A pharmaceutical composition of an aquaporin inhibitor and a preparation method thereof

Abstract

The application relates to a pharmaceutical composition of an aquaporin inhibitor and a preparation method thereof. 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 the aquaporin inhibitor and the preparation method thereof are simple in process, strong in operability, beneficial to industrial production, good in product stability, obviously lower in degradation impurity content, and capable of guaranteeing the exertion of drug efficacy.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical formulations, and more specifically to a pharmaceutical composition of an aquaporin inhibitor and a method for preparing the same. Background Technology

[0002] Aquaporins are cell membrane proteins that function as water channels to regulate the movement of water into and out of cells. While some passive diffusion or osmosis of water can occur across the cell membrane, rapid and selective movement of water involves aquaporins. These aquaporins selectively guide water molecules into and out of the cell while blocking the passage of ions and other solutes, thereby maintaining the cell's membrane potential. Aquaporins are present in virtually all life forms, from bacteria to plants to animals. In the human body, they are distributed throughout the cells of the entire body.

[0003] Aquaporin inhibitors, such as inhibitors of AQP4 and / or AQP2, can be used to treat or control water imbalance disorders, such as edema (more specifically, edema of the brain and spinal cord), 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-hydroxybenzamide (structure shown in formula (II)) as an aquaporin inhibitor. Formula (I) (structural formula below) is a prodrug of formula (II). This compound can treat or control diseases mediated by aquaporins selected from cytotoxic cerebral edema, spinal cord edema, retinal edema, optic nerve edema, cardiac edema, neuromyelitis optica, hyponatremia, retinal ischemia, and excessive fluid retention.

[0005]

[0006] Compounds of formula (I) need to be formulated into liquid preparations for intravenous injection or infusion to achieve rapid onset of action. However, there is a need to improve the solubility of compounds of formula (I) to provide a therapeutically effective amount of compounds of formula (II) for injection. However, salts of formula (I) that are more soluble can revert to N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (compounds of formula (II)) even in the solid state. WO2015069956 shows that lyophilized powders of certain salts of compounds of formula (I) can revert to compounds of formula (II) even in the solid state (approximately 1% per day or 1% over 5 days). There is an urgent need to address the issues of drug solubility and stability to provide pharmaceutical compositions that meet clinical needs.

[0007] Summary of the Invention

[0008] This application provides a pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine (also known as N-methyl-D-glucosamine).

[0009] In some embodiments, the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen 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 dihydrogen 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 dihydrogen phosphate to meglumine is 1:0.6 to 1.

[0010] In some embodiments, the pharmaceutical composition is an injectable pharmaceutical composition.

[0011] In some embodiments, the pharmaceutical composition is a lyophilized pharmaceutical composition.

[0012] In some embodiments, the pharmaceutical composition of this application further comprises a lyophilized excipient.

[0013] In some embodiments, the freeze-drying excipient is selected from one or a mixture of several selected from sucrose, lactose, mannitol, glucose, and trehalose.

[0014] In some embodiments, the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the lyophilization excipient 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 lyophilization excipient 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 lyophilization excipient is 1:5.

[0015] Optionally, the pharmaceutical composition of this application further comprises a pH adjuster. The pH adjuster of this application is selected from one or a mixture of several of hydrochloric acid, sodium hydroxide, citric acid, and phosphate buffer. In some embodiments, the pH adjuster of this application is selected from hydrochloric acid and citric acid.

[0016] In some embodiments, the pH of the pharmaceutical composition of this application is 7.5 to 9.5. In some embodiments, the pH of the pharmaceutical composition of this application is 8.0 to 9.0. In some embodiments, the pH of the pharmaceutical composition of this application is about 8.5.

[0017] In some embodiments, this 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 lyophilized excipient, and a pH adjuster.

[0018] Optionally, the pharmaceutical composition of this application may further include water for injection.

[0019] In some embodiments, this application provides a method for preparing the above-mentioned pharmaceutical composition, comprising:

[0020] a) Take 60% to 90% of the prescribed amount of water for injection, cool it to 15°C to 25°C, add meglumine to dissolve until clear, and slowly add 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate or its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate.

[0021] b) Optionally, other components may be added;

[0022] c) Add water for injection to the prescribed amount;

[0023] d) Optionally, the product obtained by filtration sterilization and freeze drying step (c) is further processed.

[0024] In some implementations, step (a) involves cooling to 20°C.

[0025] In some implementations, the other components in step (b) are selected from lyophilized excipients and pH adjusters.

[0026] In some embodiments, the freeze-drying process in step (d) is as follows: (1) holding at -50°C for 2 to 6 hours; (2) raising the temperature to -20°C to -10°C and holding for 20 to 40 hours; (3) raising the temperature to 20 to 30°C and holding for 10 to 30 hours. In some embodiments, the temperature in step (3) is raised to 25°C.

[0027] In some embodiments, step (d) freeze-drying process is as follows: (1) cooling to -50°C; (2) heating to -15°C; (3) cooling to -50°C; (4) applying vacuum; (5) cooling to -10°C; (6) increasing temperature to -5°C; and (7) increasing temperature to 25°C under vacuum.

[0028] In some embodiments, the freeze-drying process of step (d) is as follows: (1) cooling (e.g., shelf temperature) to -40°C to -60°C (e.g., -50°C) over 2-6 hours (e.g., 4 hours); (2) maintaining the temperature (e.g., shelf temperature) at -40°C to -60°C (e.g., -50°C) for 1-2 hours (e.g., 0.5 hours); (3) raising (e.g., rapidly raising) the temperature (e.g., shelf temperature) to -20°C to -10°C (e.g., -15°C); (4) maintaining the temperature at -20°C to -10°C for 1-3 hours (e.g., 2 hours); (5) lowering (e.g., rapidly lowering) the temperature (e.g., shelf temperature) to -40°C to -60°C (e.g., -50°C); (6) maintaining the temperature (e.g., shelf temperature) at -40°C to -60°C (e.g., -50°C) for 2-6 hours (e.g., 4 hours); (7) applying a vacuum. (e.g., to achieve a vacuum at 0.2 mbar); (8) to decrease the temperature (e.g., shelf temperature) to -20°C to 0°C (e.g., -10°C) over 6-10 hours (e.g., 8 hours); (9) to maintain the temperature (e.g., shelf temperature) at -20°C to 0°C (e.g., -10°C) for 8-12 hours (e.g., 10 hours); (10) to increase the temperature to -10°C to 0°C (e.g., -5°C) over 1-3 hours (e.g., 2 hours); (11) Maintain the temperature (e.g., shelf temperature) at -10°C to 0°C (e.g., -5°C) for 13-17 hours (e.g., 15 hours); (12) Increase the temperature (e.g., shelf temperature) to 20°C-30°C (e.g., 25°C) under vacuum (e.g., ultimate vacuum) for 4-8 hours (e.g., 6 hours); and (13) Maintain the temperature at 20°C-30°C (e.g., 25°C) for 10-14 hours (e.g., 12 hours).

[0029] In some embodiments, the lyophilized formulations disclosed herein are reconstituted with an aqueous solution containing sodium and / or potassium (e.g., sodium chloride, such as 0.9% NaCl, or sodium chloride and sodium lactate or sodium acetate (e.g., lactated Ringer's solution or acetate Ringer's solution)) or containing potassium chloride (e.g., potassium chloride injection). Reconstitution with water for injection or glucose may result in visible particles.

[0030] In some embodiments, the "pharmaceutically acceptable salt" of this application is selected from alkali metal salts (e.g., sodium salts, preferably disodium salts) and organic base salts (e.g., ammonium salts, preferably meglumine salts).

[0031] In some implementations, the “pharmaceuticalally acceptable solvate” of this application is a hydrate (e.g., a dihydrate).

[0032] In this application, when the pharmaceutical composition is in solid form (e.g., a lyophilized agent), the pH refers to the pH value of the solution of the solid pharmaceutical composition before lyophilization or the pH value after reconstitution.

[0033] In this 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 calculated as 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate.

[0034] Sugars (e.g., trehalose) may be provided in hydrated form. In this application, unless otherwise specified, the weight of sugars (e.g., sucrose, lactose, glucose, or trehalose) is in anhydrous form.

[0035] This invention provides a formulation that can be reconstituted into a liquid for human use via intravenous injection or infusion, exhibiting rapid onset of action, thereby enabling the use of compounds of formula (I) in the treatment of cerebral edema. Furthermore, the formulation (I) compounds and their preparation methods of this invention are simple, easy to operate, and conducive to industrial production. Moreover, the products exhibit good stability and significantly lower levels of degradation impurities (e.g., compounds of formula (II), ensuring efficacy. For example, compared to compositions containing other bases, such as sodium salts or other amino bases (e.g., arginine, lysine, and histidine), the meglumine-containing compositions disclosed herein are less likely to revert from formula (I) to formula (II). Without being bound by any theory, it is generally believed that some bases can drive a unimolecular process to revert compounds of formula (I) to formula (II). Formula (II) has poor water solubility, so even its presence in small amounts in injectable formulations may result in visible particles, rendering the formulation unusable. The lyophilized meglumine-containing compositions have fewer impurities and are suitable for injection after reconstitution.

[0036] A pharmaceutical composition (composition 1a) is provided, comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine.

[0037] Further, a solid lyophilized pharmaceutical composition (composition 1b) is provided, comprising a meglumine salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)):

[0038]

[0039] Compositions 1a and 1b are further provided as follows:

[0040] 1.1 Composition 1a, wherein the composition is a solid lyophilized pharmaceutical composition.

[0041] 1.2 Composition 1a, 1b, or 1.1, wherein the pharmaceutically acceptable salt is 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate bis(glucuronide) salt, that is, wherein the pharmaceutically acceptable salt is:

[0042] Alternatively, for example, any one of compositions 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 dihydrogen phosphate bisglumine salt).

[0043] 1.3 Any one of compositions 1a, 1b, 1.1 or 1.2, wherein the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) to meglumine is 1:0.2 to 4, for example, 1:0.4 to 2, for example, 1:0.6 to 1. Or, for example, any one of compositions 1a, 1b, 1.1 or 1.2, wherein the amount of meglumine is sufficient to provide a pH of 7 to 10 for the dissolved composition before and / or after lyophilization, 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.

[0044] 1.4 Composition 1a, 1b or any one of 1.1-1.3, wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) to meglumine is 1:1 to 5, for example, 1:2-5, for example, 1:2-4, for example, 1:2-3, for example, 1:2-2.5, for example, 1:2-2.3 (for example, 1:2.1-2.3), for example, 1:2-2.2, for example, 1:2.1-2.2, for example, 1:2.2.

[0045] 1.5 Composition 1a, 1b or any one of 1.1-1.3, wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) and protonated meglumine is 1:1 to 5, for example, 1:2-5, for example, 1:2-4, for example, 1:2-3, for example, 1:2-2.5, for example, 1:2-2.3 (for example, 1:2.1-2.3), for example, 1:2-2.2, for example, 1:2.1-2.2, for example, 1:2.2.

[0046] 1.6 Composition 1a, 1b or any one of 1.1-1.5, wherein the composition is for injection after reconstitution, for example, for intravenous injection and / or infusion.

[0047] 1.7 Any one of compositions 1a, 1b, or 1.1-1.6, wherein the composition further comprises a lyophilizing excipient. For example, any one of compositions 1a, 1b, or 1.1-1.6, wherein the lyophilizing excipient is one or a mixture of monosaccharides, disaccharides, and sugar alcohols. For example, any one of compositions 1a, 1b, or 1.1-1.6, wherein the lyophilizing excipient is a disaccharide or a mixture of disaccharides.

[0048] 1.8 Composition 1.7, wherein the lyophilization excipient is selected from one or a mixture of several of sucrose, lactose, mannitol, glucose, and trehalose, in either a free or hydrated form. For example, in composition 1.7, the lyophilization excipient is trehalose in a free or hydrated form (e.g., dihydrate). For example, in composition 1.7, the lyophilization excipient is mannitol. For example, in composition 1.7, the lyophilization excipient is sucrose. For example, in composition 1.7, the lyophilization excipient is lactose in a free or hydrated form (e.g., monohydrate).

[0049] 1.9 Composition 1.8, wherein the freeze-drying excipient is selected from one or a mixture of several of sucrose, lactose and trehalose.

[0050] 1.10 Composition 1.8, wherein the lyophilization excipient is sucrose.

[0051] 1.11 Composition 1a, 1b or any one of 1.1-1.10, wherein the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) to the lyophilized excipient is 1:1 to 10, for example 1:2.5-7.5, for example 1:2.5-5, for example 1:5.

[0052] 1.12 Composition 1a, 1b or any one of 1.1-1.11, wherein the composition further comprises a pH adjuster.

[0053] 1.13 Composition 1.12, wherein the pH adjuster is selected from one or a mixture of several of hydrochloric acid, sodium hydroxide, citric acid and phosphate buffer.

[0054] 1.14 Composition 1.12, wherein the pH adjuster is selected from hydrochloric acid and citric acid.

[0055] 1.15 Composition 1a, 1b or any one of 1.1-1.14, wherein the pH of said 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.

[0056] 1.16 Composition 1a, 1b or any one of 1.1-1.15, wherein the composition has a pH of 7 to 10 in solution prior to freeze-drying, 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.

[0057] 1.17 Composition 1a, 1b or any one of 1.1-1.16, wherein the pH of the reconstituted composition is 7-10, for example 7.5-9.5, for example 8-9, for example 8.2-9, for example 8.5-8.6, for example 8.5.

[0058] 1.18 Composition 1a, 1b or any one of 1.1-1.17, wherein the composition is reconstituted with an aqueous solution containing sodium and / or potassium (e.g., containing sodium chloride, such as 0.9% sodium chloride injection, or containing sodium chloride and sodium lactate or sodium acetate (e.g. lactated Ringer's solution or acetate Ringer's solution)) or containing potassium chloride (e.g., potassium chloride injection).

[0059] 1.19 Composition 1a, 1b or any one of 1.1-1.18, wherein the composition is a white, solid form.

[0060] 1.20 Composition 1a, 1b or any one of 1.1-1.19, wherein the composition contains ≤1% w / w of the compound of formula (II) after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C), for example, ≤0.8% w / w of the compound of formula (II) after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C), for example, ≤0.6% w / w of the compound of formula (II) after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C), for example, ≤0.5% w / w of the compound of formula (II) after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C).

[0061] 1.21 Composition 1a, 1b or any one of 1.1-1.20, wherein the composition contains ≤2% w / w total impurities (including compounds of formula (II)) after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C), for example, ≤1% w / w total impurities after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C), for example, ≤0.6% w / w total impurities after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C), for example, ≤0.5% w / w total impurities after being placed at room temperature for 6 months (e.g., after 6 months at 25°C ± 2°C).

[0062] 1.22 Composition 1a, 1b or any one of 1.1-1.21, wherein the composition contains ≤1% w / w of compound (II) after being placed at 2°C-8°C for 6 months, for example, ≤0.5% w / w of compound (II) after being placed at 2°C-8°C for 6 months, for example, ≤0.2% w / w of compound (II) after being placed at 2°C-8°C for 6 months, for example, ≤0.1% w / w of compound (II) after being placed at 2°C-8°C for 6 months.

[0063] 1.23 Composition 1a, 1b or any one of 1.1-1.22, wherein the composition contains ≤2% w / w total impurities (including compounds of formula (II)) after being placed at 2°C-8°C for 6 months, for example, ≤0.5% w / w total impurities after being placed at 2°C-8°C for 6 months, for example, ≤0.2% w / w total impurities after being placed at 2°C-8°C for 6 months, for example, ≤0.1% w / w total impurities after being placed at 2°C-8°C for 6 months.

[0064] 1.24 Compositions 1a, 1b, or any one of 1.1-1.23, wherein the composition contains ≤3% w / w water, for example ≤2% w / w water, for example ≤1.5% w / w water (e.g., after 6 months at 25°C ± 2°C and / or after 6 months at 2°C–8°C). The water content is measured, for example, by coulometric Karl Fisher analysis.

[0065] 1.25 Compositions 1a, 1b, or any one of 1.1-1.24, wherein the composition conforms to the United States Pharmacopeia (USP) before reconstitution (e.g., in a solution prior to lyophilization) and / or after reconstitution. <788> and / or the General Rules of Part IV of ChP (Pharmacopoeia of the People's Republic of China) 2020 <0903> According to the regulations.

[0066] 1.26 Composition 1a, 1b, or any one of 1.1-1.25, wherein the average number of particles present in the test unit (e.g., ≤10 test units) before lyophilization and / or after reconstitution is no more than 25 particles equal to or greater than 10 μm per milliliter and no more than 3 particles equal to or greater than 25 μm per milliliter, for example, testing formulations supplied in containers with a nominal volume equal to or greater than 100 mL (e.g., intravenous infusions or solutions for injection) (e.g., formulations supplied in containers with a nominal volume greater than 100 mL). This average number of particles presented per unit can be verified by the United States Pharmacopeia (USP). <788> The aforementioned optical obscuration counting method determines (the optical obscuration counting method can be achieved by means of, for example) (Implemented using a SIS system or a HIAC Royco particle counter). The particle count of the tested unit provides a statistically accurate assessment.

[0067] 1.27 Composition 1a, 1b, or any one of 1.1-1.26, wherein the average number of particles present in the test unit (e.g., ≤10 test units) before lyophilization and / or after reconstitution is no more than 6000 particles equal to or greater than 10 μm per container and no more than 600 particles equal to or greater than 25 μm per container, for example, testing formulations supplied in containers with a nominal volume equal to or less than 100 mL (e.g., intravenous infusions or solutions for injection) (e.g., formulations supplied in containers with a nominal volume less than 100 mL). This average number of particles presented in the unit can be verified by the United States Pharmacopeia (USP). <788> The aforementioned optical obscuration counting method determines (the optical obscuration counting method can be achieved by means of, for example) (Implemented using a SIS system or a HIAC Royco particle counter). The particle count of the tested unit provides a statistically accurate assessment.

[0068] 1.28 Composition 1a, 1b, or any one of 1.1-1.27, wherein the average number of particles present in the test unit (e.g., ≤10 test units) before lyophilization and / or after reconstitution is no more than 12 particles equal to or greater than 10 μm per milliliter and no more than 2 particles equal to or greater than 25 μm per milliliter, for example, testing formulations supplied in containers with a nominal volume equal to or greater than 100 mL (e.g., intravenous infusions or solutions for injection) (e.g., formulations supplied in containers with a nominal volume greater than 100 mL). This average number of particles presented in the unit can be verified by the United States Pharmacopeia (USP). <788> The microscopic counting method described above provides a statistically accurate assessment of the particle count of the tested unit.

[0069] 1.29 Composition 1a, 1b, or any one of 1.1-1.28, wherein the average number of particles present in the test unit (e.g., ≤10 test units) before lyophilization and / or after reconstitution is no more than 3000 particles equal to or greater than 10 μm per container and no more than 300 particles equal to or greater than 25 μm per container, for example, testing formulations supplied in containers with a nominal volume equal to or less than 100 mL (e.g., intravenous infusions or solutions for injection) (e.g., formulations supplied in containers with a nominal volume less than 100 mL). This average number of particles present in the unit can be verified by the United States Pharmacopeia (USP). <788> The microscopic counting method described above provides a statistically accurate assessment of the particle count of the tested unit.

[0070] 1.30 Composition 1a, 1b, or any one of 1.1-1.29, wherein the nephelometric turbidity units (NTU) before lyophilization and / or reconstitution are <2.2 NTU, for example ≤2, for example ≤1. The NTU can be measured using a suspension meter or a turbidimeter. Composition 1a, 1b, or any one of 1.1-1.29, wherein the solution is clearer than a turbidity standard solution (e.g., 0.5 turbidity standard solution).

[0071] 1.31 Composition 1a, 1b, or any one of 1.1-1.30, wherein the composition is lyophilized from an aqueous solution (e.g., water for injection, e.g., sterile water for injection). Composition 1a, 1b, or any one of 1.1-1.30, wherein the composition is lyophilized from an aqueous solution substantially free of (e.g., without added) organic solvents (e.g., tert-butanol).

[0072] 1.32 Composition 1a, 1b, or any one of 1.1-1.31, wherein the composition is substantially free of sodium and potassium ions before reconstitution. For example, composition 1a, 1b, or any one of 1.1-1.31, wherein the composition does not contain detectable sodium or potassium ions. For example, composition 1a, 1b, or any one of 1.1-1.31, wherein the composition contains less than 10 ppm (e.g., less than 5 ppm, e.g., less than 1 ppm) of sodium and / or potassium ions.

[0073] 1.33 Composition 1a, 1b, or any one of 1.1-1.32, wherein the composition is not prepared in conjunction with a sodium salt (e.g., NaOH, NaH2PO4, Na2HPO4, or Na3PO4) or a potassium salt (e.g., KOH, KH2PO4, K2HPO4, and K3PO4).

[0074] 1.34 Composition 1a, 1b, or any one of 1.1-1.33, wherein the composition is substantially free of sodium phosphate (e.g., NaH2PO4, Na2HPO4, and Na3PO4) and potassium phosphate (e.g., KH2PO4, K2HPO4, and K3PO4). For example, composition 1a, 1b, or any one of 1.1-1.33, wherein the composition does not contain detectable sodium phosphate (e.g., NaH2PO4, Na2HPO4, and Na3PO4) or potassium phosphate (e.g., KH2PO4, K2HPO4, and K3PO4).

[0075] 1.35 Composition 1a, 1b, or any one of 1.1-1.34, wherein the composition is not prepared in conjunction with sodium phosphate (e.g., NaH2PO4, Na2HPO4, and Na3PO4) or potassium phosphate (e.g., KH2PO4, K2HPO4, and K3PO4).

[0076] 1.36 Compositions 1a, 1b, or any one of 1.1-1.35, wherein the composition is substantially free of polysaccharides before and / or after reconstitution. As used herein, the term "polysaccharide" means a chain of 10 or more monosaccharide residues linked by glycosidic bonds. For example, compositions 1a, 1b, or any one of 1.1-1.35, wherein the composition is substantially free of polydextrose before and / or after reconstitution.

[0077] 1.37 Composition 1a, 1b, or any one of 1.1-1.36, wherein the composition is substantially free of cyclodextrin (e.g., cyclic oligosaccharides composed of (α-1,4)-linked α-D-glucopyranose) before and / or after reconstitution. For example, composition 1a, 1b, or any one of 1.1-1.36, wherein the composition is substantially free of hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin (i.e., sodium sulfobutyl ether-β-cyclodextrin) before and / or after reconstitution. For example, composition 1a, 1b, or any one of 1.1-1.36, wherein the composition does not contain detectable cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin (e.g., sodium sulfobutyl ether-β-cyclodextrin)) before and / or after reconstitution.

[0078] 1.38 Composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, and a monosaccharide (e.g., glucose). For example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate bisglumine salt and a monosaccharide (e.g., glucose). For example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate bisglumine salt and glucose. Alternatively, for example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 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 dihydrogen phosphate bisglumine salt) and a monosaccharide (e.g., glucose).

[0079] 1.39 Composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, and a disaccharide (e.g., a mixture of one or more of sucrose, lactose, or trehalose). For example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises a bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate bisglumine salt and a disaccharide (e.g., a mixture of one or more of sucrose, lactose, or trehalose). For example, compositions 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate diglucamine salt and sucrose. Or, for example, compositions 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate diglucamine salt and lactose. Or, for example, compositions 1a, 1b, or any one of 1.1-1.38, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate diglucamine salt and trehalose. Or, for example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, meglumine, meglumine salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (e.g., bis(3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate bisglumine salt), and disaccharide (e.g., one or a mixture of sucrose, lactose, or trehalose).

[0080] 1.40 Composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, meglumine, and a sugar alcohol (e.g., mannitol). For example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate bisglumine salt and a sugar alcohol (e.g., mannitol). For example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate bisglumine salt and mannitol. Alternatively, for example, composition 1a, 1b, or any one of 1.1-1.37, wherein the composition substantially comprises 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 dihydrogen phosphate bisglumine salt) and a sugar alcohol (e.g., mannitol).

[0081] 1.41 Composition 1a, 1b, or any one of 1.1-1.40, wherein the composition is reconstituted in ≤180 seconds.

[0082] 1.42 Compositions 1a, 1b, or any one of 1.1-1.41, wherein each test sample before lyophilization and / or after reconstitution contains ≤3 minute visible foreign particles (e.g., dots, short fibers less than 2 mm, and clumps). The minute visible foreign particles can be measured using a clarity analyzer (e.g., a YB-2 clarity analyzer). The testing for visible foreign particles (including the determination of minute visible foreign particles) can be performed according to the General Chapters of the Chinese Pharmacopoeia 2020, Part IV. <0904> As described in the text, this is completed.

[0083] 1.43 Composition 1a, 1b, or any one of 1.1-1.42, wherein the composition is prepared in a weight ratio of formula (I): sucrose: meglumine = 1:5:0.9-1 (e.g., 1:5:0.93). For example, the composition is prepared by using 100 mg of formula (I), 500 mg of sucrose, 80 mg of meglumine, 133 mg of an aqueous solution containing 10% meglumine, and making up to 10 mL with water for injection (e.g., sterile water for injection).

[0084] A method for preparing a pharmaceutical composition (method 1a) is also provided, the pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine.

[0085] A method for preparing a solid lyophilized pharmaceutical composition (method 1b) is also provided, the solid lyophilized pharmaceutical composition comprising a meglumine salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)):

[0086]

[0087] For example, methods for preparing compositions 1a, 1b, or 1.1-1.43 are provided.

[0088] Further methods 1a and 1b are provided as follows:

[0089] 1.1, Method 1a or Method 1b, wherein the pharmaceutical composition is any one of composition 1a, 1b, or 1.1-1.43.

[0090] 1.2, Method 1a, 1b, or 1.1, wherein 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)) is crystalline, for example, as described in U.S. Patent Publication No. 2019 / 0185496, the entirety of which is incorporated herein by reference. For example, wherein 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)) is a hydrated crystalline form (e.g., type N) or a non-solvent, non-hydrated crystalline form (e.g., type B) as described in U.S. Patent Publication No. 2019 / 0185496.

[0091] 1.3, Method 1a, 1b, 1.1, or 1.2, wherein the water (e.g., for injection, such as sterile water for injection) is cooled to 15°C-25°C (e.g., to 20°C).

[0092] 1.4, Method 1.3, wherein meglumine is added to water (e.g., added to water and dissolved until clear).

[0093] 1.5, Method 1.3 or 1.4, wherein 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) or a pharmaceutically acceptable salt thereof is added to water, for example, Method 1.3 or 1.4, wherein 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) is added to water.

[0094] 1.6. Any one of methods 1a, 1b, or 1.1-1.5, wherein 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) is mixed with meglumine.

[0095] 1.7. Any one of methods 1a, 1b, or 1.1-1.6, wherein the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) to meglumine is 1:0.2-4, for example 1:0.4-2, for example 1:0.6-1.

[0096] 1.8. Any one of methods 1a, 1b, or 1.1-1.7, wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) to meglumine is 1:1-5, for example 1:2-5, for example 1:2-4, for example 1:2-3, for example 1:2-2.5, for example 1:2-2.3 (for example 1:2.1-2.3), for example 1:2-2.2, for example 1:2.1-2.2, for example 1:2.2.

[0097] 1.9. Method 1a, 1b, or any one of 1.1-1.8, wherein 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is mixed with the lyophilized excipient.

[0098] 1.10, any one of methods 1.3-1.9, wherein the lyophilization excipient is added to water.

[0099] 1.11, Method 1.9 or 1.10, wherein the lyophilization excipient is selected from one or more mixtures of sucrose, lactose, mannitol, glucose, and trehalose, in any free or hydrated form. For example, in Method 1.9 or 1.10, the lyophilization excipient is trehalose in a free or hydrated form (e.g., dihydrate). For example, in Method 1.9 or 1.10, the lyophilization excipient is mannitol. For example, in Method 1.9 or 1.10, the lyophilization excipient is sucrose. For example, in Method 1.9 or 1.10, the lyophilization excipient is lactose in a free or hydrated form (e.g., monohydrate).

[0100] 1.12, any one of methods 1.9-1.11, wherein the freeze-drying excipient is a mixture of one or more of sucrose, lactose and trehalose.

[0101] 1.13, any one of methods 1.9-1.12, wherein the freeze-drying excipient is sucrose.

[0102] 1.14. Any one of methods 1.9-1.13, wherein the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula (I)) to the lyophilized excipient is 1:1-10, for example 1:2.5-7.5, for example 1:5.

[0103] 1.15, Method 1a, 1b, or any one of 1.1-1.14, wherein 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is mixed with a pH adjuster.

[0104] 1.16. Any one of methods 1.3-1.15, wherein the pH adjuster is added to the water.

[0105] 1.17, Method 1.15 or 1.16, wherein the pH adjuster is a mixture of one or more selected from hydrochloric acid, sodium hydroxide, citric acid and phosphate buffer.

[0106] 1.18, any one of methods 1.15-1.17, wherein the pH adjuster is selected from hydrochloric acid and citric acid.

[0107] 1.19, any one of methods 1a, 1b, or 1.1-1.18, wherein the pH value of the composition (e.g., the aqueous composition) is 7 to 10, for example 7.5 to 9.5, for example 8 to 9, for example 8.2-9, for example 8.5-8.6, for example 8.5.

[0108] 1.20, Method 1a, 1b, or any one of 1.1-1.19, wherein the method comprises filtering (e.g., sterilizing) the mixture of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and meglumine (and optionally a lyophilized excipient and optionally a pH adjuster).

[0109] 1.21, Method 1a, 1b, or any one of 1.1-1.20, wherein the method comprises sterilizing the mixture of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and meglumine (and optionally a lyophilized excipient and optionally a pH adjuster).

[0110] 1.22, Method 1a, 1b, or any one of 1.1-1.21, wherein the method comprises lyophilizing the mixture of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and meglumine (and optionally lyophilizing an excipient and optionally a pH adjuster).

[0111] 1.23, Method 1.22, wherein the freeze-drying process is as follows:

[0112] (1) Keep at -50℃ for 2-6 hours;

[0113] (2) Raise the temperature to -20 to -10℃ and keep it constant for 20 to 40 hours;

[0114] (3) Heat to 20-30℃ (e.g., 25℃) and keep at that temperature for 10-30 hours.

[0115] 1.24, Method 1.22 or 1.23, wherein the freeze-drying process is as follows: (1) cooling to -50°C; (2) heating to -15°C; (3) cooling to -50°C; (4) applying a vacuum; (5) cooling to -10°C; (6) heating to -5°C; and (7) heating to 25°C under vacuum.

[0116] 1.25. Any one of methods 1.22-1.24, wherein the freeze-drying process is as follows: (1) cooling (e.g., shelf temperature) to -40 to -60°C (e.g., -50°C) within 2 to 6 hours (e.g., within 4 hours); (2) maintaining the temperature (e.g., shelf temperature) at -40 to -60°C (e.g., -50°C) for 1 to 2 hours (e.g., 0.5 hours); (3) (e.g., rapidly) increasing the temperature (e.g., shelf temperature) to -20 to -10°C (e.g., -15°C); (4) maintaining the temperature at -20 to -10°C for 1 to 3 hours (e.g., 2 hours); (5) (e.g., rapidly) decreasing the temperature (e.g., plate temperature) to -40 to -60°C (e.g., -50°C); (6) maintaining the temperature (e.g., plate temperature) at -40 to -60°C (e.g., -50°C) for 2 to 6 hours (e.g., 4 hours); (7) (7) Apply a vacuum (e.g., to a vacuum below 0.2 mbar); (8) Cool (e.g., shelf temperature) to -20 to 0°C (e.g., -10°C) within 6 to 10 hours (e.g., 8 hours); (9) Keep (e.g., shelf temperature) at -20 to 0°C (e.g., -10°C) for 8 to 12 hours (e.g., 10 hours); (10) Heat (e.g., shelf temperature) to -10 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 to 0°C (e.g., -5°C) for 13 to 17 hours (e.g., 15 hours); (12) Increase the temperature (e.g., shelf temperature) to 20 to 30°C (e.g., 25°C) under a vacuum (e.g., ultimate vacuum) within 4 to 8 hours (e.g., 6 hours); and (13) Keep at 20 to 30°C (e.g., 25°C) for 10 to 14 hours (12 hours).

[0117] 1.26. Any one of methods 1.22-1.25, wherein the freeze-drying process is as follows:

[0118] (1) Reduce the shelf temperature to -50℃ within 4 hours and keep it warm for 0.5 hours;

[0119] (2) Increase the shelf temperature to -15℃ and keep it warm for 2 hours;

[0120] (3) Lower the temperature of the plate to -50℃ and keep it warm for 4 hours;

[0121] (4) Pump the vacuum pump to a vacuum level below 0.2 mbar;

[0122] (5) Reduce the shelf temperature to -15℃ within 8 hours and keep it warm for 10 hours;

[0123] (6) Raise the shelf temperature to -5°C within 2 hours and maintain the temperature for 15 hours; and

[0124] (7) Under vacuum (e.g., ultimate vacuum), raise the shelf temperature to 25°C within 6 hours and dry at 25°C for 12 hours. 1.27. Any one of methods 1.1-1.26, wherein the composition is prepared in a weight ratio of formula (I): sucrose: meglumine = 1:5:0.9-1 (e.g., 1:5:0.93). For example, wherein the composition is prepared before lyophilization using 100 mg of formula (I), 500 mg of sucrose, 80 mg of meglumine, 133 mg of an aqueous solution containing 10% meglumine, and made up to 10 mL with water for injection (e.g., sterile water for injection).

[0125] It also provides methods (method 2) for treating or controlling aquaporin-mediated diseases or conditions, such as water imbalance diseases or conditions, and other diseases, in patients (e.g., humans) who require such treatment.

[0126] Edema, such as cerebral or spinal cord edema, such as cerebral edema caused by head trauma, ischemic stroke, glioma, meningitis, acute mountain sickness, seizures, infection, metabolic disorders, hypoxia (including systemic hypoxia and hypoxia caused by cardiac arrest), water intoxication, liver failure, hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, lupus encephalitis, microgravity and / or radiation exposure, or invasive central nervous system surgery, such as neurosurgery, intravascular clot removal, spinal cord puncture, aneurysm repair, or deep brain stimulation; or, for example, spinal cord edema caused by spinal cord trauma, such as spinal cord compression; or optic nerve edema, such as optic nerve edema caused by microgravity and / or radiation exposure; or

[0127] retinal edema; or

[0128] Pulmonary edema; or

[0129] Hyponatremia or excessive fluid retention, such as that caused by heart failure (HF), cirrhosis, kidney disease, syndrome of inappropriate antidiuretic hormone secretion (SIADH), or infertility treatment; or

[0130] Ovarian hyperstimulation syndrome; or

[0131] Epilepsy, retinal ischemia or other eye diseases associated with 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

[0132] Fibromyalgia; or

[0133] Multiple sclerosis; or

[0134] Migraine; or

[0135] Treatment or prevention of transplant rejection, suppression of rejection of transplanted biomaterials, or control of post-transplant edema; or

[0136] To protect the heart during heart surgery,

[0137] The method includes administering to a patient a reconstituted pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine. For example, the method includes administering to a patient a reconstituted pharmaceutical composition comprising a pharmaceutically acceptable salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)). For example, the method includes administering to a patient a solution reconstituted from any one of compositions 1a, 1b, or 1.1-1.43.

[0138] The present invention further provides method 2 as follows:

[0139] 2.1 Method 2, wherein the disease or condition is described in any one of U.S. Patent Nos. 9,994,514, 9,573,885, and 9,949,991 and U.S. Patent Publication No. 2018 / 0042873.

[0140] 2.2, Method 2 or 2.1, wherein the disease or condition is cerebral edema.

[0141] 2.3, any one of methods 2, 2.1, or 2.2, wherein the disease or condition is cytotoxic (or cellular) cerebral edema.

[0142] 2.4, Method 2.3, wherein the cytotoxic cerebral edema is caused by stroke (e.g., ischemic stroke), closed head injury, traumatic brain injury, or hypoxia.

[0143] 2.5, Method 2.4, wherein the cytotoxic cerebral edema is caused by ischemic stroke.

[0144] 2.6, Method 2.4, wherein the cytotoxic cerebral edema is caused by hypoxia.

[0145] 2.7, Method 2.6, wherein the hypoxia is caused by stroke, cardiac arrest, asphyxia or other interruption of oxygen supply or cerebral blood flow.

[0146] 2.8, Method 2 or 2.1, wherein the disease or condition is spinal cord edema.

[0147] 2.9, Method 2.8, wherein the spinal cord edema is caused by spinal cord trauma (such as spinal cord compression).

[0148] 2.10, Method 2, or any one of 2.1-2.9, wherein the reconstituted solution is obtained by reconstitution of any one of compositions 1a, 1b, or 1.1-1.43.

[0149] Further, a reconstituted pharmaceutical composition is provided comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine, for use in treating any of the diseases or conditions mentioned herein, for example, for use in any of the foregoing methods, for example, for use in any of methods 2 or 2.1-2.10. For example, wherein the reconstituted pharmaceutical composition is obtained from any of compositions 1a, 1b, or 1.1-1.43. For example, the present invention further provides a reconstituted pharmaceutical composition comprising a pharmaceutically acceptable salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)) for use in treating any of the diseases or conditions mentioned herein, for example, for use in any of the foregoing methods, for example, for use in any of methods 2 or 2.1-2.10. For example, the reconstituted pharmaceutical composition is obtained from any one of compositions 1a, 1b, or 1.1-1.43.

[0150] Further, the invention provides a method for preparing a pharmaceutical preparation comprising any one of compositions 1a, 1b, or 1.1-1.43, such as a method for preparing a reconstituted pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and meglumine, for use in any of the foregoing methods, such as for use in any of methods 2 or 2.1-2.10. For example, the invention further provides a method for preparing a pharmaceutical preparation comprising any one of compositions 1a, 1b, or 1.1-1.43, such as a method for preparing a reconstituted pharmaceutical composition comprising a pharmaceutically acceptable salt thereof comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula (I)), for use in any of the foregoing methods, such as for use in any of methods 2 or 2.1-2.10. Detailed Implementation

[0151] The present invention is further described below through specific embodiments, but the embodiments described are only for illustrating the present invention and are not intended to limit the present invention.

[0152] Example 1: Lyophilized Composition

[0153] Table 1: Formulation Composition of Unit Dosage Products

[0154]

[0155]

[0156] Take 60-70% of the prescribed amount of water for injection, add the prescribed amount of meglumine, arginine, lysine, or disodium hydrogen phosphate / sodium hydroxide at a temperature of approximately 20°C, and stir until completely dissolved. Add the prescribed amount of compound (I) and stir until completely dissolved. Add the prescribed amount of mannitol and stir until completely dissolved.

[0157] Add water to bring the volume to the prescribed amount, continue stirring for 20 minutes, filter through a 0.22μm filter for sterilization, then fill, partially stopper, and freeze dry.

[0158] The above samples were subjected to content and related substance tests, and the turbidity value was measured. The detection methods are as follows:

[0159] (1) Content and related substances detection: High performance liquid chromatography (HPLC) was used to determine the content and related substances. Octadecylsilane bonded silica gel was used as the packing material (Agilent Eclipse plus C18, 150×4.6mm, 3.5μm or equivalent column); gradient elution was performed with 0.01mol / L ammonium acetate solution as mobile phase A and acetonitrile as mobile phase B.

[0160] (2) Clarity: The turbidity of the sample is measured using a turbidity meter (HACH model: TU5200). The sample solution is tested and compared with the turbidity value of standard turbidity solution No. 0.5 (turbidity value range is 1.6 to 2.2 NTU). If the turbidity value is less than that of standard turbidity solution No. 0.5, the sample is a clear solution.

[0161] (3) Moisture content: A Karl Fischer moisture analyzer was used to control the ambient humidity to be below 30% RH. One bottle of this product was taken and the total weight was measured. After opening the cap, the product was immediately poured into the moisture analyzer for measurement. The weight of the empty bottle was then measured to obtain the moisture content result.

[0162] The results are shown in Table 2.

[0163] Table 2: Stability of the lyophilized compositions in Table 1

[0164]

[0165]

[0166] Example 2: Lyophilized Composition

[0167] Table 3: Formulation Composition of Unit Dosage Products

[0168] Compound of formula (I) 100mg 100mg 100mg 100mg Mannitol 140mg 100mg 100mg 100mg meglumine 42.7mg 99.0mg 132.6mg 186.5mg Water for Injection Add to 10ml Add to 10ml Add to 10ml Add to 10ml pH 7.5 9.0 9.5 9.5

[0169] Take 60-70% of the prescribed amount of water for injection, add the prescribed amount of meglumine at a temperature of about 20°C, stir until completely dissolved, add the prescribed amount of compound (I), and stir until completely dissolved.

[0170] Add water to bring the volume to the prescribed amount, continue stirring for 20 minutes, filter through a 0.22μm filter for sterilization, then fill, partially stopper, and freeze dry.

[0171] The above samples were tested for content and related substances, and the turbidity value was measured. The results are shown in Table 4.

[0172] Table 4: Stability of the lyophilized compositions in Table 3

[0173]

[0174]

[0175] Example 3: Lyophilized Composition

[0176] Table 5. Formulation composition of unit dose products

[0177]

[0178] Take 70-80% of the prescribed amount of water for injection, add the prescribed amount of meglumine at a temperature of about 20°C, stir until completely dissolved, add the prescribed amount of compound (I), stir until completely dissolved, then add the prescribed amount of lyophilized excipient, and stir until completely dissolved.

[0179] The above solution was added to water for injection and brought to the prescribed volume. After stirring for 20 minutes, the solution was sterilized by filtration through a 0.2 μm filter, then filled, partially stoppered, and lyophilized.

[0180] The above samples were tested for content and related substances, and the turbidity value was measured. The results are shown in Table 6.

[0181] Table 6: Stability of the Lyophilized Compositions in Table 5

[0182]

[0183]

[0184] Example 4: Lyophilized Composition

[0185] Table 7: Formulation Composition of Unit Dosage Products

[0186] Compound of formula (I) 100mg sucrose 500mg meglumine 80mg 10% meglumine solution 133mg Water for Injection Add to 10ml

[0187] Take 80% of the prescribed amount of water for injection, add the prescribed amount of meglumine at a temperature of about 20°C, stir until completely dissolved, add the prescribed amount of compound (I), stir until completely dissolved, then add the prescribed amount of sucrose, and stir until completely dissolved.

[0188] The pH of the above solution was adjusted to 8.5-9 with 10% meglumine solution, water was added to bring the volume to the prescribed amount, stirring was continued for 20 minutes, and the solution was then sterilized by filtration through a 0.2μm filter before filling, semi-stopping, and lyophilizing.

[0189] Freeze-drying process:

[0190] Pre-freezing: Set the shelf temperature to drop to -50℃ over 4 hours, hold for 0.5 hours, then rapidly raise the shelf temperature to -15℃ and hold for 2 hours. Next, rapidly lower the shelf temperature to -50℃ and hold for 4 hours to completely freeze the sample. Turn on the vacuum pump to create a pre-vacuum of less than 0.2 mbar to begin sublimation.

[0191] Sublimation stage: Set the shelf temperature to -10℃ over 8 hours, maintain it for 10 hours, then raise the shelf temperature to -5℃ over 2 hours and maintain it for about 15 hours.

[0192] Analysis and drying: Extreme vacuum is applied, and the shelf temperature is set to rise to 25°C in 6 hours. Continue drying at 25°C for about 12 hours.

[0193] The above samples were tested for content and related substances, and the turbidity value was measured. The results are shown in Table 8.

[0194] Table 8: Stability of the Lyophilized Compositions in Table 7

[0195]

[0196] Example 5

[0197] Table 9

[0198]

[0199]

[0200] Table 10. Comparison of stability between HP-β-CD and sucrose formulations

[0201]

[0202] Example 6: Lyophilized Composition

[0203] Table 11: Formulation Composition of Unit Dosage Products

[0204] Compound of formula (I) 100mg sucrose 500mg meglumine 80mg 10% meglumine solution 133mg Water for Injection Add to 10ml

[0205] Table 12: Stability of the lyophilized compositions in Table 11

[0206] 0 months 0.025％ 0.025％ 0.8％ 25℃±2℃, 6 months 0.50％ 0.50％ 1.3％ 2~8℃, 6 months 0.088％ 0.088％ 1.3％ -20°±5℃, 6 months 0.041％ 0.041％ 1.1％

[0207] Example 7

[0208] Table 13.

[0209]

[0210]

[0211] The turbidity of a 0.5 turbidity standard solution is 1.6 to 2.2 NTU. A solution with a turbidity below this value is considered a clear solution.

[0212] Example 8

[0213] Table 14.

[0214]

[0215]

[0216]

[0217] The turbidity of a 0.5 turbidity standard solution is 1.6 to 2.2 NTU. A solution with a turbidity below this value is considered a clear solution.

[0218] Lyophilized formulations containing histidine, arginine, and lysine become turbid after 10 days at 25°C.

[0219] The sample containing tert-butanol became turbid after lyophilization and its pH value decreased after reconstitution.

[0220] Example 9

[0221] Reconstituted solvent

[0222] Table 15.

[0223] Water for Injection Does not comply with ChP glucose injection Similar results to aqueous solutions Sodium fructose diphosphate injection Insoluble, jelly-like 0.9% Sodium Chloride Injection Conforms to ChP Potassium chloride injection Three batches of samples (one bottle contained ≥3 fine hairs) Lactated Ringer's solution Similar results to 0.9% sodium chloride injection. Ringer's acetate solution Similar results to 0.9% sodium chloride injection.

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 hydrate thereof, meglumine, and a lyophilized excipient. The weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to meglumine is 1:0.6~1; and The freeze-drying excipient is selected from one or a mixture of several of sucrose, lactose, mannitol, glucose, and trehalose.

2. The lyophilized pharmaceutical composition of claim 1, wherein the lyophilizing excipient is selected from one or a mixture of several of sucrose, lactose, and trehalose.

3. The lyophilized pharmaceutical composition of claim 1, wherein the lyophilization excipient is sucrose.

4. The lyophilized pharmaceutical composition according to any one of claims 1-3, wherein the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the lyophilized excipient is 1:1 to 10.

5. The lyophilized pharmaceutical composition of claim 4, wherein the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the lyophilized excipient is 1:2.5-7.

5.

6. The lyophilized pharmaceutical composition of claim 4, wherein the weight ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the lyophilized excipient is 1:

5.

7. The lyophilized pharmaceutical composition according to any one of claims 1-3 and 5-6, wherein, It further includes a pH adjuster.

8. The lyophilized pharmaceutical composition of claim 7, wherein, The pH adjuster is selected from one or a mixture of several of hydrochloric acid, sodium hydroxide, citric acid, and phosphate buffer.

9. The lyophilized pharmaceutical composition of claim 8, wherein, The pH adjuster is selected from hydrochloric acid or citric acid.

10. The lyophilized pharmaceutical composition according to any one of claims 1-3, 5-6, and 8-9, wherein, The pH range is 7.5 to 9.

5.

11. The lyophilized pharmaceutical composition of claim 10, wherein, The pH value is 8.0~9.

0.

12. The lyophilized pharmaceutical composition of claim 11, wherein, The pH is 8.

5.

13. The lyophilized pharmaceutical composition according to any one of claims 1-3, 5-6, 8-9, and 11-12, wherein, The lyophilized pharmaceutical composition contains ≤1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after 6 months at room temperature.

14. The lyophilized pharmaceutical composition of claim 13, wherein, The composition has ≤3% w / w water.

15. A method for preparing the lyophilized pharmaceutical composition according to any one of claims 1-14, comprising: a) Take 60% to 90% of the prescribed amount of water for injection, cool it to 15°C to 25°C, add meglumine to dissolve until clear, and slowly add 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate or its pharmaceutically acceptable salt or its hydrate; b) Add lyophilization excipients, and optionally, add other components; c) Add water for injection to the prescribed amount; d) Optionally, the product obtained by filtration sterilization and freeze drying step (c) is prepared.

16. The preparation method according to claim 15, wherein, Step (a) Cool down to 20°C.

17. The preparation method according to claim 15, wherein, The other components mentioned in step (b) are pH adjusters.

18. The preparation method according to claim 15, wherein, The freeze-drying process in step (d) is as follows: (1) Keep at -50℃ for 2~6h; (2) Raise the temperature to -20℃~-10℃ and keep at it for 20~40h; (3) Raise the temperature to 20~30℃ and keep at it for 10~30h.

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

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