting of serine, praline, glycine, alanine, gluta› mate, arginine and combinations thereof. The composition  may further optionally include a sugar and/or polyol. The  composition may be a buffer-free and/or free of an organic  co-solvent.  [0162]  Such additives may improve the properties of the  aflibercept formulations, e.g., by reducing aggregation or  tendency for aflibercept to associate in undesired ternary or  quaternary complexes. Without wishing to be bound to a  particular theory, it is believed that amino acids such as  serine, praline and glutamate are able to stabilize aqueous  pharmaceutical compositions containing aflibercept because  they are excluded from the surface of the protein, resulting  in net conformation stabilization.  [0163]  In one embodiment, the concentration of the amino  acids in the provided formulations is between about 1 mM  and about 500 mM ( e.g., about 1 mM to about 450 mM,  about 1 mM to about 400 mM, about 1 mM to about 350  mM, about 1 mM to about 300 mM, about 1 mM to about  250 mM, about 1 mM to about 200 mM, about 1 mM to  about 180 mM, about 1 mM to about 160 mM, about 1 mM  to about 140 mM, about 1 mM to about 120 mM, about 1  mM to about 100 mM, about 1 mM to about 80 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 15 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 500 mM, about 2 mM to about 450 mM, about  2 mM to about 400 mM, about 2 mM to about 350 mM,  about 2 mM to about 300 mM, about 2 mM to about 250  mM, about 2 mM to about 200 mM, about 2 mM to about  180 mM, about 2 mM to about 160 mM, about 2 mM to  about 140 mM, about 2 mM to about 120 mM, about 2 mM  to about 100 mM, about 2 mM to about 80 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 15 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 500 mM, about 4 mM to  about 450 mM, about 4 mM to about 400 mM, about 4 mM  to about 350 mM, about 4 mM to about 300 mM, about 4  mM to about 250 mM, about 4 mM to about 200 mM, about  4 mM to about 180 mM, about 4 mM to about 160 mM,  about 4 mM to about 140 mM, about 4 mM to about 120  mM, about 4 mM to about 100 mM, about 4 mM to about  80 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 15 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 500 mM, about 6 mM to about  450 mM, about 6 mM to about 400 mM, about 6 mM to  about 350 mM, about 6 mM to about 300 mM, about 6 mM  to about 250 mM, about 6 mM to about 200 mM, about 6  mM to about 180 mM, about 6 mM to about 160 mM, about  6 mM to about 140 mM, about 6 mM to about 120 mM,  about 6 mM to about 100 mM, about 6 mM to about 80 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 15 mM, about 6 mM to about 10 mM,  about 6 mM to about 8 mM, about 8 mM to about 500 mM,  about 8 mM to about 450 mM, about 8 mM to about 400  mM, about 8 mM to about 350 mM, about 8 mM to about 