Pharmaceutical composition of aquaporin inhibitor and method for producing the same

Abstract

This application relates to a pharmaceutical composition of an aquaporin inhibitor and a method for producing the same. The pharmaceutical composition comprises 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine. The pharmaceutical composition of an aquaporin inhibitor and a method for producing the same have the following advantages: the process is simple, easy to operate, conducive to industrial production, good product stability, and a significantly reduced content of degradable impurities, which ensures pharmaceutical efficacy.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical compositions, particularly pharmaceutical compositions of aquaporin inhibitors and methods for their production.

Background Art

[0002] Aquaporin is a cell membrane protein that functions as a molecular water channel mediating the flow of water into and out of cells. Although there is a certain degree of passive diffusion or osmosis of water across the cell membrane, aquaporin is involved in the rapid and selective transport of water into and out of cells. These water channels selectively guide water molecules into and out of cells, while at the same time blocking the passage of ions and other solutes, thereby maintaining the membrane potential of cells. Aquaporin is found in virtually all living organisms, from bacteria to plants and animals. In humans, they are found in cells throughout the body.

[0003] Aquaporin inhibitors, such as inhibitors of AQP4 and / or AQP2, may be useful for the treatment or control of diseases of water imbalance, such as edema (particularly cerebral and spinal cord edema), hyponatremia and excessive fluid retention, as well as diseases such as epilepsy, retinal ischemia and other eye diseases, myocardial ischemia, myocardial ischemia / reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, and migraine.

[0004] WO2013169939 discloses N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxy-benzamide (the structure shown in formula (II)) as an aquaporin inhibitor. Formula (I) (the structure shown below) is a prodrug of formula (II). The compound can treat or control aquaporin-mediated diseases selected from cytotoxic cerebral edema, spinal cord edema, retinal edema, optic nerve edema, cardiac edema, neuromyelitis optica, hyponatremia, retinal ischemia, and excessive fluid retention. [[ID=​​​​​​ Compounds of formula (I) need to be prepared as liquid formulations for intravenous injection or infusion to achieve rapid onset of action. However, the water solubility of formula (I) needs to be improved to allow injections that provide a therapeutically effective amount of formula (II). Furthermore, the more soluble salts of formula (I) can revert to N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (compound of formula (II)) even in the solid state. WO2015069956 shows that certain lyophilized salts of formula (I) revert to formula (II) even in the solid state (approximately 1% per day or 1% over 5 days). Solving the problems of drug solubility and stability is urgent in order to provide pharmaceutical compositions that meet the requirements of clinical medicine. [ka] Formula (II) [Modes for carrying out the invention]

[0006] This application provides a pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine (also known as N-methyl-D-glucamine).

[0007] In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate to meglumine is 1:0.2 to 4. In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate to meglumine is 1:0.4 to 2. In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate to meglumine is 1:0.6 to 1.

[0008] In some embodiments, the pharmaceutical composition is an injectable pharmaceutical composition.

[0009] In some embodiments, the pharmaceutical composition is a freeze-dried pharmaceutical composition.

[0010] In some embodiments, the pharmaceutical composition of the present application further comprises a freeze-drying additive.

[0011] In some embodiments, the lyophilization additive is selected from one or a mixture of sucrose, lactose, mannitol, glucose, and trehalose.

[0012] In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to the lyophilized additive is 1:1 to 10. In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to the lyophilized additive is 1:2.5 to 7.5. In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to the lyophilized additive is 1:5.

[0013] Optionally, the pharmaceutical composition in this application further comprises a pH adjuster. The pH adjuster in this application is selected from one or a mixture of hydrochloric acid, sodium hydroxide, citric acid, and phosphate buffer. In some embodiments, the pH adjuster in this application is selected from hydrochloric acid and citric acid.

[0014] In some embodiments, the pH of the pharmaceutical composition in this application is 7.5 to 9.5. In some embodiments, the pH of the pharmaceutical composition in this application is 8.0 to 9.0. In some embodiments, the pH of the pharmaceutical composition in this application is approximately 8.5.

[0015] In some embodiments, the present application provides a pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, a lyophilization additive, and a pH adjuster.

[0016] If desired, the pharmaceutical composition in this application may further include water for injection.

[0017] In some embodiments, the present application: a) Take 60% to 90% of a specified volume of water for injection, cool it to 15°C to 25°C, add meglumine and dissolve it until clear, and slowly add 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; b) A step of adding other ingredients, if desired; c) Adding a predetermined amount of water for injection; d) If desired, the product obtained in step (c) is sterilized by filtration and freeze-dried. The present invention provides a method for producing the above-mentioned pharmaceutical composition, which includes the above-mentioned [ingredient].

[0018] In some embodiments, step (a) is to cool to 20°C.

[0019] In some embodiments, the other components in step (b) are selected from lyophilization additives and pH adjusters.

[0020] In some embodiments, the freeze-drying process in step (d) is as follows: (1) maintain at -50°C for 2 to 6 hours; (2) raise the temperature to -20°C to -10°C and maintain for 20 to 40 hours; (3) raise the temperature to 20 to 30°C and maintain for 10 to 30 hours. In some embodiments, the temperature is raised to 25°C in step (3).

[0021] In some embodiments, the lyophilization process of step (d) is as follows: (1) lower the temperature to -50°C; (2) raise the temperature to -15°C; (3) lower the temperature to -50°C; (4) apply a vacuum; (5) lower the temperature to -10°C; (6) raise the temperature to -5°C; and (7) raise the temperature to 25°C under vacuum.

[0022] In some embodiments, the lyophilization process of step (d) is as follows: (1) lower the temperature (e.g., shelf temperature) from -40°C to -60°C (e.g., -50°C) within 2 to 6 hours (e.g., within 4 hours); (2) maintain the temperature (e.g., shelf temperature) at -40°C to -60°C (e.g., -50°C) for 1 to 2 hours (e.g., 0.5 hours); (3) raise the temperature (e.g., shelf temperature) to -20°C to -10°C (e.g., -15°C) (e.g., rapidly); (4) maintain the temperature at -20°C to -10°C for 1 to 3 hours (e.g., 2 hours); (5) lower the temperature (e.g., slab temperature) from -40°C to -60°C (e.g., -50°C) (e.g., rapidly); (6) maintain the temperature (e.g., slab temperature) at -40°C to -60°C (e.g., -50°C) for 2 to 6 hours (e.g., 4 hours); (7) apply a vacuum (e.g., achieve a vacuum of less than 0.2 mbar); (8) lower the temperature (e.g., shelf temperature) from -20°C to 0°C (e.g., -10°C) within 6 to 10 hours (e.g., 8 hours); (9) maintain the temperature (e.g., shelf temperature) at -20°C to 0°C (e.g., -10°C) for 8 to 12 hours (e.g., 10 hours); (10) raise the temperature to -10°C to 0°C (e.g., -5°C) within 1 to 3 hours (e.g., 2 hours); (11) maintain the temperature (e.g., shelf temperature) at -10°C to 0°C (e.g., -5°C) for 13 to 17 hours (e.g., 15 hours); (12) raise the temperature (e.g., shelf temperature) to 20°C to 30°C (e.g., 25°C) within 4 to 8 hours (e.g., 6 hours) under vacuum (e.g., maximum vacuum); and (13) maintain the temperature at 20°C to 30°C (e.g., 25°C) for 10 to 14 hours (e.g., 12 hours).

[0023] In some embodiments, the lyophilized formulation disclosed herein is reconstituted with an aqueous solution containing sodium and / or potassium (e.g., an aqueous solution containing sodium chloride, such as 0.9% NaCl, or an aqueous solution containing sodium chloride and sodium lactate or sodium acetate (e.g., lactated Ringer's solution or acetate Ringer's solution), or an aqueous solution containing potassium chloride (e.g., potassium chloride injection solution)). Reconstitution with water for injection or glucose may result in visible particles.

[0024] In some embodiments, the "pharmaceutically acceptable salts" in the present application are selected from alkali metal salts (e.g., sodium salts, preferably disodium salts), and organic base salts (e.g., ammonium salts, preferably meglumine salts).

[0025] In some embodiments, the "pharmaceutically acceptable solvate" in the present application is a hydrate (e.g., dihydrate).

[0026] In the present application, when the pharmaceutical composition is in solid form (e.g., lyophilized formulation), the pH refers to the pH value of the solution of the solid pharmaceutical composition before lyophilization or the pH value after reconstitution.

[0027] In the present application, unless otherwise specified, the weight of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate, is based on the weight of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate.

[0028] Sugars (e.g., trehalose) may be provided in hydrated form. In the present application, unless otherwise specified, the weight of a sugar (e.g., sucrose, lactose, glucose or trehalose) is based on the weight of the sugar in anhydrous form.

[0029] The present invention provides a formulation of the compound of formula (I) that can be rapidly activated and reconstituted into a human-acceptable liquid for intravenous injection or infusion, so that the compound of formula (I) can be used in the treatment of cerebral edema. At the same time, the composition of the compound of formula (I) and the method of producing it in the present invention are simple, easy to handle, contribute to industrial production, have good product stability, contain significantly low levels of degradable impurities (e.g., the compound of formula (II)), and reliably exhibit efficacy. For example, compared to compositions containing other bases such as sodium salt bases or other amine bases (e.g., arginine, lysine, and histidine), certain compositions containing meglumine disclosed herein are shown to exhibit less reversion from formula (I) to formula (II). Although not bound by theory, it is thought that some bases may drive a monomolecule process in which formula (I) reverts to formula (II). Formula (II) has low aqueous solubility and therefore even small amounts in an injectable formulation can produce visible particles, rendering the formulation unusable. The use of meglumine results in fewer impurities in the lyophilized composition, making the composition acceptable for injection after reconstitution.

[0030] The present invention provides a pharmaceutical composition (composition 1a) comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine.

[0031] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)): [ka] Further, a solid freeze-dried pharmaceutical composition (composition 1b) containing a meglumine salt is provided.

[0032] The following compositions 1a and 1b are further provided:

[0033] 1.1. Composition 1a, wherein the composition is a solid freeze-dried pharmaceutical composition.

[0034] 1.2. The pharmaceutically acceptable salt is 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt, i.e., the pharmaceutically acceptable salt is: [ka] The composition is any of composition 1a, 1b, or 1.1. Alternatively, for example, the composition is any of composition 1a, 1b, or 1.1, wherein the composition comprises a mixture of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate, meglumine, and a meglumine salt of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate (e.g., 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt).

[0035] 1.3. Any of compositions 1a, 1b, 1.1 or 1.2, wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) dihydrogen phosphate to meglumine is 1:0.2 to 4, for example 1:0.4 to 2, for example 1:0.6 to 1. Or, any of compositions 1a, 1b, 1.1 or 1.2, for example, the amount of meglumine is sufficient to provide a pH of the dissolved composition before and / or after lyophilization of 7 to 10, for example 7.5 to 9.5, for example 8 to 9, for example 8.2 to 9, for example 8.5 to 8.6, for example 8.5.

[0036] 1.4. Composition 1a, 1b, or any of 1.1 to 1.3, wherein the molar ratio of dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) to meglumine is 1:1 to 5, e.g., 1:2 to 5, e.g., 1:2 to 4, e.g., 1:2 to 3, e.g., 1:2 to 2.5, e.g., 1:2 to 2.3 (e.g., 1:2.1 to 2.3), e.g., 1:2 to 2.2, e.g., 1:2.1 to 2.2, e.g., 1:2.2.

[0037] 1.5. Composition 1a, 1b, or any of 1.1 to 1.3, wherein the molar ratio of deprotonated dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) to deprotonated meglumine is 1:1 to 5, for example 1:2 to 5, for example 1:2 to 4, for example 1:2 to 3, for example 1:2 to 2.5, for example 1:2 to 2.3 (for example 1:2.1 to 2.3), for example 1:2 to 2.2, for example 1:2.1 to 2.2, for example 1:2.2.

[0038] 1.6. Any of compositions 1a, 1b, or 1.1-1.5, wherein the composition is intended for injection after reconstitution, for example, for intravenous injection and / or intravenous infusion.

[0039] 1.7. Any of compositions 1a, 1b, or 1.1-1.6, wherein the composition further comprises a freeze-drying additive. For example, any of compositions 1a, 1b, or 1.1-1.6, wherein the freeze-drying additive is one or a mixture of monosaccharides, disaccharides, and sugar alcohols. For example, any of compositions 1a, 1b, or 1.1-1.6, wherein the freeze-drying additive is a disaccharide or a mixture of disaccharides.

[0040] 1.8. Composition 1.7 in which the lyophilization additive is selected from one or a mixture of sucrose, lactose, mannitol, glucose, and trehalose, either in free or hydrated form. For example, Composition 1.7 in which the lyophilization additive is trehalose in free or hydrated (e.g., dihydrate) form. For example, Composition 1.7 in which the lyophilization additive is mannitol. For example, Composition 1.7 in which the lyophilization additive is sucrose. For example, Composition 1.7 in which the lyophilization additive is lactose in free or hydrated (e.g., monohydrate) form.

[0041] 1.9. Composition 1.8, wherein the freeze-dried additive is selected from one or a mixture of sucrose, lactose, and trehalose.

[0042] 1.10. Composition 1.8, wherein the freeze-drying additive is sucrose.

[0043] 1.11. Composition 1a, 1b, or any of 1.1 to 1.10, wherein the weight ratio of dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) to the freeze-dried additive is 1:1 to 10, for example 1:2.5 to 7.5, for example 1:2.5 to 5, for example 1:5.

[0044] 1.12. Any of compositions 1a, 1b, or 1.1 to 1.11, wherein the composition further comprises a pH adjuster.

[0045] 1.13. Composition 1.12, wherein the pH adjuster is selected from one or a mixture of hydrochloric acid, sodium hydroxide, citric acid, and phosphate buffer.

[0046] 1.14. Composition 1.12, wherein the pH adjuster is selected from hydrochloric acid and citric acid.

[0047] 1.15. Any of compositions 1a, 1b, or 1.1 to 1.14, wherein the pH of the composition is 7 to 10, for example 7.5 to 9.5, for example 8 to 9, for example 8.2 to 9, for example 8.5 to 8.6, for example 8.5.

[0048] 1.16. Any of compositions 1a, 1b, or 1.1 to 1.15, wherein the pH of the composition in solution before freeze-drying is 7 to 10, e.g., 7.5 to 9.5, e.g., 8 to 9, e.g., 8.2 to 9, e.g., 8.5 to 8.6, e.g., 8.5.

[0049] 1.17. Any of compositions 1a, 1b, or 1.1 to 1.16, wherein the pH of the reconstituted composition is 7 to 10, e.g., 7.5 to 9.5, e.g., 8 to 9, e.g., 8.2 to 9, e.g., 8.5 to 8.6, e.g., 8.5.

[0050] 1.18. Composition 1a, 1b, or any of 1.1 to 1.17, wherein the composition is reconstituted with an aqueous solution containing sodium and / or potassium (e.g., an aqueous solution containing sodium chloride, e.g., 0.9% sodium chloride injection, or an aqueous solution containing sodium chloride and sodium lactate or sodium acetate, e.g., Ringer's lactate solution or Ringer's acetate solution, or an aqueous solution containing potassium chloride, e.g., potassium chloride injection).

[0051] 1.19. Composition 1a, 1b, or any of 1.1 to 1.18, wherein the composition is a white mass.

[0052] 1.20. Composition 1a, 1b, or any of 1.1 to 1.19, wherein the composition contains a compound of formula (II) at ≤1% w / w after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C), a compound of formula (II) at ≤0.8% w / w after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C), a compound of formula (II) at ≤0.6% w / w after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C), or a compound of formula (II) at ≤0.5% w / w after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C).

[0053] 1.21. Composition 1a, 1b, or any of 1.1 to 1.20, wherein the composition contains ≤2% w / w total impurities (including the compound of formula (II)) after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C), ≤1% w / w total impurities after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C), ≤0.6% w / w total impurities after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C), and ≤0.5% w / w total impurities after 6 months at room temperature (e.g., after 6 months at 25°C ± 2°C).

[0054] 1.22. Composition 1a, 1b, or any of 1.1 to 1.21, wherein the composition contains a compound of formula (II) in an amount of ≤1% w / w after 6 months at 2°C to 8°C, for example, a compound of formula (II) in an amount of ≤0.5% w / w after 6 months at 2°C to 8°C, for example, a compound of formula (II) in an amount of ≤0.2% w / w after 6 months at 2°C to 8°C, for example, a compound of formula (II) in an amount of ≤0.1% w / w after 6 months at 2°C to 8°C.

[0055] 1.23. Composition 1a, 1b, or any of 1.1 to 1.22, wherein the composition contains ≤2% w / w total impurities (including the compound of formula (II)) after 6 months at 2°C to 8°C, for example ≤0.5% w / w total impurities after 6 months at 2°C to 8°C, for example ≤0.2% w / w total impurities after 6 months at 2°C to 8°C, for example ≤0.1% w / w total impurities after 6 months at 2°C to 8°C.

[0056] 1.24. Composition 1a, 1b, or any of 1.1 to 1.23, wherein the composition contains ≤3% w / w of water, e.g., ≤2% w / w of water, e.g., ≤1.5% w / w of water (e.g., after 6 months at 25°C ± 2°C and / or after 6 months at 2°C to 8°C). The amount of water can be measured, for example, by coulometric Karl Fischer analysis.

[0057] 1.25. Before reconstitution (e.g., in solution before lyophilization) and / or afterward, the composition conforms to the USP (United States Pharmacopeia) <788> and / or ChP (People's Republic of China Pharmacopoeia) 2020 Part 4 <0903> A composition 1a, 1b, or any of 1.1 to 1.24 that conforms to the above.

[0058] 1.26. Before lyophilization and / or after reconstitution, the average number of particles present in the tested unit (e.g., ≤10 units may be tested) is, for a formulation supplied in a container with a stated volume of 100 mL or more (e.g., non-enteral infusion or injection solution) (e.g., a formulation supplied in a container with a stated volume exceeding 100 mL), not more than 25 particles per mL with 10 or fewer particles, and not more than 3 particles per mL with 25 or fewer particles, according to any of composition 1a, 1b, or 1.1-1.25. The average number of particles present in the unit is according to the USP (United States Pharmacopeia) standards. <788> This can be determined by the light-shielding particle counting method described (the light-shielding particle counting method can be performed using the AccuSizer® SIS system or the HIAC Royco particle counter). The number of units tested can provide a statistically appropriate evaluation.

[0059] 1.27. Before lyophilization and / or after reconstitution, the average number of particles present in the tested units (e.g., ≤10 units may be tested) is, for formulations supplied in containers with a stated volume of 100 mL or less (e.g., non-enteral infusion or injection solution) (e.g., formulations supplied in containers with a stated volume of less than 100 mL), not exceeding 6000 particles per container with 10 or fewer particles, and not exceeding 600 particles per container with 25 or fewer particles, according to any of Composition 1a, 1b, or 1.1-1.26. The average number of particles present in the units is according to the USP (United States Pharmacopeia) standards. <788> This can be determined by the light-shielding particle counting method described (the light-shielding particle counting method can be performed using the AccuSizer® SIS system or the HIAC Royco particle counter). The number of units tested can provide a statistically appropriate evaluation.

[0060] 1.28. Before lyophilization and / or after reconstitution, the average number of particles present in the tested unit (e.g., ≤10 units may be tested) is, for formulations supplied in containers with a stated volume of 100 mL or more (e.g., non-enteral infusion or injection solution) (e.g., formulations supplied in containers with a stated volume exceeding 100 mL), not more than 12 particles with 10 or fewer particles per mL, and not more than 2 particles with 25 or fewer particles per mL, according to any of composition 1a, 1b, or 1.1 to 1.27. The average number of particles present in the unit is according to the USP <788> This can be determined by the microscopic particle counting method described. The number of units tested can provide a statistically appropriate evaluation.

[0061] 1.29. Before lyophilization and / or after reconstitution, the average number of particles present in the tested units (e.g., ≤10 units may be tested) is, for formulations supplied in containers with a stated volume of 100 mL or less (e.g., non-enteral infusion or injection solution) (e.g., formulations supplied in containers with a stated volume of less than 100 mL), not exceeding 3000 particles per container with 10 or fewer particles, and not exceeding 300 particles per container with 25 or fewer particles, according to any of composition 1a, 1b, or 1.1 to 1.28. The average number of particles present in the units is, according to USP <788> This can be determined by the microscopic particle counting method described. The number of units tested can provide a statistically appropriate evaluation.

[0062] 1.30. Any of compositions 1a, 1b, or 1.1-1.29, having a turbidimetric turbidity unit (NTU) <2.2 NTU, e.g., ≤2, e.g., ≤1. NTU can be measured using a turbidimeter or turbidimeter. Any of compositions 1a, 1b, or 1.1-1.29, having a solution that is clearer than a standard turbidity solution (e.g., a 0.5 standard turbidity solution).

[0063] 1.31. Any of compositions 1a, 1b, or 1.1 to 1.30, wherein the composition is freeze-dried from an aqueous solution (e.g., water for injection, e.g., sterile water for injection). Any of compositions 1a, 1b, or 1.1 to 1.30, wherein the composition is freeze-dried from an aqueous solution that is substantially free of organic solvents (e.g., t-butyl alcohol) (e.g., free of added organic solvents).

[0064] 1.32. The composition before reconstruction contains Na + and K + A composition that is substantially free of ions, either composition 1a, 1b, or 1.1-1.31. For example, a composition containing detectable Na + or K + Composition 1a, 1b, or any of 1.1-1.31 that contains no ions at all. For example, a composition containing less than 10 ppm (e.g., less than 5 ppm, e.g., less than 1 ppm) of Na. + and / or K + A composition containing ions, either composition 1a, 1b, or 1.1-1.31.

[0065] 1.33. Any of compositions 1a, 1b, or 1.1 to 1.32, wherein the composition is not prepared using a sodium salt (e.g., NaOH, NaH2PO4, Na2HPO4, or Na3PO4) or a potassium salt (e.g., KOH, KH2PO4, K2HPO4, and K3PO4).

[0066] 1.34. Any of compositions 1a, 1b, or 1.1 to 1.33, wherein the composition is substantially free of sodium phosphate (i.e., NaH2PO4, Na2HPO4, and Na3PO4) and potassium phosphate (i.e., KH2PO4, K2HPO4, and K3PO4). For example, any of compositions 1a, 1b, or 1.1 to 1.33, wherein the composition is completely free of detectable sodium phosphate (i.e., NaH2PO4, Na2HPO4, and Na3PO4) or potassium phosphate (i.e., KH2PO4, K2HPO4, and K3PO4).

[0067] 1.35. Any of compositions 1a, 1b, or 1.1 to 1.34, which are not prepared using sodium phosphate (i.e., NaH2PO4, Na2HPO4, and Na3PO4) or potassium phosphate (i.e., KH2PO4, K2HPO4, and K3PO4).

[0068] 1.36. Any of compositions 1a, 1b, or 1.1-1.35, wherein the composition before and / or after reconstitution is substantially free of polysaccharides. As used herein, “polysaccharide” means a chain of 10 or more monosaccharide residues linked by glycosidic bonds. For example, any of compositions 1a, 1b, or 1.1-1.35, wherein the composition before and / or after reconstitution is substantially free of dextran.

[0069] 1.37. Any of compositions 1a, 1b, or 1.1-1.36, wherein the composition before and / or after reconstitution is substantially free of cyclodextrin (i.e., cyclic oligosaccharides composed of (α-1,4)-linked α-D-glucopyranose). For example, any of compositions 1a, 1b, or 1.1-1.36, wherein the composition before and / or after reconstitution is substantially free of hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin (e.g., sulfobutyl ether-β-cyclodextrin sodium). For example, any of compositions 1a, 1b, or 1.1-1.36, wherein the composition before and / or after reconstitution is completely free of detectable cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin (e.g., sulfobutyl ether-β-cyclodextrin sodium)).

[0070] 1.38. Any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, and a monosaccharide (e.g., glucose). For example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and a monosaccharide (e.g., glucose). For example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and glucose. Alternatively, for example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of a mixture of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate, meglumine, and a meglumine salt of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate (e.g., 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt) and a monosaccharide (e.g., glucose).

[0071] 1.39. Any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, and a disaccharide (e.g., one or a mixture of sucrose, lactose, or trehalose). For example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and a disaccharide (e.g., one or a mixture of sucrose, lactose, or trehalose). For example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and sucrose. Or, for example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and lactose. Or, for example, any of compositions 1a, 1b, or 1.1 to 1.38, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and trehalose. Alternatively, for example, any of compositions 1a, 1b or 1.1 to 1.37, wherein the composition essentially consists of a mixture of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate, meglumine, and a meglumine salt of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate (e.g., 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt) and a disaccharide (e.g., one or a mixture of sucrose, lactose, or trehalose).

[0072] 1.40. Any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, and a sugar alcohol (e.g., mannitol). For example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and a sugar alcohol (e.g., mannitol). For example, any of compositions 1a, 1b, or 1.1 to 1.37, wherein the composition essentially consists of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt and mannitol. Alternatively, for example, any of compositions 1a, 1b or 1.1 to 1.37, wherein the composition essentially consists of a mixture of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate, meglumine, and a meglumine salt of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate (e.g., 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl bis-meglumine salt) and a sugar alcohol (e.g., mannitol).

[0073] 1.41. Composition 1a, 1b, or any of 1.1-1.40, whose composition is reconfigured within 180 seconds.

[0074] 1.42. Before freeze-drying and / or after reconstitution, each test sample shall contain ≤3 small visible foreign particles (e.g., spots, short fibers less than 2 mm, and blocks) of any of composition 1a, 1b, or 1.1-1.41. Small visible foreign particles may be measured using a transparency detector (e.g., a YB-2 transparency detector). The visible foreign particle test (including the determination of small visible foreign particles) is in accordance with ChP (People's Republic of China Pharmacopoeia) 2020 Part 4 <0904> It can be implemented as described above.

[0075] 1.43. Composition 1a, 1b, or any of 1.1 to 1.42, wherein the composition is made from a weight ratio of formula I:sucrose:meglumine of 1:5:0.9 to 1 (e.g., 1:5:0.93). For example, the composition is made from 100 mg of formula (I), 500 mg of sucrose, 80 mg of meglumine, 133 mg of a 10% meglumine aqueous solution, and an appropriate amount of sterile water for injection (e.g., sterile water for injection) to make 10 mL.

[0076] The present invention also provides a method for producing a pharmaceutical composition (Method 1a) comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine.

[0077] Also, dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)): [ka] The present invention provides a method (Method 1b) for producing a solid freeze-dried pharmaceutical composition containing a meglumine salt.

[0078] For example, the present invention provides a method for producing any of the compositions 1a, 1b, or 1.1 to 1.43.

[0079] Furthermore, the following methods 1a and 1b are provided:

[0080] 1.1. Method 1a or Method 1b, wherein the pharmaceutical composition is one of compositions 1a, 1b, or 1.1 to 1.43.

[0081] 1.2. Method 1a, 1b, or 1.1, wherein 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) is in a crystalline form, for example, as described in U.S. Patent Application Publication 2019 / 0185496 (which is included as a whole in this specification by appropriate attribution). For example, 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) is in a hydrate crystalline form (e.g., form N) or a solvate, anhydrous crystalline form (e.g., form B), as described in U.S. Patent Application Publication 2019 / 0185496.

[0082] 1.3. Cool water (e.g., sterile water for injection) to 15°C to 25°C (e.g., 20°C) using any of methods 1a, 1b, 1.1, or 1.2.

[0083] 1.4. Add Meglumine to water (for example, add it to water and dissolve until clear), method 1.3.

[0084] 1.5. Add 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof to water, method 1.3 or 1.4. For example, add 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) to water, method 1.3 or 1.4.

[0085] 1.6. Mix dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) with meglumine, according to any of methods 1a, 1b, or 1.1-1.5.

[0086] 1.7. Any of methods 1a, 1b, or 1.1 to 1.6, wherein the weight ratio of dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) to meglumine is 1:0.2 to 4, e.g., 1:0.4 to 2, e.g., 1:0.6 to 1.

[0087] 1.8. Any of methods 1a, 1b or 1.1 to 1.7, wherein the molar ratio of dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) to meglumine is 1:1 to 5, e.g. 1:2 to 5, e.g. 1:2 to 4, e.g. 1:2 to 3, e.g. 1:2 to 2.5, e.g. 1:2 to 2.3 (e.g. 1:2.1 to 2.3), e.g. 1:2 to 2.2, e.g. 1:2.1 to 2.2, e.g. 1:2.2.

[0088] 1.9. Method 1a, 1b, or any of 1.1 to 1.8, which involves mixing 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate with a lyophilized additive.

[0089] 1.10. Add the freeze-dried additive to the water using one of the methods 1.3 to 1.9.

[0090] 1.11. Method 1.9 or 1.10, in which the lyophilization additive is selected from one or a mixture of sucrose, lactose, mannitol, glucose, and trehalose, either in free or hydrated form. For example, Method 1.9 or 1.10, in which the lyophilization additive is trehalose, either in free or hydrated (e.g., dihydrate) form. For example, Method 1.9 or 1.10, in which the lyophilization additive is mannitol. For example, Method 1.9 or 1.10, in which the lyophilization additive is sucrose. For example, Method 1.9 or 1.10, in which the lyophilization additive is lactose, either in free or hydrated (e.g., monohydrate) form.

[0091] 1.12. Any of methods 1.9 to 1.11, wherein the freeze-dried additive is selected from one or a mixture of sucrose, lactose, and trehalose.

[0092] 1.13. The freeze-drying additive is sucrose, according to any of methods 1.9 to 1.12.

[0093] 1.14. Any of methods 1.9 to 1.13, wherein the weight ratio of dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) to the freeze-dried additive is 1:1 to 10, for example 1:2.5 to 7.5, for example 1:5.

[0094] 1.15. Mix dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl with a pH adjuster, using any of methods 1a, 1b, or 1.1-1.14.

[0095] 1.16. Add a pH adjuster to the water using one of the methods 1.3 to 1.15.

[0096] 1.17. Method 1.15 or 1.16, wherein the pH adjuster is selected from one or a mixture of hydrochloric acid, sodium hydroxide, citrate, and phosphate buffer.

[0097] 1.18. Any of methods 1.15 to 1.17, wherein the pH adjuster is selected from hydrochloric acid and citric acid.

[0098] 1.19. Any of methods 1a, 1b, or 1.1 to 1.18, wherein the pH of the composition (e.g., aqueous composition) is 7 to 10, e.g., 7.5 to 9.5, e.g., 8 to 9, e.g., 8.2 to 9, e.g., 8.5 to 8.6, e.g., 8.5.

[0099] 1.20. Any of Method 1a, 1b, or 1.1 to 1.19, wherein the method comprises a step of filtering (e.g., using a sterile filter) a mixture of dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl and meglumine (and optionally lyophilized additives and optionally pH adjusters).

[0100] 1.21. Any of Method 1a, 1b, or 1.1 to 1.20, wherein the method includes a step of sterilizing a mixture of dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl and meglumine (and optionally lyophilized additives and optionally pH adjusters).

[0101] 1.22. Any of Method 1a, 1b, or 1.1 to 1.21, wherein the method comprises the step of freeze-drying a mixture of dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl and meglumine (and optionally a freeze-drying additive and optionally a pH adjuster).

[0102] 1.23. The freeze-drying process is as follows: (1) Keep at -50°C for 2 to 6 hours; (2) Raise the temperature to -20°C to -10°C and maintain it for 20 to 40 hours; (3) Raise the temperature to 20-30°C (for example, 25°C) and maintain it for 10-30 hours. Method 1.22.

[0103] 1.24. The freeze-drying process is as follows: (1) lower the temperature to -50°C; (2) raise the temperature to -15°C; (3) lower the temperature to -50°C; (4) apply vacuum; (5) lower the temperature to -10°C; (6) raise the temperature to -5°C; and (7) raise the temperature to 25°C under vacuum, method 1.22 or 1.23.

[0104] 1.25. The freeze-drying process is as follows: (1) Lower the temperature (e.g., shelf temperature) to -40°C to -60°C (e.g., -50°C) within 2 to 6 hours (e.g., within 4 hours); (2) Maintain the temperature (e.g., shelf temperature) at -40°C to -60°C (e.g., -50°C) for 1 to 2 hours (e.g., 0.5 hours); (3) Raise the temperature (e.g., shelf temperature) to -20°C to -10°C (e.g., -15°C) (e.g., rapidly); (4) Maintain the temperature at -20°C to -10°C for 1 to 3 hours (e.g., 2 hours); (5) Lower the temperature (e.g., slab temperature) to -40°C to -60°C (e.g., -50°C) (e.g., rapidly); (6) Maintain the temperature (e.g., slab temperature) at -40°C to -60°C (e.g., -50°C) for 2 to 6 hours (e.g., 4 hours); (7) Apply a vacuum (e.g., a vacuum of less than 0.2 mbar). (8) Lower the temperature (e.g., shelf temperature) to -20°C to 0°C (e.g., -10°C) within 6 to 10 hours (e.g., 8 hours); (9) Maintain the temperature (e.g., shelf temperature) at -20°C to 0°C (e.g., -10°C) for 8 to 12 hours (e.g., 10 hours); (10) Raise the temperature to -10°C to 0°C (e.g., -5°C) within 1 to 3 hours (e.g., 2 hours); (11) Temperature (e.g., shelf temperature) (12) Maintain the temperature (e.g., shelf temperature) at -10°C to 0°C (e.g., -5°C) for 13 to 17 hours (e.g., 15 hours); (13) Raise the temperature (e.g., shelf temperature) to 20°C to 30°C (e.g., 25°C) under vacuum (e.g., maximum vacuum) for 4 to 8 hours (e.g., 6 hours); and (14) Maintain the temperature at 20°C to 30°C (e.g., 25°C) for 10 to 14 hours (e.g., 12 hours), one of methods 1.22 to 1.24.

[0105] 1.26. The freeze-drying process is as follows: (1) Lower the shelf temperature to -50°C within 4 hours and maintain the temperature for 0.5 hours; (2) Raise the shelf temperature to -15°C and maintain the temperature for 2 hours; (3) Lower the slab temperature to -50°C and maintain the temperature for 4 hours; (4) Achieve a vacuum of less than 0.2 mbar using a vacuum pump; (5) Lower the shelf temperature to -10°C within 8 hours and maintain the temperature for 10 hours; (6) Raise the shelf temperature to -5°C within 2 hours and maintain the temperature for 15 hours; and (7) Lower the shelf temperature to 25°C in no more than 6 hours under vacuum (e.g., maximum vacuum), maintain the temperature and dry at 25°C for 12 hours. Choose one of the methods 1.22 to 1.25.

[0106] 1.27. The composition is made from a weight ratio of formula I:sucrose:meglumine of 1:5:0.9 to 1 (e.g., 1:5:0.93), either by Method 1 or 1.1 to 1.26. For example, the composition before lyophilization is made from 100 mg of formula (I), 500 mg of sucrose, 80 mg of meglumine, 133 mg of a 10% meglumine aqueous solution, and an appropriate amount of sterile water for injection (e.g., sterile water for injection) to make 10 mL.

[0107] Furthermore, in patients requiring treatment (e.g., humans), aquaporins are involved in diseases or conditions, such as water imbalances and other diseases, for example, Edema, e.g., edema of the brain or spinal cord, e.g., cerebral edema, e.g., head injury, ischemic stroke, glioma, meningitis, acute altitude sickness, epileptic seizure, infection, metabolic disorder, hypoxia (including generalized hypoxia and hypoxia due to cardiac arrest), water intoxication, hepatic failure, hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, lupus encephalitis, microgravity and / or radiation exposure, or cerebral edema resulting from invasive central nervous system procedures, e.g., neurosurgery, intravascular thrombectomy, spinal puncture, aneurysm repair or deep brain stimulation, or spinal cord injury, e.g., spinal cord edema resulting from spinal cord compression; or Optic nerve edema, e.g., optic nerve edema caused by microgravity and / or radiation exposure; or Retinal edema; or Pulmonary edema; or For example, hyponatremia or fluid retention resulting from heart failure (HF), cirrhosis, nephrotic disorder, syndrome of inappropriate antidiuretic hormone secretion (SIADH), or infertility treatment; or Ovarian hyperstimulation syndrome; or Epilepsy, other eye diseases associated with retinal ischemia or abnormal 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 Fibromyalgia; or Multiple sclerosis; or Migraine; or Treatment or prevention of transplant rejection, suppression of rejection of transplanted biological material, or control of edema caused by transplantation. To treat or control; or For heart protection during cardiac surgery The present invention provides a method (Method 2) comprising administering to a patient a reconstituted pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine. For example, the method comprises administering to a patient a reconstituted pharmaceutical composition comprising a pharmaceutically acceptable salt of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (Formula (I)). For example, the method comprises administering to a patient a reconstituted solution obtained from any of compositions 1a, 1b, or 1.1 to 1.43.

[0108] Furthermore, we offer the following method 2:

[0109] 2.1. Method 2, wherein the disease or condition is described in any of U.S. Patent Nos. 9,994,514, 9,573,885 and 9,949,991, and U.S. Patent Application Publication No. 2018 / 0042873.

[0110] 2.2. If the disease or condition is cerebral edema, use method 2 or 2.1.

[0111] 2.3. If the disease or condition is cytotoxic (or cellular) cerebral edema, method 2, 2.1, or 2.2.

[0112] 2.4. If cytotoxic cerebral edema results from a stroke (e.g., ischemic stroke), closed head injury, traumatic brain injury, or hypoxia, follow method 2.3.

[0113] 2.5. Cytotoxic cerebral edema is caused by ischemic stroke, method 2.4.

[0114] 2.6. Cytotoxic cerebral edema caused by hypoxia, method 2.4.

[0115] 2.7. Hypoxia resulting from stroke, cardiac arrest, suffocation, or other interruption of oxygen supply or blood flow to the brain, method 2.6.

[0116] 2.8. If the disease or condition is spinal edema, method 2 or 2.1.

[0117] 2.9. Spinal edema may result from spinal cord trauma, e.g., spinal cord compression, as described in Method 2.8.

[0118] 2.10. Method 2 or any of 2.1 to 2.9, wherein the reconstituted solution is obtained from any of compositions 1a, 1b, or 1.1 to 1.43.

[0119] Furthermore, for use in the treatment of any of the diseases or conditions described herein, for example, for use in any of the above methods, for example, Method 2 or 2.1 to 2.10 Noi The present invention provides a reconstituted pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and meglumine, for use in any of the following: For example, the reconstituted pharmaceutical composition is obtained from any of compositions 1a, 1b, or 1.1 to 1.43. It is also provided for use in any of the above methods, for example, for use in the treatment of any of the diseases or conditions described herein, for example, for use in any of the above methods, for example, method 2 or 2.1 to 2.10. NoiThe present invention provides a reconstituted pharmaceutical composition comprising a pharmaceutically acceptable salt of dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) for use in any of the following applications. For example, the reconstituted pharmaceutical composition can be obtained from any of compositions 1a, 1b, or 1.1 to 1.43.

[0120] Furthermore, since it will be used in one of the above methods, for example, Method 2 or 2.1~2.10 Noi The present invention provides any of compositions 1a, 1b, or 1.1 to 1.43 for use in the manufacture of a pharmaceutical, for example, in the manufacture of a reconstituted pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and meglumine. Furthermore, for example, for use in any of the above methods, for example, methods 2 or 2.1 to 2.10 are provided. Noi The present invention provides any of compositions 1a, 1b, or 1.1 to 1.43 for use in the manufacture of a pharmaceutical, for example, in the manufacture of a reconstituted pharmaceutical composition comprising a pharmaceutically acceptable salt of dihydrogen dihydrogen phosphate 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl (formula (I)).

[0121] Furthermore, the present invention includes the following aspects and embodiments. [1] A pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine. [2] The pharmaceutical composition according to [1], wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to meglumine is 1:0.2 to 4. [3] The pharmaceutical composition according to [2], wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to meglumine is 1:0.4 to 2. [4] The pharmaceutical composition according to [3], wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to meglumine is 1:0.6 to 1. [5] The pharmaceutical composition according to any one of [1] to [4], wherein the pharmaceutical composition is an injectable pharmaceutical composition, preferably a lyophilized pharmaceutical composition. [6] A pharmaceutical composition according to any one of [1] to [5], further comprising a freeze-drying additive. [7] The pharmaceutical composition according to [6], wherein the freeze-dried additive is selected from one or a mixture of sucrose, lactose, mannitol, glucose, and trehalose. [8] The pharmaceutical composition according to [7], wherein the freeze-dried additive is selected from one or a mixture of sucrose, lactose, and trehalose. [9] The pharmaceutical composition according to any one of [6] to [8], wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to the freeze-dried additive is 1:1 to 10, preferably 1:2.5 to 7.5, and more preferably 1:5.

[10] A pharmaceutical composition according to any one of [1] to [9], further comprising a pH adjuster.

[11] The pharmaceutical composition according to

[10] , wherein the pH adjuster is selected from one or a mixture of hydrochloric acid, sodium hydroxide, citric acid, and phosphate buffer, preferably selected from hydrochloric acid or citric acid.

[12] The pharmaceutical composition according to any one of [1] to

[11] , wherein the pH is 7.5 to 9.5, preferably 8.0 to 9.0, and more preferably about 8.5.

[13] A pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, a lyophilization additive, and a pH adjuster.

[14] A pharmaceutical composition according to any one of [1] to

[13] , wherein the pharmaceutical composition contains ≤1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after 6 months at room temperature.

[15] A pharmaceutical composition according to any one of [1] to

[14] , wherein the composition contains ≤3% w / w water.

[16] a) Taking 60% to 90% of a specified volume of water for injection, cooling to 15°C to 25°C, adding meglumine and dissolving it until clear, and slowly adding 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; b) A step of adding other ingredients, if desired; c) Adding a predetermined amount of water for injection; d) If desired, the product obtained in step (c) is sterilized by filtration and freeze-dried. A method for producing any of the pharmaceutical compositions described in [1] to

[13] , including the above.

[17] The method according to

[16] , wherein step (a) is cooling to 20°C.

[18] The method according to

[16] or

[17] , wherein the other components in step (b) are selected from lyophilization additives and pH adjusters.

[19] The freeze-drying process of step (d) is as follows: (1) maintain at -50°C for 2 to 6 hours; (2) raise the temperature to -20°C to -10°C and maintain for 20 to 40 hours; (3) raise the temperature to 20 to 30°C and maintain for 10 to 30 hours, according to any of the methods in

[16] to

[18] .

[20] The method according to

[19] , wherein the temperature is raised to 25°C in step (3). Detailed description of the present invention The present invention will be further described through the following specific examples, but the examples described are for illustrative purposes only and do not limit the present invention. [Examples]

[0122] Example 1: Freeze-dried composition [Table 1]

[0123] Add a specified amount of meglumine, arginine, lysine, or sodium dihydrogen phosphate / sodium hydroxide to 60-70% of a specified amount of sterile water for injection at a temperature of approximately 20°C, stir until completely dissolved, stir until completely dissolved, add a specified amount of the compound of formula (I), and stir until completely dissolved. Add a specified amount of mannitol and stir until completely dissolved.

[0124] Add water to the specified amount, continue stirring for 20 minutes, filter and sterilize using a 0.22 μm filter, fill, partially cap, and freeze-dry.

[0125] The above sample is taken, its content and related substances are tested, and its turbidity value is measured. The test method is as follows:

[0126] (1) Testing of content and related substances: Testing by high-performance liquid chromatography (HPLC) using octadecylsilane-bonded silica gel as packing material (Agilent Eclipse plus C18, 150 × 4.6 mm, 3.5 μm or equivalent chromatography column); using 0.01 mol / L ammonium acetate solution as mobile phase A and acetonitrile as mobile phase B for gradient elution.

[0127] (2) Transparency: A turbidimeter (HACH model: TU5200) is used for the test. A sample of the formulation solution is taken for the test and compared to a 0.5# standard turbidity solution (turbidity range is 1.6~2.2 NTU). If the turbidity value is lower than that of the 0.5# standard solution, the formulation solution is a transparent solution.

[0128] (3) Moisture: Using a Karl Fischer moisture meter, control the ambient humidity to less than 30%, take one vial of the preparation, and weigh the total weight; immediately pour the contents into the moisture meter after opening the lid, then weigh the empty vial and measure and calculate the moisture content.

[0129] The results are shown in Table 2. [Table 2]

[0130] Example 2: Freeze-dried composition [Table 3]

[0131] A predetermined amount of meglumine is added to 60-70% of a predetermined amount of water for injection at a temperature of approximately 20°C, and stirred until completely dissolved. Then, a predetermined amount of the compound of formula (I) is added, and stirred until completely dissolved.

[0132] Add water to the specified amount, continue stirring for 20 minutes, filter and sterilize using a 0.22 μm filter, fill, partially cap, and freeze-dry.

[0133] The above samples are collected, their content and related substances are tested, and their turbidity is measured. The results are shown in Table 4. [Table 4]

[0134] Example 3: Freeze-dried composition [Table 5]

[0135] A predetermined amount of meglumine is added to 70-80% of a predetermined amount of sterile water for injection at a temperature of approximately 20°C, and stirred until completely dissolved. A predetermined amount of the compound of formula (I) is then added and stirred until completely dissolved. Subsequently, a predetermined amount of the freeze-dried additive is added and stirred until completely dissolved.

[0136] Add water to the specified amount, continue stirring for 20 minutes, filter and sterilize using a 0.22 μm filter, fill, partially cap, and freeze-dry.

[0137] The above samples are collected, their content and related substances are tested, and their turbidity is measured. The results are shown in Table 6. [Table 6]

[0138] Example 4: Freeze-dried composition [Table 7]

[0139] A predetermined amount of meglumine is added to 80% of a predetermined amount of sterile water for injection at a temperature of approximately 20°C, and stirred until completely dissolved. Then, a predetermined amount of the compound of formula (I) is added and stirred until completely dissolved. After that, a predetermined amount of sucrose is added and stirred until completely dissolved.

[0140] The pH of the above solution is adjusted to 8.5-9 with a 10% meglumine solution, water is added to the specified amount, stirring is continued for 20 minutes, sterilization is performed by filtration with a 0.2 μm filter, the container is filled, partially capped, and freeze-dried.

[0141] Freeze-drying process:

[0142] Pre-freeze-drying: Raise the shelf temperature to -50°C in no more than 4 hours, maintain the temperature for 0.5 hours, then rapidly raise the shelf temperature to -15°C and maintain the temperature for 2 hours, then rapidly lower the slab temperature to -50°C and maintain the temperature for 4 hours to obtain a complete frozen product. Turn on the vacuum pump and achieve a vacuum of less than 0.2 mbar to start sublimation.

[0143] Sublimation stage: Raise the shelf temperature to -10°C within 8 hours, maintain the temperature for 10 hours, then raise the shelf temperature to -5°C within 2 hours and maintain the temperature for approximately 15 hours.

[0144] Secondary drying: Raise the shelf temperature to 25°C under maximum vacuum for no more than 6 hours, maintain the temperature, and dry at 25°C for approximately 12 hours.

[0145] The above samples are collected, their content and related substances are tested, and their turbidity is measured. The results are shown in Table 8. [Table 8]

[0146] Example 5 [Table 9] [Table 10]

[0147] Example 6: Freeze-dried composition [Table 11] [Table 12]

[0148] Example 7 [Table 13]

[0149] Example 8 [Table 14-1] [Table 14-2]

[0150] Lyophilized preparations containing histidine, arginine, and lysine become turbid after 10 days at 25°C.

[0151] When tertiary butyl alcohol is used, the sample becomes turbid after freeze-drying, and the pH decreases after reconstruction.

[0152] Example 9 Reconstituted solvent [Table 15]

Claims

1. A lyophilized pharmaceutical composition comprising 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, and a lyophilization additive, wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to meglumine is 1:0.6 to 1, and the pharmaceutical composition contains ≤1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after 6 months at room temperature.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a pharmaceutical composition for injection.

3. The pharmaceutical composition according to claim 1 or 2, wherein the freeze-dried additive is selected from one or a mixture of sucrose, lactose, mannitol, glucose, and trehalose.

4. The pharmaceutical composition according to claim 3, wherein the freeze-dried additive is selected from one or a mixture of sucrose, lactose, and trehalose.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to the freeze-dried additive is 1:1 to 10.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to the freeze-dried additive is 1:2.5 to 7.

5.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to the freeze-dried additive is 1:

5.

8. A pharmaceutical composition according to any one of claims 1 to 7, further comprising a pH adjuster.

9. The pharmaceutical composition according to claim 8, wherein the pH adjuster is selected from one or a mixture of hydrochloric acid, sodium hydroxide, citric acid, and phosphate buffer.

10. The pharmaceutical composition according to claim 9, wherein the pH adjusting agent is selected from hydrochloric acid or citric acid.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the pH is 7.5 to 9.

5.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the pH is 8.0 to 9.

0.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pH is about 8.

5.

14. A pharmaceutical composition according to any one of claims 1 to 13, wherein the composition contains ≤3% w / w water.

15. (a) Taking 60% to 90% of a predetermined volume of water for injection, cooling it to 15°C to 25°C, adding meglumine and dissolving it until clear, and slowly adding 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; (b) Adding freeze-drying additives and, if desired, adding other components; (c) Adding a predetermined amount of water for injection; (d) If desired, the product obtained in step (c) is sterilized by filtration and freeze-dried. A method for producing the pharmaceutical composition according to any one of claims 1 to 14, including the method described above.

16. The method according to claim 15, wherein step (a) is cooling to 20°C.

17. The method according to claim 15 or 16, wherein the other component in step (b) is a pH adjuster.

18. The freeze-drying process of step (d) is as follows: (1) maintain at -50°C for 2 to 6 hours; (2) raise the temperature to -20°C to -10°C and maintain for 20 to 40 hours; (3) raise the temperature to 20 to 30°C and maintain for 10 to 30 hours, according to any one of claims 15 to 17.

19. The method according to claim 18, wherein the temperature is raised to 25°C in step (3).

20. The freeze-drying process is as follows: (1) Lower the shelf temperature to -50°C within 4 hours and maintain the temperature for 0.5 hours; (2) Raise the shelf temperature to -15°C and maintain the temperature for 2 hours; (3) Lower the slab temperature to -50°C and maintain the temperature for 4 hours; (4) Achieve a vacuum of less than 0.2 mbar using a vacuum pump; (5) Lower the shelf temperature to -10°C within 8 hours and maintain the temperature for 10 hours; (6) Raise the shelf temperature to -5°C within 2 hours and maintain the temperature for 15 hours; and (7) Raise the shelf temperature to 25°C under vacuum, preferably under maximum vacuum, within 6 hours, and maintain the temperature at 25°C for 12 hours. The method according to claim 15.

21. A pharmaceutical composition according to any one of claims 1 to 14 for treating or controlling edema.

22. The pharmaceutical composition according to claim 21, wherein the edema is cerebral edema.

23. The pharmaceutical composition according to claim 22, wherein the cerebral edema is caused by ischemic stroke.

24. The pharmaceutical composition according to claim 22 or 23, wherein the cerebral edema is cytotoxic cerebral edema.

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