U.S. patent application number 15/035006 was filed with the patent office on 2016-09-29 for novel formulations.
This patent application is currently assigned to Aeromics, Inc.. The applicant listed for this patent is AEROMICS, LLC. Invention is credited to George William FARR, Paul Robert MCGUIRK, Marc F. PELLETIER.
Application Number | 20160279155 15/035006 |
Document ID | / |
Family ID | 53042097 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160279155 |
Kind Code |
A1 |
PELLETIER; Marc F. ; et
al. |
September 29, 2016 |
NOVEL FORMULATIONS
Abstract
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.
Inventors: |
PELLETIER; Marc F.; (Shaker
Heights, OH) ; MCGUIRK; Paul Robert; (Spring Hill,
FL) ; FARR; George William; (Rocky River,
OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AEROMICS, LLC |
Cleveland |
OH |
US |
|
|
Assignee: |
Aeromics, Inc.
Cleveland
OH
|
Family ID: |
53042097 |
Appl. No.: |
15/035006 |
Filed: |
November 6, 2014 |
PCT Filed: |
November 6, 2014 |
PCT NO: |
PCT/US2014/064441 |
371 Date: |
May 6, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61900919 |
Nov 6, 2013 |
|
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|
61900946 |
Nov 6, 2013 |
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61900878 |
Nov 6, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/222 20130101;
A61P 25/00 20180101; A61P 27/02 20180101; A61P 9/00 20180101; A61K
47/18 20130101; A61P 7/08 20180101; A61K 31/167 20130101; A61P
25/06 20180101; A61P 21/00 20180101; A61P 7/10 20180101; A61P 35/00
20180101; A61P 7/00 20180101; C07F 9/09 20130101; A61P 15/00
20180101; A61P 43/00 20180101; A61P 25/08 20180101; A61P 9/04
20180101; A61K 9/0019 20130101; A61P 31/04 20180101; A61K 31/661
20130101; A61P 11/00 20180101; A61P 1/16 20180101; A61P 9/10
20180101; A61K 31/5375 20130101 |
International
Class: |
A61K 31/661 20060101
A61K031/661; A61K 47/18 20060101 A61K047/18; A61K 9/00 20060101
A61K009/00 |
Claims
1. A pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate (Formula I) ##STR00056## 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.sub.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.sub.2PO.sub.4 and/or
Na.sub.2HPO.sub.4) and/or potassium phosphate (e.g.,
KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21,
NR.sup.20R.sup.21R.sup.22, and/or a salt thereof wherein each
R.sup.20, R.sup.21, and R.sup.22 are independently C.sub.1-8 alkyl
(e.g., C.sub.1-6-alkyl, e.g. C.sub.1-4-alkyl, e.g., C.sub.2-alkyl,
e.g., --CH.sub.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.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4), e.g.,
sodium phosphate (e.g., Na.sub.2HPO.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., C.sub.2-alkyl, e.g., --CH.sub.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.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.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.sub.2HPO.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8-alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., --C.sub.2-alkyl, e.g., --CH.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8-alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., --C.sub.2-alkyl, e.g., --CH.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., --C.sub.2-alkyl, e.g., --CH.sub.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.sub.2NR.sup.20,
HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22, and/or a salt
thereof wherein each R.sup.20, R.sup.21, and R.sup.22 are
independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., --C.sub.2-alkyl, e.g., --CH.sub.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 ##STR00057##
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 ##STR00058##
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.sub.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.sub.2PO.sub.4
and/or Na.sub.2HPO.sub.4) and/or potassium phosphate (e.g.,
KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21,
NR.sup.20R.sup.21R.sup.22, and/or a salt thereof wherein each
R.sup.20, R.sup.21, and R.sup.22 are independently C.sub.1-8 alkyl
(e.g., C.sub.1-6-alkyl, e.g. C.sub.1-4-alkyl, e.g., C.sub.2-alkyl,
e.g., --CH.sub.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.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4)
and/or potassium phosphate (e.g., KH.sub.2PO.sub.4 and/or
K.sub.2HPO.sub.4), e.g., sodium phosphate (e.g.,
Na.sub.2HPO.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., C.sub.2-alkyl, e.g., --CH.sub.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.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.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.sub.2HPO.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., C.sub.2-alkyl, e.g., --CH.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., C.sub.2-alkyl, e.g., --CH.sub.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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., C.sub.2-alkyl, e.g., --CH.sub.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.sub.2NR.sup.20,
HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22, and/or a salt
thereof wherein each R.sup.20, R.sup.21, and R.sup.22 are
independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., C.sub.2-alkyl, e.g., --CH.sub.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
##STR00059##
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 ##STR00060##
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.sub.2HPO.sub.4, meglumine, and
sodium citrate, e.g., between 10 and 1500 mg of one or more of
tris(hydroxymethyl)aminomethane, Na.sub.2HPO.sub.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.sub.2HPO.sub.4, e.g., between 10 and 600 mg
Na.sub.2HPO.sub.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 ##STR00061## 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.sub.2NR.sup.20, HNR.sup.20R.sup.21,
NR.sup.20R.sup.21R.sup.22, and/or a salt thereof wherein each
R.sup.20, R.sup.21, and R.sup.22 are independently C.sub.1-8 alkyl
(e.g., C.sub.1-6-alkyl, e.g. C.sub.1-4-alkyl, e.g., C.sub.2-alkyl,
e.g., --CH.sub.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 ##STR00062##
61. A salt solution comprising Formula III ##STR00063##
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).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, e.g.,
(HO).sub.nR.sup.8NH.sub.3.sup.+,
[(HO).sub.nR.sup.8].sub.2NH.sub.2.sup.+,
[(HO).sub.nR.sup.8].sub.3NH.sup.+, wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g., ##STR00064##
63. The salt solution of any one of claims 59-62, wherein the salt
solution comprises ##STR00065##
64. The salt solution of any one of claims 59-62, wherein the salt
solution comprises ##STR00066##
65. The salt solution I of any one of claims 59-62, wherein the
salt solution comprises ##STR00067##
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
##STR00068## 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
##STR00069## 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
##STR00070## 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 ##STR00071## 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.sub.2NR.sup.20, HNR.sup.20R.sup.21, NR.sup.20R.sup.21R.sup.22,
and/or a salt thereof wherein each R.sup.20, R.sup.21, and R.sup.22
are independently C.sub.1-8 alkyl (e.g., C.sub.1-6-alkyl, e.g.
C.sub.1-4-alkyl, e.g., C.sub.2-alkyl, e.g., --CH.sub.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) ##STR00072## 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.
Description
[0001] This application claims priority to U.S. Provisional
Application No. 61/900,878 filed Nov. 6, 2013, U.S. Provisional
Application No. 61/900,946 filed Nov. 6, 2013, and U.S. Provisional
Application No. 61/900,919 filed Nov. 6, 2013.
TECHNICAL FIELD
[0002] Provided are novel formulations of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate as described below and uses thereof.
BACKGROUND
[0003] Aquaporins are cell membrane proteins that act as molecular
water channels to mediate the flow of water in and out of the
cells. While there is some degree of passive diffusion or osmosis
of water across cell membranes, the rapid and selective transport
of water in and out of cells involves aquaporins. These water
channels selectively conduct water molecules in and out of the
cell, while blocking the passage of ions and other solutes, thereby
preserving the membrane potential of the cell. Aquaporins are found
in virtually all life forms, from bacteria to plants to animals. In
humans, they are found in cells throughout the body.
[0004] Aquaporin inhibitors, e.g., inhibitors of AQP4 and/or AQP2,
may be of utility in the treatment or control of diseases of water
imbalance, for example edema (particularly edema of the brain and
spinal cord), hyponatremia, and excess fluid retention, as well as
diseases such as epilepsy, retinal ischemia and other diseases of
the eye, myocardial ischemia, myocardial ischemia/reperfusion
injury, myocardial infarction, myocardial hypoxia, congestive heart
failure, sepsis, and neuromyelitis optica, as well as
migraines.
[0005] Prior to Applicants' filings, there have been no known
specific, validated inhibitors of aquaporins, for example AQP4 or
AQP2. Certain antiepileptic or sulfonamide drugs (e.g.,
acetylsulfanilamide, acetazolamide,
6-ethoxy-benzothiazole-2-sulfonamide, topiramate, zonisamide,
phenytoin, lamotrigine, and sumatriptan) were at one point reported
to be possible inhibitors of AQP4, but this later proved to be
incorrect. Yang et al., Bioorganic and Medicinal Chemistry, 2008,
16, 7489-7493. No direct inhibitors of AQP2 have been reported.
[0006] Thus, there is a need for compounds that selectively inhibit
aquaporins. In addition, there is a need for formulations that may
be used to deliver compounds that selectively inhibit aquaporins
and may be administered easily to patients.
BRIEF SUMMARY
[0007] Provided are pharmaceutical compositions comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate (Formula I).
##STR00001##
and uses thereof.
[0008] Also provided are kits comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate.
[0009] 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, for example,
[0010] edema of the brain or spinal cord, e.g., cerebral edema,
e.g. cerebral edema consequent to head trauma, ischemic stroke,
glioma, meningitis, acute mountain sickness, epileptic seizure,
infection, metabolic disorder, hypoxia (including general systemic
hypoxia and hypoxia due to cardiac arrest), water intoxication,
hepatic failure, hepatic encephalopathy, diabetic ketoacidosis,
abscess, eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis,
cardiac arrest, microgravity and/or radiation exposure, or an
invasive central nervous system procedure, e.g., neurosurgery,
endovascular clot removal, spinal tap, aneurysm repair, or deep
brain stimulation or, e.g., spinal cord edema consequent to spinal
cord trauma, e.g., spinal cord compression; or [0011] optic nerve
edema, e.g., optic nerve edema consequent to microgravity and/or
radiation exposure; or [0012] retinal edema; or [0013] pulmonary
edema; or [0014] hyponatremia or excessive fluid retention, e.g.,
consequent to heart failure (HF), liver cirrhosis, nephrotic
disorder, syndrome of inappropriate antidiuretic hormone secretion
(SIADH), or infertility treatment; or [0015] ovarian
hyperstimulation syndrome; or [0016] epilepsy, retinal ischemia or
other diseases of the eye associated with abnormalities in
intraocular pressure and/or tissue hydration, myocardial ischemia,
myocardial ischemia/reperfusion injury, myocardial infarction,
myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis
optica, or glioblastoma; or [0017] fibromyalgia; or [0018] multiple
sclerosis; or [0019] migraines, comprising administering to a
patient in need thereof a pharmaceutical composition comprising a
therapeutically effective amount of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate.
[0020] Further areas of applicability of the present disclosure
will become apparent from the detailed description provided
hereinafter. It should be understood that the detailed description
and specific examples, while indicating the preferred embodiment of
the disclosure, are intended for purposes of illustration only and
are not intended to limit the scope of the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 depicts percent survival curves for the water
toxicity mouse model using 0.76 mg/kg
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1).
[0022] FIG. 2 depicts inhibition of cerebral edema formation by
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) in the mouse water toxicity model by MRI brain volume
analysis, with n=14 mice/treatment. A time course of edema
formation is shown comparing no drug vs.
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) at 0.76 mg/kg. The first time point at 5.67 min
coincides with the scan slice at the middle of the brain during the
first post-injection scan. Other time points are placed in a
similar manner. The data is fitted to a single exponential
equation: [0023] V/V.sub.0=V.sub.i+dV.sub.max(1-e.sup.(-kt)); where
V/V.sub.0=relative brain volume, V.sub.i=initial relative brain
volume, dV.sub.max=maximum change in relative brain volume, k=first
order rate constant (min.sup.-1), and t=time in minutes.
[0024] FIG. 3 depicts the calcein fluorescence end-point assay used
for high throughput screening.
[0025] FIG. 4 depicts hit validation using the Cell Bursting
Aquaporin Assay; inset shows the structure of
5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide (Compound
3).
[0026] FIG. 5 depicts reduction in intracranial pressure (ICP) in
the mouse water toxicity model with
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) at 0.76 mg/kg.
[0027] FIG. 6 depicts plasma and serum levels of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) converted from
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis ethanolamine salt.
[0028] FIG. 7 depicts mouse middle cerebral artery occlusion (MCAo)
model of ischemic stroke.
[0029] FIG. 8 depicts relative change in hemispheric brain volume
in the mouse middle cerebral artery occlusion (MCAo) model.
[0030] FIG. 9 depicts neurological outcome following MCAo in mice
treated with saline (no drug, ) or
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (.largecircle.) (Compound 5).
[0031] FIG. 10 depicts plasma and serum levels of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) converted from a solution of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and Tris-Base.
DETAILED DESCRIPTION
[0032] The following description of the preferred embodiments is
merely exemplary in nature and is in no way intended to limit the
present disclosure, its application, or uses.
[0033] As used herein, "therapeutically effective amount" refers to
an amount effective, when administered to a human or non-human
patient, to provide a therapeutic benefit such as amelioration of
symptoms, slowing of disease progression, or prevention of disease.
The specific dose of substance administered to obtain a therapeutic
benefit will, of course, be determined by the particular
circumstances surrounding the case, including, for example, the
specific substance administered, the route of administration, the
condition being treated, and the individual being treated.
[0034] As used herein, "sodium phosphate" refers to sodium
dihydrogen phosphate (NaH.sub.2PO.sub.4), disodium hydrogen
phosphate (Na.sub.2HPO.sub.4), and trisodium phosphate
(Na.sub.3PO.sub.4).
[0035] As used herein, "potassium phosphate" refers to potassium
dihydrogen phosphate (KH.sub.2PO.sub.4), dipotassium hydrogen
phosphate (K.sub.2HPO.sub.4), and tripotassium phosphate
(K.sub.3PO.sub.4).
[0036] As used herein, "bolus" refers to administration of a
therapeutic agent in a single injection that lasts for a relatively
short period of time, e.g., about 60 minutes or less, about 30
minutes or less, about 20 minutes or less, about 10 minutes or
less, about 5 minutes or less, e.g., about 3 minutes or less. A
bolus may rapidly deliver a therapeutically effective amount of a
therapeutic agent to the blood.
[0037] As used herein, "patient" includes human or non-human (i.e.,
animal) patient. In a particular embodiment, the invention
encompasses both human and nonhuman. In another embodiment, the
invention encompasses nonhuman. In another embodiment, the term
encompasses human.
[0038] As used herein, "fairly rapid" with respect to onset of
action means that the time it takes after a compound is
administered for a response to be observed is 30 minutes or less,
for example 20 minutes or less, for example 15 minutes or less, for
example 10 minutes or less, for example 5 minutes or less, for
example 1 minute or less.
[0039] As used herein, "alkyl" is a saturated hydrocarbon moiety,
preferably having one to six carbon atoms, preferably having one to
four carbon atoms, which may be linear or branched. A
"C.sub.1-4-alkyl" is an alkyl having one to four carbon atoms.
[0040] As used herein "alkylene" is a saturated hydrocarbon moiety,
preferably having one to six carbon atoms, preferably having one to
four carbon atoms, which may be linear or branched and which has
two points of attachment. A C.sub.1-4-alkylene is an alkylene
having from one to four carbon atoms. For example, C.sub.1-alkylene
is methylene (--CH.sub.2--).
[0041] As used herein, "alkoxy" is an alkyl ether radical,
alkyl-O--, wherein the term alkyl is as defined above. A
"C.sub.1-4-alkoxy" is an alkoxy having one to four carbon
atoms.
[0042] As used herein, "aryl" is a mono or polycyclic (e.g.,
bicyclic) aromatic hydrocarbon, preferably phenyl, which may be
optionally substituted, e.g., optionally substituted with one or
more groups independently selected from C.sub.1-6 alkyl (e.g.,
methyl), halogen (e.g., Cl or F), C.sub.1-6-haloalkyl (e.g.,
trifluoromethyl), hydroxy, and carboxy. In some embodiments, aryl,
in addition to being substituted with the groups disclosed herein,
is further substituted with an aryl or a heteroaryl to form, e.g.,
biphenyl or pyridylphenyl.
[0043] As used herein, "heteroaryl" is an mono or polycyclic (e.g.,
bicyclic) aromatic moiety wherein one or more of the atoms making
up the aromatic ring is sulfur or nitrogen rather than carbon,
e.g., pyridyl or thiadiazolyl, which may be optionally substituted,
e.g., optionally substituted with one or more groups independently
selected from C.sub.1-6 alkyl (e.g., methyl), halogen (e.g., Cl or
F), C.sub.1-6-haloalkyl (e.g., trifluoromethyl), hydroxy, and
carboxy.
[0044] As used herein, "hydroxy" is --OH.
[0045] As used herein, "carboxy" is --COOH.
[0046] As used herein, "halogen" as used herein is F, Cl, Br, or
I.
[0047] As used herein, "haloalkyl" is a saturated hydrocarbon
moiety, preferably having one to six carbon atoms, preferably
having one to four carbon atoms, which may be linear or branched,
and is mono-, di- or tri-substituted with halogen. For di- or
tri-substituted haloalkyl, the halogens may be the same (e.g.,
dichloromethyl) or different (e.g., chlorofluoromethyl).
[0048] Expression of Aquaporin-4 (AQP4) is upregulated in animal
models of trauma, stroke and water intoxication, as well as around
human malignant brain tumors. Aquaporin-4 (AQP4) has been shown to
play a critical role in the development of cerebral and spinal cord
edema. AQP4 provides the primary route for water movement across
the blood-brain barrier (BBB) and glia limitans. AQP4 knockout
mice, without the APQ4 gene, have improved survival compared to
wild-type mice in models of ischemic stroke, water toxicity,
bacterial meningitis, and spinal cord compression.
[0049] Cerebral edema (CE) may be generally divided into 2 major
categories: vasogenic and cytotoxic. Vasogenic cerebral edema may
occur when a breach in the BBB allows water and solutes to diffuse
into the brain. It has been reported that AQP4-null mice have
increased brain edema in a model of subarachnoid hemorrhage,
suggesting that AQP4 may be required for the clearance of water
collected in intercellular space. In contrast, cytotoxic cerebral
edema may be initiated by ischemia which may result in reduced
plasma osmolality rather than a disrupted BBB. Ischemia may lead to
a drop in ATP levels, which is thought to slow the Na--K ATPase
pump resulting in an uptake of Na.sup.+ and Cl.sup.- through
leakage pathways. The net effect may be a cellular osmotic
imbalance, drawing H.sub.2O into cells--astrocytes more so than
neurons--and leading to increased intracranial pressure (ICP).
Mouse models for ischemic stroke, water toxicity, bacterial
meningitis, and spinal-cord compression fall into this category. In
these models, AQP4-null mice have been reported to have reduced CE
pointing to AQP4 as the central pathway for water movement into the
brain during the formation of cytotoxic CE. However, cytotoxic and
vasogenic edema are not sharply divided categories; an injury that
initially causes cytotoxic edema may be followed later, e.g.,
within the next hours to days, by vasogenic edema. This may suggest
different treatments for cerebral edema at different times.
[0050] AQP4 inhibitors may be of further utility for certain
ailments where control of AQP4-medited water movement may augment
neuroexcitation (by alteration of neuronal potassium homeostasis)
and prove beneficial by reducing neuronal excitation, for example
ailments such as fibromyalgia, multiple sclerosis, migraines and
seizures (in particular but not limited to seizures associated with
epilepsy).
[0051] Aquaporin-2 (AQP2) is the primary route of water movement at
the collecting duct in the kidney. Blocking this water channel
would lower water reabsorption without incurring electrolyte
imbalances or interfering with vasopressin receptor-mediated
signaling. Evidence that an AQP2 blocker would not produce
electrolyte imbalances, and instead be an effective treatment for
hyponatremia, comes from patients with diabetes insipidus who lack
functional AQP2. They exhibit chronic aquaresis but--if normal
hydration is maintained--do not demonstrate any other consequence
of their long-term loss of AQP2 function.
[0052] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is a prodrug of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1, shown below).
##STR00002##
[0053] Certain uses of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide are
described in International Patent Application No.
PCT/US2013/040194, which is incorporated herein by reference in
entirety.
[0054] In stroke or other severely debilitating diseases or
conditions, for example where the patient may be unconscious or
unable to swallow, an IV infusion or IV bolus may be preferred. In
addition, when a patient has suffered a stroke, or traumatic brain
or spinal cord injury, rapid achievement of therapeutically
effective amounts of a therapeutic agent, may be important to a
successful therapeutic outcome. In the acute care settings in the
hospital, particularly for stroke, traumatic brain injury, and
myocardial infarction, best practices are to administer drugs via
IV. However, a therapeutic agent with only a limited solubility in
water and/or physiological media and/or limited stability, may make
parenteral administration, e.g., intravenous, intramuscular,
intraperitoneal, subcutaneous, epidural, sublingual, or
intracerebral, of the therapeutic agent challenging. While
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is
an aquaporin inhibitor, its solubility in water is 3.8 .mu.g/ml.
Alanine and di-alanine prodrugs of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide are
insoluble in water and pH 7.4 water (Example 16). A prodrug salt
form of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide does
show improved solubility--specifically, the solubility of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt in water is 1 mg/ml. However, prodrug salt
forms of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide may
revert to
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide even
in the solid state. For instance,
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
hydrogen phosphate mono sodium salt ("mono sodium salt"),
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis sodium salt ("bis sodium salt"), and
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis ethanolamine salt ("bis ethanolamine salt") show
hydrolysis in the solid state at about 1% per day. Thus, stable
pharmaceutical compositions which may allow rapid achievement of
therapeutically effective amounts of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide are
needed.
[0055] Accordingly, in one embodiment, provided are novel
formulations of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate which may allow rapid achievement of
therapeutically effective amounts of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.
[0056] In one embodiment, provided is a pharmaceutical composition
(Composition I) comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate (Formula I) and a pharmaceutically acceptable
excipient.
[0057] Further provided is Composition I as follows: [0058] 1.1
Composition I wherein the composition comprises 0.1 or 0.25 mg to
2.0 g of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., from about 0.1 or 0.25 mg to 75 or 600
mg, e.g., from about 0.1 or 0.25 or 1 or 2 or 5 or 10 or 15 or 20
mg to 50, 75, 100, 125, 150, 200, 300, 350, 400, 500, or 600 mg, or
1 g, 1.5 g, or 2.0 g, e.g., from about 5 to 50, 75, 100, 125, 150,
200, 300, 350, 400, 500, or 600 mg, or 1 g, 1.5 g, or 2 g, e.g.,
from about 5 to 500 mg, e.g., from about 5 to 300 or 350 mg, e.g.,
from about 5 to 200 mg, e.g., from about 25 to 500 mg, e.g., from
about 25 to 300 or 350 mg, e.g., from about 25 to 200 mg, e.g.,
from about 15, 20, 30, 35, 50, or 100 to 150, 200, 300, 350, 400,
450, 500, 550, or 600 mg, e.g., from about 0.5 or 1 mg to 50 mg,
e.g., from about 0.5 or 1 mg to 20 mg, e.g., from about 0.5 or 1 mg
to 10 mg, e.g., from about 1 or 2 or 5 mg to 10 or 20 mg, e.g.,
from about 1 or 2 or 3 or 4 to 5 mg, e.g., about 35 mg, e.g., about
350 mg, or wherein the composition comprises
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate in an amount sufficient to provide 0.1 or 0.25
mg to 2.0 g of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
e.g., in an amount sufficient to provide from about 0.1 or 0.25 mg
to 75 or 600 mg, e.g., from about 0.1 or 0.25 or 1 or 2 or 5 or 10
or 15 or 20 mg to 50, 75, 100, 125, 150, 200, 300, 350, 400, 500,
or 600 mg, or 1 g, 1.5 g, or 2.0 g, e.g., from about 5 to 50, 75,
100, 125, 150, 200, 300, 350, 400, 500, or 600 mg, or 1 g, 1.5 g,
or 2 g, e.g., from about 5 to 500 mg, e.g., from about 5 to 300 or
350 mg, e.g., from about 5 to 200 mg, e.g., from about 25 to 500
mg, e.g., from about 25 to 300 or 350 mg, e.g., from about 25 to
200 mg, e.g., from about 15, 20, 30, 35, 50, or 100 to 150, 200,
300, 350, 400, 450, 500, 550, or 600 mg, e.g., from about 0.5 or 1
mg to 50 mg, e.g., from about 0.5 or 1 mg to 20 mg, e.g., from
about 0.5 or 1 mg to 10 mg, e.g., from about 1 or 2 or 5 mg to 10
or 20 mg, e.g., from about 1 or 2 or 3 or 4 to 5 mg, e.g., about 35
mg, e.g., about 350 mg. [0059] 1.2 Composition I wherein the
composition comprises
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate in an amount sufficient to provide a dose of
0.01 or 0.1 or 0.5 mg/kg to 1 or 5 or 10 or 15 mg/kg of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
e.g., a dose of about 0.05 to 1 or 5 mg/kg, e.g., a dose of about
0.05 to 0.1, 0.2, 0.3, 0.4, 0.5, 1, 5, 10 or 20 mg/kg, e.g., a dose
of about 0.5 to 1, 2, 3, 4, 5 or 10 or 20 mg/kg, e.g, a dose of
about 1 to 2, 3, 4, 5, 10, 20 or 50 mg/kg. [0060] 1.3 Composition
I, 1.1, or 1.2 wherein the pharmaceutically acceptable excipient
comprises one or more bases, e.g., a base wherein upon dissolution
of the composition in a solvent, e.g., 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, e.g., 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, e.g., wherein
the one or more bases are one or more of: [0061] a) a
C.sub.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), [0062] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0063]
c) an amine and/or a salt thereof (e.g., morpholine, piperazine,
benethamine, benzathine, trimethylglycine, chloroprocaine,
hydrabamine, an amino acid (e.g., arginine and/or lysine), a mono-
and/or poly-hydroxyalkylamine, and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0064] d) a metal chloride salt (e.g., zinc chloride),
[0065] e) 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), [0066] f) 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), and/or [0067] g) 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), [0068] h) 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.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0069] 1.4 Composition I, 1.1, or
1.2 wherein the pharmaceutically acceptable excipient comprises one
or more bases, e.g., a base 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, e.g., 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, e.g., wherein the one or more bases are one
or more of: [0070] 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), [0071] 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.sub.2PO.sub.4
and/or Na.sub.2HPO.sub.4) and/or potassium phosphate (e.g.,
KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4), e.g., sodium phosphate
(e.g., Na.sub.2HPO.sub.4)), [0072] 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0073] 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), [0074] 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), [0075] 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 [0076] g) a metal borate salt (e.g., an
alkali borate salt, e.g., sodium borate), e.g., one or more of
sodium citrate, Na.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0077] 1.5 Composition 1.3 or 1.4
wherein the composition comprises 1 or 5 mg to 200 or 500 mg of the
one or more bases, e.g., from about 1 or 5 or 10 mg to 15, 20, 25,
30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000,
or 1500 mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250,
400, 450, 500, 600, 700, 800, 1000, or 1500 mg. [0078] 1.6
Composition 1.3-1.5 wherein the one or more bases comprise one or
more of a metal citrate salt (e.g., sodium citrate) and a metal
phosphate salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4).
[0079] 1.7 Composition 1.3-1.6 wherein the one or more bases
comprise a metal citrate salt (e.g., sodium citrate). [0080] 1.8
Composition 1.7 wherein the composition comprises 1 or 5 mg to 200
or 500 mg of a metal citrate salt (e.g., sodium citrate), e.g.,
from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150,
200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from
about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700,
800, 1000, or 1500 mg. [0081] 1.9 Composition 1.3-1.8 wherein the
one or more bases comprise a metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4). [0082] 1.10 Composition 1.9
wherein the composition comprises 1 or 5 mg to 200 or 500 mg of a
metal phosphate salt, e.g., sodium phosphate, e.g., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0083] 1.11 Composition 1.3-1.10 wherein the one or more bases
comprise sodium phosphate, e.g., Na.sub.2HPO.sub.4. [0084] 1.12
Composition 1.11 wherein the composition comprises 1 or 5 mg to 200
or 500 mg sodium phosphate, e.g., Na.sub.2HPO.sub.4, e.g., from
about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200,
250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from about
15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800,
1000, or 1500 mg. [0085] 1.13 Composition 1.3-1.12 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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. [0086] 1.14 Composition 1.13 wherein the composition
comprises 1 or 5 mg to 200 or 500 mg of the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0087] 1.15 Composition
1.3-1.14 wherein the one or more bases comprise a mono- and/or
poly-hydroxyalkylamine and/or a salt thereof, e.g., (HO).sub.n
R.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0088] 1.16
Composition 1.15 wherein the composition comprises 1 or 5 mg to 200
or 500 mg of the mono- and/or poly-hydroxyalkylamine and/or salt
thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0089] 1.17 Composition 1.3-1.16 wherein the one or more bases
comprise (HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0090] 1.18
Composition 1.17 wherein the composition comprises 1 or 5 mg to 200
or 500 mg of (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0091] 1.19 Composition 1.3-1.18 wherein the one or more bases
comprise tris(hydroxymethyl)aminomethane and/or meglumine, e.g.,
tris(hydroxymethyl)aminomethane, e.g., meglumine. [0092] 1.20
Composition 1.19 wherein the composition comprises 1 or 5 mg to 200
or 500 mg tris(hydroxymethyl)aminomethane, e.g., from about 1 or 5
or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg and/or wherein the composition comprises 1 or 5 mg to 200 or 500
mg meglumine, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30,
40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or
1500 mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400,
450, 500, 600, 700, 800, 1000, or 1500 mg. [0093] 1.21 Composition
1.3-1.20 wherein the one or more bases comprise a
tris(hydroxymethyl)aminomethane salt, e.g.,
tris(hydroxymethyl)aminomethane acetate. [0094] 1.22 Composition
1.21 wherein the composition comprises 1 or 5 mg to 200 or 500 mg
of the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate), e.g., from about 1 or 5
or 10 mg to 15, 20, 25, 30, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g, from about 15, 20, 30, or 50
to 100, 200, 250, 400, 450, 500, 600, or 700 mg, e.g., from about 1
or 5 mg to 200 or 500 mg tris(hydroxymethyl)aminomethane acetate,
e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75,
100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg,
e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500,
600, 700, 800, 1000, or 1500 mg. [0095] 1.23 Composition 1.3-1.22
wherein the one or more bases comprise a base, e.g., an amine
and/or a salt thereof, 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. [0096] 1.24 Composition 1.23 wherein the composition comprises 1
or 5 mg to 200 or 500 mg of a base, e.g., an amine and/or a salt
thereof, 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, e.g.,
from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150,
200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from
about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700,
800, 1000, or 1500 mg. [0097] 1.25 Composition 1.1-1.24 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, e.g,
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 2:1.
[0098] 1.26 Composition 1.1-1.25 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, 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. [0099] 1.27
Composition 1.26 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal citrate salt (e.g., sodium citrate)
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. [0100] 1.28 Composition 1.26 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4) is at least 1:1, e.g., 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. [0101]
1.29 Composition 1.26 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the amine and/or salt thereof (e.g.,
morpholine, an amino acid (e.g., arginine), a mono- and/or
poly-hydroxyalkylamine, and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, 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. [0102] 1.30 Composition 1.29 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the mono- and/or poly-hydroxyalkylamine
and/or salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), 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. [0103] 1.31
Composition 1.30 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 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. [0104] 1.32 Composition
1.31 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to tris(hydroxymethyl)aminomethane 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. [0105]
1.33 Composition 1.31 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the tris(hydroxymethyl)aminomethane salt
(e.g, tris(hydroxymethyl)aminomethane acetate) 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, e.g.,
wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to tris(hydroxymethyl)aminomethane acetate 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. [0106] 1.34 Composition 1.26 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a base, e.g., an amine and/or a salt
thereof, 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, 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.
[0107] 1.35 Composition I or 1.1-1.34 wherein the composition
comprises one or more bulking agents which may provide an adequate
structure to the lyophilized cake, e.g., one or more of mannitol,
lactose, sucrose, trehalose, sorbitol, glucose, raffinose,
arginine, glycine, histidine, dextran (e.g., dextran 40),
polyvinylpyrrolidone, polyethylene glycol, and polypropylene
glycol, e.g., one or more of mannitol, glucose, sucrose, lactose,
trehalose, and dextran (e.g., dextran 40). [0108] 1.36 Composition
I or 1.1-1.35 wherein the composition comprises 5 or 10 or 50 mg to
2 or 5 g of one or more bulking agents, e.g., from about 50 or 100
mg to 200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g of one
or more bulking agents. [0109] 1.37 Composition I or 1.1-1.36
wherein the composition comprises dextran (e.g., dextran 40).
[0110] 1.38 Composition 1.37 wherein the composition comprises 5 or
10 or 50 mg to 2 or 5 g dextran (e.g., dextran 40), e.g., from
about 50 mg or 100 mg to 200, 300, 500, or 800 mg, or 1, 1.5, 2, 3,
4, or 5 g dextran (e.g., dextran 40). [0111] 1.39 Composition I or
1.1-1.38 wherein the composition comprises one or more solubilizing
agents, e.g., ethylenediamine tetraacetic acid (EDTA) or a salt
thereof (e.g., calcium disodium EDTA, disodium EDTA, sodium EDTA),
alpha cyclodextrin, hydroxypropyl-
.beta.-cyclodextrin, polysorbate 80, tert-butanol, isopropanol,
dichloromethane, ethanol, acetone, and glycerol; one or more
collapse temperature modifiers which may shift the overall collapse
temperature higher, e.g., one or more of dextran, Ficoll.RTM.,
gelatin, and hydroxyethyl starch; one or more tonicity modifiers,
e.g., one or more of sodium chloride, potassium chloride, sucrose,
mannitol, glucose, and lactose; and one or more antimicrobial
agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0112] 1.40 Composition I
or 1.1-1.39 wherein the composition is a solid, e.g., the
pharmaceutically acceptable excipient, e.g, the one or more bases
is a solid. [0113] 1.41 Composition I or 1.1-1.40 wherein the
composition is lyophilized. [0114] 1.42 Composition I or 1.1-1.41
wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is lyophilized, e.g., by freezing, primary
drying, and secondary drying. [0115] 1.43 Composition 1.42 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is lyophilized, e.g., by freezing, primary
drying, and secondary drying, prior to admixture with the
pharmaceutically acceptable excipient. [0116] 1.44 Composition I or
1.1-1.43 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is crystalline. [0117] 1.45 Composition I or
1.1-1.44 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is amorphous. [0118] 1.46 Composition I or
1.1-1.45 which is suitable for constitution, or reconstitution if
lyophilized, with a solvent, e.g., an aqueous solution, into a
pharmaceutically acceptable liquid (e.g., a solution or suspension,
e.g., a solution). [0119] 1.47 Composition I or 1.1-1.46 wherein
the composition is admixed with a solvent, 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. [0120] 1.48 Composition I or 1.1-1.47 wherein
the composition is admixed with 0.5 to 500 mL solvent, e.g., an
aqueous solution, e.g., from about 1 or 2 mL to 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or
500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or
200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g.,
about 3.5 or 35 mL. [0121] 1.49 Composition I or 1.1-1.48 wherein
the composition is admixed with 0.5 to 500 mL 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,
e.g., from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to
5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0122] 1.50 Composition I or 1.1-1.49 wherein the composition is
admixed with sterile water for injection or a sterile solution
comprising sodium chloride (e.g., 0.9% sodium chloride injection).
[0123] 1.51 Composition I or 1.1-1.50 wherein the composition is
admixed with sterile water for injection. [0124] 1.52 Composition
1.51 wherein the composition is admixed with 0.5 to 500 mL sterile
water for injection, e.g., from about 1 or 2 mL to 500 mL, e.g.,
from about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150, 200,
300 or 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75,
100, or 200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100 mL,
e.g., about 3.5 or 35 mL. [0125] 1.53 Composition I or 1.1-1.52
wherein the composition is admixed with a sterile solution
comprising sodium chloride (e.g., 0.9% sodium chloride injection).
[0126] 1.54 Composition 1.53 wherein the composition is admixed
with 0.5 to 500 mL a sterile solution comprising sodium chloride
(e.g., 0.9% sodium chloride injection), e.g., from about 1 or 2 mL
to 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75,
100, 150, 200, 300 or 500 mL, e.g., from about 1 or 2 mL to 5, 10,
25, 50, 75, 100, or 200 mL, e.g., from about 3.5 or 5 to 10, 25,
50, or 100 mL, e.g., about 3.5 or 35 mL. [0127] 1.55 Composition
1.47-1.54 wherein the composition comprises Formula II
[0127] ##STR00003## [0128] 1.56 Composition 1.47-1.55 wherein the
composition comprises at least a 1:1 molar ratio of Formula II to a
cation of the base, e.g., at least a 2:1 molar ratio of Formula II
to the cation of the base. [0129] 1.57 Composition 1.47-1.54
wherein the composition comprises Formula III
[0129] ##STR00004## [0130] 1.58 Composition 1.47-1.54 or 1.57
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. [0131] 1.59 Composition 1.47-1.58 wherein the
concentration of Formula II or Formula III, e.g., the concentration
of Formula II, e.g, the concentration of Formula III, is 0.01 or
0.02 or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about
0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100,
125, 150, 175, 200, 250 mM, or 1000 mM, e.g. from about 1 to 2, 5,
10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20,
25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about
2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM.
[0132] 1.60 Composition 1.47-1.59 wherein the solvent, e.g., the
sterile solution, comprises one or more pharmaceutically acceptable
bases, e.g., a base wherein upon dissolution of the composition in
the solvent, e.g, 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, e.g., a base wherein a conjugate acid of
the pharmaceutically acceptable 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, e.g., wherein
the one or more pharmaceutically acceptable bases are one or more
of: [0133] a) a C.sub.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), [0134] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0135]
c) 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0136] d) a metal chloride salt (e.g., zinc chloride),
[0137] e) 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), [0138] f) a
hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or
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), [0139] g) 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 [0140] h) a
metal borate salt (e.g., an alkali borate salt, e.g., sodium
borate), e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4,
tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0141] 1.61 Composition 1.47-1.60
wherein the solvent, e.g., the sterile solution, comprises one or
more pharmaceutically acceptable bases, e.g., a base wherein upon
dissolution of the composition in the solvent, e.g., the sterile
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, e.g., a
base wherein a conjugate acid of the pharmaceutically acceptable
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, e.g., wherein the one or more
pharmaceutically acceptable bases is one or more of: [0142] 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), [0143] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4)
and/or potassium phosphate (e.g., KH.sub.2PO.sub.4 and/or
K.sub.2HPO.sub.4)), [0144] 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0145] 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), [0146] 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), [0147] 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 [0148] g) a metal borate salt (e.g., an
alkali borate salt, e.g., sodium borate), e.g., one or more of
sodium citrate, Na.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0149] 1.62 Composition 1.61
wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the base, e.g., sodium citrate, sodium
phosphate (e.g., Na.sub.2HPO.sub.4),
tris(hydroxymethyl)aminomethane, tris(hydroxymethyl)aminomethane
salt (e.g., tris(hydroxymethyl)aminomethane acetate), and/or
meglumine form a salt. [0150] 1.63 Composition 1.60-1.62 wherein
the solvent, e.g., the sterile solution, comprises 1 or 5 mg to 200
or 500 mg of the one or more bases, e.g., from about 1 or 5 or 10
mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50,
or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg.
[0151] 1.64 Composition 1.60-1.63 wherein the concentration of each
of the one or more bases is 0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1
or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10,
15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250 mM, or
1000 mM e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., wherein the concentration of
each of the one or more bases is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of each of the
one or more bases is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of
Formula III, e.g., about 5 to 10, e.g. about 5, e.g., about 10.
[0152] 1.65 Composition 1.60-1.64 wherein the one or more bases
comprise one or more of a metal citrate salt (e.g., sodium citrate)
and a metal phosphate salt (e.g., sodium phosphate, e.g.,
Na.sub.2HPO.sub.4). [0153] 1.66 Composition 1.60-1.65 wherein the
one or more bases comprise a metal citrate salt (e.g., sodium
citrate). [0154] 1.67 Composition 1.66 wherein the solvent, e.g.,
the sterile solution, comprises 1 or 5 mg to 200 or 500 mg of the
metal citrate salt (e.g., sodium citrate), e.g., from about 1 or 5
or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0155] 1.68 Composition 1.66 wherein the concentration of the
metal citrate salt (e.g., sodium citrate) is 0.01 or 0.02 or 0.05
or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or
0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175,
200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25,
40, 50 or 60 mM, e. e.g., from about 5, 10, 15, 20, 25, or 50 to
100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200
mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of the metal citrate salt is 2 or 3 to 5, 6, 8, 10,
15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the metal citrate salt is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0156] 1.69 Composition 1.60-1.68 wherein the one
or more bases comprise a metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4). [0157] 1.70 Composition 1.69
wherein the solvent, e.g., the sterile solution, comprises 1 or 5
mg to 200 or 500 mg of the metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4), e.g., from about 1 or 5 or 10
mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50,
or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg.
[0158] 1.71 Composition 1.69 wherein the concentration of the metal
phosphate salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4),
is 0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g.,
from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50,
60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from about 1
to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about 5, 10,
15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM,
e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or
1000 mM, e.g., wherein the concentration of each of the metal
phosphate salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4) is
2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g.,
about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein
the concentration of the metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4) is 2 or 3 to 5, 6, 8, 10, 15 or
20 equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0159] 1.72 Composition 1.60-1.71 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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. [0160] 1.73 Composition 1.72 wherein the solvent, e.g.,
the sterile solution, comprises 1 or 5 mg to 200 or 500 mg of the
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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0161] 1.74 Composition 1.72
wherein the concentration of the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, is 0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM,
e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40,
50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from
about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about
5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000
mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500,
or 1000 mM, e.g., wherein the concentration of each of the the
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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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 is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula
II, e.g., about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5,
e.g., wherein the concentration of each of the the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein wherein
each R.sup.8 is independently C.sub.1-8alkyl (e.g.,
C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3,
e.g., --CH.sub.3) and n is 0 or C.sub.1-8-alkylene (e.g.,
C.sub.1-6-alkylene, e.g., C.sub.1-4-alkylene, e.g.,
--CH.sub.2--CH.sub.2--, e.g., --C(CH.sub.2).sub.3--, e.g., one
R.sup.8 is --CH.sub.3 and another R.sup.8 is --(CH.sub.2).sub.6--)
and each n is independently 1-8 (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 is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0162] 1.75 Composition 1.60-1.74 wherein the one
or more bases comprise a mono- and/or poly-hydroxyalkylamine and/or
a salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0163] 1.76
Composition 1.75 wherein the solvent, e.g., the sterile solution,
comprises 1 or 5 mg to 200 or 500 mg of the mono- and/or
poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0164] 1.77 Composition 1.75 wherein the concentration of the
mono- and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 0.01 or 0.02 or
0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein
the concentration of the mono- and/or poly-hydroxyalkylamine and/or
salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the mono- and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0165] 1.78 Composition 1.60-1.77 wherein
the one or more bases comprise (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0166] 1.79
Composition 1.78 wherein the solvent, e.g., the sterile solution,
comprises 1 or 5 mg to 200 or 500 mg of (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0167] 1.80 Composition 1.78 wherein the concentration of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8-alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 0.01 or 0.02 or
0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein
the concentration of (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10
[0168] 1.81 Composition 1.60-1.80 wherein the one or more bases
comprise tris(hydroxymethyl)aminomethane and/or meglumine, e.g.,
tris(hydroxymethyl)aminomethane, e.g., meglumine. [0169] 1.82
Composition 1.81 wherein the solvent, e.g., the sterile solution,
comprises 1 or 5 mg to 200 or 500 mg of
tris(hydroxymethyl)aminomethane, e.g., from about 1 or 5 or 10 mg
to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400,
450, 500, 1000, or 1500 mg, e.g, from about 15, 20, 30, or 50 to
100, 200, 250, 400, 450, 500, 600, or 700 mg and/or wherein the
composition comprises 1 or 5 mg to 200 or 500 mg meglumine, e.g.,
from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150,
200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from
about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700,
800, 1000, or 1500 mg. [0170] 1.83 Composition 1.81 wherein the
concentration of tris(hydroxymethyl)aminomethane is 0.01 or 0.02 or
0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein
the concentration of tris(hydroxymethyl)aminomethane is 2 or 3 to
5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or
5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein the
concentration of tris(hydroxymethyl)aminomethane is 2 or 3 to 5, 6,
8, 10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10,
e.g. about 5, e.g., about 10 and/or wherein the concentration of
tris(hydroxymethyl)aminomethane is 0.01 or 0.02 or 0.05 or 0.1 or
0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1,
2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250,
or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60
mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250,
300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of meglumine is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of meglumine is
2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula III, e.g.,
about 5 to 10, e.g. about 5, e.g., about 10. [0171] 1.84
Composition 1.60-1.83 wherein the one or more bases comprise a
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate). [0172] 1.85 Composition
1.84 wherein the solvent, e.g., the sterile solution, comprises 1
or 5 mg to 200 or 500 mg of a tris(hydroxymethyl)aminomethane salt
(e.g., tris(hydroxymethyl)aminomethane acetate), e.g., from about 1
or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250,
300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20,
30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or
1500 mg. [0173] 1.86 Composition 1.84 wherein the concentration of
the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 0.01 or 0.02 or 0.05 or
0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5
to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175,
200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25,
40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 2 or 3 to 5, 6, 8, 10,
15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 2 or 3 to 5, 6, 8, 10,
15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0174] 1.87 Composition 1.60-1.86 wherein
the one or more bases comprise a buffering agent, e.g., an amine
and/or a salt thereof, 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. [0175] 1.88 Composition 1.87 wherein the solvent, e.g., the
sterile solution, comprises 1 or 5 mg to 200 or 500 mg of the base,
e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75,
100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg,
e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500,
600, 700, 800, 1000, or 1500 mg. [0176] 1.89 Composition 1.87
wherein the concentration of the base is 0.01 or 0.02 or 0.05 or
0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5
to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175,
200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25,
40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of the one or more bases is 2 or 3 to 5, 6, 8, 10, 15
or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g.
about 2.5, e.g., about 5, e.g., wherein the concentration of the
one or more bases is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of
Formula III, e.g., about 5 to 10, e.g. about 5, e.g., about 10.
[0177] 1.90 Composition 1.44-1.89 wherein the solvent, e.g., the
sterile solution comprises one or more bulking agents, e.g., one or
more of maltose, mannose, ribose, cyclodextrin, mannitol, lactose,
sucrose, trehalose, sorbitol, glucose, raffinose, arginine,
glycine, histidine, dextran (e.g., dextran 40),
polyvinylpyrrolidone, polyethylene glycol, and polypropylene
glycol, e.g., one or more of mannitol, glucose, sucrose, lactose,
trehalose, and dextran (e.g., dextran 40). [0178] 1.91 Composition
1.44-1.90 wherein the solvent, e.g., the sterile solution,
comprises 5 or 10 or 50 mg to 2 or 5 g of one or more bulking
agents, e.g., from about 50 or 100 mg to 200, 300, 500, or 800 mg,
or 1, 1.5, 2, 3, 4, or 5 g of one or more bulking agents. [0179]
1.92 Composition 1.44-1.91 wherein the solvent, e.g., the sterile
solution, comprises dextran (e.g., dextran 40). [0180] 1.93
Composition 1.92 wherein the solvent, e.g. the sterile solution,
comprises 5 or 10 or 50 mg to 2 or 5 g dextran (e.g., dextran 40),
e.g., from about 50 or 100 mg to 200, 300, 500, or 800 mg, or 1,
1.5, 2, 3, 4, or 5 g dextran (e.g., dextran 40). [0181] 1.94
Composition 1.44-1.93 wherein the solvent, e.g., the sterile
solution, comprises one or more solubilizing agents, e.g.,
ethylenediamine tetraacetic acid (EDTA) or a salt thereof (e.g.,
calcium disodium EDTA, disodium EDTA, sodium EDTA), alpha
cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, polysorbate 80,
tert-butanol, isopropanol, dichloromethane, ethanol, acetone, and
glycerol; one or more collapse temperature modifiers which may
shift the overall collapse temperature higher, e.g., one or more of
dextran, Ficoll.RTM., gelatin, and hydroxyethyl starch; one or more
tonicity modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, and glucose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0182] 1.95 Composition
1.44-1.94 wherein the pH after admixture with the solvent, e.g.,
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. [0183] 1.96 Composition
1.44-1.95 wherein the pH after admixture with the solvent, e.g.,
the aqueous solution, is further adjusted, e.g., adjusted to
achieve a pH 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, e.g., wherein the pH is adjusted with
NaOH. [0184] 1.97 Composition 1.44-1.96 wherein the composition is
filtered after admixture with the solvent, e.g., the aqueous
solution, to remove particles and microbes, e.g., filtered prior to
injection. [0185] 1.98 Composition 1.44-1.97 wherein the
composition is administered about 24 hours, 12 hours, 10 hours, 8
hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 15 minutes, 10
minutes, 5 minutes, 3 minutes, 2 minutes or 1 minute or less after
admixture. [0186] 1.99 Composition 1.44-1.98 wherein the
composition comprises Formula II
[0186] ##STR00005## [0187] 1.100 Composition 1.44-1.99 wherein the
composition comprises at least a 1:1 molar ratio of Formula II to a
cation of the base. [0188] 1.101 Composition 1.44-1.98 wherein the
composition comprises Formula III
[0188] ##STR00006## [0189] 1.102 Composition 1.44-1.98 or 1.101
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. [0190] 1.103 Composition I or 1.1-1.102 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.
[0191] 1.104 Composition 1.103 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). [0192] 1.105 Composition 1.104 wherein the
composition is for injection intramuscularly, e.g., IM bolus and/or
IM infusion, e.g., IM bolus followed by IM infusion. [0193] 1.106
Composition 1.104 or 1.105 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.
[0194] 1.107 Composition 1.2-1.106 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the one or more bases are milled together.
[0195] 1.108 Composition I wherein the composition is formulated
for oral administration. [0196] 1.109 Composition 1.108 wherein the
composition is a tablet, capsule, solution, suspension, or the
like. [0197] 1.110 Composition I wherein the 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 one or more bases, e.g., one or more of
tris(hydroxymethyl)aminomethane, Na.sub.2HPO.sub.4, meglumine, and
sodium citrate, e.g., between 10 and 1500 mg of one or more of
tris(hydroxymethyl)aminomethane, Na.sub.2HPO.sub.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. [0198] 1.111 Composition 1.110 wherein the
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. [0199] 1.112 Composition
1.110 wherein the 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.sub.2HPO.sub.4, e.g., between 10 and 600 mg
Na.sub.2HPO.sub.4, e.g., between about 20 and 500, e.g., between
about 40 and 500 mg. [0200] 1.113 Composition 1.110 wherein the
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. [0201] 1.114 Composition 1.110 wherein
the 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. [0202] 1.115 Composition 1.110-1.115 wherein the
composition is admixed with a solvent, 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, e.g., about 3 to 50 mL,
e.g., about 3.5 to 35 mL. [0203] 1.116 Composition 1.110-1.115
wherein the composition is admixed with a sterile water for
injection, e.g., wherein the composition is admixed with 1 mL to
100 mL, e.g., about 3 to 50 mL, e.g., about 3.5 to 35 mL. [0204]
1.117 Composition 1.110-1.115 wherein the 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, e.g., about 3 to 50 mL, e.g., about
3.5 to 35 mL. [0205] 1.118 Composition I or 1.1-1.117 wherein the
composition comprises one or more additional therapeutic agents,
e.g., one or more additional therapeutic agents for cerebral edema,
stroke, traumatic brain injury, glioma (e.g., glioblastoma),
meningitis, acute mountain sickness, infection, metabolic disorder,
hypoxia, water intoxication, hepatic failure, hepatic
encephalopathy, diabetic ketoacidosis, abscess, eclampsia,
Creutzfeldt-Jakob disease, lupus cerebritis, optic nerve edema,
hyponatremia, fluid retention, ovarian hyperstimulation syndrome,
epilepsy, retinal ischemia or other diseases of the eye associated
with abnormalities in intraocular pressure and/or tissue hydration,
myocardial ischemia, myocardial ischemia/reperfusion injury,
myocardial infarction, myocardial hypoxia, congestive heart
failure, sepsis, neuromyelitis optica, or migraines. [0206] 1.119
Composition I or 1.1-1.118 wherein the composition comprises one or
more additional therapeutic agents, e.g., one or more additional
therapeutic agents for pulmonary edema, fibromyalgia, or multiple
sclerosis. [0207] 1.120 Composition I or 1.1-1.119 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.
[0208] 1.121 Composition I or 1.1-1.120 wherein the composition
comprises less than 10%, 15%, or 20% of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
e.g., less than 5, 4, 3, or 2% of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide for
at least one week, e.g., for at least 1, 2, 4, 6, 8, or 12 months.
[0209] 1.122 Composition I or 1.1-1.121 wherein the composition is
administered concurrently or sequentially, in either order, with
one or more additional therapeutic agents, e.g., one or more
additional therapeutic agents for cerebral edema, stroke, traumatic
brain injury, glioma (e.g., glioblastoma), meningitis, acute
mountain sickness, infection, metabolic disorder, hypoxia, water
intoxication, hepatic failure, hepatic encephalopathy, diabetic
ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, lupus
cerebritis, optic nerve edema, hyponatremia, fluid retention,
ovarian hyperstimulation syndrome, epilepsy, retinal ischemia or
other diseases of the eye associated with abnormalities in
intraocular pressure and/or tissue hydration, myocardial ischemia,
myocardial ischemia/reperfusion injury, myocardial infarction,
myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis
optica, or migraines. [0210] 1.123 Composition I or 1.1-1.122
wherein the composition is administered concurrently or
sequentially, in either order, with one or more additional
therapeutic agents, e.g., one or more additional therapeutic agents
for pulmonary edema, fibromyalgia, or multiple sclerosis. [0211]
1.124 Composition I or 1.1-1.123 wherein the 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, vida
infra.
[0212] In some embodiments, when
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, is provided as a solid that is to be admixed
with a solvent, e.g., a sterile solution, to provide a
pharmaceutically acceptable liquid, it is typically provided as a
powder and admixed immediately or shortly before administration to
the patient. In some embodiments, the powdered
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate may be packaged in a container, for example,
in a vial to which is added the solvent, e.g., the sterile
solution. Alternatively, the contents of the vial may be added to
the solvent, e.g., the sterile solution, in a separate container.
In some embodiments, the powdered
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is packaged in a sachet, such as a foil
package, that can be opened and the contents added to the solvent,
e.g., the sterile solution. In some embodiments, the powdered
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is formulated as a tablet that dissolves when
it is added to the solvent, e.g., the sterils solution.
[0213] In yet another embodiment, a pharmaceutical composition
comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, is prepared by admixing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate with a pharmaceutically acceptable excipient.
In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the pharmaceutically acceptable excipient
are milled together. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is crystalline. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is amorphous. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is lyophilized. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the pharmaceutically acceptable excipient,
e.g., Composition I, e.g., composition 1.1-1.124, are
lyophilized.
[0214] In yet another embodiment, a pharmaceutical composition
comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, is prepared by admixing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate with a sterile solution, e.g., sterile water
for injection or a sterile solution comprising sodium chloride
(e.g., 0.9% sodium chloride injection), to form a pharmaceutically
acceptable liquid. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with the sterile solution
immediately or shortly before administration. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with a base, e.g., sodium citrate,
sodium phosphate (e.g., Na.sub.2HPO.sub.4),
tris(hydroxymethyl)aminomethane, and/or a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate) prior to
admixture with the sterile solution, e.g., sterile water for
injection or a sterile solution comprising sodium chloride (e.g.,
0.9% sodium chloride injection). In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with a base, e.g., sodium citrate,
sodium phosphate (e.g., Na.sub.2HPO.sub.4),
tris(hydroxymethyl)aminomethane, and/or a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate) and/or a
bulking agent, e.g., dextran (e.g., dextran 40), prior to admixture
with the sterile solution, e.g., sterile water for injection or a
sterile solution comprising sodium chloride (e.g., 0.9% sodium
chloride injection). In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate admixed with the base and/or the bulking agent
is lyophilized. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate admixed with the base and/or the bulking agent
are milled together. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with a sterile solution comprising
a base, e.g., sodium citrate, sodium phosphate (e.g.,
Na.sub.2HPO.sub.4), tris(hydroxymethyl)aminomethane, and/or a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate). In some
embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with a sterile solution comprising
a base, e.g., sodium citrate, sodium phosphate (e.g.,
Na.sub.2HPO.sub.4), tris(hydroxymethyl)aminomethane base, and/or a
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) and/or a bulking agent. In
some embodiments, the admixture of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the sterile solution is agitated, e.g.,
any mode of agitation that results in a clear liquid, e.g.,
mechanical agitation, sonication, conventional mixing, conventional
stirring and the combinations thereof. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate admixed with the sterile solution is
lyophilized. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate admixed with the sterile solution is
crystalline. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate admixed with the sterile solution is
amorphous.
[0215] In one embodiment, Composition I, e.g., composition
1.1-1.124, is prepared by admixing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate with a solvent, e.g., a sterile water for
injection or a sterile solution comprising sodium chloride (e.g.,
0.9% sodium chloride injection). In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with a base, e.g., sodium citrate,
sodium phosphate (e.g., Na.sub.2HPO.sub.4),
tris(hydroxymethyl)aminomethane, and/or a
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) and/or a bulking agent,
e.g., dextran (e.g., dextran 40), prior to admixture with the
solvent, e.g. an aqueous solution. In some embodiments, the
solvent, e.g., the aqueous solution, comprises a base, e.g., sodium
citrate, sodium phosphate (e.g., Na.sub.2HPO.sub.4),
tris(hydroxymethyl)aminomethane, and/or a
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) and/or a bulking agent,
e.g., dextran (e.g., dextran 40). In some embodiments, the
admixture of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the solvent, e.g., the aqueous solution,
is agitated after admixture, e.g., by any mode of agitation that
results in a clear liquid, e.g., mechanical agitation, sonication,
conventional mixing, conventional stirring and the combinations
thereof. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is lyophilized. In some embodiments, the
admixture of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the base and/or bulking agent is
lyophilized. In some embodiments, the admixture of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the base and/or bulking agent is milled
together. In some embodiments,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with the solvent, e.g., the sterile
solution, immediately or shortly before administration.
[0216] Pharmaceutical compositions disclosed herein, e.g.,
Composition I, e.g., composition 1.1-1.124, may be contained in a
sterilized vessel such as syringes, vials or ampoules of various
sizes and capacities.
[0217] The pH of the pharmaceutical compositions disclosed herein
when dissolved in solvent, e.g., an aqueous solution, e.g.,
Composition I, e.g., composition 1.1-1.124, may be adjusted to
achieve the desired pH by addition of a metal hydroxide salt (e.g.,
NaOH and/or KOH, e.g., NaOH) to the composition.
[0218] In some embodiments, the base is a solid.
[0219] The bases used herein may form a buffer with the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate. If a solution of the base described herein
and bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen
phosphate is too basic, the phosphate group may be cleaved. On the
other hand, if the solution is too acidic, the solubility of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate may decrease.
[0220] In some embodiments, "base" is any inorganic or organic
Bronsted base.
[0221] Further provided is a method for increasing the stability of
a solid state formulation comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, wherein the method comprises milling
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate with a base, e.g., with
tris(hydroxymethyl)aminomethane for later reconstitution as an
aqueous solution for injection.
[0222] Further provided is a method for lessening the potential for
precipitation of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide and
allows for IV administration comprising comprises milling
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate with a base, e.g., with
tris(hydroxymethyl)aminomethane and reconstituting as an aqueous
solution for injection.
[0223] Further provided is a method for increasing the aqueous
solubility, dissolution and bioavailability of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
comprising preparing Formula II
##STR00007##
by reacting a compound of Formula I
##STR00008##
with a free base, e.g., tris(hydroxymethyl)aminomethane, e.g.,
meglumine.
[0224] Further provided is a method for increasing the aqueous
solubility, dissolution and bioavailability of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
comprising preparing Formula III
##STR00009##
by reacting a compound of Formula I
##STR00010##
with a free base, e.g., tris(hydroxymethyl)aminomethane, e.g.,
meglumine.
[0225] Further provided is a method (Method I) of making a
pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, wherein the method comprises admixing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and a pharmaceutically acceptable
excipient.
[0226] Further provided is Method I as follows: [0227] 1.1 Method I
wherein the pharmaceutically acceptable excipient comprises one or
more bases. [0228] 1.2 Method I or 1.1 comprising admixing 0.1 or
0.25 mg to 2.0 g of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., from about 0.1 or 0.25 mg to 75 or 600
mg, e.g., from about 0.1 or 0.25 or 1 or 2 or 5 or 10 or 15 or 20
mg to 50, 75, 100, 125, 150, 200, 300, 350, 400, 500, or 600 mg, or
1 g, 1.5 g, or 2.0 g, e.g., from about 5 to 50, 75, 100, 125, 150,
200, 300, 350, 400, 500, or 600 mg, or 1 g, 1.5 g, or 2 g, e.g.,
from about 5 to 500 mg, e.g., from about 5 to 300 or 350 mg, e.g.,
from about 5 to 200 mg, e.g., from about 25 to 500 mg, e.g., from
about 25 to 300 or 350 mg, e.g., from about 25 to 200 mg, e.g.,
from about 15, 20, 30, 35, 50 or 100 to 150, 200, 300, 350, 400,
450, 500, 550, or 600 mg, e.g., from about 0.5 or 1 mg to 50 mg,
e.g., from about 0.5 or 1 mg to 20 mg, e.g., from about 0.5 or 1 mg
to 10 mg, e.g., from about 1 or 2 or 5 mg to 10 or 20 mg, e.g.,
from about 1 or 2 or 3 or 4 to 5 mg, e.g., about 35 mg, e.g., about
350 mg, or wherein the composition admixing an amount of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate sufficient to provide 0.1 or 0.25 mg to 2.0 g
of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
e.g., from about 0.1 or 0.25 mg to 75 or 600 mg, e.g., from about
0.1 or 0.25 or 1 or 2 or 5 or 10 or 15 or 20 mg to 50, 75, 100,
125, 150, 200, 300, 350, 400, 500, or 600 mg, or 1 g, 1.5 g, or 2.0
g, e.g., from about 5 to 50, 75, 100, 125, 150, 200, 300, 350, 400,
500, or 600 mg, or 1 g, 1.5 g, or 2 g, e.g., from about 5 to 500
mg, e.g., from about 5 to 300 or 350 mg, e.g., from about 5 to 200
mg, e.g., from about 25 to 500 mg, e.g., from about 25 to 300 or
350 mg, e.g., from about 25 to 200 mg, e.g., from about 15, 20, 30,
35, 50 or 100 to 150, 200, 300, 350, 400, 450, 500, 550, or 600 mg,
e.g., from about 0.5 or 1 mg to 50 mg, e.g., from about 0.5 or 1 mg
to 20 mg, e.g., from about 0.5 or 1 mg to 10 mg, e.g., from about 1
or 2 or 5 mg to 10 or 20 mg, e.g., from about 1 or 2 or 3 or 4 to 5
mg, e.g., about 35 mg, e.g., about 350 mg, with one or more bases.
[0229] 1.3 Method I, 1.1 or 1.2 comprising admixing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate in an amount sufficient to provide a dose of
0.01 or 0.1 or 0.5 mg/kg to 1 or 5 or 10 or 15 mg/kg of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
e.g., a dose of about 0.05 to 1 or 5 mg/kg, e.g., a dose of about
0.05 to 0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg with one or more bases.
[0230] 1.4 Method 1.1-1.3 wherein upon dissolution of the
composition in a solvent, e.g., the 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, e.g., 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, e.g., wherein
the one or more bases are one or more of: [0231] a) a
C.sub.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), [0232] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0233]
c) an amine and/or a salt thereof (e.g., morpholine, an amino acid
(e.g., arginine and/or lysine), a mono- and/or
poly-hydroxyalkylamine, and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0234] d) a metal chloride salt (e.g., zinc chloride),
[0235] e) 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), [0236] f) a
hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or
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), [0237] g) 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 [0238] h) a
metal borate salt (e.g., an alkali borate salt, e.g., sodium
borate), e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4,
tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0239] 1.5 Method 1.1-1.4 wherein
upon dissolution of the composition in a solvent, e.g., the 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, e.g., 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, e.g., wherein
the one or more bases are one or more of: [0240] 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),
[0241] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or
potassium phosphate (e.g., KH.sub.2PO.sub.4 and/or
K.sub.2HPO.sub.4)), [0242] 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0243] 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), [0244] 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), [0245] 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 [0246] g) a metal borate salt (e.g., an
alkali borate salt, e.g., sodium borate), e.g., one or more of
sodium citrate, Na.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0247] 1.6 Method 1.1-1.5
comprising admixing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate with 1 or 5 mg to 200 or 500 mg of the one or
more bases, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0248] 1.7 Method 1.1-1.6
wherein the one or more bases comprise one or more of a metal
citrate salt (e.g., sodium citrate) and a metal phosphate salt
(e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4). [0249] 1.8
Method 1.1-1.7 wherein the one or more bases comprise a metal
citrate salt (e.g., sodium citrate). [0250] 1.9 Method 1.8 wherein
the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg of
a metal citrate salt (e.g., sodium citrate), e.g., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0251] 1.10 Method 1.1-1.9 wherein the one or more bases
comprise a metal phosphate salt (e.g., sodium phosphate, e.g.,
Na.sub.2HPO.sub.4). [0252] 1.11 Method 1.10 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg of
a metal phosphate salt (e.g., sodium phosphate, e.g.,
Na.sub.2HPO.sub.4), e.g., from about 1 or 5 or 10 mg to 15, 20, 25,
30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000,
or 1500 mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250,
400, 450, 500, 600, 700, 800, 1000, or 1500 mg. [0253] 1.12 Method
1.1-1.11 wherein the one or more bases comprise Na.sub.2HPO.sub.4.
[0254] 1.13 Method 1.12 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg
Na.sub.2HPO.sub.4, e.g., from about 1 or 5 or 10 mg to 15, 20, 25,
30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000,
or 1500 mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250,
400, 450, 500, 600, 700, 800, 1000, or 1500 mg. [0255] 1.14 Method
1.1-1.13 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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. [0256] 1.15 Method 1.14 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg of
the 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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0257] 1.16 Method 1.1-1.15
wherein the one or more bases comprise a mono- and/or
poly-hydroxyalkylamine and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R
.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0258] 1.17 Method
1.16 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg of
the mono- and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0259] 1.18 Method 1.1-1.17 wherein the one or more bases
comprise (HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0260] 1.19 Method
1.18 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0261] 1.20 Method 1.1-1.19 wherein the one or more bases
comprise tris(hydroxymethyl)aminomethane and/or meglumine, e.g.,
tris(hydroxymethyl)aminomethane, e.g., meglumine. [0262] 1.21
Method 1.20 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg
tris(hydroxymethyl)aminomethane, e.g., from about 1 or 5 or 10 mg
to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400,
450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50, or 100
to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg and/or
wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg
meglumine, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0263] 1.22 Method 1.1-1.21
wherein the one or more bases comprise a
tris(hydroxymethyl)aminomethane salt, e.g.,
tris(hydroxymethyl)aminomethane acetate. [0264] 1.23 Method 1.22
wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg of
the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate), e.g., from about 1 or 5
or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg, e.g., 1 or 5 mg to 200 or 500 mg
tris(hydroxymethyl)aminomethane acetate, e.g., from about 1 or 5 or
10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg tris(hydroxymethyl)aminomethane
acetate, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400,
450, 500, 600, 700, 800, 1000, or 1500 mg
tris(hydroxymethyl)aminomethane acetate. [0265] 1.24 Method
1.1-1.23 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. [0266] 1.25 Method 1.24 wherein
the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with 1 or 5 mg to 200 or 500 mg of
the base, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0267] 1.26 Method 1.1-1.25
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.
[0268] 1.27 Method 1.1-1.26 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. [0269]
1.28 Method 1.27 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal citrate salt (e.g., sodium citrate)
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. [0270] 1.29 Method 1.27 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4) 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. [0271] 1.30 Method 1.27
wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to an amine and/or salt thereof (e.g.,
morpholine, an amino acid (e.g., arginine), a mono- and/or
poly-hydroxyalkylamine, and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, 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. [0272] 1.31 Method 1.27 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the mono- and/or poly-hydroxyalkylamine
and/or salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) 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. [0273] 1.32
Method 1.27 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, is 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. [0274] 1.33 Method 1.27 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to tris(hydroxymethyl)aminomethane 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. [0275]
1.34 Method 1.27 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the tris(hydroxymethyl)aminomethane salt
(e.g., tris(hydroxymethyl)aminomethane acetate) 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. [0276]
1.35 Method 1.27 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to 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 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. [0277] 1.36 Method I or 1.1-1.35 further comprising admixing
with one or more bulking agents which may provide an adequate
structure to the lyophilized cake, e.g., one or more of mannitol,
lactose, sucrose, trehalose, sorbitol, glucose, raffinose,
arginine, glycine, histidine, dextran (e.g., dextran 40),
polyvinylpyrrolidone, polyethylene glycol, and polypropylene
glycol, e.g., one or more of mannitol, glucose, sucrose, lactose,
trehalose, and dextran (e.g., dextran 40). [0278] 1.37 Method I or
1.1-1.36 further comprising admixing with 5 or 10 or 50 mg to 2 or
5 g of one or more bulking agents, e.g., from about 50 or 100 mg to
200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g of one or more
bulking agents. [0279] 1.38 Method I or 1.1-1.37 further comprising
admixing with dextran (e.g., dextran 40). [0280] 1.39 Method I or
1.1-1.38 further comprising admixing with 5 or 10 or 50 mg to 2 or
5 g dextran (e.g., dextran 40), e.g., from about 50 mg or 100 mg to
200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g dextran (e.g.,
dextran 40). [0281] 1.40 Method I or 1.1-1.39 further comprising
admixing with one or more solubilizing agents, e.g.,
ethylenediamine tetraacetic acid (EDTA) or a salt thereof (e.g.,
calcium disodium EDTA, disodium EDTA, sodium EDTA), alpha
cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, polysorbate 80,
tert-butanol, isopropanol, dichloromethane, ethanol, acetone, and
glycerol; one or more collapse temperature modifiers which may
shift the overall collapse temperature higher, e.g., one or more of
dextran, Ficoll
.RTM., gelatin, and hydroxyethyl starch; one or more tonicity
modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, glucose, and lactose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0282] 1.41 Method I or
1.1-1.40 further comprising milling the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the one or more bases. [0283] 1.42 Method
I or 1.1-1.41 further comprising lyophilizing the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the one or more bases, e.g., by freezing,
primary drying, and secondary drying. [0284] 1.43 Method I or
1.1-1.42 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is lyophilized, e.g., by freezing, primary
drying, and secondary drying, prior to admixture with the
pharmaceutically acceptable excipient. [0285] 1.44 Method I or
1.1-1.43 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is crystalline. [0286] 1.45 Method I or
1.1-1.44 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is amorphous. [0287] 1.46 Method I or 1.1-1.45
further comprising constituting or reconstituting, if lyophilized,
the composition with a solvent, e.g., the aqueous solution, into a
pharmaceutically acceptable liquid (e.g., a solution or suspension,
e.g., a solution). [0288] 1.47 Method I or 1.1-1.46 further
comprising admixing the composition with a solvent, 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. [0289] 1.48 Method I or 1.1-1.47 further
comprising admixing the composition with 0.5 to 500 mL solvent,
e.g., an aqueous solution, e.g., from about 1 or 2 mL to 500 mL,
e.g., from about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150,
200, 300 or 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50,
75, 100, or 200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100
mL, e.g., about 3.5 or 35 mL. [0290] 1.49 Method I or 1.1-1.48
further comprising admixing the composition with 0.5 to 500 mL
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, e.g., from about 1 or 2 mL to 500 mL, e.g.,
from about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150, 200,
300 or 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75,
100, or 200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100 mL,
e.g., about 3.5 or 35 mL. [0291] 1.50 Method I or 1.1-1.49 further
comprising admixing the composition with sterile water for
injection or a sterile solution comprising sodium chloride (e.g.,
0.9% sodium chloride injection). [0292] 1.51 Method I or 1.1-1.50
further comprising admixing the composition with sterile water for
injection. [0293] 1.52 Method 1.51 wherein the composition is
admixed with 0.5 to 500 mL sterile water for injection, e.g., from
about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25,
30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from about 1 or
2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from about 3.5 or
5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL. [0294] 1.53
Method I or 1.1-1.52 further comprising admixing the composition
with a sterile solution comprising sodium chloride (e.g., 0.9%
sodium chloride injection). [0295] 1.54 Method 1.53 wherein the
composition is admixed with 0.5 to 500 mL a sterile solution
comprising sodium chloride (e.g., 0.9% sodium chloride injection),
e.g., from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to
5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0296] 1.55 Method 1.47-1.54 wherein the composition comprises
Formula II
[0296] ##STR00011## [0297] 1.56 Method 1.47-1.55 wherein the
composition comprises at least a 1:1 molar ratio of Formula II to a
cation of the base. [0298] 1.57 Method 1.47-1.54 wherein the
composition comprises Formula III
[0298] ##STR00012## [0299] 1.58 Method 1.47-1.54 or 1.57 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. [0300] 1.59 Method 1.47-1.58 wherein the concentration of
Formula II or Formula III, e.g., the concentration of Formula II,
e.g, the concentration of Formula III, is 0.01 or 0.02 or 0.05 or
0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5
to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175,
200, 250 mM, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25,
40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM. [0301] 1.60 Method
1.47-1.59 wherein the solvent, e.g., the sterile solution,
comprises a base, e.g., a base wherein upon dissolution of the
composition in the solvent, e.g., the sterile 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, e.g., a base with 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 between 6 and 11, e.g., between 6.5 and 10, e.g., between 7 and
9, e.g., wherein the base is one or more of: [0302] a) a
C.sub.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), [0303] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0304]
a) 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0305] b) a metal chloride salt (e.g., zinc chloride),
[0306] c) 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), [0307] d) a
hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or
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), [0308] e) 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 [0309] f) a
metal borate salt (e.g., an alkali borate salt, e.g., sodium
borate), e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4,
tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0310] 1.61 Method 1.47-1.60
wherein the solvent, e.g., the sterile solution, comprises a base,
e.g., a base wherein upon dissolution of the composition in the
solvent, e.g., the sterile 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, e.g., a base with 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, e.g., wherein
the base is one or more of: [0311] 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), [0312] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0313]
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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0314] 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), [0315] 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), [0316] 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 [0317] g) a metal borate salt (e.g., an
alkali borate salt, e.g., sodium borate), e.g., one or more of
sodium citrate, Na.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0318] 1.62 Method 1.61 wherein
the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the base, e.g., sodium citrate, sodium
phosphate (e.g., Na.sub.2HPO.sub.4),
tris(hydroxymethyl)aminomethane, and/or a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), form a
salt. [0319] 1.63 Method 1.60-1.62 wherein the solvent, e.g., the
sterile solution, comprises 1 or 5 mg to 200 or 500 mg of the one
or more base, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30,
40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or
1500 mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400,
450, 500, 600, 700, 800, 1000, or 1500 mg. [0320] 1.64 Method
1.60-1.63 wherein the concentration of each of the one or more
bases is 0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM,
e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40,
50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from
about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about
5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000
mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500,
or 1000 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of each of the one or more bases is 2 or 3 to 5, 6,
8, 10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to
10, e.g. about 2.5, e.g., about 5, e.g., wherein the concentration
of each of the one or more bases is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0321] 1.65 Method 1.60-1.64 wherein the one or
more bases comprise one or more of a metal citrate salt (e.g.,
sodium citrate) and a metal phosphate salt (e.g., sodium phosphate,
e.g., Na.sub.2HPO.sub.4). [0322] 1.66 Method 1.60-1.65 wherein the
one or more bases comprise a metal citrate salt (e.g., sodium
citrate). [0323] 1.67 Method 1.66 wherein the solvent, e.g., the
sterile solution, comprises 1 or 5 mg to 200 or 500 mg of a metal
citrate salt (e.g., sodium citrate), e.g., from about 1 or 5 or 10
mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50,
or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg.
[0324] 1.68 Method 1.67 wherein the concentration of the metal
citrate salt (e.g., sodium citrate) is 0.01 or 0.02 or 0.05 or 0.1
or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to
1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200,
250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50
or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15,
20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g.,
about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000
mM, e.g., wherein the concentration of the metal citrate salt is 2
or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g.,
about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein
the concentration of the metal citrate salt is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0325] 1.69 Method 1.60-1.68 wherein the
one or more bases comprise metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4). [0326] 1.70 Method 1.69
wherein the solvent, e.g., the sterile solution, comprises 1 or 5
mg to 200 or 500 mg of a metal phosphate salt (e.g, sodium
phosphate, e.g., Na.sub.2HPO.sub.4), e.g., from about 1 or 5 or 10
mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50,
or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg.
[0327] 1.71 Method 1.70 wherein the concentration of the metal
phosphate salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4),
is 0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g.,
from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50,
60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from about 1
to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about 5, 10,
15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM,
e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or
1000 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of the metal phosphate salt (e.g., sodium phosphate,
e.g., Na.sub.2HPO.sub.4) is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of the metal
phosphate salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4) is
2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula III, e.g.,
about 5 to 10, e.g. about 5, e.g., about 10. [0328] 1.72 Method
1.60-1.71 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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. [0329] 1.73 Method 1.72 wherein the solvent, e.g., the
sterile solution, comprises 1 or 5 mg to 200 or 500 mg of the 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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8
].sub.3N, and/or a salt thereof wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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 and 11, e.g., between 6.5 and 10, e.g., between
7 and 9, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0330] 1.74 Method 1.72
wherein the concentration of the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, is 0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM,
e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40,
50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from
about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about
5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000
mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500,
or 1000 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the 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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0331] 1.75 Method 1.60-1.74 wherein the
one or more bases comprise a mono- and/or poly-hydroxyalkylamine
and/or a salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0332] 1.76 Method
1.75 wherein the solvent, e.g., the sterile solution, comprises 1
or 5 mg to 200 or 500 mg of the mono- and/or poly-hydroxyalkylamine
and/or salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0333] 1.77 Method 1.76 wherein the concentration of the mono-
and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 0.01 or 0.02 or
0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., wherein the concentration of the mono-
and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
each of the mono- and/or poly-hydroxyalkylamine and/or salt
thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0334] 1.78 Method 1.60-1.77 wherein the
one or more bases comprise (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0335] 1.79 Method
1.78 wherein the solvent, e.g., the sterile solution, comprises 1
or 5 mg to 200 or 500 mg of (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0336] 1.80 Method 1.78 wherein the concentration of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 0.01 or 0.02 or
0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., wherein the concentration of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10.
[0337] 1.81 Method 1.60-1.80 wherein the one or more bases comprise
tris(hydroxymethyl)aminomethane and/or meglumine, e.g.,
tris(hydroxymethyl)aminomethane, e.g, meglumine. [0338] 1.82 Method
1.81 wherein the solvent, e.g., the sterile solution, comprises 1
or 5 mg to 200 or 500 mg of tris(hydroxymethyl)aminomethane, e.g.,
from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150,
200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from
about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700,
800, 1000, or 1500 mg and/or wherein the solvent, e.g., the sterile
solution, comprises 1 or 5 mg to 200 or 500 mg of meglumine, e.g.,
from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150,
200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from
about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700,
800, 1000, or 1500 mg. [0339] 1.83 Method 1.81 wherein the
concentration of tris(hydroxymethyl)aminomethane is 0.01 or 0.02 or
0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., wherein the concentration of
tris(hydroxymethyl)aminomethane is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of
tris(hydroxymethyl)aminomethane is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10 and/or wherein the concentration of meglumine is
0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from
about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60,
75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from about 1 to
2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15,
20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g.,
about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000
mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250,
300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of meglumine is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of meglumine is
2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula III, e.g.,
about 5 to 10, e.g. about 5, e.g., about 10. [0340] 1.84 Method
1.60-1.83 wherein the one or more bases comprise a
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate). [0341] 1.85 Method 1.84
wherein the solvent, e.g., the sterile solution, comprises 1 or 5
mg to 200 or 500 mg of the tris(hydroxymethyl)aminomethane salt
(e.g., tris(hydroxymethyl)aminomethane acetate), e.g., from about 1
or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250,
300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20,
30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or
1500 mg. [0342] 1.86 Method 1.84 wherein the concentration of the
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 0.01 or 0.02 or 0.05 or
0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5
to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175,
200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25,
40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM. [0343] 1.87 Method
1.60-1.86 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. [0344] 1.88 Method 1.87 wherein
the solvent, e.g., the sterile solution, comprises 1 or 5 mg to 200
or 500 mg of the base, e.g., from about 1 or 5 or 10 mg to 15, 20,
25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500,
1000, or 1500 mg, e.g., from about 15, 20, 30, 50, or 100 to 200,
250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg. [0345] 1.89
Method 1.87 wherein the concentration of the base is 0.01 or 0.02
or 0.05 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., wherein the concentration of the base is 2
or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g.,
about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein
the concentration of the base is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0346] 1.90 Method 1.47-1.89 wherein the solvent,
e.g., the sterile solution comprises one or more bulking agents,
e.g., one or more of maltose, mannose, ribose, cyclodextrin,
mannitol, lactose, sucrose, trehalose, sorbitol, glucose,
raffinose, arginine, glycine, histidine, dextran (e.g., dextran
40), polyvinylpyrrolidone, polyethylene glycol, and polypropylene
glycol, e.g., one or more of mannitol, glucose, sucrose, lactose,
trehalose, and dextran (e.g., dextran 40). [0347] 1.91 Method
1.47-1.90 wherein the solvent, e.g., the sterile solution,
comprises 5 or 10 or 50 mg to 2 or 5 g of one or more bulking
agents, e.g., from about 50 or 100 mg to 200, 300, 500, or 800 mg,
or 1, 1.5, 2, 3, 4, or 5 g of one or more bulking agents. [0348]
1.92 Method 1.47-1.91 wherein the solvent, e.g., the sterile
solution, comprises dextran (e.g., dextran 40). [0349] 1.93 Method
1.92 wherein the solvent, e.g. the sterile solution, comprises 5 or
10 or 50 mg to 2 or 5 g dextran (e.g., dextran 40), e.g., from
about 50 or 100 mg to 200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4,
or 5 g dextran (e.g., dextran 40). [0350] 1.94 Method 1.47-1.93
wherein the solvent, e.g., the sterile solution, comprises one or
more solubilizing agents, e.g., ethylenediamine tetraacetic acid
(EDTA) or a salt thereof (e.g., calcium disodium EDTA, disodium
EDTA, sodium EDTA), alpha cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin, polysorbate 80, tert-butanol,
isopropanol, dichloromethane, ethanol, acetone, and glycerol; one
or more collapse temperature modifiers which may shift the overall
collapse temperature higher, e.g., one or more of dextran,
Ficoll.RTM., gelatin, and hydroxyethyl starch; one or more tonicity
modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, and glucose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0351] 1.95 Method
1.47-1.94 wherein the pH after admixture with the solvent, e.g., an
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. [0352] 1.96 Method 1.47-1.95
wherein the pH after admixture with the solvent, e.g., an aqueous
solution, is further adjusted, e.g., adjusted to achieve a pH
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, e.g., wherein the pH is adjusted with NaOH. [0353]
1.97 Method 1.47-1.96 further comprising filtering after admixture
with the solvent, e.g., an aqueous solution, to remove particles
and microbes, e.g., filtered prior to injection. [0354] 1.98 Method
1.47-1.97 wherein the composition comprises Formula II
[0354] ##STR00013## [0355] 1.99 Method 1.47-1.98 wherein the
composition comprises at least a 1:1 molar ratio of Formula II to a
cation of the base. [0356] 1.100 Composition 1.47-1.96 wherein the
composition comprises Formula III
[0356] ##STR00014## [0357] 1.101 Method 1.47-1.96 or 1.100 wherein
the composition comprises at least a 1:2 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. [0358] 1.102 Method 1.47-1.101 wherein upon dissolution of
the composition in the solvent, e.g., the 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. [0359] 1.103 Method
I or 1.1-1.102 further comprising admixing the composition with one
or more additional therapeutic agents, e.g., one or more additional
therapeutic agents for cerebral edema, stroke, traumatic brain
injury, glioma (e.g., glioblastoma), meningitis, acute mountain
sickness, infection, metabolic disorder, hypoxia, water
intoxication, hepatic failure, hepatic encephalopathy, diabetic
ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, lupus
cerebritis, optic nerve edema, hyponatremia, fluid retention,
ovarian hyperstimulation syndrome, epilepsy, retinal ischemia or
other diseases of the eye associated with abnormalities in
intraocular pressure and/or tissue hydration, myocardial ischemia,
myocardial ischemia/reperfusion injury, myocardial infarction,
myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis
optica, or migraines. [0360] 1.104 Method I or 1.1-1.103 further
comprising admixing the composition with one or more additional
therapeutic agents, e.g., one or more additional therapeutic agents
for pulmonary edema, fibromyalgia, or multiple sclerosis.
[0361] In yet another embodiment, provided is a salt solution (Salt
Solution I) comprising a solvent, e.g., an aqueous solution, and a
salt formed from a compound of Formula I
##STR00015##
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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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.
[0362] Further provided is Salt Solution I as follows: [0363] 1.1
Salt Solution I wherein the salt solution comprises Formula II
[0363] ##STR00016## [0364] 1.2 Salt Solution I or 1.1 wherein the
salt solution comprises Formula III
[0364] ##STR00017## [0365] 1.3 Salt Solution I, 1.1, or 1.2 wherein
the salt solution comprises a protonated and/or unprotonated mono-
and/or poly-hydroxyalkylamine, e.g., e.g.,
(HO).sub.nR.sup.8NH.sub.3, [(HO).sub.nR.sup.8].sub.2NH.sub.2,
[(HO).sub.nR.sup.8].sub.3NH, e.g., (HO).sub.nR.sup.8NH.sub.3,
[(HO).sub.nR.sup.8].sub.2NH.sub.2, [(HO).sub.nR.sup.8].sub.3NH,
wherein each R.sup.8 is independently C.sub.1-8alkyl (e.g.,
C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3,
e.g., --CH.sub.3) and n is 0 or C.sub.1-8-alkylene (e.g.,
C.sub.1-6-alkylene, e.g., C.sub.1-4-alkylene, e.g.,
--CH.sub.2--CH.sub.2--, e.g., --C(CH.sub.2).sub.3--, e.g., one
R.sup.8 is --CH.sub.3 and another R.sup.8 is --(CH.sub.2).sub.6--)
and each n is independently 1-8 (e.g., 1, 2, 3, 4, 5, or 6),
e.g.,
[0365] ##STR00018## [0366] 1.4 Salt Solution I or 1.1-1.3 wherein
the salt solution comprises
[0366] ##STR00019## [0367] 1.5 Salt Solution I or 1.1-1.4 wherein
the salt solution comprises
[0367] ##STR00020## [0368] 1.6 Salt Solution I or 1.1-1.5 wherein
the salt solution comprises
[0368] ##STR00021## [0369] 1.7 Salt Solution I or 1.1-1.6 wherein
the salt solution comprises at least a 1:1 molar ratio of Formula
II to the protonated amine. [0370] 1.8 Salt Solution I or 1.1-1.7
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. [0371] 1.9 Salt Solution 1.8 wherein the salt
solution comprises at least a 1:2 molar ratio of Formula II to the
protonated mono- and/or poly-hydroxyalkylamine, e.g.,
(HO).sub.nR.sup.8NH.sub.3.sup.+,
[(HO).sub.nR.sup.8].sub.2NH.sub.2.sup.+,
[(HO).sub.nR.sup.8].sub.3NH.sup.+, wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0371] ##STR00022## 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. [0372] 1.10 Salt Solution 1.8-1.10 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula II to
(HO).sub.nR.sup.8NH.sub.3.sup.+,
[(HO).sub.nR.sup.8].sub.2NH.sub.2.sup.+,
[(HO).sub.nR.sup.8].sub.3NH.sup.+, wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0372] ##STR00023## 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. [0373] 1.11 Salt Solution 1.8-1.10 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula II to
[0373] ##STR00024## 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. [0374] 1.12 Salt Solution 1.8-1.10 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula II to
[0374] ##STR00025## 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. [0375] 1.13 Salt Solution I or 1.1-1.6 wherein the salt
solution comprises at least a 1:2 molar ratio of Formula III 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. [0376] 1.14 Salt Solution 1.14 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula III to the
protonated mono- and/or poly-hydroxyalkylamine, e.g.,
(HO).sub.nR.sup.8NH.sub.3.sup.+,
[(HO).sub.nR.sup.8].sub.2NH.sub.2.sup.+,
[(HO).sub.nR.sup.8].sub.3NH.sup.+, wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0376] ##STR00026## 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. [0377] 1.15 Salt Solution 1.14-1.15 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula III to
(HO).sub.nR.sup.8NH.sub.3.sup.+,
[(HO).sub.nR.sup.8].sub.2NH.sub.2.sup.+,
[(HO).sub.nR.sup.8].sub.3NH.sup.+, wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0377] ##STR00027## 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. [0378] 1.16 Salt Solution 1.14-1.16 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula III to
[0378] ##STR00028## 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. [0379] 1.17 Salt Solution 1.14-1.16 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula III to
[0379] ##STR00029## 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. [0380] 1.18 Salt Solution 1.14-1.16 wherein the salt solution
comprises at least a 1:2 molar ratio of Formula III to
[0380] ##STR00030## 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. [0381] 1.19 Salt Solution I or 1.1-1.19 wherein the solvent
is 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. [0382] 1.20 Salt Solution I or 1.1-1.20
wherein the salt solution comprises 0.5 to 500 mL solvent, e.g., an
aqueous solution, e.g., from about 1 or 2 mL to 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or
500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or
200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g.,
about 3.5 or 35 mL. [0383] 1.21 Salt Solution I or 1.1-1.21 wherein
the salt solution comprises 0.5 to 500 mL 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, e.g., from about 1 or 2
mL to 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 30, 35, 50,
75, 100, 150, 200, 300 or 500 mL, e.g., from about 1 or 2 mL to 5,
10, 25, 50, 75, 100, or 200 mL, e.g., from about 3.5 or 5 to 10,
25, 50, or 100 mL, e.g., about 3.5 or 35 mL. [0384] 1.22 Salt
Solution I or 1.1-1.22 wherein the salt solution comprises sterile
water for injection or a sterile solution comprising sodium
chloride (e.g., 0.9% sodium chloride injection). [0385] 1.23 Salt
Solution I or 1.1-1.23 wherein the salt solution comprises sterile
water for injection. [0386] 1.24 Salt Solution 1.24 wherein the
salt solution comprises 0.5 to 500 mL sterile water for injection,
e.g., from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to
5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0387] 1.25 Salt Solution I or 1.1-1.25 wherein the salt solution
comprises a sterile solution comprising sodium chloride (e.g., 0.9%
sodium chloride injection). [0388] 1.26 Salt Solution 1.26 wherein
the salt solution comprises 0.5 to 500 mL of a sterile solution
comprising sodium chloride (e.g., 0.9% sodium chloride injection),
e.g., from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to
5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0389] 1.27 Salt Solution I or 1.1-1.27 wherein the concentration
of Formula II or Formula III, e.g., the concentration of Formula
II, e.g, the concentration of Formula III is 0.01 or 0.02 or 0.05
or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or
0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175,
200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25,
40, 50 or 60 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM. [0390] 1.28 Salt
Solution I or 1.1-1.28 wherein the salt solution comprises one or
more bulking agents, e.g., one or more of maltose, mannose, ribose,
cyclodextrin, mannitol, lactose, sucrose, trehalose, sorbitol,
glucose, raffinose, arginine, glycine, histidine, dextran (e.g.,
dextran 40), polyvinylpyrrolidone, polyethylene glycol, and
polypropylene glycol, e.g., one or more of mannitol, glucose,
sucrose, lactose, trehalose, and dextran (e.g., dextran 40). [0391]
1.29 Salt Solution I or 1.1-1.29 wherein the salt solution
comprises 5 or 10 or 50 mg to 2 or 5 g of one or more bulking
agents, e.g., from about 50 or 100 mg to 200, 300, 500, or 800 mg,
or 1, 1.5, 2, 3, 4, or 5 g of one or more bulking agents. [0392]
1.30 Salt Solution I or 1.1-1.30 wherein the salt solution
comprises dextran (e.g., dextran 40). [0393] 1.31 Salt Solution
1.31 wherein the salt solution comprises 5 or 10 or 50 mg to 2 or 5
g dextran (e.g., dextran 40), e.g., from about 50 or 100 mg to 200,
300, 500, or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g dextran (e.g.,
dextran 40). [0394] 1.32 Salt Solution I or 1.1-1.32 wherein the
salt solution comprises one or more solubilizing agents, e.g.,
ethylenediamine tetraacetic acid (EDTA) or a salt thereof (e.g.,
calcium disodium EDTA, disodium EDTA, sodium EDTA), alpha
cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, polysorbate 80,
tert-butanol, isopropanol, dichloromethane, ethanol, acetone, and
glycerol; one or more collapse temperature modifiers which may
shift the overall collapse temperature higher, e.g., one or more of
dextran, Ficoll.RTM., gelatin, and hydroxyethyl starch; one or more
tonicity modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, and glucose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0395] 1.33 Salt Solution
I or 1.1-1.33 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.
[0396] 1.34 Salt Solution I or 1.1-1.34 wherein the salt solution
is filtered to remove particles and microbes, e.g., filtered prior
to injection. [0397] 1.35 Salt Solution I or 1.1-1.35 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.
[0398] 1.36 Salt Solution 1.36 wherein the salt solution 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). [0399] 1.37 Salt Solution 1.36 wherein the salt
solution is for injection intramuscularly, e.g., IM bolus and/or IM
infusion, e.g., IM bolus followed by IM infusion. [0400] 1.38 Salt
Solution 1.37 or 1.38 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.
[0401] 1.39 Salt Solution I or 1.1-1.39 wherein the salt solution
comprises one or more additional therapeutic agents, e.g., one or
more additional therapeutic agents for cerebral edema, stroke,
traumatic brain injury, glioma (e.g., glioblastoma), meningitis,
acute mountain sickness, infection, metabolic disorder, hypoxia,
water intoxication, hepatic failure, hepatic encephalopathy,
diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob
disease, lupus cerebritis, optic nerve edema, hyponatremia, fluid
retention, ovarian hyperstimulation syndrome, epilepsy, retinal
ischemia or other diseases of the eye associated with abnormalities
in intraocular pressure and/or tissue hydration, myocardial
ischemia, myocardial ischemia/reperfusion injury, myocardial
infarction, myocardial hypoxia, congestive heart failure, sepsis,
neuromyelitis optica, or migraines. [0402] 1.40 Salt Solution I or
1.1-1.40 wherein the salt solution comprises one or more additional
therapeutic agents, e.g., one or more additional therapeutic agents
for pulmonary edema, fibromyalgia, or multiple sclerosis. [0403]
1.41 Salt Solution I or 1.1-1.41 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.
[0404] 1.42 Salt Solution I or 1.1-1.42 wherein the salt solution
comprises less than 10%, 15%, or 20% of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
e.g., less than 5, 4, 3, or 2% of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide for
at least one week, e.g., for at least 1, 2, 4, 6, 8, or 12 months.
[0405] 1.43 Salt Solution I or 1.1-1.43 wherein the salt solution
is administered concurrently or sequentially, in either order, with
one or more additional therapeutic agents, e.g., one or more
additional therapeutic agents for cerebral edema, stroke, traumatic
brain injury, glioma (e.g., glioblastoma), meningitis, acute
mountain sickness, infection, metabolic disorder, hypoxia, water
intoxication, hepatic failure, hepatic encephalopathy, diabetic
ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, lupus
cerebritis, optic nerve edema, hyponatremia, fluid retention,
ovarian hyperstimulation syndrome, epilepsy, retinal ischemia or
other diseases of the eye associated with abnormalities in
intraocular pressure and/or tissue hydration, myocardial ischemia,
myocardial ischemia/reperfusion injury, myocardial infarction,
myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis
optica, or migraines. [0406] 1.44 Salt Solution I or 1.1-1.44
wherein the salt solution is administered concurrently or
sequentially, in either order, with one or more additional
therapeutic agents, e.g., one or more additional therapeutic agents
for pulmonary edema, fibromyalgia, or multiple sclerosis. [0407]
1.45 Salt Solution I or 1.1-1.45 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,
vida infra.
[0408] In yet another embodiment, provided is a method (Method II)
for making a salt solution, e.g., Salt Solution I, e.g., Salt
Solution 1.1-1.46, comprising admixing a compound of Formula I
##STR00031##
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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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 a solvent, e.g., an aqueous solution.
[0409] Further provided is Method II as follows: [0410] 2.1 Method
II comprising admixing the compound of Formula I with a mono-
and/or poly-hydroxyalkylamine and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH, and/or
[(HO).sub.nR.sup.8].sub.3N and/or a salt thereof, wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0410] ##STR00032## and/or a salt thereof, 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. [0411] 2.2 Method II or 2.1 comprising admixing the
compound of Formula I with (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, and/or [(HO).sub.nR.sup.8].sub.3N
and/or salt thereof (e.g., acetate, e.g.,
tris(hydroxymethyl)aminomethane acetate), wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0411] ##STR00033## and/or a salt thereof. [0412] 2.3 Method II,
2.1, or 2.2 comprising admixing the compound of Formula I with
[0412] ##STR00034## and/or a salt thereof (e.g.,
tris(hydroxymethyl)aminomethane acetate). [0413] 2.4 Method II or
2.1-2.3 comprising admixing the compound of Formula I with
[0413] ##STR00035## and/or a salt thereof. [0414] 2.5 Method II or
2.1-2.4 comprising admixing the compound of Formula I with
[0414] ##STR00036## and/or a salt thereof. [0415] 2.6 Method II or
2.1-2.5 wherein Formula II and the amine and/or salt thereof are
admixed in at least a 1:1 molar ratio. [0416] 2.7 Method II or
2.1-2.6 wherein Formula II and the amine and/or salt thereof are
admixed in at least a 1:2 molar ratio, 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. [0417] 2.8 Method II or 2.1-2.7
wherein Formula II and the mono- and/or poly-hydroxyalkylamine
and/or salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, and/or [(HO).sub.nR.sup.8].sub.3N
and/or salt thereof and/or salt thereof (e.g., acetate, e.g.,
tris(hydroxymethyl)aminomethane acetate), wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0417] ##STR00037## and/or a salt thereof, 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, are admixed in at least a 1:2 molar ratio, 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. [0418] 2.9 Method II or
2.1-2.8 wherein Formula II and (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, and/or [(HO).sub.nR.sup.8].sub.3N
and/or salt thereof (e.g., acetate, e.g.,
tris(hydroxymethyl)aminomethane acetate), wherein each R.sup.8 is
independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl, e.g.,
C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n
is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(e.g., 1, 2, 3, 4, 5, or 6), e.g.,
[0418] ##STR00038## and/or a salt thereof are admixed in at least a
1:2 molar ratio, 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. [0419] 2.10 Method II or 2.1-2.9 wherein Formula II and
[0419] ##STR00039## and/or a salt thereof are admixed in at least a
1:2 molar ratio, 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. [0420] 2.11 Method II or 2.1-2.10 wherein Formula II and
[0420] ##STR00040## and/or a salt thereof are admixed in at least a
1:2 molar ratio, 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. [0421] 2.12 Method II or 2.1-2.11 wherein Formula II and
[0421] ##STR00041## [0422] and/or a salt thereof are admixed in at
least a 1:2 molar ratio, 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. [0423] 2.13 Method II or 2.1-2.12 wherein the solvent is 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. [0424] 2.14 Method II or 2.1-2.13 wherein
there is 0.5 to 500 mL of solvent, e.g., an aqueous solution, e.g.,
from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to 5,
10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0425] 2.15 Method II or 2.1-2.14 wherein there is 0.5 to 500 mL of
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, e.g., from about 1 or 2 mL to 500 mL, e.g.,
from about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150, 200,
300 or 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75,
100, or 200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100 mL,
e.g., about 3.5 or 35 mL. [0426] 2.16 Method II or 2.1-2.15 wherein
the solvent comprises sterile water for injection or a sterile
solution comprising sodium chloride (e.g., 0.9% sodium chloride
injection). [0427] 2.17 Method II or 2.1-2.16 wherein the solvent
comprises sterile water for injection. [0428] 2.18 Method II or
2.1-2.17 wherein the solvent comprises 0.5 to 500 mL sterile water
for injection, e.g., from about 1 or 2 mL to 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or
500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or
200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g.,
about 3.5 or 35 mL. [0429] 2.19 Method II or 2.1-2.18 wherein the
solvent comprises a sterile solution comprising sodium chloride
(e.g., 0.9% sodium chloride injection). [0430] 2.20 Method 2.19
wherein the solvent comprises 0.5 to 500 mL of a sterile solution
comprising sodium chloride (e.g., 0.9% sodium chloride injection),
e.g., from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to
5, 10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0431] 2.21 Method II or 2.1-2.20 wherein the concentration of the
compound of Formula I is 0.01 or 0.02 or 0.05 or 0.1 or 0.5 or 1 or
2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10,
15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000
mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM. [0432] 2.22 Method II or 2.1-2.21
wherein the solvent, e.g., an aqueous solution, comprises one or
more bulking agents, e.g., one or more of maltose, mannose, ribose,
cyclodextrin, mannitol, lactose, sucrose, trehalose, sorbitol,
glucose, raffinose, arginine, glycine, histidine, dextran (e.g.,
dextran 40), polyvinylpyrrolidone, polyethylene glycol, and
polypropylene glycol, e.g., one or more of mannitol, glucose,
sucrose, lactose, trehalose, and dextran (e.g., dextran 40). [0433]
2.23 Method II or 2.1-2.22 wherein the solvent, e.g., an aqueous
solution, comprises 5 or 10 or 50 mg to 2 or 5 g of one or more
bulking agents, e.g., from about 50 or 100 mg to 200, 300, 500, or
800 mg, or 1, 1.5, 2, 3, 4, or 5 g of one or more bulking agents.
[0434] 2.24 Method II or 2.1-2.23 wherein the solvent, e.g., an
aqueous solution, comprises dextran (e.g., dextran 40). [0435] 2.25
Method II or 2.1-2.24 wherein the solvent, e.g., an aqueous
solution, comprises 5 or 10 or 50 mg to 2 or 5 g dextran (e.g.,
dextran 40), e.g., from about 50 or 100 mg to 200, 300, 500, or 800
mg, or 1, 1.5, 2, 3, 4, or 5 g dextran (e.g., dextran 40). [0436]
2.26 Method II or 2.1-2.25 wherein the solvent, e.g., an aqueous
solution, comprises one or more solubilizing agents, e.g.,
ethylenediamine tetraacetic acid (EDTA) or a salt thereof (e.g.,
calcium disodium EDTA, disodium EDTA, sodium EDTA), alpha
cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, polysorbate 80,
tert-butanol, isopropanol, dichloromethane, ethanol, acetone, and
glycerol; one or more collapse temperature modifiers which may
shift the overall collapse temperature higher, e.g., one or more of
dextran, Ficoll.RTM., gelatin, and hydroxyethyl starch; one or more
tonicity modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, and glucose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0437] 2.27 Method II or
2.1-2.26 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. [0438]
2.28 Method II or 2.1-2.27 further comprising filter the salt
solution to remove particles and microbes, e.g., filtered prior to
injection. [0439] 2.29 Method II or 2.1-2.28 further comprising
admixing the salt Solution with one or more additional therapeutic
agents, e.g., one or more additional therapeutic agents for
cerebral edema, stroke, traumatic brain injury, glioma (e.g.,
glioblastoma), meningitis, acute mountain sickness, infection,
metabolic disorder, hypoxia, water intoxication, hepatic failure,
hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia,
Creutzfeldt-Jakob disease, lupus cerebritis, optic nerve edema,
hyponatremia, fluid retention, ovarian hyperstimulation syndrome,
epilepsy, retinal ischemia or other diseases of the eye associated
with abnormalities in intraocular pressure and/or tissue hydration,
myocardial ischemia, myocardial ischemia/reperfusion injury,
myocardial infarction, myocardial hypoxia, congestive heart
failure, sepsis, neuromyelitis optica, or migraines. [0440] 2.30
Method II or 2.1-2.29 further comprising admixing the salt solution
with one or more additional therapeutic agents, e.g., one or more
additional therapeutic agents for pulmonary edema, fibromyalgia, or
multiple sclerosis.
[0441] In yet another embodiment, provided is a kit (Kit I)
comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate.
[0442] Further provided is Kit I as follows: [0443] 1.1 Kit I
wherein the kit comprises 0.1 or 0.25 mg to 2.0 g
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., from about 0.1 or 0.25 mg to 75 or 600
mg, e.g., from about 0.1 or 0.25 or 1 or 2 mg to 50, 75, 100, 125,
150, 200, 300, 350, 400, 500, or 600 mg, or 1 g, 1.5 g, or 2.0 g,
e.g., from about 5 to 50, 75, 100, 125, 150, 200, 300, 350, 400,
500, or 600 mg, or 1 g, 1.5 g, or 2, e.g., from about 5 to 500 mg,
e.g., from about 5 to 300 or 350 mg, e.g., from about 5 to 200 mg,
e.g., from about 25 to 500 mg, e.g., from about 25 to 300 or 350
mg, e.g., from about 25 to 200 mg, e.g., from about 15, 20, 30, 35,
50 or 100 to 150, 200, 300, 350, 400, 450, 500, 550, or 600 mg,
e.g., from about 0.5 or 1 mg to 50 mg, e.g., from about 0.5 or 1 mg
to 20 mg, e.g., from about 0.5 or 1 mg to 10 mg, e.g., from about 1
or 2 or 5 mg to 10 or 20 mg, eg., from about 1 or 2 or 3 or 4 or 5
mg, e.g., about 35 mg, e.g. about 35 mg, or wherein the kit
comprises
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate in an amount sufficient to provide 0.1 or 0.25
mg to 2.0 g of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
e.g., from about 0.1 or 0.25 mg to 75 or 600 mg, e.g., from about
0.1 or 0.25 or 1 or 2 mg to 50, 75, 100, 125, 150, 200, 300, 350,
400, 500, or 600 mg, or 1 g, 1.5 g, or 2.0 g, e.g., from about 5 to
50, 75, 100, 125, 150, 200, 300, 350, 400, 500, or 600 mg, or 1 g,
1.5 g, or 2 g, e.g., from about 5 to 500 mg, e.g., from about 5 to
300 or 350 mg, e.g., from about 5 to 200 mg, e.g., from about 25 to
500 mg, e.g., from about 25 to 300 or 350 mg, e.g., from about 25
to 200 mg, e.g., from about 15, 20, 30, 35, 50 or 100 to 150, 200,
300, 350, 400, 450, 500, 550, or 600 mg, e.g., from about 0.5 or 1
mg to 50 mg, e.g., from about 0.5 or 1 mg to 20 mg, e.g., from
about 0.5 or 1 mg to 10 mg, e.g., from about 1 or 2 or 5 mg to 10
or 20 mg, eg., from about 1 or 2 or 3 or 4 or 5 mg, e.g., about 35
mg, e.g. about 35 mg. [0444] 1.2 Kit I or 1.1 wherein the kit
comprises one or more pharmaceutically acceptable excipients.
[0445] 1.3 Kit 1.2 wherein the one or more pharmaceutically
acceptable excipients comprise one or more of bases, bulking
agents, solubilizing agents, collapse temperature modifiers,
tonicity modifiers, and antimicrobial agents. [0446] 1.4 Kit 1.2 or
1.3 wherein the one or more pharmaceutically acceptable excipients
comprise one or more bases, e.g., a base wherein upon dissolution
of the composition in a solvent, e.g., an aqueous solution, the
solution 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, e.g., 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, e.g., wherein
the one or more bases are one or more of: [0447] a) a
C.sub.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), [0448] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0449]
c) 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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 between 6 and 11, e.g., between 6.5 and 10, e.g., between 7
and 9, [0450] d) a metal chloride salt (e.g., zinc chloride),
[0451] e) 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), [0452] f) a
hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or
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), [0453] g) 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), [0454] h) a metal
borate salt (e.g., an alkali borate salt, e.g., sodium borate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4,
tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0455] 1.5 Kit 1.2-1.4 wherein the
one or more pharmaceutically acceptable excipients comprise one or
more bases, e.g., a base wherein upon dissolution of the
composition in a solvent, e.g., an aqueous solution, the solution
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, e.g., 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, e.g., wherein the one or more bases
are one or more of: [0456] 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), [0457] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0458]
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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0459] 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), [0460] 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), [0461] 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 [0462] g) a metal borate salt (e.g., an
alkali borate salt, e.g., sodium borate), e.g., one or more of
sodium citrate, Na.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0463] 1.6 Kit 1.3-1.5 wherein the
kit comprises 1 or 5 mg to 200 or 500 mg of one or more bases,
e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75,
100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg,
e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500,
600, 700, 800, 1000, or 1500 mg. [0464] 1.7 Kit 1.3-1.5 wherein the
concentration of each of the one or more bases is 0.01 or 0.1 or
0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1,
2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250,
or 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60
mM, e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20,
25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about
2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., wherein the concentration of
each of the one or more bases is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of each of the
one or more bases is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of
Formula III, e.g., about 5 to 10, e.g. about 5, e.g., about 10.
[0465] 1.8 Kit 1.3-1.6 wherein the one or more bases comprise one
or more of a metal citrate salt (e.g., sodium citrate) and a metal
phosphate salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4).
[0466] 1.9 Kit 1.3-1.8 wherein the one or more bases comprise a
metal citrate salt (e.g., sodium citrate). [0467] 1.10 Kit 1.9
wherein the kit comprises 1 or 5 mg to 200 or 500 mg of the metal
citrate salt (e.g., sodium citrate), e.g., from about 1 or 5 or 10
mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50,
or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg.
[0468] 1.11 Kit 1.9 wherein the concentration of the metal citrate
salt (e.g., sodium citrate) is 0.01 or 0.1 or 0.5 or 1 or 2 to 250
mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25,
40, 50, 60, 75, 100, 125, 150, 175, 200, 250, of 1000 mM, e.g. from
about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about
5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15,
20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g.,
about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000
mM, e.g., wherein the concentration of the metal citrate salt
(e.g., sodium citrate) is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of the metal
citrate salt (e.g., sodium citrate) is 2 or 3 to 5, 6, 8, 10, 15 or
20 equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0469] 1.12 Kit 1.3-1.11 wherein the one or more
bases comprise a metal phosphate salt (e.g., sodium phosphate,
e.g., Na.sub.2HPO.sub.4). [0470] 1.13 Kit 1.12 wherein the kit
comprises 1 or 5 mg to 200 or 500 mg of the metal phosphate salt
(e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4), e.g., from about
1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250,
300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20,
30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or
1500 mg. [0471] 1.14 Kit 1.12 wherein the concentration of the
metal phosphate salt (e.g., sodium phosphate, e.g.,
Na.sub.2HPO.sub.4), is 0.01 or 0.1 or 0.5 or 1 or 2 to 250 mM,
e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40,
50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from
about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about
5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15,
20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g.,
about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000
mM, e.g., wherein the concentration of the metal phosphate salt
(e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4) is 2 or 3 to 5,
6, 8, 10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5
to 10, e.g. about 2.5, e.g., about 5, e.g., wherein the
concentration of the metal phosphate salt (e.g., sodium phosphate,
e.g., Na.sub.2HPO.sub.4) is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0472] 1.15 Kit 1.3-1.14 wherein the kit comprises
Na.sub.2HPO.sub.4. [0473] 1.16 Kit 1.15 wherein the kit comprises 1
or 5 mg to 200 or 500 mg Na.sub.2HPO.sub.4, e.g., from about 1 or 5
or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg.
[0474] 1.17 Kit 1.15 wherein the concentration of Na.sub.2HPO.sub.4
is 0.01 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or
0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125,
150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10, 15,
20, 25, 40, 50 or 60 mM, e.g., from about 5 to 50 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of each of Na.sub.2HPO.sub.4 is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
Na.sub.2HPO.sub.4 is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of
Formula III, e.g., about 5 to 10, e.g. about 5, e.g., about 10.
[0475] 1.18 Kit 1.3-1.17 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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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. [0476] 1.19 Kit 1.18 wherein the kit comprises 1 or 5 mg
to 200 or 500 mg of the amine and/or a salt thereof (e.g.,
morpholine, an amino (e.g., arginine), a mono- and/or
poly-hydroxyalkylamine, and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0477] 1.20 Kit 1.18 wherein
the concentration of the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, is 0.01 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from
about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60,
75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from about 1 to
2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about 5 to 50 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15, 20, 25,
or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2,
20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g.,
wherein the concentration of each of the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
each of the 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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0478] 1.21 Kit 1.3-1.20 wherein the one
or more bases comprise a mono- and/or poly-hydroxyalkylamine and/or
a salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0479] 1.22 Kit 1.21
wherein the kit comprises 1 or 5 mg to 200 or 500 mg of the mono-
and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0480] 1.23 Kit 1.21 wherein the concentration of the mono-
and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 0.01 or 0.1 or 0.5
or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2,
5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or
1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60
mM, e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20,
25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about
2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., wherein the concentration of
each of the mono- and/or poly-hydroxyalkylamine and/or salt
thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the mono- and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) agents is 2 or 3 to 5,
6, 8, 10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10,
e.g. about 5, e.g., about 10. [0481] 1.24 Kit 1.3-1.23 wherein the
one or more bases comprise (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0482] 1.25 Kit 1.24
wherein the kit comprises 1 or 5 mg to 200 or 500 mg of the
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0483] 1.26 Kit 1.24 wherein the concentration of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8
is --CH.sub.3 and another R.sup.8 is --(CH.sub.2).sub.6--) and each
n is independently 1-8 (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), is 0.01
or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or
0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175,
200, 250, of 1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25,
40, 50 or 60 mM, e.g., from about 5 to 50 mM, e.g., from about 5,
10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM,
e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or
1000 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein the
concentration of (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0484] 1.27 Kit 1.3-1.26 wherein the one
or more bases comprise tris(hydroxymethyl)aminomethane and/or
meglumine, e.g, tris(hydroxymethyl)aminomethane, e.g., meglumine.
[0485] 1.28 Kit 1.27 wherein the kit comprises 1 or 5 mg to 200 or
500 mg tris(hydroxymethyl)aminomethane, e.g., from about 1 or 5 or
10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50,
or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg
and/or wherein the kit comprises 1 or 5 mg to 200 or 500 mg
meglumine, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0486] 1.29 Kit 1.27 wherein
the concentration of a tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 0.01 or 0.1 or 0.5 or 1
or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10,
15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000
mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM,
e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or
50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20,
or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM. [0487] 1.30
Kit 1.3-1.29 wherein the one or more bases comprise the
tris(hydroxymethyl)aminomethane salt, e.g.,
tris(hydroxymethyl)aminomethane acetate. [0488] 1.31 Kit 1.30
wherein the composition comprises 1 or 5 mg to 200 or 500 mg of the
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate), e.g., from about 1 or 5
or 10 mg to 15, 20, 25, 30, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg tris(hydroxymethyl)aminomethane
salt (e.g., tris(hydroxymethyl)aminomethane acetate), e.g., 1 or 5
mg to 200 or 500 mg tris(hydroxymethyl)aminomethane acetate, e.g.,
from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150,
200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from
about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700,
800, 1000, or 1500 mg. [0489] 1.32 Kit 1.30 wherein the
concentration of the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 0.01 or 0.1 or 0.5 or 1
or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10,
15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000
mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM,
e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or
50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20,
or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., wherein the concentration of the
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 2 or 3 to 5, 6, 8, 10,
15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 2 or 3 to 5, 6, 8, 10,
15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0490] 1.33 Kit 1.3-1.33 wherein the one
or more bases comprise a base, e.g., an amine and/or a salt
thereof, 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. [0491]
1.34 Kit 1.34 wherein the kit comprises 1 or 5 mg to 200 or 500 mg
of the base, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30,
40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or
1500 mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400,
450, 500, 600, 700, 800, 1000, or 1500 mg. [0492] 1.35 Kit 1.34
wherein the concentration of the base is 0.01 or 0.1 or 0.5 or 1 or
2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10,
15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000
mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM,
e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or
50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20,
or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., wherein the concentration of the base is 2
or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g.,
about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein
the concentration of of the base is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0493] 1.36 Kit 1.3-1.35 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.
[0494] 1.37 Kit 1.3-1.36 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. [0495]
1.38 Kit 1.37 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal citrate salt (e.g., sodium citrate)
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. [0496] 1.39 Kit 1.37 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4) 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. [0497] 1.40 Kit 1.37
wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the amine and/or salt thereof (e.g.,
morpholine, amino acid (e.g., arginine), mono- and/or
poly-hydroxyalkylamine, and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, 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. [0498] 1.41 Kit 1.40 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the mono- and/or poly-hydroxyalkylamine
and/or salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), 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. [0499] 1.42 Kit
1.41 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 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. [0500] 1.43 Kit 1.42
wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to tris(hydroxymethyl)aminomethane 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. [0501]
1.44 Kit 1.42 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a tris(hydroxymethyl)aminomethane salt
(e.g., tris(hydroxymethyl)aminomethane acetate) 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. [0502]
1.45 Kit 1.37 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a base, e.g., an amine and/or a salt
thereof, 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, 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.
[0503] 1.46 Kit 1.2-1.45 wherein the kit comprises one or more
bulking agents which may provide an adequate structure to the
lyophilized cake, e.g., one or more of mannitol, lactose, sucrose,
trehalose, sorbitol, glucose, raffinose, arginine, glycine,
histidine, dextran (e.g., dextran 40), polyvinylpyrrolidone,
polyethylene glycol, and polypropylene glycol, e.g., one or more of
mannitol, glucose, sucrose, lactose, trehalose, and dextran (e.g.,
dextran 40). [0504] 1.47 Kit 1.46 wherein the kit comprises 5 or 10
or 50 mg to 2 or 5 g of one or more bulking agents, e.g., from
about 50 or 100 mg to 200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4,
or 5 g of one or more bulking agents.
[0505] 1.48 Kit 1.2-1.247 wherein the kit comprises dextran (e.g.,
dextran 40). [0506] 1.49 Kit 1.48 wherein the kit comprises 5 or 10
or 50 mg to 2 or 5 g dextran (e.g., dextran 40), e.g., from about
50 or 100 mg to 200, 300, 500, or 800 mg, 1, 1.5, 2, 3, 4, or 5 g
dextran (e.g., dextran 40). [0507] 1.50 Kit 1.2-1.49 wherein the
composition comprises one or more solubilizing agents, e.g.,
ethylenediamine tetraacetic acid (EDTA) or a salt thereof (e.g.,
calcium disodium EDTA, disodium EDTA, sodium EDTA), alpha
cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, polysorbate 80,
tert-butanol, isopropanol, dichloromethane, ethanol, acetone, and
glycerol; one or more collapse temperature modifiers which may
shift the overall collapse temperature higher, e.g., one or more of
dextran, Ficoll.RTM., gelatin, and hydroxyethyl starch; one or more
tonicity modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, glucose, and lactose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0508] 1.51 Kit 1.2-1.50
wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the one pharmaceutically acceptable
excipients are in the same container or in one or more different
containers. [0509] 1.52 Kit 1.51 wherein the one or more
pharmaceutically acceptable excipients comprise one or more bases,
e.g., a base wherein upon dissolution of the composition in a
solvent, e.g., an aqueous solution, e.g., an aqueous solution, the
solution 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, e.g., 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, e.g., wherein
the one or more bases are one or more of: [0510] a) a
C.sub.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), [0511] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0512]
c) 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0513] d) a metal chloride salt (e.g., zinc chloride),
[0514] e) 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), [0515] f) a
hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or
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), [0516] g) 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 [0517] h) a
metal borate salt (e.g., an alkali borate salt, e.g., sodium
borate), e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4,
tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane, wherein the one or more bases are
in the same container as
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate or in one or more different containers. [0518]
1.53 Kit 1.51 or 1.52 wherein the one or more pharmaceutically
acceptable excipients comprise one or more bases, e.g., a base
wherein upon dissolution of the composition in a solvent, e.g., an
aqueous solution, the solution 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,
e.g., 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, e.g.,
wherein the one or more bases are one or more of: [0519] 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), [0520] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4)
and/or potassium phosphate (e.g., KH.sub.2PO.sub.4 and/or
K.sub.2HPO.sub.4)), [0521] 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0522] 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), [0523] 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), [0524] 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 [0525] g) a metal borate salt (e.g., an
alkali borate salt, e.g., sodium borate), e.g., one or more of
sodium citrate, Na.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane, wherein the one or more bases are
in the same container as
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate or in one or more different containers. [0526]
1.54 Kit 1.52 or 1.53 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and one or more of a metal citrate salt (e.g.,
sodium citrate) and a metal phosphate salt (e.g., sodium phosphate,
e.g., Na.sub.2HPO.sub.4) are in the same container or in one or
more different containers. [0527] 1.55 Kit 1.54 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the metal citrate salt (e.g., sodium
citrate) are in the same container or in different containers.
[0528] 1.56 Kit 1.54 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4) are in the same container or in
different containers. [0529] 1.57 Kit 1.52 or 1.53 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and one or more of 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, are in the same container or in different containers.
[0530] 1.58 Kit 1.57 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and one or more of a mono- and/or
poly-hydroxyalkylamine and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) are in the same
container or in different containers. [0531] 1.59 Kit 1.58 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and one or more of (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) are in the same
container or in different containers. [0532] 1.60 Kit 1.59 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and tris(hydroxymethyl)aminomethane are in the
same container or in different containers. [0533] 1.61 Kit 1.59
wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and tris(hydroxymethyl)aminomethane acetate
are in the same container or in different containers. [0534] 1.62
Kit 1.53 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and a base, e.g., an amine and/or a salt
thereof, 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, are in
the same container or in different containers. [0535] 1.63 Kit
1.51-1.62 wherein the kit comprises one or more bulking agents,
e.g., one or more of mannitol, lactose, sucrose, trehalose,
sorbitol, glucose, raffinose, arginine, glycine, histidine, dextran
(e.g., dextran 40), polyvinylpyrrolidone, polyethylene glycol, and
polypropylene glycol, e.g., one or more of mannitol, glucose,
sucrose, lactose, trehalose, and dextran (e.g., dextran 40),
wherein the one or more bulking agents are in the same container as
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate or any other component of the kit or in one or
more different containers. [0536] 1.64 Kit 1.63 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and dextran (e.g., dextran 40) are in the same
container or in different containers.
[0537] 1.65 Kit 1.51-1.64 wherein the kit comprises one or more
solubilizing agents, e.g., ethylenediamine tetraacetic acid (EDTA)
or a salt thereof (e.g., calcium disodium EDTA, disodium EDTA,
sodium EDTA), alpha cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin, polysorbate 80, tert-butanol,
isopropanol, dichloromethane, ethanol, acetone, and glycerol; one
or more collapse temperature modifiers, e.g., one or more of
dextran, Ficoll.RTM., gelatin, and hydroxyethyl starch; one or more
tonicity modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, glucose, and lactose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal), wherein the one or more
solubilizing agents, collapse temperature modifiers, tonicity
modifiers, and antimicrobial agents are in the same container as
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate or any other component of the kit or in one or
more different containers, e.g., in any combination in any number
of different containers. [0538] 1.66 Kit I or 1.1-1.65 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is crystalline. [0539] 1.67 Kit I or 1.1-1.65
wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is amorphous. [0540] 1.68 Kit I or 1.1-1.65
wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is lyophilized, e.g., by freezing, primary
drying, and secondary drying. [0541] 1.69 Kit 1.2-1.68 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and the one or more pharmaceutically
acceptable excipients are lyophilized. [0542] 1.70 Kit I or
1.1-1.69 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is suitable for constitution, or
reconstitution if lyophilized, with a solvent, e.g., an aqueous
solution, into a pharmaceutically acceptable liquid (e.g., a
solution or suspension, e.g., a solution). [0543] 1.71 Kit I or
1.1-1.70 wherein the kit comprises a solvent, 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. [0544] 1.72 Kit I or 1.1-1.71 wherein the kit
comprises 0.5 to 500 mL solvent, e.g., an aqueous solution, e.g.,
from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to 5,
10, 25, 30, 35, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from
about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0545] 1.73 Kit I or 1.1-1.72 wherein the kit comprises 0.5 to 500
mL 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, e.g., from about 1 or 2 mL to 500 mL, e.g.,
from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, 150, 200, 300 or
500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75,
100, or 200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100 mL,
e.g., about 3.5 or 35 mL. [0546] 1.74 Kit I or 1.1-1.73 wherein the
kit comprises sterile water for injection or a sterile solution
comprising sodium chloride (e.g., 0.9% sodium chloride injection).
[0547] 1.75 Kit 1.74 wherein the kit comprises 0.5 to 500 mL
sterile water for injection, e.g., from about 1 or 2 mL to 500 mL,
e.g., from about 1 or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, 150,
200, 300 or 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50,
75, 100, or 200 mL, e.g., from about 3.5 or 5 to 10, 25, 50, or 100
mL, e.g., about 3.5 or 35 mL. [0548] 1.76 Kit I or 1.1-1.75 wherein
the kit comprises sterile solution comprising sodium chloride
(e.g., 0.9% sodium chloride injection). [0549] 1.77 Kit 1.76
wherein the kit comprises 0.5 to 500 mL of a sterile solution
comprising sodium chloride (e.g., 0.9% sodium chloride injection),
e.g., from about 1 or 2 mL to 500 mL, e.g., from about 1 or 2 mL to
5, 10, 25, 50, 75, 100, 150, 200, 300 or 500 mL, e.g., from about 1
or 2 mL to 5, 10, 25, 30, 35, 50, 75, 100, or 200 mL, e.g., from
about 3.5 or 5 to 10, 25, 50, or 100 mL, e.g., about 3.5 or 35 mL.
[0550] 1.78 Kit 1.71-1.77 wherein the solvent, e.g., the sterile
solution, comprises one or more bases, e.g., a base wherein upon
dissolution of the composition in a solvent, e.g., an aqueous
solution, the solution 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, e.g., 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, e.g., wherein
the one or more bases are one or more of: [0551] a) a
C.sub.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), [0552] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0553]
c) 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0554] d) a metal chloride salt (e.g., zinc chloride),
[0555] e) 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), [0556] f) a
hydroxide and/or alkoxide salt, e.g., a metal hydroxide and/or
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), [0557] g) 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 [0558] h) a
metal borate salt (e.g., an alkali borate salt, e.g., sodium
borate), e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4,
tris(hydroxymethyl)aminomethane, and a
tris(hydroxymethyl)aminomethane salt (e.g., tris acetate), e.g.,
one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0559] 1.79 Kit 1.71-1.78 wherein
the solvent, e.g., the sterile solution, comprises one or more
pharmaceutically acceptable bases, e.g., one or more bases wherein
upon dissolution of the composition in a solvent the solution 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, e.g., 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, e.g., wherein the one or more base are
one or more of: [0560] 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), [0561] 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.sub.2PO.sub.4 and/or Na.sub.2HPO.sub.4) and/or potassium
phosphate (e.g., KH.sub.2PO.sub.4 and/or K.sub.2HPO.sub.4)), [0562]
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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, [0563] 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), [0564] 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), [0565] 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 [0566] g) a metal borate salt (e.g., an
alkali borate salt, e.g., sodium borate), e.g., one or more of
sodium citrate, Na.sub.2HPO.sub.4, tris(hydroxymethyl)aminomethane,
and a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate),
e.g., one or more of sodium citrate, Na.sub.2HPO.sub.4, and
tris(hydroxymethyl)aminomethane, e.g., one or more of sodium
citrate and Na.sub.2HPO.sub.4, e.g., Na.sub.2HPO.sub.4, e.g.,
tris(hydroxymethyl)aminomethane. [0567] 1.80 Kit 1.78 or 1.79
wherein the solvent, e.g., the sterile solution, comprises 1 or 5
mg to 200 or 500 mg of the base, e.g., from about 1 or 5 or 10 mg
to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400,
450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50, or 100
to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg. [0568]
1.81 Kit 1.78 or 1.79 wherein the concentration of each of the one
or more bases is 0.01 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from
about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60,
75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from about 1 to
2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about 5 to 50 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15, 20, 25,
or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2,
20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g.,
wherein the concentration of each of the one or more bases is 2 or
3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g., about
2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein the
concentration of each of the one or more bases is 2 or 3 to 5, 6,
8, 10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10,
e.g. about 5, e.g., about 10. [0569] 1.82 Kit 1.78-1.81 wherein the
solvent, e.g. the sterile solution, comprises one or more of a
metal citrate salt (e.g., sodium citrate) and a metal phosphate
salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4). [0570] 1.83
Kit 1.1.78-1.82 wherein the solvent, e.g. the sterile solution,
comprises a metal citrate salt (e.g., sodium citrate). [0571] 1.84
Kit 1.83 wherein the solvent, e.g., the sterile solution, comprises
1 or 5 mg to 200 mg or 500 mg of the metal citrate salt (e.g.,
sodium citrate), e.g., from about 1 or 5 mg to 200 or 500 mg, e.g.,
from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150,
200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from
about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700,
800, 1000, or 1500 mg. [0572] 1.85 Kit 1.83 wherein the
concentration of the metal citrate salt (e.g., sodium citrate) is
from about 0.01 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from about
0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 100,
125, 150, 175, 200, 250, or 1000 mM, e.g. from about 1 to 2, 5, 10,
15, 20, 25, 40, 50 or 60 mM, e.g., from about 5 to 50 mM, e.g.,
from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400,
500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10,
50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15, 20, 25, or 50
to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or
200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., wherein
the concentration of the metal citrate salt (e.g., sodium citrate)
is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g.,
about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein
the concentration of the metal citrate salt (e.g., sodium citrate)
is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula III,
e.g., about 5 to 10, e.g. about 5, e.g., about 10.
[0573] 1.86 Kit 1.78-1.85 wherein the solvent, e.g., the sterile
solution, comprises a metal phosphate salt (e.g., sodium phosphate,
e.g., Na.sub.2HPO.sub.4). [0574] 1.87 Kit 1.86 wherein the solvent,
e.g., the sterile solution, comprises 1 or 5 mg to 200 mg or 500 mg
of the metal phosphate salt (e.g., sodium phosphate, e.g.,
Na.sub.2HPO.sub.4), e.g., from about 1 or 5 mg to 200 or 500 mg,
e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75,
100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg,
e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500,
600, 700, 800, 1000, or 1500 mg. [0575] 1.88 Kit 1.86 wherein the
concentration of the metal phosphate salt (e.g., sodium phosphate,
e.g., Na.sub.2HPO.sub.4), is from 0.01 or 0.1 or 0.5 or 1 or 2 to
250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20,
25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g.
from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from
about 5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from about 5,
10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM,
e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or
1000 mM, e.g., wherein the concentration of each of the metal
phosphate salt (e.g., sodium phosphate, e.g., Na.sub.2HPO.sub.4) is
2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g.,
about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein
the concentration of the metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4) is 2 or 3 to 5, 6, 8, 10, 15 or
20 equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0576] 1.89 Kit 1.78-1.88 wherein the wherein the
solvent, e.g., the sterile solution, comprises Na.sub.2HPO.sub.4.
[0577] 1.90 Kit 1.89 wherein the solvent, e.g., the sterile
solution, comprises 1 or 5 mg to 200 or 500 mg Na.sub.2HPO.sub.4,
e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75,
100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg,
e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500,
600, 700, 800, 1000, or 1500 mg. [0578] 1.91 Kit 1.89 wherein the
concentration of Na.sub.2HPO.sub.4 is 0.01 or 0.1 or 0.5 or 1 or 2
to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15,
20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM,
e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g.,
from about 5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to
100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200
mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from about
5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000
mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500,
or 1000 mM, e.g., wherein the concentration of Na.sub.2HPO.sub.4 is
2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of Formula II, e.g.,
about 2.5 or 5 to 10, e.g. about 2.5, e.g., about 5, e.g., wherein
the concentration of Na.sub.2HPO.sub.4 is 2 or 3 to 5, 6, 8, 10, 15
or 20 equivalents of Formula III, e.g., about 5 to 10, e.g. about
5, e.g., about 10. [0579] 1.92 Kit 1.78-1.91 wherein the solvent,
e.g., the sterile solution, comprises 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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. [0580] 1.93 Kit 1.92 wherein the wherein the solvent,
e.g., the sterile solution, comprises 1 or 5 mg to 200 or 500 mg of
the 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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500
mg, e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450,
500, 600, 700, 800, 1000, or 1500 mg. [0581] 1.94 Kit 1.92 wherein
the concentration of the 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.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, is 0.01 or 0.1 or 0.5 or 1 or 2 to 250 mM, e.g., from
about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25, 40, 50, 60,
75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from about 1 to
2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about 5 to 50 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15, 20, 25,
or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2,
20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g.,
wherein the concentration of the amine and/or a salt thereof (e.g.,
morpholine, an amino acid a (e.g., arginine), a mono- and/or
poly-hydroxyalkylamine, and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the 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., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0582] 1.95 Kit 1.78-1.94 wherein the
solvent, e.g., the sterile solution, comprises a mono- and/or
poly-hydroxyalkylamine and/or a salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0583] 1.96 Kit 1.95
wherein the solvent, e.g., the sterile solution, comprises 1 or 5
mg to 200 or 500 mg of the mono- and/or poly-hydroxyalkylamine
and/or salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0584] 1.97 Kit 1.95 wherein the concentration of the mono-
and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 0.01 or 0.1 or 0.5
or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2,
5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or
1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60
mM, e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20,
25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about
2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., wherein the concentration of
each of the mono- and/or poly-hydroxyalkylamine and/or salt
thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or a
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the mono- and/or poly-hydroxyalkylamine and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or a salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10.
[0585] 1.98 Kit 1.78-1.97 wherein the solvent, e.g., the sterile
solution, comprises (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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). [0586] 1.99 Kit 1.98
wherein the solvent, e.g., the sterile solution, comprises 1 or 5
mg to 200 or 500 mg of the (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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., from about 1 or
5 or 10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300,
350, 400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30,
50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500
mg. [0587] 1.100 Kit 1.98 wherein the concentration of the
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), is 0.01 or 0.1 or 0.5
or 1 or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2,
5, 10, 15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or
1000 mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60
mM, e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20,
25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about
2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM,
e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300,
400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5,
10, 50, 500, 500, or 1000 mM, e.g., wherein the concentration of
the (HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the (HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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) is 2 or 3 to 5, 6, 8,
10, 15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0588] 1.101 Kit 1.78-1.100 wherein the
solvent, e.g., the sterile solution, comprises
tris(hydroxymethyl)aminomethane. [0589] 1.102 Kit 1.101 wherein the
solvent, e.g., the sterile solution, comprises 1 or 5 mg to 200 or
500 mg tris(hydroxymethyl)aminomethane, e.g., from about 1 or 5 or
10 mg to 15, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 1000, or 1500 mg, e.g., from about 15, 20, 30, 50,
or 100 to 200, 250, 400, 450, 500, 600, 700, 800, 1000, or 1500 mg.
[0590] 1.103 Kit 1.101 wherein the concentration of
tris(hydroxymethyl)aminomethane is 0.01 or 0.1 or 0.5 or 1 or 2 to
250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20,
25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g.
from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from
about 5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100,
200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM,
e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from about 5,
10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM,
e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or
1000 mM, e.g., wherein the concentration of
tris(hydroxymethyl)aminomethane is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula II, e.g., about 2.5 or 5 to 10, e.g. about
2.5, e.g., about 5, e.g., wherein the concentration of
tris(hydroxymethyl)aminomethane is 2 or 3 to 5, 6, 8, 10, 15 or 20
equivalents of Formula III, e.g., about 5 to 10, e.g. about 5,
e.g., about 10. [0591] 1.104 Kit 1.78-1.103 wherein the solvent,
e.g., the sterile solution, comprises a
tris(hydroxymethyl)aminomethane salt, e.g.,
tris(hydroxymethyl)aminomethane acetate. [0592] 1.105 Kit 1.104
wherein the solvent, e.g., the sterile solution, comprises 1 or 5
mg to 200 or 500 mg of the tris(hydroxymethyl)aminomethane salt
(e.g., tris(hydroxymethyl)aminomethane acetate), e.g., from about 1
or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75 100, 150, 200, 250,
300, 350, 400, 450, or 500 mg tris(hydroxymethyl)aminomethane salt
(e.g., tris(hydroxymethyl)aminomethane acetate), e.g., 1 or 5 mg to
200 or 500 mg tris(hydroxymethyl)aminomethane acetate, e.g., from
about 1 or 5 or 10 mg to 15, 20, 25, 30, 50, 75, 100, 150, 200,
250, 300, 350, 400, 450, 500, 1000, or 1500 mg, e.g., from about
15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500, 600, 700, 800,
1000, or 1500 mg. [0593] 1.106 Kit 1.105 wherein the concentration
of the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 0.01 or 0.1 or 0.5 or 1
or 2 to 250 mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10,
15, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000
mM, e.g. from about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM,
e.g., from about 5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or
50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g., about 2, 20,
or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000 mM, e.g., from
about 5, 10, 15, 20, 25, or 50 to 100, 200, 250, 300, 400, 500, or
1000 mM, e.g., about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500,
500, or 1000 mM, e.g., wherein the concentration of the
tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 2 or 3 to 5, 6, 8, 10,
15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to 10,
e.g. about 2.5, e.g., about 5, e.g., wherein the concentration of
the tris(hydroxymethyl)aminomethane salt (e.g.,
tris(hydroxymethyl)aminomethane acetate) is 2 or 3 to 5, 6, 8, 10,
15 or 20 equivalents of Formula III, e.g., about 5 to 10, e.g.
about 5, e.g., about 10. [0594] 1.107 Kit 1.78-1.106 wherein the
solvent, e.g., the sterile solution, comprises a base, e.g., an
amine and/or a salt thereof, 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. [0595] 1.108 Kit 1.107 wherein the solvent, e.g., the
sterile solution, comprises 1 or 5 mg to 200 or 500 mg of the base,
e.g., from about 1 or 5 or 10 mg to 15, 20, 25, 30, 40, 50, 75,
100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, or 1500 mg,
e.g., from about 15, 20, 30, 50, or 100 to 200, 250, 400, 450, 500,
600, 700, 800, 1000, or 1500 mg. [0596] 1.109 Kit 1.107 wherein the
concentration of the base is 0.01 or 0.1 or 0.5 or 1 or 2 to 250
mM, e.g., from about 0.01 or 0.1 or 0.5 to 1, 2, 5, 10, 15, 20, 25,
40, 50, 60, 75, 100, 125, 150, 175, 200, 250, or 1000 mM, e.g. from
about 1 to 2, 5, 10, 15, 20, 25, 40, 50 or 60 mM, e.g., from about
5 to 50 mM, e.g., from about 5, 10, 15, 20, 25, or 50 to 100, 200,
250, 300, 400, 500, or 1000 mM, e.g., about 2, 20, or 200 mM, e.g.,
about 5, 10, 50, 500, 500, or 1000 mM, e.g., from about 5, 10, 15,
20, 25, or 50 to 100, 200, 250, 300, 400, 500, or 1000 mM, e.g.,
about 2, 20, or 200 mM, e.g., about 5, 10, 50, 500, 500, or 1000
mM, e.g., wherein the concentration of the base is 2 or 3 to 5, 6,
8, 10, 15 or 20 equivalents of Formula II, e.g., about 2.5 or 5 to
10, e.g. about 2.5, e.g., about 5, e.g., wherein the concentration
of the base is 2 or 3 to 5, 6, 8, 10, 15 or 20 equivalents of
Formula III, e.g., about 5 to 10, e.g. about 5, e.g., about 10.
[0597] 1.110 Kit 1.78-1.109 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.
[0598] 1.111 Kit 1.78-1.110 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
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. [0599]
1.112 Kit 1.111 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal citrate salt (e.g., sodium citrate)
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. [0600] 1.113 Kit 1.111 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a metal phosphate salt (e.g., sodium
phosphate, e.g., Na.sub.2HPO.sub.4) 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. [0601] 1.114 Kit 1.111
wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the amine and/or salt thereof (e.g.,
morpholine, amino acid (e.g., arginine), mono- and/or
poly-hydroxyalkylamine, and/or salt thereof, e.g.,
(HO).sub.nR.sup.8NH.sub.2, [(HO).sub.nR.sup.8].sub.2NH,
[(HO).sub.nR.sup.8].sub.3N, and/or salt thereof wherein each
R.sup.8 is independently C.sub.1-8alkyl (e.g., C.sub.1-6-alkyl,
e.g., C.sub.1-4-alkyl, e.g., --CH.sub.2CH.sub.3, e.g., --CH.sub.3)
and n is 0 or C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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, 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. [0602] 1.115 Kit 1.114 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the mono- and/or poly-hydroxyalkylamine
and/or salt thereof, e.g., (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3--, e.g., one R.sup.8 is --CH.sub.3 and another
R.sup.8 is --(CH.sub.2).sub.6--) and each n is independently 1-8
(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), 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. [0603] 1.116
Kit 1.115 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to (HO).sub.nR.sup.8NH.sub.2,
[(HO).sub.nR.sup.8].sub.2NH, [(HO).sub.nR.sup.8].sub.3N, and/or
salt thereof wherein each R.sup.8 is independently C.sub.1-8alkyl
(e.g., C.sub.1-6-alkyl, e.g., C.sub.1-4-alkyl, e.g.,
--CH.sub.2CH.sub.3, e.g., --CH.sub.3) and n is 0 or
C.sub.1-8-alkylene (e.g., C.sub.1-6-alkylene, e.g.,
C.sub.1-4-alkylene, e.g., --CH.sub.2--CH.sub.2--, e.g.,
--C(CH.sub.2).sub.3
--, e.g., one R.sup.8 is --CH.sub.3 and another R.sup.8 is
--(CH.sub.2).sub.6--) and each n is independently 1-8 (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), is 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. [0604] 1.117 Kit 1.116
wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to tris(hydroxymethyl)aminomethane is at least
1:2, e.g., at least about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 to
1:10, 1:15, 1:20, or 1:30, e.g., at least about 1:3, 1:4, 1:5, 1:6,
1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, e.g., at least about
1:10. [0605] 1.118 Kit 1.116 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to the tris(hydroxymethyl)aminomethane salt
(e.g., tris(hydroxymethyl)aminomethane acetate) 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. [0606]
1.119 Kit 1.111 wherein the molar ratio of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a base, e.g., an amine and/or a salt
thereof, 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, 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.
[0607] 1.120 Kit 1.71-1.119 wherein the solvent, e.g., the sterile
solution, comprises one or more bulking agents, e.g., one or more
of maltose, mannose, ribose, cyclodextrin, mannitol, lactose,
sucrose, trehalose, sorbitol, glucose, raffinose, arginine,
glycine, histidine, dextran (e.g., dextran 40),
polyvinylpyrrolidone, polyethylene glycol, and polypropylene
glycol, e.g., one or more of mannitol, glucose, sucrose, lactose,
trehalose, and dextran (e.g., dextran 40). [0608] 1.121 Kit
1.71-1.120 wherein the solvent, e.g., the sterile solution,
comprises 5 or 10 or 50 mg to 2 or 5 g of one or more bulking
agents, e.g., from about 50 or 100 mg to 200, 300, 500, or 800 mg,
or 1, 1.5, 2, 3, 4, or 5 g of one or more bulking agents. [0609]
1.122 Kit 1.71-1.121 wherein the solvent, e.g., the sterile
solution, comprises dextran (e.g., dextran 40). [0610] 1.123 Kit
1.122 wherein the solvent, e.g. the sterile solution, comprises 5
or 10 or 50 mg to 2 or 5 g dextran (e.g., dextran 40), e.g., from
about 50 or 100 mg to 200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4,
or 5 g dextran (e.g., dextran 40). [0611] 1.124 Kit 1.71-1.123
wherein the solvent, e.g., the sterile solution, comprises one or
more solubilizing agents, e.g., ethylenediamine tetraacetic acid
(EDTA) or a salt thereof (e.g., calcium disodium EDTA, disodium
EDTA, sodium EDTA), alpha cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin, polysorbate 80, tert-butanol,
isopropanol, dichloromethane, ethanol, acetone, and glycerol; one
or more collapse temperature modifiers which may shift the overall
collapse temperature higher, e.g., one or more of dextran,
Ficoll.RTM., gelatin, and hydroxyethyl starch; one or more tonicity
modifiers, e.g., one or more of sodium chloride, potassium
chloride, sucrose, mannitol, and glucose; and one or more
antimicrobial agents, e.g., one or more of benzyl alcohol, phenol,
2-phenoxyethanol, m-cresol, chlorobutanol, parabens (e.g., methyl
paraben, ethyl paraben, propyl paraben), benzalkonium chloride,
benzethonium chloride, myristyl gamma-picolinium salt (e.g.,
myristyl gamma-picolinium chloride), and organomercury compounds
and salts (e.g., phenyl mercuric acetate, phenyl mercuric borate,
phenyl mercuric nitrate, and thimerosal). [0612] 1.125 Kit
1.71-1.124 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is admixed with the solvent, e.g., an aqueous
solution, to form a solution wherein the pH 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.
[0613] 1.126 Kit 1.71-1.125 wherein the solution is filtered to
remove particles and microbes, e.g., filtered prior to injection.
[0614] 1.127 Kit 1.71-1.126 wherein the solution is administered
about 24 hours, 12 hours, 10 hours, 8 hours, 2 hours, 1 hour, 30
minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 3 minutes,
2 minutes or 1 minute or less after admixture. [0615] 1.128 Kit I
or 1.1-1.127 wherein the kit comprises one or more additional
therapeutic agents, e.g., one or more additional therapeutic agents
for cerebral edema, stroke, traumatic brain injury, glioma (e.g.,
glioblastoma), meningitis, acute mountain sickness, infection,
metabolic disorder, hypoxia, water intoxication, hepatic failure,
hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia,
Creutzfeldt-Jakob disease, lupus cerebritis, optic nerve edema,
hyponatremia, fluid retention, ovarian hyperstimulation syndrome,
epilepsy, retinal ischemia or other diseases of the eye associated
with abnormalities in intraocular pressure and/or tissue hydration,
myocardial ischemia, myocardial ischemia/reperfusion injury,
myocardial infarction, myocardial hypoxia, congestive heart
failure, sepsis, neuromyelitis optica, or migraines. [0616] 1.129
Kit I or 1.1-1.128 wherein the kit comprises one or more additional
therapeutic agents, e.g., one or more additional therapeutic agents
for pulmonary edema, fibromyalgia, or multiple sclerosis. [0617]
1.130 Kit I or 1.1-1.129 wherein the kit comprises instructions for
using 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to treat or control a disease or condition
mediated by an aquaporin, e.g., diseases or conditions of water
imbalance and other diseases, for example, edema of the brain or
spinal cord, e.g., cerebral edema, e.g. cerebral edema consequent
to head trauma, ischemic stroke, glioma, meningitis, acute mountain
sickness, epileptic seizure, infection, metabolic disorder, hypoxia
(including general systemic hypoxia and hypoxia due to cardiac
arrest), water intoxication, hepatic failure, hepatic
encephalopathy, diabetic ketoacidosis, abscess, eclampsia,
Creutzfeldt-Jakob disease, lupus cerebritis, cardiac arrest,
microgravity and/or radiation exposure, or an invasive central
nervous system procedure, e.g., neurosurgery, endovascular clot
removal, spinal tap, aneurysm repair, or deep brain stimulation or,
e.g., spinal cord edema consequent to spinal cord trauma, e.g.,
spinal cord compression; or optic nerve edema, e.g., optic nerve
edema consequent to microgravity and/or radiation exposure; or
retinal edema; or hyponatremia or excessive fluid retention, e.g.,
consequent to heart failure (HF), liver cirrhosis, nephrotic
disorder, syndrome of inappropriate antidiuretic hormone secretion
(SIADH), or infertility treatment; or ovarian hyperstimulation
syndrome; or epilepsy, retinal ischemia or other diseases of the
eye associated with abnormalities in intraocular pressure and/or
tissue hydration, myocardial ischemia, myocardial
ischemia/reperfusion injury, myocardial infarction, myocardial
hypoxia, congestive heart failure, sepsis, neuromyelitis optica, or
glioblastoma; or migraines. [0618] 1.131 Kit I or 1.1-1.130 wherein
the kit comprises instructions for using
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to treat or control a disease or condition
mediated by an aquaporin, e.g., diseases or conditions of water
imbalance and other diseases, for example, pulmonary edema,
fibromyalgia, or multiple sclerosis. [0619] 1.132 Kit I or
1.1-1.131 wherein the kit comprises instructions for administering
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a patient in need thereof. [0620] 1.133 Kit
I or 1.1-1.132 wherein the kit comprises instructions for mixing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and one or more pharmaceutically acceptable
excipients. [0621] 1.134 Kit I wherein the kit comprises a
pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., a composition of
1.1-1.73. [0622] 1.135 Kit 1.134 wherein the kit comprises
instructions for using the pharmaceutical composition to treat or
control a disease or condition mediated by an aquaporin, e.g.,
diseases or conditions of water imbalance and other diseases, for
example, edema of the brain or spinal cord, e.g., cerebral edema,
e.g. cerebral edema consequent to head trauma, ischemic stroke,
glioma, meningitis, acute mountain sickness, epileptic seizure,
infection, metabolic disorder, hypoxia (including general systemic
hypoxia and hypoxia due to cardiac arrest), water intoxication,
hepatic failure, hepatic encephalopathy, diabetic ketoacidosis,
abscess, eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis,
cardiac arrest, microgravity and/or radiation exposure, or an
invasive central nervous system procedure, e.g., neurosurgery,
endovascular clot removal, spinal tap, aneurysm repair, or deep
brain stimulation or, e.g., spinal cord edema consequent to spinal
cord trauma, e.g., spinal cord compression; or optic nerve edema,
e.g., optic nerve edema consequent to microgravity and/or radiation
exposure; or retinal edema; or hyponatremia or excessive fluid
retention, e.g., consequent to heart failure (HF), liver cirrhosis,
nephrotic disorder, syndrome of inappropriate antidiuretic hormone
secretion (SIADH), or infertility treatment; ovarian
hyperstimulation syndrome; or epilepsy, retinal ischemia or other
diseases of the eye associated with abnormalities in intraocular
pressure and/or tissue hydration, myocardial ischemia, myocardial
ischemia/reperfusion injury, myocardial infarction, myocardial
hypoxia, congestive heart failure, sepsis, neuromyelitis optica, or
glioblastoma; or migraines. [0623] 1.136 Kit 1.134 wherein the kit
comprises instructions for using the pharmaceutical composition to
treat or control a disease or condition mediated by an aquaporin,
e.g., diseases or conditions of water imbalance and other diseases,
for example, pulmonary edema, fibromyalgia, or multiple sclerosis.
[0624] 1.137 Kit 1.134 wherein the kit comprises instructions for
administering the pharmaceutical composition to a patient in need
thereof. [0625] 1.138 Kit 1.134 wherein the kit comprises
instructions for preparing the pharmaceutical composition. [0626]
1.139 Kit I or 1.1-1.138 wherein the kit 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, vida infra.
[0627] In some embodiments, the kit is prepared by transferring a
liquid comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate to a container, e.g., a vial, in a
predetermined volume first and then subjecting the liquid to a
lyophilization process. Alternatively, liquid can be lyophilized in
a large volume and then a predetermined amount of the lyophilized
preparation can be placed in a container.
[0628] In yet another embodiment, provided is a method (Method A)
of treating or controlling a disease or condition mediated by an
aquaporin comprising administering to a patient in need thereof a
pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124.
[0629] Further provided is Method A as follows: [0630] A.1 Method A
wherein the aquaporin is AQP4. [0631] A.2 Method A or A.1 wherein
the condition to be treated or controlled is edema, e.g. edema of
the brain or spinal cord, e.g., cerebral edema, e.g. cerebral edema
consequent to head trauma, ischemic stroke, glioma, meningitis,
acute mountain sickness, epileptic seizure, infection, metabolic
disorder, water intoxication, hepatic failure, hepatic
encephalopathy, or diabetic ketoacidosis or, e.g., spinal cord
edema, e.g., spinal cord edema consequent to spinal cord trauma,
e.g., spinal cord compression. [0632] A.3 Method A, A.1, or A.2
further comprising a treatment selected from one or more of the
following: optimal head and neck positioning to facilitate venous
outflow, e.g. head elevation 30.degree.; avoidance of dehydration;
systemic hypotension; maintenance of normothermia or hypothermia;
aggressive measures; osmotherapy, e.g., using mannitol or
hypertonic saline; hyperventilation; therapeutic pressor therapy to
enhance cerebral perfusion; administration of barbiturates to
reduce cerebral metabolism (CMO.sub.2); hemicraniectomy;
administration of aspirin; administration of amantadine;
intravenous thrombolysis (e.g. using rtPA); mechanical clot
removal; angioplasty; and/or stents. [0633] A.4 Method A.2 wherein
the patient is at elevated risk of cerebral edema, e.g., due to
head trauma, ischemic stroke, glioma, meningitis, acute mountain
sickness, epileptic seizure, infection, metabolic disorder, water
intoxication, hepatic failure, hepatic encephalopathy, or diabetic
ketoacidosis. [0634] A.5 Method A.2 wherein the patient has
suffered a stroke, head injury, or spinal injury. [0635] A.6 Method
A.5 wherein the patient has suffered a stroke, head injury or
spinal injury within 12 hours, e.g. within 6 hours, preferably
within 3 hours of commencing treatment. [0636] A.7 Method A.2
wherein the patient is at elevated risk of suffering a stroke, head
injury or spinal injury, e.g., in combat or in an athletic
competition. [0637] A.8 Method A or A.1-A.7 wherein the patient
already has cerebral edema. [0638] A.9 Method A or A.1-A.8 wherein
the condition to be treated or controlled is cerebral edema
consequent to a stroke or a traumatic brain injury. [0639] A.10
Method A or A.1-A.9 wherein the condition to be treated or
controlled is cerebral edema consequent to a middle cerebral artery
stroke. [0640] A.11 Method A or A.1-A.9 wherein the condition to be
treated or controlled is cerebral edema consequent to closed head
trauma. [0641] A.12 Method A or A.1-A.4 wherein the condition to be
treated or controlled is cerebral edema consequent to an epileptic
seizure. [0642] A.13 Method A or A.1-A.4 wherein the condition to
be treated or controlled is cerebral edema consequent to an
infection. [0643] A.14 Method A or A.1-A.4 wherein the condition to
be treated or controlled is cerebral edema consequent to a
metabolic disorder. [0644] A.15 Method A or A.1-A.4 wherein the
condition to be treated or controlled is cerebral edema consequent
to glioma. [0645] A.16 Method A or A.1-A.4 wherein the condition to
be treated or controlled is cerebral edema consequent to
meningitis. [0646] A.17 Method A or A.1-A.4 wherein the condition
to be treated or controlled is cerebral edema consequent to acute
mountain sickness. [0647] A.18 Method A or A.1-A.4 wherein the
condition to be treated or controlled is cerebral edema consequent
to water intoxication. [0648] A.19 Method A or A.1-A.4 wherein the
condition to be treated or controlled is cerebral edema consequent
to hepatic failure, hepatic encephalopathy, or diabetic
ketoacidosis. [0649] A.20 Method A or A.1-A.3 wherein the condition
to be treated or controlled is cerebral edema consequent to an
abscess. [0650] A.21 Method A or A.1-A.3 wherein the condition to
be treated or controlled is cerebral edema consequent to eclampsia.
[0651] A.22 Method A or A.1-A.3 wherein the condition to be treated
or controlled is cerebral edema consequent to Creutzfeldt-Jakob
disease. [0652] A.23 Method A or A.1-A.3 wherein the condition to
be treated or controlled is cerebral edema consequent to lupus
cerebritis. [0653] A.24 Method A or A.1-A.3 wherein the condition
to be treated or controlled is edema consequent to hypoxia, e.g.,
general systemic hypoxia, e.g., hypoxia caused by an interruption
of blood perfusion, for example wherein the edema is cerebral edema
consequent to hypoxia caused by cardiac arrest, stroke, or other
interruption of blood perfusion to the brain, or wherein the edema
is cardiac edema consequent to cardiac ischemia or other
interruption of blood flow to the heart. [0654] A.25 Method A or
A.1-A.3 wherein the condition to be treated or controlled is
cerebral edema consequent to microgravity and/or radiation
exposure, e.g., exposure from space flight or from working with
radioactive materials or from working in radioactive areas. [0655]
A.26 Method A or A.1-A.3 wherein the condition to be treated or
controlled is cerebral edema consequent to an invasive central
nervous system procedure, e.g., neurosurgery, endovascular clot
removal, spinal tap, aneurysm repair, or deep brain stimulation.
[0656] A.27 Method A.25 or A.26 wherein the patient is at elevated
risk of edema, e.g., due to microgravity and/or radiation exposure,
neurosurgery, endovascular clot removal, spinal tap, aneurysm
repair, or deep brain stimulation. [0657] A.28 Method A.25 or A.26
wherein the patient already has edema. [0658] A.29 Method A or
A.1-A.28 wherein the edema is cytotoxic cerebral edema or is
primarily cytotoxic cerebral edema. [0659] A.30 Method A, A.1-A.19,
or A.24 wherein the edema is cytotoxic cerebral edema or is
primarily cytotoxic cerebral edema. [0660] A.31 Method A, A.1, or
A.2 wherein the condition to be treated or controlled is spinal
cord edema, e.g., spinal cord edema consequent to a spinal cord
trauma, e.g., spinal cord compression. [0661] A.32 Method A.31
wherein the condition to be treated or controlled is spinal cord
edema consequent to spinal cord compression. [0662] A.33 Method A,
A.1, or A.2 wherein the condition to be treated or controlled is
optic nerve edema, e.g., optic nerve edema consequent to
microgravity and/or radiation exposure, e.g., exposure from space
flight or from working with radioactive materials or from working
in radioactive areas. [0663] A.34 Method A, A.1, or A.2 wherein the
condition to be treated or controlled is retinal edema. [0664] A.35
Method A, A.1, or A.2 wherein the condition to be treated or
controlled is pulmonary edema. [0665] A.36 Method A or A.1 wherein
the condition to be treated or controlled is epilepsy. [0666] A.37
Method A or A.1 wherein the condition to be treated or controlled
is retinal ischemia or other diseases of the eye associated with
abnormalities in intraocular pressure and/or tissue hydration.
[0667] A.38 Method A or A.1 wherein the condition to be treated or
controlled is myocardial ischemia. [0668] A.39 Method A or A.1,
wherein the condition to be treated or controlled is myocardial
ischemia/reperfusion injury. [0669] A.40 Method A or A.1 wherein
the condition to be treated or controlled is myocardial infarction.
[0670] A.41 Method A or A.1 wherein the condition to be treated or
controlled is myocardial hypoxia. [0671] A.42 Method A or A.1
wherein the condition to be treated or controlled is congestive
heart failure. [0672] A.43 Method A or A.1 wherein the condition to
be treated or controlled is sepsis. [0673] A.44 Method A or A.1
wherein the condition to be treated or controlled is a migraine.
[0674] A.45 Method A or A.1 wherein the condition to be treated or
controlled is neuromyelitis optica. [0675] A.46 Method A or A.1
wherein the condition to be treated or controlled is glioblastoma.
[0676] A.47 Method A or A.1 wherein the condition to be treated or
controlled is fibromyalgia. [0677] A.48 Method A or A.1 wherein the
condition to be treated or controlled is multiple sclerosis. [0678]
A.49 Method A wherein the aquaporin is AQP2. [0679] A.50 Method A
or A.49 wherein the condition to be treated or controlled is
hyponatremia or excessive fluid retention, e.g., consequent to
heart failure (HF), for example congestive heart failure, liver
cirrhosis, nephrotic disorder, syndrome of inappropriate
antidiuretic hormone secretion (SIADH), or infertility treatment.
[0680] A.51 Method A, A.49, or A.50 wherein the condition to be
treated or controlled is ovarian hyperstimulation syndrome. [0681]
A.52 Method A, A.49, or A.50 further comprising one or more of
restriction of dietary sodium, fluid and/or alcohol; and/or
administration of one or more diuretics, vasopressin receptor
antagonists, angiotensin converting enzyme (ACE) inhibitors,
aldosterone inhibitors, angiotensin receptor blockers (ARBs),
beta-adrenergic antagonists (beta-blockers), and/or digoxin. [0682]
A.53 Method A or A.1-A.42 wherein the pharmaceutical composition is
administered orally. [0683] A.54 Method A or A.1-A.52 wherein the
pharmaceutical composition is administered parenterally. [0684]
A.55 Method A.54 wherein the pharmaceutical composition is
administered by injection, e.g., subcutaneously, intramuscularly,
intravenously, or intrathecally, e.g., a bolus injected
subcutaneously, intramuscularly, intravenously, or intrathecally.
[0685] A.56 Method A.55 wherein the pharmaceutical composition is
administered intravenously, e.g., IV bolus and/or IV infusion,
e.g., IV bolus followed by IV infusion. [0686] A.57 Method A or
A.1-A.56 wherein the patient is human. [0687] A.58 Method A or
A.1-A.57 wherein the onset of action after administration of the
pharmaceutical composition is fairly rapid.
[0688] In yet another embodiment, provided is a method (Method B)
of treating or controlling edema, e.g. edema of the brain or spinal
cord, e.g., cerebral edema, e.g. cerebral edema consequent to head
trauma, ischemic stroke, glioma, meningitis, acute mountain
sickness, epileptic seizure, infection, metabolic disorder,
hypoxia, water intoxication, hepatic failure, hepatic
encephalopathy, diabetic ketoacidosis, abscess, eclampsia,
Creutzfeldt-Jakob disease, lupus cerebritis, cardiac arrest,
microgravity and/or radiation exposure, or invasive central nervous
system procedures, e.g., neurosurgery, endovascular clot removal,
spinal tap, aneurysm repair, or deep brain stimulation or, e.g.,
optic nerve edema, e.g., optic nerve edema consequent to
microgravity and/or radiation exposure or, e.g., retinal edema or,
e.g., spinal cord edema, e.g., spinal cord edema consequent to
spinal cord trauma, e.g., spinal cord compression, or e.g.,
pulmonary edema, comprising administering a pharmaceutical
composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, to a patient in need thereof.
[0689] Further provided is Method B as follows: [0690] B.1 Method B
further comprising a treatment selected from one or more of the
following: optimal head and neck positioning to facilitate venous
outflow, e.g. head elevation 30.degree.; avoidance of dehydration;
systemic hypotension; maintenance of normothermia or hypothermia;
aggressive measures; osmotherapy, e.g., using mannitol or
hypertonic saline; hyperventilation; therapeutic pressor therapy to
enhance cerebral perfusion; administration of barbiturates to
reduce cerebral metabolism (CMO.sub.2); hemicraniectomy;
administration of aspirin; administration of amantadine;
intravenous thrombolysis (e.g. using rtPA); mechanical clot
removal; angioplasty; and/or stents. [0691] B.2 Method B wherein
the patient is at elevated risk of cerebral edema, e.g., due to
head trauma, ischemic stroke, glioma, meningitis, acute mountain
sickness, epileptic seizure, infection, metabolic disorder, water
intoxication, hepatic failure, hepatic encephalopathy, or diabetic
ketoacidosis. [0692] B.3 Method B wherein the patient has suffered
a stroke, head injury, or spinal injury. [0693] B.4 Method B.3
wherein the patient has suffered a stroke, head injury or spinal
injury within 12 hours, e.g. within 6 hours, preferably within 3
hours of commencing treatment. [0694] B.5 Method B wherein the
patient is at elevated risk of suffering a stroke, head injury or
spinal injury, e.g., in combat or in an athletic competition.
[0695] B.6 Method B or B.1-B.5 wherein the patient already has
cerebral edema. [0696] B.7 Method B or B.1-B.6 wherein the
condition to be treated or controlled is cerebral edema consequent
to a stroke or a traumatic brain injury. [0697] B.8 Method B or
B.1-B.7 wherein the condition to be treated or controlled is
cerebral edema consequent to a middle cerebral artery stroke.
[0698] B.9 Method B or B.1-B.7 wherein the condition to be treated
or controlled is cerebral edema consequent to a closed head trauma.
[0699] B.10 Method B, B.1, or B.2 wherein the condition to be
treated or controlled is cerebral edema consequent to an epileptic
seizure. [0700] B.11 Method B, B.1, or B.2 wherein the condition to
be treated or controlled is cerebral edema consequent to an
infection. [0701] B.12 Method B, B.1, or B.2 wherein the condition
to be treated or controlled is cerebral edema consequent to a
metabolic disorder. [0702] B.13 Method B, B.1, or B.2 wherein the
condition to be treated or controlled is cerebral edema consequent
to glioma. [0703] B.14 Method B, B.1, or B.2 wherein the condition
to be treated or controlled is cerebral edema consequent to
meningitis. [0704] B.15 Method B, B.1, or B.2 wherein the condition
to be treated or controlled is cerebral edema consequent to acute
mountain sickness. [0705] B.16 Method B, B.1, or B.2 wherein the
condition to be treated or controlled is cerebral edema consequent
to water intoxication. [0706] B.17 Method B, B.1, or B.2 wherein
the condition to be treated or controlled is cerebral edema
consequent to hepatic failure, hepatic encephalopathy, or diabetic
ketoacidosis. [0707] B.18 Method B or B.1 wherein the condition to
be treated or controlled is cerebral edema consequent to an
abscess. [0708] B.19 Method B or B.1 wherein the condition to be
treated or controlled is cerebral edema consequent to eclampsia.
[0709] B.20 Method B or B.1 wherein the condition to be treated or
controlled is cerebral edema consequent to Creutzfeldt-Jakob
disease. [0710] B.21 Method B or B.1 wherein the condition to be
treated or controlled is cerebral edema consequent to lupus
cerebritis. [0711] B.22 Method B or B.1 wherein the condition to be
treated or controlled is edema consequent to hypoxia, e.g., general
systemic hypoxia, e.g., hypoxia caused by an interruption of blood
perfusion, for example wherein the edema is cerebral edema
consequent to hypoxia caused by cardiac arrest, stroke, or other
interruption of blood perfusion to the brain, or wherein the edema
is cardiac edema consequent to cardiac ischemia or other
interruption of blood flow to the heart. [0712] B.23 Method B or
B.1 wherein the condition to be treated or controlled is cerebral
edema consequent to microgravity exposure, e.g., exposure from
space flight or from working with radioactive materials or from
working in radioactive areas. [0713] B.24 Method B or B.1 wherein
the condition to be treated or controlled is cerebral edema
consequent to invasive central nervous system procedures, e.g.,
neurosurgery, endovascular clot removal, spinal tap, aneurysm
repair, or deep brain stimulation. [0714] B.25 Method B.23 or B.24
wherein the patient is at elevated risk of edema, e.g., due to
microgravity and/or radiation exposure, neurosurgery, endovascular
clot removal, spinal tap, aneurysm repair, or deep brain
stimulation. [0715] B.26 Method B.23 or B.24 wherein the patient
already has edema. [0716] B.27 Method B or B.1-B.26 wherein the
edema is cytotoxic cerebral edema or is primarily cytotoxic
cerebral edema. [0717] B.28 Method B, B.1-B.17, or B.22 wherein the
edema is cytotoxic cerebral edema or is primarily cytotoxic
cerebral edema. [0718] B.29 Method B wherein the condition to be
treated or controlled is spinal cord edema, e.g., spinal cord edema
consequent to spinal cord trauma, e.g., spinal cord compression.
[0719] B.30 Method B.29 wherein the condition to be treated or
controlled is spinal cord edema consequent to spinal cord
compression. [0720] B.31 Method B wherein the condition to be
treated or controlled is optic nerve edema, e.g., optic nerve edema
consequent to microgravity and/or radiation exposure, e.g.,
exposure from space flight or from working with radioactive
materials or from working in radioactive areas. [0721] B.32 Method
B wherein the condition to be treated or controlled is retinal
edema. [0722] B.33 Method B wherein the condition to be treated or
controlled is pulmonary edema. [0723] B.34 Method B or B.1-B.33
wherein the duration of treatment with the pharmaceutical
composition is less than 21 days, e.g., less than 2 weeks, e.g.,
one week or less. [0724] B.35 Method B or B.1-B.34 wherein the
pharmaceutical composition is administered orally. [0725] B.36
Method B or B.1-B.34 wherein the pharmaceutical composition is
administered parenterally. [0726] B.37 Method B.36 wherein the
pharmaceutical composition is administered by injection, e.g.,
subcutaneously, intramuscularly, intravenously, or intrathecally,
e.g., a bolus administered subcutaneously, intramuscularly,
intravenously, or intrathecally. [0727] B.38 Method B.37 wherein
the pharmaceutical composition is administered intravenously, e.g.,
IV bolus and/or IV infusion, e.g., IV bolus followed by IV
infusion. [0728] B.39 Method B or B.1-B.38 wherein the patient is
human. [0729] B.40 Method B or B.1-B.39 wherein the onset of action
after administration of the pharmaceutical composition is fairly
rapid. [0730] B.41 Method B or B.1-B.40 wherein the
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate binds to AQP4.
[0731] In yet another embodiment, provided is a method (Method C)
of treating or controlling a condition selected from hyponatremia
and excessive fluid retention, e.g., consequent to heart failure
(HF), for example congestive heart failure, liver cirrhosis,
nephrotic disorder, syndrome of inappropriate antidiuretic hormone
secretion (SIADH), or infertility treatment, comprising
administering a pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, to a patient in need thereof.
[0732] Further provided is Method C as follows: [0733] C.1 Method C
further comprising one or more of restriction of dietary sodium,
fluid and/or alcohol; and/or administration of one or more
diuretics, vasopressin receptor antagonists, angiotensin converting
enzyme (ACE) inhibitors, aldosterone inhibitors, angiotensin
receptor blockers (ARBs), beta-adrenergic antagonists
(beta-blockers), and/or digoxin. [0734] C.2 Method C or C.1 wherein
the pharmaceutical composition is administered orally. [0735] C.3
Method C or C.1 wherein the pharmaceutical composition is
administered parenterally. [0736] C.4 Method C.3 wherein the
pharmaceutical composition is administered by injection, e.g.,
subcutaneously, intramuscularly, intravenously, or intrathecally,
e.g., a bolus injected subcutaneously, intramuscularly,
intravenously, or intrathecally. [0737] C.5 Method C.4 wherein the
pharmaceutical composition is administered intravenously, e.g., IV
bolus and/or IV infusion, e.g., IV bolus followed by IV infusion.
[0738] C.6 Method C or C.1-C.5 wherein the patient is human. [0739]
C.7 Method C or C.1-C.6 wherein the onset of action after
administration of the pharmaceutical composition is fairly rapid.
[0740] C.8 Method C or C.1-C.7 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate binds to AQP2.
[0741] In yet another embodiment, provided is a method (Method D)
of treating or controlling a condition selected from epilepsy,
retinal ischemia or other diseases of the eye associated with
abnormalities in intraocular pressure and/or tissue hydration,
myocardial ischemia, myocardial ischemia/reperfusion injury,
myocardial infarction, myocardial hypoxia, congestive heart
failure, sepsis, neuromyelitis optica, glioblastoma, fibromyalgia,
multiple sclerosis, and a migraine comprising administering a
pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, to a patient in need thereof.
[0742] Further provided is Method D as follows: [0743] D.1 Method D
wherein the condition to be treated or controlled is retinal
ischemia or other diseases of the eye associated with abnormalities
in intraocular pressure and/or tissue hydration. [0744] D.2 Method
D wherein the condition to be treated or controlled is myocardial
ischemia. [0745] D.3 Method D wherein the condition to be treated
or controlled is myocardial ischemia/reperfusion injury. [0746] D.4
Method D wherein the condition to be treated or controlled is
myocardial infarction. [0747] D.5 Method D wherein the condition to
be treated or controlled is myocardial hypoxia. [0748] D.6 Method D
wherein the condition to be treated or controlled is congestive
heart failure. [0749] D.7 Method D wherein the condition to be
treated or controlled is sepsis. [0750] D.8 Method D wherein the
condition to be treated or controlled is neuromyelitis optica.
[0751] D.9 Method D wherein the condition to be treated or
controlled is glioblastoma. [0752] D.10 Method D wherein the
condition to be treated or controlled is fibromyalgia. [0753] D.11
Method D wherein the condition to be treated or controlled is
multiple sclerosis. [0754] D.12 Method D wherein the condition to
be treated or controlled is a migraine. [0755] D.13 Method D or
D.1-D.12 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered orally. [0756] D.14 Method D
or D.1-D.12 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered parenterally. [0757] D.15
Method D.14 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered by injection, e.g.,
subcutaneously, intramuscularly, intravenously, or intrathecally,
e.g., a bolus injected subcutaneously, intramuscularly,
intravenously, or intrathecally. [0758] D.16 Method D.15 wherein
the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered intravenously, e.g., IV bolus
and/or IV infusion, e.g., IV bolus followed by IV infusion. [0759]
D.17 Method D or D.1-D.16 wherein the patient is human. [0760] D.18
Method D or D.1-D.17 wherein the onset of action after
administration of the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is fairly rapid. [0761] D.19 Method D or
D.1-D.18 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate binds to AQP4.
[0762] In yet another embodiment, provided is a method (Method E)
of treating or controlling a disease or condition mediated by an
aquaporin comprising administering to a patient in need thereof a
pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, in an amount effective to inhibit the aquaporin, for
example
[0763] Further provided is Method E as follows: [0764] E.1 Method E
wherein the aquaporin is AQP4. [0765] E.2 Method E or E.1 wherein
the condition to be treated or controlled is selected from edema,
e.g. edema of the brain or spinal cord, e.g., cerebral edema, e.g.
cerebral edema consequent to head trauma, ischemic stroke, glioma,
meningitis, acute mountain sickness, epileptic seizure, infection,
metabolic disorder, water intoxication, hepatic failure, hepatic
encephalopathy, or diabetic ketoacidosis or, e.g., spinal cord
edema, e.g., spinal cord edema consequent to spinal cord trauma,
e.g., spinal cord compression. [0766] E.3 Method E, E.1, or E.2
further comprising a treatment selected from one or more of the
following: optimal head and neck positioning to facilitate venous
outflow, e.g. head elevation 30.degree.; avoidance of dehydration;
systemic hypotension; maintenance of normothermia or hypothermia;
aggressive measures; osmotherapy, e.g., using mannitol or
hypertonic saline; hyperventilation; therapeutic pressor therapy to
enhance cerebral perfusion; administration of barbiturates to
reduce of cerebral metabolism (CMO.sub.2); hemicraniectomy;
administration of aspirin; administration of amantadine;
intravenous thrombolysis (e.g. using rtPA); mechanical clot
removal; angioplasty; and/or stents. [0767] E.4 Method E.2 wherein
the patient is at elevated risk of cerebral edema, e.g., due to
head trauma, ischemic stroke, glioma, meningitis, acute mountain
sickness, epileptic seizure, infection, metabolic disorder, water
intoxication, hepatic failure, hepatic encephalopathy, or diabetic
ketoacidosis. [0768] E.5 Method E.2 wherein the patient has
suffered a stroke, head injury, or spinal injury. [0769] E.6 Method
E.5 wherein the patient has suffered a stroke, head injury or
spinal injury within 12 hours, e.g. within 6 hours, preferably
within 3 hours of commencing treatment. [0770] E.7 Method E.2
wherein the patient is at elevated risk of suffering a stroke, head
injury or spinal injury, e.g., in combat or in an athletic
competition. [0771] E.8 Method E or E.1-E.7 wherein the patient
already has cerebral edema. [0772] E.9 Method E or E.1-E.8 wherein
the condition to be treated or controlled is cerebral edema
consequent to a stroke or a traumatic brain injury. [0773] E.10
Method E or E.1-E.9 wherein the condition to be treated or
controlled is cerebral edema consequent to a middle cerebral artery
stroke. [0774] E.11 Method E or E.1-E.9 wherein the condition to be
treated or controlled is cerebral edema consequent to a closed head
trauma. [0775] E.12 Method E or E.1-E.4 wherein the condition to be
treated or controlled is cerebral edema consequent to an epileptic
seizure. [0776] E.13 Method E or E.1-E.4 wherein the condition to
be treated or controlled is cerebral edema consequent an infection.
[0777] E.14 Method E or E.1-E.4 wherein the condition to be treated
or controlled is cerebral edema consequent to a metabolic disorder.
[0778] E.15 Method E or E.1-E.4 wherein the condition to be treated
or controlled is cerebral edema consequent to glioma. [0779] E.16
Method E or E.1-E.4 wherein the condition to be treated or
controlled is cerebral edema consequent to meningitis. [0780] E.17
Method E or E.1-E.4 wherein the condition to be treated or
controlled is cerebral edema consequent to acute mountain sickness.
[0781] E.18 Method E or E.1-E.4 wherein the condition to be treated
or controlled is cerebral edema consequent to water intoxication.
[0782] E.19 Method E or E.1-E.4 wherein the condition to be treated
or controlled is cerebral edema consequent to hepatic failure,
hepatic encephalopathy, or diabetic ketoacidosis. [0783] E.20
Method E or E.1-E.3 wherein the condition to be treated or
controlled is cerebral edema consequent to an abscess. [0784] E.21
Method E or E.1-E.3 wherein the condition to be treated or
controlled is cerebral edema consequent to eclampsia. [0785] E.22
Method E or E.1-E.3 wherein the condition to be treated or
controlled is cerebral edema consequent to Creutzfeldt-Jakob
disease. [0786] E.23 Method E or E.1-E.3 wherein the condition to
be treated or controlled is cerebral edema consequent to lupus
cerebritis. [0787] E.24 Method E or E.1-E.3 wherein the condition
to be treated or controlled is edema consequent to hypoxia, e.g.,
general systemic hypoxia, e.g., hypoxia caused by an interruption
of blood perfusion, for example wherein the edema is cerebral edema
consequent to hypoxia caused by cardiac arrest, stroke, or other
interruption of blood perfusion to the brain, or wherein the edema
is cardiac edema consequent to cardiac ischemia or other
interruption of blood flow to the heart. [0788] E.25 Method E or
E.1-E.3 wherein the condition to be treated or controlled is
cerebral edema consequent to microgravity and/or radiation
exposure, e.g., exposure from space flight or from working with
radioactive materials or from working in radioactive areas. [0789]
E.26 Method E or E.1-E.3 wherein the condition to be treated or
controlled is cerebral edema consequent to invasive central nervous
system procedures, e.g., neurosurgery, endovascular clot removal,
spinal tap, aneurysm repair, or deep brain stimulation. [0790] E.27
Method E.25 or E.26 wherein the patient is at elevated risk of
edema, e.g., due to microgravity and/or radiation exposure,
neurosurgery, endovascular clot removal, spinal tap, aneurysm
repair, or deep brain stimulation. [0791] E.28 Method E.25 or E.26
wherein the patient already has edema. [0792] E.29 Method E or
E.1-E.28 wherein the edema is cytotoxic cerebral edema or is
primarily cytotoxic cerebral edema. [0793] E.30 Method E, E.1-E.19,
or E.24 wherein the edema is cytotoxic cerebral edema or is
primarily cytotoxic cerebral edema. [0794] E.31 Method E, E.1, or
E.2 wherein the condition to be treated or controlled is spinal
cord edema, e.g., spinal cord edema consequent to spinal cord
trauma, e.g., spinal cord compression. [0795] E.32 Method E.31
wherein the condition to be treated or controlled is spinal cord
edema consequent to spinal cord compression. [0796] E.33 Method E,
E.1 or E.2 wherein the condition to be treated or controlled is
optic nerve edema, e.g., optic nerve edema consequent to
microgravity and/or radiation exposure, e.g., exposure from space
flight or from working with radioactive materials or from working
in radioactive areas. [0797] E.34 Method E, E.1, or E.2 wherein the
condition to be treated or controlled is retinal edema. [0798] E.35
Method E, E.1, or E.2 wherein the condition to be treated or
controlled is pulmonary edema. [0799] E.36 Method E or E.1 wherein
the condition to be treated or controlled is epilepsy. [0800] E.37
Method E or E.1 wherein the condition to be treated or controlled
is retinal ischemia or other diseases of the eye associated with
abnormalities in intraocular pressure and/or tissue hydration.
[0801] E.38 Method E or E.1 wherein the condition to be treated or
controlled is myocardial ischemia. [0802] E.39 Method E or E.1
wherein the condition to be treated or controlled is myocardial
ischemia/reperfusion injury. [0803] E.40 Method E or E.1 wherein
the condition to be treated or controlled is myocardial infarction.
[0804] E.41 Method E or E.1 wherein the condition to be treated or
controlled is myocardial hypoxia. [0805] E.42 Method E or E.1
wherein the condition to be treated or controlled is congestive
heart failure. [0806] E.43 Method E or E.1 wherein the condition to
be treated or controlled is sepsis. [0807] E.44 Method E or E.1
wherein the condition to be treated or controlled is a migraine.
[0808] E.45 Method E or E.1 wherein the condition to be treated or
controlled is neuromyelitis optica. [0809] E.46 Method E or E.1
wherein the condition to be treated or controlled is glioblastoma.
[0810] E.47 Method E or E.1 wherein the condition to be treated or
controlled is fibromyalgia. [0811] E.48 Method E or E.1 wherein the
condition to be treated or controlled is multiple sclerosis. [0812]
E.49 Method E wherein the aquaporin is AQP2. [0813] E.50 Method E
or E.49 wherein the condition to be treated is hyponatremia or
excessive fluid retention, e.g., consequent to heart failure (HF),
for example congestive heart failure, liver cirrhosis, nephrotic
disorder, syndrome of inappropriate antidiuretic hormone secretion
(SIADH), or infertility treatment. [0814] E.51 Method E, E.49, or
E.50 wherein the condition to be treated or controlled is ovarian
hyperstimulation syndrome. [0815] E.52 Method E, E.49, or E.50
further comprising one or more of restriction of dietary sodium,
fluid and/or alcohol; and/or administration of one or more
diuretics, vasopressin receptor antagonists, angiotensin converting
enzyme (ACE) inhibitors, aldosterone inhibitors, angiotensin
receptor blockers (ARBs), beta-adrenergic antagonists
(beta-blockers), and/or digoxin. [0816] E.53 Method E or E.1-E.52
wherein the duration of treatment with the pharmaceutical
composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is less than 21 days, e.g., less than 2 weeks,
e.g., one week or less. [0817] E.54 Method E or E.1-E.53 wherein
the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate e is administered orally. [0818] E.55 Method E
or E.1-E.53 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered parenterally. [0819] E.56
Method E.55 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered by injection, e.g.,
subcutaneously, intramuscularly, intravenously, or intrathecally,
e.g., a bolus injected subcutaneously, intramuscularly,
intravenously, or intrathecally. [0820] E.57 Method E.56 wherein
the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered intravenously, e.g., IV bolus
and/or IV infusion, e.g., IV bolus followed by IV infusion. [0821]
E.58 Method E or E.1-E.57 wherein the patient is human. [0822] E.59
Method E or E.1-E.58 wherein the onset of action after
administration of the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is fairly rapid.
[0823] In a further embodiment, provided is a method (Method F) of
inhibiting an aquaporin in vivo comprising administering a
pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, in an amount effective to inhibit the aquaporin.
[0824] Further provided is Method F as follows: [0825] F.1 Method F
wherein the aquaporin is AQP4. [0826] F.2 Method F wherein the
aquaporin is AQP2. [0827] F.3 Method F, F.1, or F.2 wherein the
pharmaceutical composition is administered orally. [0828] F.4
Method F, F.1, or F.2 wherein the pharmaceutical composition is
administered parenterally. [0829] F.5 Method of F.4 wherein the
pharmaceutical composition is administered intravenously, e.g., IV
bolus and/or IV infusion, e.g., IV bolus followed by IV
infusion.
[0830] In a further embodiment, provided is a method (Method G) to
inhibit an aquaporin in a patient suffering from a disease or
condition mediated by an aquaporin comprising administering an
effective amount of a pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, to inhibit the aquaporin.
[0831] Further provided is Method G as follows: [0832] G.1 Method G
wherein the aquaporin is AQP4. [0833] G.2 Method G or G.1 wherein
the condition to be treated or controlled is edema, e.g. edema of
the brain or spinal cord, e.g., cerebral edema, e.g. cerebral edema
consequent to head trauma, ischemic stroke, glioma, meningitis,
acute mountain sickness, epileptic seizure, infection, metabolic
disorder, water intoxication, hepatic failure, hepatic
encephalopathy, or diabetic ketoacidosis or, e.g., spinal cord
edema, e.g., spinal cord edema consequent to spinal cord trauma,
e.g., spinal cord compression. [0834] G.3 Method G, G.1, or G.2
further comprising a treatment selected from one or more of the
following: optimal head and neck positioning to facilitate venous
outflow, e.g. head elevation 30.degree.; avoidance of dehydration;
systemic hypotension; maintenance of normothermia or hypothermia;
aggressive measures; osmotherapy, e.g., using mannitol or
hypertonic saline; hyperventilation; therapeutic pressor therapy to
enhance cerebral perfusion; administration of barbiturates to
reduce cerebral metabolism (CMO.sub.2); hemicraniectomy;
administration of aspirin; administration of amantadine;
intravenous thrombolysis (e.g. using rtPA); mechanical clot
removal; angioplasty; and/or stents. [0835] G.4 Method G.2 wherein
the patient is at elevated risk of cerebral edema, e.g., due to
head trauma, ischemic stroke, glioma, meningitis, acute mountain
sickness, epileptic seizure, infection, metabolic disorder, water
intoxication, hepatic failure, hepatic encephalopathy, or diabetic
ketoacidosis. [0836] G.5 Method G.2 wherein the patient has
suffered a stroke, head injury, or spinal injury. [0837] G.6 Method
G.5 wherein the patient has suffered a stroke, head injury or
spinal injury within 12 hours, e.g. within 6 hours, preferably
within 3 hours of commencing treatment. [0838] G.7 Method G.2
wherein the patient is at elevated risk of suffering a stroke, head
injury or spinal injury, e.g., in combat or in an athletic
competition. [0839] G.8 Method G or G.1-A.7 wherein the patient
already has cerebral edema. [0840] G.9 Method G or G.1-A.8 wherein
the condition to be treated or controlled is cerebral edema
consequent to a stroke or a traumatic brain injury. [0841] G.10
Method G or G.1-A.9 wherein the condition to be treated or
controlled is cerebral edema consequent to a middle cerebral artery
stroke. [0842] G.11 Method G or G.1-G.9 wherein the condition to be
treated or controlled is cerebral edema consequent to closed head
trauma. [0843] G.12 Method G or G.1-G.4 wherein the condition to be
treated or controlled is cerebral edema consequent to an epileptic
seizure. [0844] G.13 Method G or G.1-G.4 wherein the condition to
be treated or controlled is cerebral edema consequent to an
infection. [0845] G.14 Method G or G.1-G.4 wherein the condition to
be treated or controlled is cerebral edema consequent to a
metabolic disorder. [0846] G.15 Method G or G.1-G.4 wherein the
condition to be treated or controlled is cerebral edema consequent
to glioma. [0847] G.16 Method G or G.1-G.4 wherein the condition to
be treated or controlled is cerebral edema consequent to
meningitis. [0848] G.17 Method G or G.1-G.4 wherein the condition
to be treated or controlled is cerebral edema consequent to acute
mountain sickness. [0849] G.18 Method G or G.1-G.4 wherein the
condition to be treated or controlled is cerebral edema consequent
to water intoxication. [0850] G.19 Method G or G.1-G.4 wherein the
condition to be treated or controlled is cerebral edema consequent
to hepatic failure, hepatic encephalopathy, or diabetic
ketoacidosis. [0851] G.20 Method G or G.1-G.3 wherein the condition
to be treated or controlled is cerebral edema consequent to an
abscess. [0852] G.21 Method G or G.1-G.3 wherein the condition to
be treated or controlled is cerebral edema consequent to eclampsia.
[0853] G.22 Method G or G.1-G.3 wherein the condition to be treated
or controlled is cerebral edema consequent to Creutzfeldt-Jakob
disease. [0854] G.23 Method G or G.1-G.3 wherein the condition to
be treated or controlled is cerebral edema consequent to lupus
cerebritis. [0855] G.24 Method G or G.1-G.3 wherein the condition
to be treated or controlled is edema consequent to hypoxia, e.g.,
general systemic hypoxia, e.g., hypoxia caused by an interruption
of blood perfusion, for example wherein the edema is cerebral edema
consequent to hypoxia caused by cardiac arrest, stroke, or other
interruption of blood perfusion to the brain, or wherein the edema
is cardiac edema consequent to cardiac ischemia or other
interruption of blood flow to the heart. [0856] G.25 Method G or
G.1-G.3 wherein the condition to be treated or controlled is
cerebral edema consequent to microgravity and/or radiation
exposure, e.g., exposure from space flight or from working with
radioactive materials or from working in radioactive areas. [0857]
G.26 Method G or G.1-G.3 wherein the condition to be treated or
controlled is cerebral edema consequent to an invasive central
nervous system procedure, e.g., neurosurgery, endovascular clot
removal, spinal tap, aneurysm repair, or deep brain stimulation.
[0858] G.27 Method G.25 or G.26 wherein the patient is at elevated
risk of edema, e.g., due to microgravity and/or radiation exposure,
neurosurgery, endovascular clot removal, spinal tap, aneurysm
repair, or deep brain stimulation. [0859] G.28 Method G.25 or G.26
wherein the patient already has edema. [0860] G.29 Method G or
G.1-G.28 wherein the edema is cytotoxic cerebral edema or is
primarily cytotoxic cerebral edema. [0861] G.30 Method G, G.1-G.19,
or G.24 wherein the edema is cytotoxic cerebral edema or is
primarily cytotoxic cerebral edema. [0862] G.31 Method G, G.1, or
G.2 wherein the condition to be treated or controlled is spinal
cord edema, e.g., spinal cord edema consequent to a spinal cord
trauma, e.g., spinal cord compression. [0863] G.32 Method G.31
wherein the condition to be treated or controlled is spinal cord
edema consequent to spinal cord compression. [0864] G.33 Method G,
G.1, or G.2 wherein the condition to be treated or controlled is
optic nerve edema, e.g., optic nerve edema consequent to
microgravity and/or radiation exposure, e.g., exposure from space
flight or from working with radioactive materials or from working
in radioactive areas. [0865] G.34 Method G, G.1, or G.2 wherein the
condition to be treated or controlled is retinal edema. [0866] G.35
Method G, G.1, or G.2 wherein the condition to be treated or
controlled is pulmonary edema. [0867] G.36 Method G or G.1 wherein
the condition to be treated or controlled is epilepsy. [0868] G.37
Method G or G.1 wherein the condition to be treated or controlled
is retinal ischemia or other diseases of the eye associated with
abnormalities in intraocular pressure and/or tissue hydration.
[0869] G.38 Method G or G.1 wherein the condition to be treated or
controlled is myocardial ischemia. [0870] G.39 Method G or G.1
wherein the condition to be treated or controlled is myocardial
ischemia/reperfusion injury. [0871] G.40 Method G or G.1 wherein
the condition to be treated or controlled is myocardial infarction.
[0872] G.41 Method G or G.1 wherein the condition to be treated or
controlled is myocardial hypoxia. [0873] G.42 Method G or G.1
wherein the condition to be treated or controlled is congestive
heart failure. [0874] G.43 Method G or G.1 wherein the condition to
be treated or controlled is sepsis. [0875] G.44 Method G or G.1
wherein the condition to be treated or controlled is a migraine.
[0876] G.45 Method G or G.1 wherein the condition to be treated or
controlled is neuromyelitis optica. [0877] G.46 Method G or G.1
wherein the condition to be treated or controlled is glioblastoma.
[0878] G.47 Method G or G.1 wherein the condition to be treated or
controlled is fibromyalgia. [0879] G.48 Method G or G.1 wherein the
condition to be treated or controlled is multiple sclerosis. [0880]
G.49 Method G wherein the aquaporin is AQP2. [0881] G.50 Method G
or G.49 wherein the condition to be treated or controlled is
hyponatremia or excessive fluid retention, e.g., consequent to
heart failure (HF), for example congestive heart failure, liver
cirrhosis, nephrotic disorder, syndrome of inappropriate
antidiuretic hormone secretion (SIADH), or infertility treatment.
[0882] G.51 Method G, G.49, or G.50 wherein the condition to be
treated or controlled is ovarian hyperstimulation syndrome. [0883]
G.52 Method G, G.49, or G.50 further comprising one or more of
restriction of dietary sodium, fluid and/or alcohol; and/or
administration of one or more diuretics, vasopressin receptor
antagonists, angiotensin converting enzyme (ACE) inhibitors,
aldosterone inhibitors, angiotensin receptor blockers (ARBs),
beta-adrenergic antagonists (beta-blockers), and/or digoxin. [0884]
G.53 Method G or G.1-G.52 wherein the pharmaceutical composition
comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered orally. [0885] G.54 Method G
or G.1-G.52 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered parenterally. [0886] G.55
Method G.54 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered by injection, e.g.,
subcutaneously, intramuscularly, intravenously, or intrathecally,
e.g., a bolus injected subcutaneously, intramuscularly,
intravenously, or intrathecally. [0887] G.56 Method G.55 wherein
the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered intravenously, e.g., IV bolus
and/or IV infusion, e.g., IV bolus followed by IV infusion. [0888]
G.57 Method G or G.1-G.56 wherein the patient is human. [0889] G.58
Method G or G.1-G.57 wherein the onset of action after
administration of the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is fairly rapid.
[0890] In yet another embodiment, provided is a method (Method H)
of treating or controlling a condition selected from fibromyalgia
and multiple sclerosis comprising administering a pharmaceutical
composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, to a patient in need thereof.
[0891] Further provided is Method H as follows: [0892] H.1 Method H
wherein the condition to be treated or controlled is fibromyalgia.
[0893] H.2 Method H wherein the condition to be treated or
controlled is multiple sclerosis. [0894] H.3 Method H, H.1, or H.2
wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered orally. [0895] H.4 Method H,
H.1, or H.2 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered parenterally. [0896] H.5
Method H.4 wherein the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered by injection, e.g.,
subcutaneously, intramuscularly, intravenously, or intrathecally,
e.g., a bolus injected subcutaneously, intramuscularly,
intravenously, or intrathecally. [0897] H.6 Method H.5 wherein the
pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is administered intravenously, e.g., IV bolus
and/or IV infusion, e.g., IV bolus followed by IV infusion. [0898]
H.7 Method H or H.1-H.6 wherein the patient is human. [0899] H.8
Method H or H.1-H.7 wherein the onset of action after
administration of the pharmaceutical composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is fairly rapid. [0900] H.9 Method H or
H.1-H.8 wherein
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate binds to AQP4.
[0901] In yet another embodiment, provided is a pharmaceutical
composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, for use in treating or controlling a disease or
condition mediated by an aquaporin.
[0902] In yet another embodiment, provided is a pharmaceutical
composition comprising
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate, e.g., Composition I, e.g., composition
1.1-1.124, for use in any of Methods A, e.g., A.1-A.58, any of
Methods B, e.g., B.1-B.41, any of Methods C, e.g., C.1-C.8, any of
Methods D, e.g., D.1-D.19, any of Methods E, e.g., E.1-E.59, any of
Methods F, e.g., F.1-F.5, any of Methods G, e.g., G.1-G.58, and any
of Methods H, e.g., H.1-H.9.
[0903] A dose or method of administration of the dose of the
present disclosure is not particularly limited. Dosages employed in
practicing the present disclosure will of course vary depending,
e.g. on the particular disease or condition to be treated, the
particular compound used, the mode of administration, and the
therapy desired. The pharmaceutical compositions may be
administered by any suitable route, including orally, parenterally,
transdermally, or by inhalation. In stroke or other severely
debilitating diseases or conditions, for example where the patient
may be unconscious or unable to swallow, an IV infusion and/or IV
bolus may be preferred. In general, satisfactory results, e.g. for
the treatment of diseases as hereinbefore set forth are indicated
to be obtained on oral administration at dosages of the order from
about 0.01 to 15.0 mg/kg. In larger mammals, for example humans, an
indicated daily dosage for oral administration will accordingly be
in the range of from about 0.75 to 1000 mg per day, conveniently
administered once, or in divided doses 2 to 3 times, daily or in
sustained release form. Unit dosage forms for oral administration
thus for example may comprise from about 0.2 to 75 mg or 150 mg,
e.g. from about 0.2 or 2.0 mg to 50, 75, 100, 125, 150 or 200 mg of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate together with a pharmaceutically acceptable
diluent or carrier therefor. When the pharmaceutical composition is
used via injection (subcutaneously, intramuscularly or
intravenously) the dose may be 0.1 or 0.25 mg to 500 mg per day,
e.g., from about 0.25 mg to 75 or 150 mg, e.g., from about 0.1 or
0.25 or 2.0 mg to 50, 75, 100, 125, 150, 200, 300, 400, or 500 mg,
by bolus or if IV by bolus or infusion.
[0904] The pharmaceutical compositions as hereinbefore described
for use in the methods of the invention may be used as a sole
therapeutic agent, but may also be used in combination or for
co-administration with other active agents, for example in
conjunction with conventional therapies for cerebral edema, stroke,
traumatic brain injury, glioma (e.g., glioblastoma), meningitis,
acute mountain sickness, infection, metabolic disorder, hypoxia,
water intoxication, hepatic failure, hepatic encephalopathy,
diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob
disease, lupus cerebritis, optic nerve edema, hyponatremia, fluid
retention, ovarian hyperstimulation syndrome, epilepsy, retinal
ischemia or other diseases of the eye associated with abnormalities
in intraocular pressure and/or tissue hydration, myocardial
ischemia, myocardial ischemia/reperfusion injury, myocardial
infarction, myocardial hypoxia, congestive heart failure, sepsis,
neuromyelitis optica, or migraines.
[0905] Further provided is crystalline
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate.
[0906] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate includes its polymorphs, hydrates, solvates
and complexes.
[0907] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate may be made using the methods as described and
exemplified herein and by methods similar thereto and by methods
known in the chemical art. Such methods include, but not limited
to, those described below. If not commercially available, starting
materials for these processes may be made by procedures which are
selected from the chemical art using techniques which are similar
or analogous to the synthesis of known compounds.
[0908] As used throughout, ranges are used as shorthand for
describing each and every value that is within the range. Any value
within the range can be selected as the terminus of the range. In
addition, all references cited herein are hereby incorporated by
referenced in their entireties. In the event of a conflict in a
definition in the present disclosure and that of a cited reference,
the present disclosure controls.
[0909] Terms and Abbreviations:
ala=alanine Boc=tert-butyloxycarbonyl
DCC=dicyclohexylcarbodiimide
DMAP=4-(dimethylamino)pyridine
[0910] DMF=dimethylformamide Hunig's base=N,N-diisopropylethylamine
TFA=trifluoroacetic acid
EXAMPLES
Example 1
2-{[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate
Step 1:
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
##STR00042##
[0912] 5-chloro salicylic acid (8.75 g, 50 mmol, 1 eq) is dissolved
in toluene (300 mL) under N.sub.2 atmosphere then phosphorus
trichloride (2.2 mL, 25 mmol, 0.5 eq) is added dropwise followed by
3,5-bis(trifluoromethyl)aniline (10 g, 43.7 mmol, 0.87 eq). The
reaction mixture is stirred under reflux for 12 h then cooled to
room temperature. The reaction mixture is quenched with NaHCO.sub.3
saturated solution and stirred for 10 min. To this solution is
added 1M HCl (100 mL) until the pH of the aqueous layer is 5 and
the aqueous layer is extracted with ethyl acetate (2.times.300 mL).
The combined organics are then dried over sodium sulfate and
concentrated in vacuo to yield the crude product which is purified
by flash chromatography (5-20% EtOAc/hex). The yield of pure
product as a white solid is 16 g (yield 85%) which is >95% pure
by .sup.1H NMR. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 11.35
(bs, 1H), 10.85 (bs, 1H), 8.40 (s, 2H), 7.80-7.79 (m, 2H), 7.50
(dd, 1H), 7.00 (d, 1H).
Step 2:
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
bis(2-(trimethylsilyl)ethyl) phosphate
##STR00043##
[0914]
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (4.0
g, 0.01 mol, 1 eq) is dissolved in CH.sub.3CN (104 mL) then DMAP
(0.08 g, 0.001 mol, 0.06 eq), Hunig's base (7.36 mL, 0.021 mol, 2
eq) and CCl.sub.4 (8.02 g, 0.052 mol, 5 eq) are added in this
order. The solution is cooled to 0.degree. C. and
bis[2-(trimethylsilyl)ethyl]phosphonate
(HP(O)(OCH.sub.2CH.sub.2Si(CH.sub.3).sub.3).sub.2 (4.66 g, 0.016
mol, 1.5 eq) in CH.sub.3CN (5 mL) is added dropwise. The reaction
mixture is stirred at room temperature for 20 h then water is added
and extracted twice with EtOAc. The combined organic layers are
washed with a saturated solution of NaCl, dried over
Na.sub.2SO.sub.4, filtered and the solvent is concentrated in vacuo
to give the crude material which is used as such for next step.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 10.20 (bs, 1H), 8.32 (s,
2H), 7.90 (s, 1H), 7.62 (s, 1H), 7.45-7.40 (m, 1H), 7.30-7.28 (m,
1H), 4.40-4.30 (m, 4H), 1.20-1.00 (m, 4H), 0.0 (s, 18H).
Step 3:
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate
##STR00044##
[0916] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
bis(2-(trimethylsilyl)ethyl) phosphate (6.64 g, 0.01 mol, 1 eq) is
dissolved in a mixture TFA:Water (5:1, 50 mL). The reaction mixture
is stirred at room temperature for 2 h then solvent is concentrated
in vacuo. The resulting white solid is dissolved in Et.sub.2O (20
mL) then concentrated in vacuo. This operation is repeated twice or
until the compound becomes much less soluble in Et.sub.2O. The
resulting material is suspended in a mixture Et.sub.2O:Hex (6:1, 50
mL) and filtered to give the desire material as light red solid.
Finally, the solid is dissolved in water (100 mL), filtered and the
resulting aqueous solution is freeze dried to give the desired
product as a white solid (yield 76% over two steps, 97% pure by
HPLC). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.38 (s, 2H),
7.78 (s, 1H), 7.70 (s, 1H), 7.55-7.50 (m, 1H), 7.45-7.43 (m,
1H).
Example 2
[0917] A 95% pure lot of
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate is purified as follows. 15 g is dissolved in
1.2 L of water with 120 mM of sodium hydroxide and extracted with
500 ml ethyl acetate to remove phenol and non acid impurities. The
aqueous layer is acidified with concentrated HCl to pH 1.2 and
extracted with ethyl acetate 1 L followed by 600 ml. The ethyl
acetate layer is dried MgSO.sub.4 and sodium sulphate, filtered,
and evaporated to give about 13 g of 98% pure
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate. NMR showed 1 mole of ethyl acetate trapped in
solid. Ethyl acetate is removed by adding 100 ml of methanol and
evaporating.
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate is stable at RT for a week or more. Sample
kept at RT. It is soluble at 5 mg/mL in 1% Na.sub.2HPO.sub.4 giving
pH of about 7. Dissolved in 2% Na.sub.2HPO.sub.4 at 5 mg/mL gives
pH of 7.4
Example 3
[0918] Mouse Water Toxicity Model--Survival Curves: The in vivo
efficacies of the compounds are tested using the mouse water
toxicity model, where a mouse is injected with water at 20% of its
body weight. Manley, G. T. et al. Aquaporin-4 deletion in mice
reduces brain edema after acute water intoxication and ischemic
stroke. Nat Med 6, 159-163 (2000); Gullans, S. R. & Verbalis,
J. G. Control of brain volume during hyperosmolar and hypoosmolar
conditions. Annual Review of Medicine 44, 289-301 (1993). The
resulting euvolemic hyponatremia rapidly leads to CE, making this a
practical model to test an inhibitor of the CNS aquaporin,
AQP4b.
[0919] The ability of mice to survive H.sub.2O toxicity is
determined in three experiments using 10-12 mice each (16-19 weak
old male/female). Deionized water is prepared for injection with
either 0.39 mg/kg phenylbenzamide (placebo) or 0.76 mg/kg with test
compound. FIG. 1 shows the combined results of these experiments
(n=33 placebo, n=34
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide).
Percent survival of the
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
cohorts improves 3.2 fold and the time to 50% survival for animals
treated with
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is
improved by roughly 52 min.
[0920] Mouse Water Toxicity Model--Brain Volume by Magnetic
Resonance Imaging (MRI): MRI is used to measure changes in brain
volume in response to water shock, using the water toxicity model.
As described for the survival and brain water content studies
above, mice are injected, IP, with a water bolus alone or water
bolus and test compound at 0.76 mg/kg, and changes in brain volume
as detected by MRI are monitored. Mouse brain volumes are assessed
using MRI scans collected with a 9.4T Bruker Biospec MRI scanner at
the Case Center for Imaging Research at Case Western Reserve
University. This imaging method is found to provide sufficient
contrast and resolution to sensitively detect changes in total
brain volume in the mouse water toxicity model for cerebral edema.
High resolution T2-weighted sagittal scans (resolution=0.1
mm.times.0.1 mm.times.0.7 mm) of the mouse head are obtained prior
to water injection, 5.67 min post water injection, and then every
5.2 minutes until the animal expires from the water loading. Each
scan contains twenty-five 0.7 mm contiguous imaging slices of which
14-15 slices contain a portion of the brain. The cross sectional
area of the brain in each imaging slice is measured by manual
region-of-interest selection using ImageJ. Brain volumes are then
calculated for each scan by summing the individual cross sectional
brain areas and multiplying by the slice thickness (0.7 mm).
[0921] Treatment with
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) at 0.76 mg/kg reduces the rate of CE development from
0.081 to 0.032 min.sup.-1 (or 2.5-fold) fit to a single exponential
model (FIG. 2). Also, the extent of CE during the period of
observation is reduced (FIG. 2). Moreover, plasma levels in the
same assay are found to range between 0.03-0.06 .mu.g as determined
by LC-MS/MS (performed at Lerner Center, Cleveland Clinic,
Cleveland, Ohio) and are sufficient to show efficacy in this model
for CE.
TABLE-US-00001 TABLE 1 Efficacy of compounds on CE formation in the
mouse water toxicity model AQP Cerebral Edema Inhibition Cell-Based
Rate by MRI Compound Assay (%) (min.sup.-1) No Drug 0 0.081 N-[3,5-
47.9 0.032 bis(trifluoromethyl)phenyl]-5-
chloro-2-hydroxybenzamide
For no drug and
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
n=14 mice each.
Example 4
High Throughput Screening Assay
[0922] Under hypotonic shock, both untransfected cells and cells
expressing an unrelated transmembrane protein (CD81, at levels
equivalent to AQP4b) swell slowly but remain intact. These
observations are used to develop our high-throughput screening
assay (HTS).
[0923] After hypotonic shock in a 384 well plate format, we return
osmolality to normal (300 mOsm) by adding 2.times. concentrated
phosphate buffered saline supplemented to 2 .mu.M with a
nonfluorescent acetoxymethyl derivative of calcein (calcein-AM) to
each well. Intact cells take up calcein-AM and convert it to the
fluorescent dye calcein--giving a quantitative measure of the
remaining intact cells. Burst cells do not convert the precursor to
the dye. Water uptake by AQP4-expressing cells is relatively rapid,
with most test cells bursting within 4 min of hypotonic shock,
whereas most cells expressing CD81 remain viable after 8 min.
Intracellular conversion of calcein-AM provides a strong and easily
detectable signal at 535 nM in our assay (FIG. 3).
[0924] Calcein Fluorescence End-Point Assay:
[0925] Cells are seeded 24 hr before assay to reach 100%
confluence. Culture medium is replaced with H.sub.2O for 5:30 min
(osmotic shock). Osmolality is then normalized with the addition of
2.times.PBS plus 2 .mu.M calcein-AM. Cells are then incubated at
37.degree. C. for an additional 30 min and fluorescence measured on
a plate-reader. Rows 1-22 are seeded with CHO-AQP4 cells, and rows
23-24, with CHO-CD81 cells (384 well plate). Note, all plate edges
are discarded. Relative Fluorescence Intensity is calculated as the
fluorescence intensity (FI) of each well divided by the mean FI of
AQP4 cells treated with DMSO (control). Criteria for a successful
assay: coefficients of variation (CVs)<15%, and Z-factors
>0.5. Statistical analysis shows that 5.5 min of osmotic shock
provides the optimal signal-to-noise ratio.
TABLE-US-00002 TABLE 2 Statistics for endpoint `calcein` assay in
FIG. 3; 5:30 min time point shown: Mean StDev CV Z' S/B AQP4 581618
66311 11% 0.629 5.0 CD81 2910106 221240 8%
[0926] As will be observed, the signal for the CD81 cells is ca.
5.times. higher than the signal for the APQ4 cells, because by 5.5
mins, most of the AQP4 cells have burst, while most of the CD81
cells remain intact. Inhibition of AQP4 would therefore be expected
to provide a higher signal, more like the CD81 cells.
[0927] This assay is applied in a pilot screen of the MicroSource
GenPlus 960 and the Maybridge Diversity.TM. 20 k libraries
(approximately 21,000 compounds tested, each compound at 10-20
.mu.M).
[0928] From this assay, a specific chemical series is identified,
phenylbenzamides, which represents 3 out of the top 234 hits.
[0929] Hits from the HTS are validated using the same assay using a
different plating arrangement. In FIG. 4, we show this validation
assay used to examine
5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide. Cells are
seeded in a 96 well multiplate format with the plates edges omitted
(lanes 1 and 24) and an entire column (n=16) is used to test the
ability of a compound to block AQP4-mediated cell bursting upon
H.sub.2O shock. CHO cells expressing CD81 are seeded in lanes 2-3
as a control, and CHO cells expressing AQP4, in lanes 4-23. Cells
are treated with 0.1% DMSO in 10% FBS, DMEM (even numbered columns)
or 10 .mu.M
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (odd
number columns) in 0.1% DMSO, 10% FBS, DMEM for 30 minutes. The
cells are shocked with H.sub.2O for 5:30 minutes, then osmolality
returned to 300 mOsm in the presence of 1 .mu.M calcein-AM, as
described above. The cells are incubated at 37.degree. C. for 30
minutes and the relative fluorescence measured (ex 495/em 535 nM)
on a fluorescence multiplate reader. The data in FIG. 7 represents
the average relative fluorescence units (RFU.+-.SEM, n=16).
Example 5
Water Toxicity Model for CE: Intracranial Pressure (ICP)
[0930] ICP is monitored using a Samba 420 Sensor, pressure
transducer, with a Samba 202 control unit (Harvard Apparatus,
Holliston, Mass.). This ICP monitoring system consists of a 0.42 mm
silicon sensor element mounted on an optical fiber. A 20-gauge
syringe needle is implanted through the cisterna magna to a depth
of .about.1 cm. The needle then acts as a guide for insertion of
the Samba Sensor and the site of implantation and the open end of
the needle are sealed with 100% silicone sealant. A baseline ICP
reading is established followed by a water bolus IP injection (20%
weight of animal) with or without
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. ICP
is monitored until the animal expires from the water load.
[0931] Adjusting for the slight rise in ICP observed in the animals
when they are monitored without the water bolus injection (FIG. 5,
No Water Toxicity),
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) at 0.76 mg/kg reduces the relative rate of ICP rise by
36%, from 3.6.times.10.sup.-3 min.sup.-1 to 2.3.times.10.sup.-3
min.sup.-1 (n=6 mice/treatment, mean.+-.SEM).
Example 5
Conversion from
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt to
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
[0932] Plasma or serum levels of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate are measured by LC-MS/MS at the Mass
Spectrometry II Core facility at the Lerner Research Institute of
the Cleveland Clinic Foundation. Measurements are taken at 15
minutes and 24 hours after a 10 mg/kg i.p. loading dose and 1 mg/ml
at 8 .mu.l/h maintenance dose (delivered by an Alzet i.p. osmotic
pump, Durect Corp., Cupertino, Calif.) of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt (n=5 mice/time point, mean.+-.SEM)
(FIG. 6). After initial processing to remove proteins (75%
acetonitrile extraction),
5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide is introduced to
improve quantitation using multiple reaction monitoring (MRM).
Samples are analyzed by tandem LC-MS/MS using C18 reversed-phase
chromatography and mass analysis with a triple-quadrapole mass
spectrometer. The LC method is sufficient to separate
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) from
5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide and subsequent
MRM gave reliable quantitation with a linear response from
0.004-0.4 ng of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) for its most abundant daughter ion. The dashed line in
FIG. 6 is the relative effective plasma concentration of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) observed in the mouse water toxicity model. Inclusion
of an Alzet osmotic pump (Durect Corp., Cupertino, Calif.)
containing
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt in the peritoneum is sufficient, in
conjunction with an initial loading dose, to sustain
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) above the expected efficacious plasma concentration of
20 ng/ml for 24 hours (FIG. 6).
[0933] The solubility of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide in
water is 3.8 .mu.g/ml. The solubility of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt in water is 1 mg/ml.
Initial experiments show rapid bioconversion of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt to
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide when
added to mouse plasma in vitro. Less than 5 minutes at 20.degree.
C. is sufficient to render
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt undetectable. In addition,
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt is undetectable in plasma samples
taken from mice injected IP with
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt. Instead,
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is
detected at a concentration consistent with good bioavailability
and near-complete conversion of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt. With
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate bis ethanolamine salt doses of 10 mg/kg and IP injection
volumes in saline (0.5 ml for a 30 g mouse), that give serum
concentrations of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide in
excess of 400 ng/ml (FIG. 6) can be used. Key PK parameters in mice
are: rate of absorption 0.12 min.sup.-1; rate of elimination 0.017
min.sup.-1.
Example 6
Animal Stroke Model
[0934] Most ischemic strokes (.about.80%) occur in the region of
the middle cerebral artery (MCA). To mimic this injury in mice, an
intraluminal monofilament model of middle cerebral artery occlusion
(MCAo) is used. Occlusion is achieved by inserting a surgical
filament into the external carotid artery (ECA) and threading it
forward into the internal carotid artery (ICA) until the tip blocks
the origin of the MCA. The resulting cessation of blood flow gives
rise to subsequent brain infarction in the MCA territory (Longa, E.
Z. et al., Reversible Middle Cerebral Artery Occlusion Without
Craniectomy in Rats, Stroke, 20, 84-91 (1989)). This technique is
used to study a temporary occlusion in which the MCA is blocked for
one hour. The filament is then removed allowing reperfusion to
occur for 24 hours before the animal's brain is imaged using
T2-weighted scans in a 9.4T Bruker MRI scanner at the Case Center
for Imaging Research (FIG. 7). FIG. 7 shows a single slice from a
T2-weighted MR image depicting the center of the brain showing
cerebral cortex, hippocampus, thalamus, amygdala and hypothalamus
for a "Normal" mouse (left panels) and a mouse which receives MCAo
for one hour followed by 24 hours of reperfusion (right panels).
Dashed lines mark the midline of the brain and show a large shift
in the MCAo brain due to cerebral edema. Solid line highlights the
region of infarct in the MCAo brain.
[0935] Survival--
[0936] Mice are treated with
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (Compound 5) using a 2 mg/kg i.p. loading
dose and 1 mg/ml at 8 .mu.l/h maintenance dose (delivered by an
i.p. osmotic pump) of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt, or given saline (controls; n=17) using an
identical approach. In this model, we observed a 29.4% improvement
in overall survival at 24 h when animals are treated with
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (X.sup.2(1)=4.26; P<0.05).
[0937] Cerebral Edema--
[0938] Mice are given saline or treated with
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (Compound 5) by multi-dosing at 5 mg/kg
i.p. every three hours (n=8 per treatment). This dosing regimen is
sufficient to maintain a plasma concentration of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
>20 ng/ml for the duration of the study. Ipsilateral and
contralateral hemispheric volume is measured from the T2-weighted
MR images of mice 24 hours post-icus. Relative change in
hemispheric volume is calculated as a percent of the difference
between ipsilateral brain volume (V.sub.i) and contralateral brain
volume (V.sub.c) relative to the contralateral brain volume
(Percent Change in Hemispheric Brain
Volume=((V.sub.i-V.sub.c)/V.sub.c).times.100%.
[0939] Control animals show swelling in the ipsilateral hemisphere
with a relative change in ipsilateral brain volume of
13.4%.+-.1.9%, while animals given
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (Compound 5) show a 4.2.+-.1.7% change
(P=0.003, .+-.SEM, see FIG. 8). This represents a 3.2-fold
reduction in brain swelling after MCAo.
[0940] Neurological Outcome--
[0941] In the same experiment as above, animals are scored for
neurological outcome on a simple 5 point scale described in Manley,
G. T. et al., Aquaporin-4 Deletion in Mice Reduces Brain Edema
After Acute Water Intoxication and Ischemic Stroke, Nature
Medicine, 6, 159-163 (2000). An improvement in neurological outcome
is observed for animals given
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (Compound 5). Control animals have an
average neurological score of 2.77.+-.0.66, while animals given
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (Compound 5) have an average score of
0.88.+-.0.31 (FIG. 9, inset, P=0.025, n=9 per treatment). Animals
given 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (Compound 5) did not progress into a state
of severe paralysis or death.
[0942] The data from the MCAo stroke model together with the water
toxicity (brain edema) model link the pharmacology of
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate disodium salt (Compound
5)/N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) with improved outcomes in stroke.
Example 7
2-{[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate
##STR00045##
[0943] Step 1:
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
##STR00046##
[0945] 5-chloro salicylic acid (8.75 g, 50 mmol, 1 eq) is dissolved
in toluene (300 mL) under N.sub.2 atmosphere then phosphorus
trichloride (2.2 mL, 25 mmol, 0.5 eq) is added dropwise followed by
aniline (10 g, 43.7 mmol, 0.87 eq). The reaction mixture is stirred
under reflux for 12 h then cooled to room temperature. The reaction
mixture is quenched with NaHCO.sub.3 saturated solution and stirred
for 10 min. To this solution is added 1M HCl (100 mL) until the pH
of the aqueous layer is 5 and the aqueous layer is extracted with
ethyl acetate (2.times.300 mL). The combined organics are then
dried over sodium sulfate and concentrated in vacuo to yield the
crude product which is purified by flash chromatography (5-20%
EtOAc/hex). The yield of pure product as a white solid is 16 g
(yield 85%) which is >95% pure by .sup.1H NMR. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 11.35 (bs, 1H), 10.85 (bs, 1H), 8.40 (s,
2H), 7.80-7.79 (m, 2H), 7.50 (dd, 1H), 7.00 (d, 1H).
Step 2:
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
bis(2-(trimethylsilyl)ethyl) phosphate
##STR00047##
[0947]
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (4.0
g, 0.01 mol, 1 eq) is dissolved in CH.sub.3CN (104 mL) then DMAP
(0.08 g, 0.001 mol, 0.06 eq), Hunig's base (7.36 mL, 0.021 mol, 2
eq) and CCl.sub.4 (8.02 g, 0.052 mol, 5 eq) are added in this
order. The solution is cooled to 0.degree. C. and
HP(O)(OCH.sub.2CH.sub.2Si(CH.sub.3).sub.3).sub.2 (4.66 g, 0.016
mol, 1.5 eq) in CH.sub.3CN (5 mL) is added dropwise. The reaction
mixture is stirred at room temperature for 20 h then water is added
and extracted twice with EtOAc. The combined organic layers are
washed with a saturated solution of NaCl, dried over
Na.sub.2SO.sub.4, filtered and the solvent is concentrated in vacuo
to give the crude material which is used as such for next step.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 10.20 (bs, 1H), 8.32 (s,
2H), 7.90 (s, 1H), 7.62 (s, 1H), 7.45-7.40 (m, 1H), 7.30-7.28 (m,
1H), 4.40-4.30 (m, 4H), 1.20-1.00 (m, 4H), 0.0 (s, 18H).
Step 3:
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate
##STR00048##
[0949] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
bis(2-(trimethylsilyl)ethyl) phosphate (6.64 g, 0.01 mol, 1 eq) is
dissolved in a mixture TFA:Water (5:1, 50 mL). The reaction mixture
is stirred at room temperature for 2 h then solvent is concentrated
in vacuo. The resulting white solid is dissolved in Et.sub.2O (20
mL) then concentrated in vacuo. This operation is repeated twice or
until the compound becomes much less soluble in Et.sub.2O. The
resulting material is suspended in a mixture Et.sub.2O:Hex (6:1, 50
mL) and filtered to give the desire material as light red solid.
Finally, the solid is dissolved in water (100 mL), filtered and the
resulting aqueous solution is freeze dried to give the desired
product as a white solid (yield 76% over two steps, 97% pure by
HPLC). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.38 (s, 2H),
7.78 (s, 1H), 7.70 (s, 1H), 7.55-7.50 (m, 1H), 7.45-7.43 (m,
1H).
Example 8
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis ethanolamine salt
##STR00049##
[0951] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate (2.14 g, 0.005 mol, 1 eq) is dissolved in MeOH
(46 mL) then ethanolamine (0.56 mL, 0.009 mol, 2 eq) is added. The
reaction mixture is stirred at room temperature for 2 h then
solvent is concentrated in vacuo to give the desired product as a
white solid (yield 84%, 97% pure by HPLC). .sup.1H NMR (300 MHz,
D.sub.2O): .delta. 8.15 (s, 2H), 7.85 (d, 2H), 7.37-7.34 (m, 2H),
3.62 (t, 4H), 2.95 (t, 4H).
Example 9
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis diethanolamine salt
##STR00050##
[0953] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate (300 mg, 0.647 mmol, 1 eq) is dissolved in
MeOH (3.2 mL) then diethanolamine (0.124 mL, 1.294 mmol, 2 eq) is
added. The reaction mixture is stirred at room temperature for 2 h
then solvent is concentrated in vacuo to give the desire product as
a yellow foam (yield 100%, 95% pure by HPLC). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.52 (s, 2H), 7.76 (s, 1H), 7.62 (s, 1H),
7.48 (d, 1H), 7.37 (d, 1H), 3.55 (s, 8H), 2.80 (s, 8H).
Example 10
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis triethanolamine salt
##STR00051##
[0955] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate (300 mg, 0.647 mmol, 1 eq) is dissolved in
MeOH (3.2 mL) then triethanolamine (0.172 mL, 1.294 mmol, 2 eq) is
added. The reaction mixture is stirred at room temperature for 2 h
then solvent is concentrated in vacuo to give the desired product
as a yellow oil (yield 100%, 98% pure by HPLC). .sup.1H NMR (500
MHz, DMSO-d.sub.6): .delta. 8.50 (s, 2H), 7.76 (s, 1H), 7.62 (s,
1H), 7.52 (d, 1H), 7.29 (d, 1H), 3.55 (s, 12H), 2.82 (s, 12H).
Example 11
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis sodium salt (Compound 5)
##STR00052##
[0957] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate (300 mg, 0.647 mmol, 1 eq) is suspended in
water (6.4 mL) then NaOH (1M) (1.29 mL, 1.294 mmol, 2 eq) is added.
The reaction mixture is stirred at room temperature for 2 h then
the solution is filtered and freeze dried to give the desired
product as a white solid (yield 100%, 93% pure by HPLC).
Example 12
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis potassium salt
##STR00053##
[0959] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate (300 mg, 0.647 mmol, 1 eq) is suspended in
water (6.4 mL) then KOH (1M) (1.29 mL, 1.294 mmol, 2 eq) is added.
The reaction mixture is stirred at room temperature for 2 h then
the solution is filtered and freeze dried to give the desired
product as a white solid (yield 100%, 82% pure by HPLC).
Example 13
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
hydrogen phosphate mono sodium salt,
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis sodium salt, and
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis ethanolamine salt
[0960] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
hydrogen phosphate mono sodium salt,
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis sodium salt, and
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis ethanolamine salt are made as follows: 2 mM of
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate is dissolved in ethanol 50 ml and appropriate
equivalents of each base are added. Evaporation gives salts which
are dissolved in water and freeze dried.
Example 14
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
hydrogen phosphate mono ethanolamine salt
##STR00054##
[0962] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
hydrogen phosphate mono ethanolamine salt is made as follows: 1 g
of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate is dissolved in isopropanol and 1 eq ethanol
amine is added. Evaporation gave
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
hydrogen phosphate mono ethanolamine salt.
Example 15
Stability and Solubility
[0963] To understand the stability and solubility of the novel
prodrug salts a 95% pure lot of
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate is purified as follows. 15 g is dissolved in
1.2 L of water with 120 mM of sodium hydroxide and extracted with
500 ml ethyl acetate to remove phenol and non acid impurities. The
aqueous layer is acidified with concentrated HCl to pH 1.2 and
extracted with ethyl acetate 1 L followed by 600 ml. The ethyl
acetate layer is dried MgSO.sub.4 and sodium sulphate, filtered,
and evaporated to give about 13 g of 98% pure
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate. NMR showed 1 mole of ethyl acetate trapped in
solid. Ethyl acetate is removed by adding 100 ml of methanol and
evaporating.
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate is stable at RT for a week or more. Sample
kept at RT. It is soluble at 5 mg/mL in 1% Na.sub.2HPO.sub.4 giving
pH of about 7. Dissolved in 2% Na.sub.2HPO.sub.4 at 5 mg/mL gives
pH of 7.4
[0964] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
hydrogen phosphate mono sodium salt ("mono sodium salt"),
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis sodium salt ("bis sodium salt"), and
2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
phosphate bis ethanolamine salt ("bis ethanolamine salt") are made
and freeze dried as in Example 7. In all cases stability studies
show hydrolysis in the solid state at about 1% per day.
Solubilities are about 5 mg/mL for mono sodium salt and 10 mg/mL
for both bis sodium and bis ethanolamine salt in water.
[0965] Final pH of solutions are about 7.5 for the bis ethanolamine
salt, pH 8.5 for mono sodium salt, and pH 9.5 for bis sodium salt
in water. In all cases solutions of these salts show less than 1%
phenol over 12 hrs. Longer term their stability is the same as the
solid samples (about 1% per day at RT). Hydrolysis rate is expected
to be faster at higher pH.
[0966] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl
dihydrogen phosphate mono ethanolamine salt ("mono ethanolamine
salt") is made as in Example 8. Surprisingly, the mono ethanolamine
salt only shows about 1% hydrolysis after 5 days at RT. Its
solubility in water is about 5 mg/ml. Solubility is expected to be
higher at higher pH.
Example 16
Synthesis of ala and ala ala prodrugs of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
##STR00055##
[0968] To 750 mg of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (2
mM) in 10 ml of DMF was added 360 mg (2 mM) of boc ala followed by
400 mg DCC (2 mM). Reaction is stirred for 3 hrs. and then
filtered. To DMF is added 200 ml water and extracted with ethyl
acetate. Extract is dried and evaporated. Purified on combi flash
hexane to 50% ethyl acetate. Yield 800 mg of Compound 11 wherein
R.sub.2=Boc.
[0969] To 800 mg Compound 11 wherein R.sub.2=Boc in 6 ml THF is
added 3 ml of 4N HCl in dioxane and stirred overnight. Product
precipitates. 30 ml ether is added and product is filtered off,
washed with ether, and dried to give 500 mg of Compound 12 as an
HCl salt as a white powder.
[0970] Compound 12 wherein R.sub.2 is CH.sub.3C(O)CH(CH3)NHBoc is
synthesized using the same method but when tried to filter off,
solid it turned into an oil. Ether is added and decanted several
times. Finally compound solidifies. The solid is sticky and
hygroscopic. Yield is about 100 mg.
[0971] Solubility
[0972] Both prodrugs are insoluble in water and pH 7.4 water even
after stirring for 4-5 hrs., as determined by HPLC analysis of
filtrate.
Example 17
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate (Formula I) and
tris(hydroxymethyl)aminomethane
[0973] 2.5 to 5 equivalents of tris(hydroxymethyl)aminomethane is
added to
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate (Formula I). Water is added and the mixture is
stirred or sonicated. Yields 10 mg/ml to 20 mg/ml solutions stable
for at least 24 hrs.
[0974] HPLC conditions for assaying the stability of compositions
formed from
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate and a base, e.g.,
tris(hydroxymethyl)aminomethane are as follows:
[0975] Hplc condition c18 SB Agilent 4.6.times.125 mm column 3 or 5
u
[0976] At 1.5 mil per min 10% to 100% acetonitrile with 2 g
ammonium acetate per 4 l of water
[0977] Using waters 2695 hplc running millennium 32 software
[0978] No baseline subtraction
[0979] Solid state compositions of the invention falling under
Composition I show about 1% of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide over
a four month period at room temperature as measured under the HPLC
conditions above.
[0980] Reconsistuted compositions of the invention falling under
Composition I show 1-2% degradation over a 24 hour period.
Example 18
Conversion from
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
phosphate Tris-Base solution to
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
[0981] The
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate is dissolved at 10 mg/mL in 0.07% aqueous
Tris-Base. This solution is then diluted to 5 mg/ml with water and
used to fill an Alzet osmotic pump (DURECT, Corp., model 2001D,
delivery at 8 ul/hr for 24 hrs). Surgery is performed on an
anesthetized mouse under sterile conditions to implant the pump in
the peritoneal cavity. Once the abdominal incision is closed with
sutures, muscle layer followed by skin, an IP bolus of 10 mg/kg is
given. For this bolus the 10 mg/mL
2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl
dihydrogen phosphate solution is diluted to 1 mg/ml with water and
the appropriate volume administered. At 15 min, 6 hr, 18 hr and 24
hr post injection blood is drawn by tail laceration, serum prepared
and stored at -20 C for later processing. In preparation for
LC-MS/MS, an aliquot of the serum sample is diluted 4-fold with
acetonitrile to precipitate proteins and ensure soluble release of
the parent compound
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. The
protein is removed by centrifugation and the supernatant diluted to
37.5% acetonitrile using water.
5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide is added as an
internal standard and the sample run on LC-MS/MS. In this
experiment n=3. See FIG. 10. The dashed line in FIG. 10 is the
relative effective plasma concentration of
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound 1) observed in the mouse water toxicity model.
* * * * *