STABLE OPHTHALMIC FORMULATIONS OF A FLUORINATED INTEGRIN ANTAGONIST

1 . An aqueous, ophthalmic solution, comprising:

a. from 4.7% (w/v) to 5.3% (w/v) of a compound of Formula I:

b. from 14% (w/v) to 18% (w/v) of a cyclodextrin;

c. from 0.1% (w/v) to 5% (w/v) of a buffer;

d. from 0.01% (w/v) to 1% (w/v) of a preservative; and

e. at least 75% (w/v) water;

wherein the solution has a pH in the range of 7.5 to 8.7.

2 . The solution of claim 1 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.

3 . The solution of claim 1 or 2 , wherein the solution comprises from 15% (w/v) to 18% (w/v) of the cyclodextrin.

4 . The solution of claim 1 or 2 , wherein the solution comprises from 15% (w/v) to 17% (w/v) of the cyclodextrin.

5 . The solution of claim 1 or 2 , wherein the solution comprises from 15% (w/v) to 16% (w/v) of the cyclodextrin.

6 . The solution of claim 1 or 2 , wherein the solution comprises from 15.2% (w/v) to 15.8% (w/v) of the cyclodextrin.

7 . The solution of claim 1 or 2 , wherein the solution comprises from 15.3% (w/v) to 15.7% (w/v) of the cyclodextrin.

8 . The solution of claim 1 or 2 , wherein the solution comprises from 15.4% (w/v) to 15.6% (w/v) of the cyclodextrin.

9 . The solution of claim 1 or 2 , wherein the solution comprises 15.5% (w/v) of the cyclodextrin.

10 . The solution of any one of claims 1-9 , wherein the buffer comprises an organic acid

11 . The solution of any one of claims 1-9 , wherein the buffer comprises boric acid.

12 . The solution of any one of claims 1-9 , wherein the buffer is a mixture of boric acid and an alkali metal borate.

13 . The solution of any one of claims 1-9 , wherein the buffer is a mixture of boric acid and sodium borate.

14 . The solution of any one of claims 1-13 , wherein the solution comprises from 0.1% (w/v) to 2.5% (w/v) of the buffer.

15 . The solution of any one of claims 1-13 , wherein the solution comprises from 0.25% (w/v) to 2.5% (w/v) of the buffer.

16 . The solution of any one of claims 1-13 , wherein the solution comprises from 0.5% (w/v) to 1.5% (w/v) of the buffer.

17 . The solution of any one of claims 1-13 , wherein the solution comprises from 0.75% (w/v) to 1.25% (w/v) of the buffer.

18 . The solution of any one of claims 1-13 , wherein the solution comprises from 0.8% (w/v) to 1.2% (w/v) of the buffer.

19 . The solution of any one of claims 1-13 , wherein the solution comprises from 0.9% (w/v) to 1.1% (w/v) of the buffer.

20 . The solution of any one of claims 1-13 , wherein the solution comprises 1% (w/v) of the buffer.

21 . The solution of any one of claims 1-20 , wherein the preservative comprises a benzalkonium salt.

22 . The solution of any one of claims 1-20 , wherein the preservative comprises a benzalkonium halide.

23 . The solution of any one of claims 1-20 , wherein the preservative comprises benzalkonium chloride.

24 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.01% (w/v) to 0.1% (w/v) of the preservative.

25 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.01% (w/v) to 0.05% (w/v) of the preservative.

26 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.012% (w/v) to 0.05% (w/v) of the preservative.

27 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.015% (w/v) to 0.05% (w/v) of the preservative.

28 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.012% (w/v) to 0.03% (w/v) of the preservative.

29 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.012% (w/v) to 0.025% (w/v) of the preservative.

30 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.015% (w/v) to 0.025% (w/v) of the preservative.

31 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.012% (w/v) to 0.02% (w/v) of the preservative.

32 . The solution of any one of claims 1-23 , wherein the solution comprises from 0.015% (w/v) to 0.02% (w/v) of the preservative.

33 . The solution of any one of claims 1-23 , wherein the solution comprises 0.02% (w/v) of the preservative.

34 . The solution of any one of claims 1-33 , further comprising a chelating agent.

35 . The solution of any one of claims 1-33 , further comprising from 0.001% (w/v) to 2% (w/v) of a chelating agent.

36 . The solution of any one of claims 1-33 , further comprising from 0.01% (w/v) to 1% (w/v) of a chelating agent.

37 . The solution of any one of claims 1-33 , further comprising from 0.01% (w/v) to 0.5% (w/v) of a chelating agent.

38 . The solution of any one of claims 1-33 , further comprising from 0.05% (w/v) to 0.5% (w/v) of a chelating agent.

39 . The solution of any one of claims 1-33 , further comprising from 0.05% (w/v) to 0.1% (w/v) of a chelating agent.

40 . The solution of any one of claims 1-33 , further comprising from 0.01% (w/v) to 0.1% (w/v) of a chelating agent.

41 . The solution of any one of claims 1-33 , further comprising 0.1% (w/v) of a chelating agent.

42 . The solution of any one of claims 34-41 , wherein the chelating agent comprises ethylenediaminetetraacetic acid or a salt thereof.

43 . The solution of any one of claims 34-41 , wherein the chelating agent is sodium ethylenediaminetetraacetate.

44 . The solution of any one of claims 1-43 , wherein the solution comprises at least 77% (w/v) water.

45 . The solution of any one of claims 1-43 , wherein the solution comprises at least 78% (w/v) water.

46 . The solution of any one of claims 1-45 , wherein the solution has a pH in the range of 7.5 to 8.5.

47 . The solution of any one of claims 1-45 , wherein the solution has a pH in the range of 7.8 to 8.5.

48 . The solution of any one of claims 1-45 , wherein the solution has a pH in the range of 7.8 to 8.2.

49 . The solution of any one of claims 1-45 , wherein the solution has a pH in the range of 7.9 to 8.1.

50 . The solution of any one of claims 1-45 , wherein the solution has a pH of 8.0.

51 . The solution of any one of claims 1-50 , wherein the cyclodextrin has a molecular weight in the range of from about 1200 g/mol to about 1600 g/mol.

52 . The solution of any one of claims 1-50 , wherein the cyclodextrin has a molecular weight in the range of from about 1300 g/mol to about 1500 g/mol.

53 . The solution of any one of claims 1-50 , wherein the cyclodextrin has a molecular weight in the range of from about 1350 g/mol to about 1450 g/mol.

54 . The solution of any one of claims 1-50 , wherein the cyclodextrin has a molecular weight of about 1400 g/mol.

55 . The solution of any one of claims 1-54 , wherein the cyclodextrin is a 2-hydroxypropyl-β-cyclodextrin in which the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the β-cyclodextrin is in the range of from about 0.5 to about 0.85.

56 . The solution of any one of claims 1-54 , wherein the cyclodextrin is a 2-hydroxypropyl-β-cyclodextrin in which the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the β-cyclodextrin is in the range of from about 0.5 to about 0.8.

57 . The solution of any one of claims 1-54 , wherein the cyclodextrin is a 2-hydroxypropyl-β-cyclodextrin in which the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the β-cyclodextrin is in the range of from about 0.55 to about 0.77.

58 . The solution of any one of claims 1-54 , wherein the cyclodextrin is a 2-hydroxypropyl-β-cyclodextrin in which the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the β-cyclodextrin is in the range of from about 0.59 to about 0.73.

59 . The solution of any one of claims 1-58 , further comprising a tonicity modifier.

60 . The solution of any one of claims 1-58 , further comprising about 0.01% (w/w) to about 5% (w/w) of a tonicity modifier.

61 . The solution of any one of claims 1-58 , further comprising about 0.1% (w/w) to about 2% (w/w) of a tonicity modifier.

62 . An aqueous, ophthalmic solution, comprising:

a. from 4.9% (w/v) to 5.1% (w/v) of a compound of Formula I:

b. from 15% (w/v) to 16% (w/v) of 2-hydroxypropyl-β-cyclodextrin;

c. from 0.5% (w/v) to 1.5% (w/v) of a buffer comprising boric acid;

d. from 0.01% (w/v) to 0.2% (w/v) of a benzalkonium salt; and

e. at least 75% (w/v) water;

wherein the solution has a pH in the range of 7.8 to 8.5.

63 . An aqueous, ophthalmic solution, comprising:

a. 5.5% (w/v) of a compound of Formula I:

b. about 15.5% (w/v) of 2-hydroxypropyl-β-cyclodextrin;

c. about 1% (w/v) of a buffer comprising boric acid;

d. about 0.02% (w/v) of a benzalkonium salt; and

e. at least 75% (w/v) water;

wherein the solution has a pH in the range of 7.8 to 8.5.

64 . An aqueous, ophthalmic solution, comprising:

a. 5.5% (w/v) of a compound of Formula I:

b. 15.5% (w/v) of 2-hydroxypropyl-β-cyclodextrin;

c. 1% (w/v) of a buffer comprising boric acid;

d. 0.02% (w/v) of a benzalkonium salt; and

e. at least 75% (w/v) water;

wherein the solution has a pH in the range of 7.8 to 8.5.

65 . The solution of any one of claims 1 - 65 , wherein the solution contains less than 1% (w/w) of a precipitate that is (S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)imidazolidin-1-yl)propanoic acid hydrate.

66 . The solution of any one of claims 1-65 , wherein the solution contains less than 0.5% (w/w) of a precipitate that is (S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)imidazolidin-1-yl)propanoic acid hydrate.

67 . The solution of any one of claims 1-65 , wherein the solution contains less than 0.1% (w/w) of a precipitate that is (S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)imidazolidin-1-yl)propanoic acid hydrate.

68 . An aqueous, ophthalmic solution, consisting of:

a. from 4.9% (w/v) to 5.1% (w/v) of a compound of Formula I:

b. from 15% (w/v) to 16% (w/v) of 2-hydroxypropyl-β-cyclodextrin;

c. from 0.5% (w/v) to 1.5% (w/v) of a buffer comprising boric acid;

d. from 0.01% (w/v) to 0.5% (w/v) of a benzalkonium salt;

e. at least 75% (w/v) water; and

f. one or more excipients independently selected from the group consisting of a pH adjuster and a tonicity modifier;

wherein the solution has a pH in the range of 7.8 to 8.5.

69 . An aqueous, ophthalmic solution, consisting of:

a. 5.5% (w/v) of a compound of Formula I:

b. about 15.5% (w/v) of 2-hydroxypropyl-β-cyclodextrin;

c. about 1% (w/v) of a buffer comprising boric acid;

d. about 0.02% (w/v) of a benzalkonium salt; and

e. at least 75% (w/v) water; and

f. one or more excipients independently selected from the group consisting of a pH adjuster and a tonicity modifier;

wherein the solution has a pH in the range of 7.8 to 8.5.

70 . An aqueous, ophthalmic solution, consisting of:

a. 5.5% (w/v) of a compound of Formula I:

b. 15.5% (w/v) of 2-hydroxypropyl-β-cyclodextrin;

c. 1% (w/v) of a buffer comprising boric acid;

d. 0.02% (w/v) of a benzalkonium salt; and

e. at least 75% (w/v) water; and

f. one or more excipients independently selected from the group consisting of a pH adjuster and a tonicity modifier;

wherein the solution has a pH in the range of 7.8 to 8.5.

71 . The solution of any one of claims 68-70 , wherein the one or more excipients is a pH adjuster.

72 . The solution of any one of claims 62-71 , wherein the benzalkonium salt is a benzalkonium halide.

73 . The solution of any one of claims 62-71 , wherein the benzalkonium salt is benzalkonium chloride.

74 . The solution of any one of claims 62-73 , wherein the 2-hydroxypropyl-β-cyclodextrin has a molecular weight in the range of from about 1300 g/mol to about 1500 g/mol.

75 . The solution of any one of claims 62-73 , wherein the 2-hydroxypropyl-β-cyclodextrin has a molecular weight in the range of from about 1350 g/mol to about 1450 g/mol.

76 . The solution of any one of claims 62-73 , wherein the 2-hydroxypropyl-β-cyclodextrin has a molecular weight of about 1400 g/mol.

77 . The solution of any one of claims 62-76 , wherein the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the 2-hydroxypropyl-β-cyclodextrin is in the range of from about 0.5 to about 0.85.

78 . The solution of any one of claims 62-76 , wherein the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the 2-hydroxypropyl-β-cyclodextrin is in the range of from about 0.5 to about 0.8.

79 . The solution of any one of claims 62-76 , wherein the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the 2-hydroxypropyl-β-cyclodextrin is in the range of from about 0.55 to about 0.77.

80 . The solution of any one of claims 62-76 , wherein the mole ratio of 2-hydroxylpropyl substituents per glucose moiety in the 2-hydroxypropyl-β-cyclodextrin is in the range of from about 0.59 to about 0.73.

81 . The solution of any one of claims 62-80 , wherein the solution has a pH in the range of 7.8 to 8.2.

82 . The solution of any one of claims 62-80 , wherein the solution has a pH of 8.0.

83 . The solution of any one of claims 1-82 , wherein less than 1% of the compound of Formula I degrades upon storage at 25° C. for 2 weeks.

84 . The solution of any one of claims 1-82 , wherein less than 0.5% of the compound of Formula I degrades upon storage at 25° C. for 2 weeks.

85 . The solution of any one of claims 1-82 , wherein less than 0.1% of the compound of Formula I degrades upon storage at 25° C. for 2 weeks.

86 . The solution of any one of claims 1-85 , wherein less than 1% of the compound of Formula I degrades upon storage at 25° C. for 24 weeks.

87 . The solution of any one of claims 1-85 , wherein less than 0.5% of the compound of Formula I degrades upon storage at 25° C. for 24 weeks.

88 . The solution of any one of claims 1-87 , wherein less than 1% of the compound of Formula I degrades upon storage at 40° C. for 2 weeks.

89 . The solution of any one of claims 1-87 , wherein less than 0.5% of the compound of Formula I degrades upon storage at 40° C. for 2 weeks.

90 . The solution of any one of claims 1-87 , wherein less than 0.1% of the compound of Formula I degrades upon storage at 40° C. for 2 weeks.

91 . The solution of any one of claims 1-90 , wherein less than 1% of the compound of Formula I degrades upon storage at 40° C. for 24 weeks.

92 . The solution of any one of claims 1-90 , wherein less than 0.5% of the compound of Formula I degrades upon storage at 40° C. for 24 weeks.

93 . The solution of any one of claims 1-92 , wherein storage of the solution at 25° C. for 2 weeks results in a formulation containing less than 1% (w/w) of any solid precipitate that forms from the solution.

94 . The solution of any one of claims 1-92 , wherein storage of the solution at 25° C. for 24 weeks results in a formulation containing less than 1% (w/w) of any solid precipitate that forms from the solution.

95 . The solution of any one of claims 1-94 , wherein storage of the solution at 40° C. for 2 weeks results in a formulation containing less than 1% (w/w) of any solid precipitate that forms from the solution.

96 . The solution of any one of claims 1-95 , wherein storage of the solution at 40° C. for 24 weeks results in a formulation containing less than 1% (w/w) of any solid precipitate that forms from the solution.

97 . The solution of any one of claims 1-92 , wherein after storage of the solution at 25° C. for 2 weeks, there is no solid precipitate that forms from the solution.

98 . The solution of any one of claims 1-92 , wherein after storage of the solution at 25° C. for 24 weeks, there is no solid precipitate that forms from the solution.

99 . The solution of any one of claims 1-92 , wherein after storage of the solution at 40° C. for 2 weeks, there is no solid precipitate that forms from the solution.

100 . The solution of any one of claims 1-92 , wherein after storage of the solution at 40° C. for 24 weeks, there is no solid precipitate that forms from the solution.

101 . The solution of any one of claims 93-100 , wherein the solid precipitate comprises (S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)imidazolidin-1-yl)propanoic acid monohydrate.

102 . The solution of any one of claims 93-100 , wherein the solid precipitate is (S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)imidazolidin-1-yl)propanoic acid monohydrate.

103 . An aqueous, ophthalmic solution, comprising:

a. from about 4% (w/v) to about 6% (w/v) of a compound of Formula II or a pharmaceutically acceptable salt thereof:

b. from 14% (w/v) to 18% (w/v) of a cyclodextrin;

c. a buffer;

d. a preservative; and

e. at least 75% (w/v) water;

wherein the solution has a pH in the range of 7.5 to 8.7.

104 . The solution of claim 103 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.

105 . The solution of claim 103 or 104 , wherein the solution comprises from 15% (w/v) to 18% (w/v) of the cyclodextrin.

106 . The solution of claim 103 or 104 , wherein the solution comprises from 15% (w/v) to 17% (w/v) of the cyclodextrin.

107 . The solution of claim 103 or 104 , wherein the solution comprises from 15% (w/v) to 16% (w/v) of the cyclodextrin.

108 . The solution of claim 103 or 104 , wherein the solution comprises from 15.2% (w/v) to 15.8% (w/v) of the cyclodextrin.

109 . The solution of claim 103 or 104 , wherein the solution comprises 15.5% (w/v) of the cyclodextrin.

110 . The solution of any one of claims 103-109 , wherein the buffer comprises boric acid.

111 . The solution of any one of claims 103-110 , wherein the preservative comprises a benzalkonium salt.

112 . A method of treating a disorder mediated by an αv integrin, comprising topically administering to an eye of a subject in need thereof a therapeutically effective amount of a solution any one of claims 1-111 to treat the disorder.

113 . The method of claim 112 , wherein the αv integrin is an αvβ3 or αvβ5 integrin.

114 . The method of claim 112 , wherein the disorder is macular degeneration, diabetic retinopathy, macular edema, diabetic macular edema, or macular edema following retinal vein occlusion.

115 . The method of claim 112 , wherein the disorder is diabetic retinopathy.

116 . The method of any one of claims 112-115 , wherein the subject is an adult human.

117 . The compound (S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)imidazolidin-1-yl)propanoic acid hydrate.

118 . The compound of claim 117 , wherein the compound is (S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)imidazolidin-1-yl)propanoic acid monohydrate.

119 . The compound of claim 117 or 118 , wherein the compound is in crystalline form.

120 . A method of preparing an aqueous, ophthalmic solution, the method comprising:

a. providing a first mixture comprising water, a cyclodextrin, and a compound of Formula I:

b. admixing a preservative and the first mixture, to thereby provide the aqueous, ophthalmic solution.

121 . The method of claim 120 , wherein the aqueous, ophthalmic solution has a pH in the range of 7.5 to 8.7.

122 . The method of claim 120 or 121 , wherein the preservative is benzalkonium halide.

123 . The method of claim 120 or 121 , wherein the preservative is benzalkonium chloride.

124 . The method of claim 120 or 121 , wherein the first mixture further comprises a buffer.

125 . The method of claim 124 , wherein the buffer comprises an organic acid.

126 . The method of claim 124 , wherein the buffer comprises boric acid.

127 . The method of any one of claims 120-126 , wherein solution comprises at least 75% w/w water.