This application relates to the field of pharmaceutical compositions, in particular to a pharmaceutical composition of an aquaporin inhibitor and a preparation method thereof.
Aquaporins are cell membrane proteins that act as molecular water channels to mediate the flow of water in and out of the cells. While there is some degree of passive diffusion or osmosis of water across cell membranes, the rapid and selective transport of water in and out of cells involves aquaporins. These water channels selectively conduct water molecules in and out of the cell, while blocking the passage of ions and other solutes, thereby preserving the membrane potential of the cell. Aquaporins are found in virtually all life forms, from bacteria to plants to animals. In humans, they are found in cells throughout the body.
Aquaporin inhibitors, e.g., inhibitors of AQP4 and/or AQP2, may be of utility in the treatment or control of diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord), hyponatremia, and excess fluid retention, as well as diseases such as epilepsy, retinal ischemia and other diseases of the eye, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines.
WO2013169939 discloses N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxy-benzamide (structure shown in formula (II)) as an aquaporin inhibitor. Formula (I) (structure shown below) is a prodrug of formula (II). The compounds can treat or control aquaporin-mediated diseases selected from cytotoxic brain edema, spinal cord edema, retinal edema, optic nerve edema, cardiac edema, optic neuromyelitis, hyponatremia, retinal ischemia, and excessive fluid retention.
The formula (I) compound needs to be prepared as a liquid formulation for intravenous injection or infusion to achieve rapid onset of action. However, the aqueous solubility of formula (I) needs to be improved to allow for an injection that provides a therapeutically effective amount of formula (II). Yet, salts of formula (I), which are more soluble, can revert to N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (formula (II) compound) even in the solid state. WO2015069956 shows that certain lyophilized salts of formula (I) revert to formula (II) even in the solid state (about 1% per day or 1% in 5 days). There is an urgent need to solve the problem of drug solubility and stability in order to provide a pharmaceutical composition that fulfills the requirements of clinical medication.
The application provides a pharmaceutical composition, which 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, and meglumine (also called N-methyl-D-glucamine).
In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to meglumine is 1:0.2˜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˜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˜1.
In some embodiments, the pharmaceutical composition is an injectable pharmaceutical composition.
In some embodiments, the pharmaceutical composition is a lyophilized pharmaceutical composition.
In some embodiments, the pharmaceutical composition in the present application further comprises a lyophilization excipient.
In some embodiments, the lyophilization excipient is selected from one or a mixture of sucrose, lactose, mannitol, glucose, and trehalose. In some embodiments, the lyophilization excipient is selected from one or a mixture of sucrose, lactose, and trehalose.
In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to lyophilization excipient is 1:1˜10. In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to lyophilization excipient is 1:2.5˜7.5. In some embodiments, the weight ratio of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate to lyophilization excipient is 1:5.
Optionally, the pharmaceutical composition in the present application further comprises a pH adjusting agent. The pH adjusting agent in the present application is selected from one or a mixture of hydrochloric acid, sodium hydroxide, citric acid, and phosphate buffer. In some embodiments, the pH adjusting agent in the present application is selected from hydrochloric acid and citric acid.
In some embodiments, the pH of the pharmaceutical composition in the present application is 7.5 to 9.5. In some embodiments, the pH of the pharmaceutical composition in the present application is 8.0 to 9.0. In some embodiments, the pH of the pharmaceutical composition in the present application is about 8.5.
In some embodiments, the application provides a pharmaceutical composition, which comprises 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 excipient and a pH adjusting agent.
Optionally, the pharmaceutical composition in the present application further includes water for injection.
In some embodiments, the application provides a method for preparing the above-mentioned pharmaceutical composition, including:
In some embodiments, step (a) is cooled to 20° C.
In some embodiments, the other components in step (b) are selected from lyophilization excipients and pH adjusting agents.
In some embodiments, the lyophilizing process in step (d) is as follows: (1) preserve at −50° C. for 2˜6 h; (2) raise temperature to −20° C. to −10° C. and preserve for 20˜40 h; (3) raise temperature to 20˜30° C. and preserve for 10˜30 h. In some embodiments, the temperature is raised to 25° C. in step (3).
In some embodiments, the lyophilizing process in step (d) is as follows: (1) decrease temperature to −50° C.; (2) increase temperature to −15° C.; (3) decrease temperature to −50° C.; (4) apply vacuum; (5) decrease temperature to −10° C.; (6) raise temperature to −5° C.; and (7) raise temperature to 25° C. under vacuum.
In some embodiments, the lyophilizing process in step (d) is as follows: (1) decrease temperature (e.g., shelf temperature) to −40° C. to −60° C. (e.g., −50° C.) within 2-6 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 1-2 hours (e.g., 0.5 hours); (3) increase (e.g., rapidly) temperature (e.g., shelf temperature) to −20° C. to −10° C. (e.g., −15° C.); (4) maintain the temperature at −20° C. to −10° C. for 1-3 hours (e.g., 2 hours); (5) decrease (e.g., rapidly) temperature (e.g., slab temperature) to −40° C. to −60° C. (e.g., −50° C.); (6) maintain the temperature (e.g., slab temperature) at −40° C. to −60° C. (e.g., −50° C.) for 2-6 hours (e.g., 4 hours); (7) apply vacuum (e.g., to achieve vacuum below 0.2 mbar); (8) decrease temperature (e.g., shelf temperature) to −20° C. to 0° C. (e.g., −10° C.) within 6-10 hours (e.g., 8 hours); (9) maintain the temperature (e.g., shelf temperature) at −20° C. to 0° C. (e.g., −10° C.) for 8-12 hours (e.g., 10 hours); (10) raise temperature to −10° C. to 0° C. (e.g., −5° C.) within 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) raise temperature (e.g., shelf temperature) to 20° C.-30° C. (e.g., 25° C.) under vacuum (e.g., ultimate vacuum) within 4-8 hours (e.g., 6 hours); and (13) maintain temperature 20° C.-30° C. (e.g., 25° C.) for 10-14 hours (e.g., 12 hours).
In some embodiments, the lyophilized formulation disclosed herein is reconstituted with an aqueous solution comprising sodium and/or potassium (e.g., comprising sodium chloride, e.g., 0.9% NaCl or comprising sodium chloride and sodium lactate or sodium acetate (e.g., Lactated Ringer's or Acetated Ringer's)) or comprising potassium chloride (e.g., potassium chloride injection)). Reconstitution with water for injection or glucose may result in visible particles.
In some embodiments, the “pharmaceutically acceptable salt” in the present application is selected from alkali metal salts (such as sodium salt, preferably disodium salt), organic base salt (such as ammonium salt, preferably meglumine salt).
In some embodiments, the “pharmaceutically acceptable solvate” in the present application is hydrate (eg, dihydrate).
In this application, when the pharmaceutical composition is in a solid form (for example, a lyophilized formulation), the pH refers to the pH value of the solution of the solid pharmaceutical composition before lyophilization and/or the pH value after reconstitution.
In this application, unless otherwise specified, the weight of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is by the weight of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate.
Sugars (e.g., trehalose) may be provided in hydrate form. In this application, unless otherwise specified, the weight of sugar (e.g., sucrose, lactose, glucose, or trehalose) is by the weight of the sugar in anhydrate form.
The invention provides a formulation that can be reconstituted to a liquid that is acceptable to the human body for intravenous injection or infusion, which can quickly take effect, so that the formula (I) compound can be used for treatment in the field of cerebral edema. At the same time, the composition of formula (I) compound in the present invention and its preparation method are simple, with great operability, which is conducive to industrial production, and the product has good stability, and the content of degradation impurities (such as the formula (II) compound) is significantly less, which ensures exerting of pharmaceutical efficacy. For instance, compared to compositions comprising other bases, such as a sodium salt base or other amine bases (e.g., arginine, lysine, and histidine), specific compositions comprising meglumine disclosed herein show less reversion of formula (I) to formula (II). Without being bound by theory, it is believed that some bases may drive a unimolecular process that results in formula (I) reverting to formula (II). Formula (II) has poor aqueous solubility, thus even small amounts of it in a formulation for injection may result in visible particles, rendering the formulation unusable. With meglumine, impurities in the lyophilized composition are less and the composition is acceptable for injection after reconstitution.
Provided is a pharmaceutical composition (Composition 1a) 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.
Further provided is a solid lyophilized pharmaceutical composition (Composition 1b ) comprising a meglumine salt of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate (formula (I)):
Further provided are Composition 1a and 1b as follows:
Or, for instance, any 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 phosphate bis-meglumine salt).
Also provided is a method of making a pharmaceutical composition (Method 1a) 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 provided is a method of making a solid lyophilized pharmaceutical composition (Method 1b) comprising a meglumine salt of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate (formula (I)):
For instance, provided is a method of making any of Compositions 1a, 1b, or 1.1-1.43.
Further provided are Methods 1a and 1b as follows:
Also provided is a method (Method 2) of treating or controlling a disease or condition mediated by an aquaporin, e.g., diseases or conditions of water imbalance and other diseases, for example,
Further provided is Method 2 as follows:
Further provided is 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 to treat any of the diseases or conditions discussed herein, for instance, for use in any of the foregoing methods, e.g., for use in any of Methods 2 or 2.1-2.10. For instance, wherein the reconstituted pharmaceutical composition is obtained from any of Compositions 1a, 1b, or 1.1-1.43. For instance, further provided is 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 to treat any of the diseases or conditions discussed herein, for instance, for use in any of the foregoing methods, e.g., for use in any of Methods 2 or 2.1-2.10. For instance, wherein the reconstituted pharmaceutical composition is obtained from any of Compositions 1a, 1b, or 1.1-1.43.
Further provided is any of Compositions 1a, 1b, or 1.1-1.43 in the manufacture of a medicament, for instance, in the manufacture of 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, e.g., for use in any of Methods 2 or 2.1-2.10. For instance, further provided is any of Compositions 1a, 1b, or 1.1-1.43 in the manufacture of a medicament, for instance, in the manufacture of 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 any of the foregoing methods, e.g., for use in any of Methods 2 or 2.1-2.10.
The invention is further described through specific examples hereinafter, but the described examples are used only to illustrate the present invention and not to limit the present invention.
Add the prescription amount of meglumine, arginine, lysine, or disodium hydrogen phosphate/sodium hydroxide to 60-70% of the prescription amount of water for injection at a temperature of about 20° C., stir until it is completely dissolved, and add the prescription amount of formula (I) compound, stir until completely dissolved. Add the prescribed amount of mannitol and stir until completely dissolved.
Replenish the water to the prescribed volume, continue to stir for 20 minutes, filter sterilize through a 0.22 μm filter, fill, half stoppering, and lyophilize.
Take the above samples to test the content and related substances, and measure the turbidity value. The test method is as follows:
The results are shown in Table 2.
Add prescription amount of meglumine to 60-70% of the prescription amount of water for injection at a temperature of about 20° C., stir until it is completely dissolved, add the prescription amount of formula (I) compound, and stir until completely dissolved.
Replenish the water to the prescribed volume, continue to stir for 20 minutes, filter sterilize through a 0.22 μm filter, fill, half stoppering, and lyophilize.
Take the above samples to test the content and related substances, and measure the turbidity value. The results are shown in Table 4.
Add the prescription amount of meglumine to 70-80% of the prescription amount of water for injection at a temperature of about 20° C., stir until it is completely dissolved, add the prescription amount of formula (I) compound, stir until completely dissolved, and then add the prescription amount of lyophilized excipient and stir until completely dissolved.
Replenish the water to the prescribed volume, continue to stir for 20 minutes, filter sterilize through a 0.22 μm filter, fill, half stoppering, and lyophilize.
Take the above samples to test the content and related substances, and measure the turbidity value. The results are shown in Table 6.
Add the prescription amount of meglumine to 80% of the prescription amount of water for injection at a temperature of about 20° C., stir until it is completely dissolved, add the prescription amount of formula (I) compound, stir until the dissolution is complete, then add the prescription amount of sucrose, and stir until completely dissolved.
Adjust the pH of the above solution to 8.5-9 with 10% meglumine solution, replenish water to the prescribed volume, continue to stir for 20 minutes, filter sterilize through a 0.2 μm filter, fill, half stoppering, and lyophilize.
Pre-lyophilizing: decrease the shelf temperature to −50° C. within 4 h, and maintain the temperature for 0.5 h, then rapidly increase the shelf temperature to −15° C., and maintain the temperature for 2 h, then rapidly decrease the slab temperature to −50° C., and maintain the temperature for 4 h to achieve a completely frozen product. Turn on the vacuum pump to achieve a vacuum below 0.2 mbar, and the sublimation starts.
Sublimation stage: decrease the shelf temperature to −10° C. within 8 h and maintain the temperature for 10 h, then raise the shelf temperature to −5° C. within 2 h and maintain the temperature for about 15 h.
Secondary drying: raise the shelf temperature to 25° C. within 6 h under ultimate vacuum, and maintain the temperature to dry at 25° C. for about 12 h.
Take the above samples to test the content and related substances, and measure the turbidity value. The results are shown in Table 8.
Lyophilized preparations with histidine, arginine, and lysine are turbid after 10 days at 25° C. With tertiary butyl alcohol, samples are turbid after lyophilization and pH decreases after reconstitution.
Number | Date | Country | Kind |
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202010779964.6 | Aug 2020 | CN | national |
Filing Document | Filing Date | Country | Kind |
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PCT/CN2021/110506 | 8/4/2021 | WO |