NOVEL FORMULATIONS
Provided are novel formulations of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate as described below and uses thereof. Also provided are kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate. Also provided is a method of treating or controlling a disease or condition mediated by an aquaporin, e.g., diseases or conditions of water imbalance and other diseases.
1 . A pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I)
and a pharmaceutically acceptable excipient.
2 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises 10 to 600 mg of Formula I.
3 . The pharmaceutical composition of claim 1 or 2 , wherein the pharmaceutically acceptable excipient comprises one or more bases.
4 . The pharmaceutical composition of claim 3 , wherein upon dissolution of the composition in an aqueous solution the composition has a pH between 7, 7.5, or 8 and 10.5, e.g., between about 7, 7.5, or 8 and 9.5, e.g., between about 7 or 7.5 and 8, e.g., between about 7.5 and 8.5, e.g., about 7.5, e.g., about 8.5, e.g., between about 8 and 8.5, e.g., about 8.2.
5 . The pharmaceutical composition of claim 3 or 4 , wherein a conjugate acid of the one or more bases has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9.
6 . The pharmaceutical composition of any one of claims 3 - 5 , wherein the one or more bases are one or more of:
a) a C 1-8 -alkyl mono-, di-, or tri-carboxylic acid salt, e.g., a citrate salt, e.g, a metal citrate salt (e.g., an alkali and/or alkaline citrate salt, e.g., an alkali citrate salt, e.g., sodium citrate and/or potassium citrate), e.g., a tartrate salt (e.g., a metal tartrate salt, an alkali tartrate, e.g., sodium tartrate), e.g., a succinate salt (e.g., a metal succinate salt, e.g., an alkali succinate, e.g., disodium succinate), and/or e.g., a lactate salt (e.g., a metal lactate salt, e.g., an alkali lactate, e.g., sodium lactate),
b) a phosphate salt, e.g., a metal phosphate salt (e.g., an alkali and/or alkaline phosphate salt, e.g., an alkali phosphate salt, e.g., sodium phosphate (e.g., NaH 2 PO 4 and/or Na 2 HPO 4 ) and/or potassium phosphate (e.g., KH 2 PO 4 and/or K 2 HPO 4 )),
c) an amine and/or a salt thereof (e.g., morpholine, piperazine, benethamine, benzathine, trimethylglycine, hydrabamine, an amino acid (e.g., arginine and/or lysine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, dimethylethanolamine, diethylamine, diethylethanolamine, and/or diethanolamine), e.g., any of the preceding wherein a conjugate acid of the amine and/or salt thereof has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9,
d) an acetate salt, e.g., a metal acetate salt (e.g., an alkali and/or alkaline acetate salt, e.g., an alkali acetate salt, e.g., sodium acetate and/or potassium acetate),
e) a hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or metal alkoxide salt (e.g., choline hydroxide, lithium hydroxide, aluminum hydroxide, e.g., an alkali and/or alkaline hydroxide salt, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and/or magnesium ethoxide, e.g., sodium hydroxide),
f) a carbonate and/or bicarbonate salt, e.g., a metal carbonate and/or metal bicarbonate salt (e.g., an alkali and/or alkaline carbonate salt, e.g., an alkali and/or alkaline bicarbonate salt, e.g., sodium bicarbonate), and/or
g) a borate salt, e.g., a metal borate salt (e.g., an alkali borate salt, e.g., sodium borate), e.g., one or more of sodium citrate, Na 2 HPO 4 , tris(hydroxymethyl)aminomethane, and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g., one or more of sodium citrate, Na 2 HPO 4 , and tris(hydroxymethyl)aminomethane, e.g., one or more of sodium citrate and Na 2 HPO 4 , e.g., Na 2 HPO 4 , e.g., tris(hydroxymethyl)aminomethane.
7 . The pharmaceutical composition of any one of claims 3 - 5 , wherein the one or more bases are one or more of:
a) a metal citrate salt (e.g., an alkali and/or alkaline citrate salt, e.g., an alkali citrate salt, e.g., sodium citrate and/or potassium citrate),
b) a metal phosphate salt (e.g., an alkali and/or alkaline phosphate salt, e.g., an alkali phosphate salt, e.g., sodium phosphate (e.g., NaH 2 PO 4 and/or Na 2 HPO 4 ) and/or potassium phosphate (e.g., KH 2 PO 4 and/or K 2 HPO 4 ), e.g., sodium phosphate (e.g., Na 2 HPO 4 )),
c) an amine and/or a salt thereof (e.g., morpholine, an amino acid (e.g., arginine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine), e.g., any of the preceding wherein a conjugate acid of the amine and/or salt thereof has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9,
d) a metal acetate salt (e.g., an alkali and/or alkaline acetate salt, e.g., an alkali acetate salt, e.g., sodium acetate and/or potassium acetate),
e) a metal hydroxide salt (e.g., an alkali and/or alkaline hydroxide salt, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, and/or magnesium hydroxide, e.g., sodium hydroxide),
f) a metal carbonate and/or bicarbonate salt (e.g., an alkali and/or alkaline carbonate salt, e.g., an alkali and/or alkaline bicarbonate salt, e.g., sodium bicarbonate), and/or
g) a metal borate salt (e.g., an alkali borate salt, e.g., sodium borate),
e.g., one or more of sodium citrate, Na 2 HPO 4 , tris(hydroxymethyl)aminomethane, and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g., one or more of sodium citrate, Na 2 HPO 4 , and tris(hydroxymethyl)aminomethane, e.g., one or more of sodium citrate and Na 2 HPO 4 , e.g., Na 2 HPO 4 , e.g., tris(hydroxymethyl)aminomethane.
8 . The pharmaceutical composition of any one of claims 3 - 7 , wherein the composition comprises 10 to 1500 mg of the one or more bases.
9 . The pharmaceutical composition of any one of claims 3 - 8 , wherein the one or more bases comprise a metal citrate salt (e.g., sodium citrate), a metal phosphate salt (e.g., sodium phosphate, e.g., Na 2 HPO 4 ), and an amine and/or a salt thereof (e.g., morpholine, an amino acid (e.g., arginine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 -alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., —C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
10 . The pharmaceutical composition of any one of claims 3 - 9 , wherein the one or bases comprise an amine and/or a salt thereof (e.g., morpholine, an amino acid (e.g., arginine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 -alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., —C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
11 . The pharmaceutical composition of any one of claims 3 - 10 , wherein the one or more bases comprise a mono- and/or poly-hydroxyalkylamine and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., —C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
12 . The pharmaceutical composition of any one of claims 3 - 11 , wherein the one or more bases comprise H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., —C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
13 . The pharmaceutical composition of any one of claims 3 - 12 , wherein the one or more bases comprise tris(hydroxymethyl)aminomethane, meglumine, and or a tris(hydroxymethyl)aminomethane salt (e.g., tris(hydroxymethyl)aminomethane acetate).
14 . The pharmaceutical composition of any one of claims 3 - 13 , wherein the one or more bases comprise a base, wherein a conjugate acid of the base has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9.
15 . The pharmaceutical composition of any one of claims 3 - 14 , wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the one or more bases is at least 1:1.
16 . The pharmaceutical composition of any one of claims 3 - 15 , wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the one or more bases is at least 1:2, e.g., at least about 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5, e.g., at least about 1:5, e.g. at least about 1:10.
17 . The pharmaceutical composition of any one of claims 1 - 16 , wherein the pharmaceutical composition is a solid, e.g., the pharmaceutically acceptable excipient, e.g, the one or more bases is a solid.
18 . The pharmaceutical composition of any one of claims 3 - 17 , wherein the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and the one or more bases are milled together.
19 . The pharmaceutical composition of any one of claims 1 - 18 , wherein the pharmaceutical composition is suitable for constitution, or reconstitution if lyophilized, with a aqueous solution into a pharmaceutically acceptable liquid (e.g., a solution or suspension, e.g., a solution).
20 . The pharmaceutical composition of any one of claims 1 - 19 , wherein the composition is admixed with an aqueous solution, e.g., a sterile solution, e.g., sterile water for injection, a sterile solution comprising dextrose (e.g., dextrose injection 5%), a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection), a sterile solution comprising benzyl alcohol (e.g., bacteriostatic water for injection with benzyl alcohol or bacteriostatic sodium chloride for injection with benzyl alcohol), or Lactated Ringer's.
21 . The pharmaceutical composition of claim 20 , wherein the composition is admixed with 0.5 to 500 mL of an aqueous solution.
22 . The pharmaceutical composition of claim 20 or 21 , wherein the pharmaceutical composition comprises Formula II
23 . The pharmaceutical composition of any one of claims 20 - 22 , wherein the composition comprises at least a 1:1 molar ratio of Formula II to a cation of the base.
24 . The pharmaceutical composition of claim 20 or 21 , wherein the composition comprises Formula III
25 . The pharmaceutical composition of any one of claims 20 , 21 , or 24 , wherein the composition comprises at least a 1:2 molar ratio of Formula III to a cation of the base, e.g., at least about 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5, e.g., at least about 1:5, e.g. at least about 1:10.
26 . The pharmaceutical composition of any one of claims 20 - 25 , wherein the concentration of Formula II or Formula III, e.g., the concentration of Formula II, e.g, the concentration of Formula III, is 1 to 250 mM.
27 . The pharmaceutical composition of any one of claims 20 - 26 , wherein the aqueous solution, e.g., the sterile solution, comprises one or more bases.
28 . The pharmaceutical composition of claim 27 , wherein upon dissolution of the composition in an aqueous solution the composition has a pH between 7, 7.5, or 8 and 10.5, e.g., between about 7, 7.5, or 8 and 9.5, e.g., between about 7 or 7.5 and 8, e.g., between about 7.5 and 8.5, e.g., about 7.5, e.g., about 8.5, e.g., between about 8 and 8.5, e.g., about 8.2.
29 . The pharmaceutical composition of claim 27 or 28 , wherein a conjugate acid of the base has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9.
30 . The pharmaceutical composition of any one of claims 27 - 29 , wherein the one or more bases are one or more of:
a) a C 1-8 -alkyl mono-, di-, or tri-carboxylic acid salt, e.g., a citrate salt, e.g, a metal citrate salt (e.g., an alkali and/or alkaline citrate salt, e.g., an alkali citrate salt, e.g., sodium citrate and/or potassium citrate), e.g., a tartrate salt (e.g., a metal tartrate salt, an alkali tartrate, e.g., sodium tartrate), e.g., a succinate salt (e.g., a metal succinate salt, e.g., an alkali succinate, e.g., disodium succinate), and/or e.g., a lactate salt (e.g., a metal lactate salt, e.g., an alkali lactate, e.g., sodium lactate),
b) a phosphate salt, e.g., a metal phosphate salt (e.g., an alkali and/or alkaline phosphate salt, e.g., an alkali phosphate salt, e.g., sodium phosphate (e.g., NaH 2 PO 4 and/or Na 2 HPO 4 ) and/or potassium phosphate (e.g., KH 2 PO 4 and/or K 2 HPO 4 )),
c) an amine and/or a salt thereof (e.g., morpholine, piperazine, benethamine, benzathine, trimethylglycine, hydrabamine, an amino acid (e.g., arginine and/or lysine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, dimethylethanolamine, diethylamine, diethylethanolamine, and/or diethanolamine), e.g., any of the preceding wherein a conjugate acid of the amine and/or salt thereof has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9,
d) an acetate salt, e.g., a metal acetate salt (e.g., an alkali and/or alkaline acetate salt, e.g., an alkali acetate salt, e.g., sodium acetate and/or potassium acetate),
e) a hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or metal alkoxide salt (e.g., a quarternary ammonium hydroxide, e.g., ammonium hydroxide and/or choline hydroxide, lithium hydroxide, aluminum hydroxide, e.g., an alkali and/or alkaline hydroxide salt, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and/or magnesium ethoxide, e.g., sodium hydroxide),
f) a carbonate and/or bicarbonate salt, e.g., a metal carbonate and/or metal bicarbonate salt (e.g., an alkali and/or alkaline carbonate salt, e.g., an alkali and/or alkaline bicarbonate salt, e.g., sodium bicarbonate), and/or
g) a borate salt, e.g., a metal borate salt (e.g., an alkali borate salt, e.g., sodium borate),
e.g., one or more of sodium citrate, Na 2 HPO 4 , tris(hydroxymethyl)aminomethane, and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g., one or more of sodium citrate, Na 2 HPO 4 , and tris(hydroxymethyl)aminomethane, e.g., one or more of sodium citrate and Na 2 HPO 4 , e.g., Na 2 HPO 4 , e.g., tris(hydroxymethyl)aminomethane.
31 . The pharmaceutical composition of any one of claims 27 - 30 , wherein the one or more bases are one or more of:
a) a metal citrate salt (e.g., an alkali and/or alkaline citrate salt, e.g., an alkali citrate salt, e.g., sodium citrate and/or potassium citrate),
b) a metal phosphate salt (e.g., an alkali and/or alkaline phosphate salt, e.g., an alkali phosphate salt, e.g., sodium phosphate (e.g., NaH 2 PO 4 and/or Na 2 HPO 4 ) and/or potassium phosphate (e.g., KH 2 PO 4 and/or K 2 HPO 4 ), e.g., sodium phosphate (e.g., Na 2 HPO 4 )),
c) an amine and/or a salt thereof (e.g., morpholine, an amino acid (e.g., arginine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine), e.g., any of the preceding wherein a conjugate acid of the amine and/or salt thereof has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9,
d) a metal acetate salt (e.g., an alkali and/or alkaline acetate salt, e.g., an alkali acetate salt, e.g., sodium acetate and/or potassium acetate),
e) a metal hydroxide salt (e.g., an alkali and/or alkaline hydroxide salt, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, and/or magnesium hydroxide, e.g., sodium hydroxide),
f) a metal carbonate and/or bicarbonate salt (e.g., an alkali and/or alkaline carbonate salt, e.g., an alkali and/or alkaline bicarbonate salt, e.g., sodium bicarbonate), and/or
g) a metal borate salt (e.g., an alkali borate salt, e.g., sodium borate),
e.g., one or more of sodium citrate, Na 2 HPO 4 , tris(hydroxymethyl)aminomethane, and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g., one or more of sodium citrate, Na 2 HPO 4 , and tris(hydroxymethyl)aminomethane, e.g., one or more of sodium citrate and Na 2 HPO 4 , e.g., Na 2 HPO 4 , e.g., tris(hydroxymethyl)aminomethane.
32 . The pharmaceutical composition of any one of claims 27 - 31 , wherein the one or more bases comprise a metal citrate salt (e.g., sodium citrate), a metal phosphate salt (e.g., sodium phosphate, e.g., Na 2 HPO 4 ), and an amine and/or a salt thereof (e.g., morpholine, an amino acid (e.g., arginine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
33 . The pharmaceutical composition of any one of claims 27 - 32 , wherein the one or more bases comprise an amine and/or a salt thereof (e.g., morpholine, an amino acid (e.g., arginine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
34 . The pharmaceutical composition of any one of claims 27 - 33 , wherein the one or more bases comprise a mono- and/or poly-hydroxyalkylamine and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
35 . The pharmaceutical composition of any one of claims 27 - 34 , wherein the one or more bases comprise e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, and/or diethanolamine).
36 . The pharmaceutical composition of any one of claims 27 - 35 , wherein the one or more bases comprise tris(hydroxymethyl)aminomethane, meglumine, and or a tris(hydroxymethyl)aminomethane salt (e.g., tris(hydroxymethyl)aminomethane acetate).
37 . The pharmaceutical composition of any one of claims 27 - 36 , wherein the one or more bases comprise a base, wherein a conjugate acid of the base has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9.
38 . The pharmaceutical composition of any one of claims 27 - 37 , wherein the pH after admixture with the aqueous solution is between pH 7 and pH 10.5, e.g., between pH 7 and pH 9.5, e.g., between pH 7 and pH 8, e.g., between 7.5 and 8.5, e.g., 7.5, e.g., 8.5, e.g., 8.2.
39 . The pharmaceutical composition of any one of claims 27 - 38 , wherein the pharmaceutical composition comprises Formula II
40 . The pharmaceutical composition of claim 39 , wherein the pharmaceutical composition comprises at least a 1:1 molar ratio of Formula II to cation of the base.
41 . The pharmaceutical composition of claim 39 , wherein the pharmaceutical composition comprises Formula III
42 . The pharmaceutical composition of claim 41 , wherein the composition comprises at least a 1:2 molar ratio of Formula III to a cation of the base, e.g., at least about 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5, e.g., at least about 1:5, e.g. at least about 1:10.
43 . The pharmaceutical composition of any one of claims 1 - 42 , wherein the composition is for injection, e.g., subcutaneously, intramuscularly, intravenously, or intrathecally, e.g., intramuscularly or intravenously, e.g., a bolus injected subcutaneously, intramuscularly, intravenously, or intrathecally.
44 . The pharmaceutical composition of any one of claims 1 - 43 , wherein the composition is for injection intravenously, e.g., IV bolus and/or IV infusion, e.g., IV bolus followed by IV infusion, e.g., a loading bolus (e.g., 10 or 20 to 30, 50, 70, 75, 100, 140, 150, 200, 300 or 400 mg per day administered by a loading bolus dose, e.g., about 50 to 200 or 250 mg per day administered by a loading bolus dose, e.g., about 70 to 140 mg per day administered by a loading bolus dose, e.g., a concentration of the dissolved salt administered by a loading bolus dose of 1 to 4, 5, 8, 10, 15, 20, 30, or 50 mM per day, e.g., a concentration of the dissolved salt administered by a loading bolus dose of about 2 to 5, 10, 15, or 20 mM per day, e.g., a concentration of the dissolved salt administered by a loading bolus dose of about 4 to 8 or 9 mM per day) and then an IV infusion over 24 hours for 3 days (e.g., at a rate of 1, 2, 3, 5, 6, 7, 8, 10, 15, 20, 25, 30, or 50 mg/hr for 24 hours, e.g., at a rate of 3, 6, or 15 mg/hr).
45 . The pharmaceutical composition of any one of claims 1 - 43 , wherein the composition is for injection intramuscularly, e.g., IM bolus and/or IM infusion, e.g., IM bolus followed by IM infusion.
46 . The pharmaceutical composition of any one of claims 44 or 45 , wherein the infusion, e.g., IV or IM, is administered over about 10 or 30 minutes to 72 hours, e.g., about 30 minutes to 24 hours, e.g, about 30 minutes to 12 hours, e.g., about 30 minutes to 8 hours, e.g., about 30 minutes to 6 hours, e.g., about 30 minutes to 4 hours, e.g., about 30 minutes to 2 hours, e.g., about 30 minutes to 1 hour, e.g., about 72 hours.
47 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises between 20 and 500 mg 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), e.g., between about 25 and 450 mg, e.g., between about 30 and 400 mg, e.g., between about 35 and 350 mg, and a base, e.g., one or more of tris(hydroxymethyl)aminomethane, Na 2 HPO 4 , meglumine, and sodium citrate, e.g., between 10 and 1500 mg of one or more of tris(hydroxymethyl)aminomethane, Na 2 HPO 4 , meglumine, and sodium citrate, e.g., between about 15 and 1000 mg, e.g., between about 20 and 600 mg, e.g., between about 50 and 200 mg, e.g., between about 50 and 150 mg, e.g., between 10 and 1500 mg of the base, e.g., between about 15 and 1000 mg, e.g., between about 20 and 600 mg, e.g., between about 50 and 200 mg, e.g., between about 50 and 150 mg.
48 . The pharmaceutical composition of claim 47 , wherein the pharmaceutical composition comprises between 20 and 500 mg 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), e.g., between about 25 and 450 mg, e.g., between about 30 and 400 mg, e.g., between about 35 and 350 mg, and tris(hydroxymethyl)aminomethane, e.g., between 10 and 600 mg tris(hydroxymethyl)aminomethane, e.g., between about 20 and 500, e.g., between about 40 and 500 mg.
49 . The pharmaceutical composition of claim 47 , wherein the pharmaceutical composition comprises between 20 and 500 mg 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), e.g., between about 25 and 450 mg, e.g., between about 30 and 400 mg, e.g., between about 35 and 350 mg, and Na 2 HPO 4 , e.g., between 10 and 600 mg Na 2 HPO 4 , e.g., between about 20 and 500, e.g., between about 40 and 500 mg.
50 . The pharmaceutical composition of claim 47 , wherein the pharmaceutical composition comprises between 20 and 500 mg 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), e.g., between about 25 and 450 mg, e.g., between about 30 and 400 mg, e.g., between about 35 and 350 mg, and meglumine, e.g., between 20 and 900 mg meglumine, e.g., between about 30 and 800, e.g., between about 60 and 500 mg, e.g, between about 70 and 400 mg.
51 . The pharmaceutical composition of claim 47 , wherein the pharmaceutical composition comprises between 20 and 500 mg 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), e.g., between about 25 and 450 mg, e.g., between about 30 and 400 mg, e.g., between about 35 and 350 mg, and sodium citrate, e.g., between 30 and 1500 mg sodium citrate, e.g., between about 40 and 1200, e.g., between about 50 and 1000 mg, e.g, between about 80 and 600 mg, e.g., between about 100 and 500 mg.
52 . The pharmaceutical composition of any one of claims 47 - 51 , wherein the pharmaceutical composition is admixed with an aqueous solution, e.g., sterile water for injection, a sterile solution comprising dextrose (e.g., dextrose injection 5%), a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection), a sterile solution comprising benzyl alcohol (e.g., bacteriostatic water for injection with benzyl alcohol or bacteriostatic sodium chloride for injection with benzyl alcohol), or Lactated Ringer's, e.g., wherein the composition is admixed with 1 mL to 100 mL of an aqueous solution e.g., about 3 to 50 mL, e.g., about 3.5 to 35 mL.
53 . The pharmaceutical composition of any one of claims 47 - 52 , wherein the pharmaceutical composition is admixed with a sterile water for injection, e.g., wherein the composition is admixed with 1 mL to 100 mL sterile water for injection, e.g., about 3 to 50 mL, e.g., about 3.5 to 35 mL.
54 . The pharmaceutical composition of any one of claims 47 - 53 , wherein the pharmaceutical composition is admixed with a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection), e.g., wherein the composition is admixed with 1 mL to 100 mL a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection), e.g., about 3 to 50 mL, e.g., about 3.5 to 35 mL.
55 . The pharmaceutical composition of any one of claims 1 - 54 , wherein the composition is stable for at least one week at room temperature, e.g., for at least 1, 2, 4, 6, 8, or 12 months, e.g., the composition has <20% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <15% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <10% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <5% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, 1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, or <1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.
56 . The pharmaceutical composition of any one of claims 1 - 55 , wherein the pharmaceutical composition is for use in any of the methods described herein, e.g., for use in Method A, e.g., Method A.1-A.58, for use in Method B, e.g., Method B.1-B.41, e.g., for use in Method C, e.g., C.1-C.8, e.g., for use in Method D, e.g., D.1-D.19, e.g., for use in Method E, e.g., E.1-E.59, e.g., for use in Method F, e.g., F.1-F.5, e.g., for use in Method G, e.g., G.1-G.58, e.g., for use in Method H, e.g., H.1-H.9.
57 . A method of making the pharmaceutical composition of any one of claims 1 - 56 comprising admixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and a pharmaceutically acceptable excipient.
58 . A kit comprising the pharmaceutical composition of any one of claims 1 - 56 .
59 . A salt solution comprising water and a salt formed from a compound of Formula I
and an amine and/or a salt thereof (e.g., morpholine, piperazine, benethamine, benzathine, trimethylglycine, hydrabamine, 4-(2-hydroxyethyl)morpholine, 1-2-hydroxyethyl)-pyrrolidine, an amino acid (e.g., arginine and/or lysine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, dimethylethanolamine, diethylamine, diethylethanolamine, and/or diethanolamine), e.g., any of the preceding wherein a conjugate acid of the amine and/or salt thereof has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9.
60 . A salt solution comprising Formula II
61 . A salt solution comprising Formula III
62 . The salt solution of any one of claims 59 - 61 , wherein the salt solution comprises a a protonated and/or unprotonated mono- and/or poly-hydroxyalkylamine, e.g., (HO) n R 8 NH 2 , [(HO) n R 8 ] 2 NH, [(HO) n R 8 ] 3 N, e.g., (HO) n R 8 NH 3 + , [(HO) n R 8 ] 2 NH 2 + , [(HO) n R 8 ] 3 NH + , wherein each R 8 is independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g., C 1-4 -alkyl, e.g., —CH 2 CH 3 , e.g., —CH 3 ) and n is 0 or C 1-8 -alkylene (e.g., C 1-6 -alkylene, e.g., C 1-4 -alkylene, e.g., —CH 2 —CH 2 —, e.g., —C(CH 2 ) 3 —, e.g., one R 8 is —CH 3 and another R 8 is —(CH 2 ) 6 —) and each n is independently 1-8 (e.g., 1, 2, 3, 4, 5, or 6), e.g.,
63 . The salt solution of any one of claims 59 - 62 , wherein the salt solution comprises
64 . The salt solution of any one of claims 59 - 62 , wherein the salt solution comprises
65 . The salt solution I of any one of claims 59 - 62 , wherein the salt solution comprises
66 . The salt solution of any one of claims 59 - 65 , wherein the salt solution comprises at least a 1:1 molar ratio of Formula II to the protonated amine.
67 . The salt solution of any one of claims 59 - 65 , wherein the salt solution comprises at least a 1:2 molar ratio of Formula II to the protonated amine, e.g., at least about 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5, e.g., at least about 1:5, e.g. at least about 1:10.
68 . The salt solution of any one of claims 59 - 62 , wherein the salt solution comprises at least a 1:2 molar ratio of Formula II to
e.g., at least about 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5, e.g., at least about 1:5, e.g. at least about 1:10.
69 . The salt solution of any one of claims 59 - 62 , wherein the salt solution comprises at least a 1:2 molar ratio of Formula II to
e.g., at least about 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5, e.g., at least about 1:5, e.g. at least about 1:10.
70 . The salt solution of any one of claims 59 - 62 , wherein the salt solution comprises at least a 1:2 molar ratio of Formula II to
e.g., at least about 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:2.5, e.g., at least about 1:5, e.g. at least about 1:10.
71 . The salt solution of any one of claims 59 - 70 , wherein the salt solution comprises a sterile solution, e.g., sterile water for injection, a sterile solution comprising dextrose (e.g., dextrose injection 5%), a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection), a sterile solution comprising benzyl alcohol (e.g., bacteriostatic water for injection with benzyl alcohol or bacteriostatic sodium chloride for injection with benzyl alcohol), or Lactated Ringer's.
72 . The salt solution of any one of claims 59 - 71 , wherein the salt solution comprises 0.5 to 500 mL water.
73 . The salt solution of any one of claims 59 - 72 , wherein the salt solution comprises sterile water for injection.
74 . The salt solution of any one of claims 59 - 73 , wherein the salt solution comprises sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection).
75 . The salt solution of any one of claims 59 - 74 , wherein the concentration of Formula II or Formula III, e.g., the concentration of Formula II, e.g, the concentration of Formula III is 1 to 250 mM.
76 . The salt solution of any one of claims 59 - 75 , wherein the pH of the salt solution is between pH 7 and pH 10.5, e.g., between pH 7 and pH 9.5, e.g., between pH 7 and pH 8, e.g., between 7.5 and 8.5, e.g., 7.5, e.g., 8.5, e.g., 8.2.
77 . The salt solution of any one of claims 59 - 76 , wherein the salt solution is for injection, e.g., subcutaneously, intramuscularly, intravenously, or intrathecally, e.g., intramuscularly or intravenously, e.g., a bolus injected subcutaneously, intramuscularly, intravenously, or intrathecally.
78 . The salt solution of claim 77 , wherein the salt solution is for injection intravenously, e.g., IV bolus and/or IV infusion, e.g., IV bolus followed by IV infusion.
79 . The salt solution of claim 77 , wherein the salt solution is for injection intramuscularly, e.g., IM bolus and/or IM infusion, e.g., IM bolus followed by IM infusion.
80 . The salt solution of any one of claims 59 - 79 , wherein the salt solution is stable for at least one week, e.g., for at least 1, 2, 4, 6, 8, or 12 months.
81 . The salt solution of any one of claims 59 - 80 , wherein the salt solution is stable for at least one week, at room temperature, e.g., for at least 1, 2, 4, 6, 8, or 12 months, e.g., the composition has <20% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <15% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <10% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <5% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, 1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, or <1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.
82 . The salt solution of any one of claims 59 - 81 , wherein the salt solution is for use in any of the methods described herein, e.g., for use in Method A, e.g., Method A.1-A.58, for use in Method B, e.g., Method B.1-B.41, e.g., for use in Method C, e.g., C.1-C.8, e.g., for use in Method D, e.g., D.1-D.19, e.g., for use in Method E, e.g., E.1-E.59, e.g., for use in Method F, e.g., F.1-F.5, e.g., for use in Method G, e.g., G.1-G.58, for use in Method H, e.g., H.1-H.9.
83 . A method for making the salt solution of any one of claims 59 - 82 comprising admixing a compound of Formula I
and an amine and/or a salt thereof (e.g., morpholine, piperazine, benethamine, benzathine, trimethylglycine, hydrabamine, 4-(2-hydroxyethyl)morpholine, 1-2-hydroxyethyl)-pyrrolidine, an amino acid (e.g., arginine and/or lysine), a mono- and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g., H 2 NR 20 , HNR 20 R 21 , NR 20 R 21 R 22 , and/or a salt thereof wherein each R 20 , R 21 , and R 22 are independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g. C 1-4 -alkyl, e.g., C 2 -alkyl, e.g., —CH 3 ) optionally substituted with one or more —OH (e.g., optionally substituted with 1-8 —OH, e.g., 1, 2, 3, 4, 5, or 6), e.g., tris(hydroxymethyl)aminomethane (also known as tris base) and/or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as tris acetate), meglumine, dimethylethanolamine, diethylamine, diethylethanolamine, and/or diethanolamine), e.g., any of the preceding wherein a conjugate acid of the amine and/or salt thereof has a pKa between 6, 7, 8, 9, or 10 and 11, e.g., between about 6, 7, 8, or 9 and 10, e.g., between about 7 and 9, e.g., between about 8 and 9, in an aqueous solution.
84 . A pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I)
and tris(hydroxymethyl)aminomethane.
85 . The pharmaceutical composition of claim 84 , wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to tris(hydroxymethyl)aminomethane is 1:2 to 1:10.
86 . The pharmaceutical composition of claim 84 or 85 , wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to tris(hydroxymethyl)aminomethane is 1:2.5 to 1:5.
87 . The pharmaceutical composition of any one of claims 84 - 86 , wherein the wherein the composition is admixed with an aqueous solution, e.g., a sterile solution, e.g., sterile water for injection, a sterile solution comprising dextrose (e.g., dextrose injection 5%), a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection), a sterile solution comprising benzyl alcohol (e.g., bacteriostatic water for injection with benzyl alcohol or bacteriostatic sodium chloride for injection with benzyl alcohol), or Lactated Ringer's.