Method for producing lyophilized sulfaprodyl powder injection, and the product and its uses.

Abstract

The present invention provides a method for producing sulfaprodil lyophilized powder for injection, and the resulting product and uses thereof. Specifically, the method comprises the following steps: adding sulfaprodil for injection, filtering after sulfaprodil is completely dissolved, adjusting the pH of the filtrate with an alkaline aqueous solution, adding a certain amount of water for injection, filling with an inert gas for protection, sterilizing and filtering to obtain a sulfaprodil solution, and lyophilizing to obtain a sulfaprodil lyophilized powder for injection.

Description

Detailed Description of the Invention

[0001] Technical Field Citation to Related Applications This application claims priority based on Chinese Patent Application No. 202010729677.4 filed on July 27, 2020, entitled "Method for Preparing Salfaprodil Lyophilized Powder for Injection, and Product and Use Thereof", the entire content of which is incorporated into this application by reference.

[0002] Technical Field The present invention belongs to the technical field of pharmaceutical preparations, and relates to a method for preparing a Salfaprodil lyophilized powder for injection, the Salfaprodil lyophilized powder for injection prepared by the method, the product, and the pharmaceutical use thereof.

[0003] Background Art Salfaprodil has a chemical name of potassium 2-hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoate, and its structural formula is as follows.

[0004] Chemical Formula

[0005] Salfaprodil is a moderately potent N-methyl-D-aspartate (NMDA) receptor antagonist and also acts as a strong antioxidant to exert a dual neuroprotective effect, which can simultaneously block NMDA receptor-mediated excitotoxicity and the body's oxidative stress response. Its neuroprotective effect can last for 28 days or more, and it provides a wide range of neuroprotective effects while extending the therapeutic time window.

[0006] CN1309703C discloses that sulfaprodyl can be used to treat typical or pathological neurological disorders in cerebrovascular and neurological diseases and symptoms. Specifically, sulfaprodyl is used for thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, cerebral aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia, and tissue hypoxia. Sulfaprodyl can also be effectively used for neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, cerebellar degeneration, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, epilepsy, polyinfarct dementia, and encephalitis.

[0007] Conventional lyophilized formulations utilize diverse manufacturing methods and are widely used for various injectable powders. However, when manufacturing sulfaprodyl for injection using conventional methods used for other products (for example, the lyophilization method for fludarabine phosphate, CN104771369B), the product does not easily form a uniform and fine crystalline form due to differences in the crystallization behavior of the active ingredients with different pharmacological effects during lyophilization. Furthermore, after redissolution, precipitation occurs in the product, reducing stability and resulting in defects such as obvious layering in the appearance. Therefore, there is an urgent need to develop a lyophilization formulation method suitable for sulfaprodyl for injection.

[0008] [Summary of the Invention] [Problems the invention aims to solve] To eliminate the defects present when manufacturing sulfaprodyl for injection using conventional freeze-drying technology, the present invention provides a method for manufacturing sulfaprodyl for injection that exhibits excellent moldability, a clear appearance of the solution before freeze-drying, good resolubility of the freeze-dried product, excellent transparency after resolubility, low impurity content, excellent stability, and allows for quality control, as well as a product manufactured thereby.

[0009] [Means for solving the problem] The present invention is realized in the following manner.

[0010] First, the present invention provides a method for producing a lyophilized sulfaprodyl powder injection, comprising the following steps: adding sulfaprodyl to sterile water for injection and dissolving it; filtering the solution; adjusting the pH of the filtrate using an alkaline aqueous solution; adding sterile water for injection to bring the volume to a fixed level; and filling the solution with an inert gas for protection; performing sterile filtration to obtain a sulfaprodyl solution; and subsequently lyophilizing the solution to obtain a lyophilized sulfaprodyl powder injection.

[0011] Preferably, in the above manufacturing method, the pore size of the filtration membrane used for filtration and sterilization filtration is independently 0.2 to 1.0 μm.

[0012] More preferably, in the above manufacturing method, the material of the filter membrane used for filtration and sterilization filtration is independently polyethersulfone (PES), polytetrafluoroethylene (PTFE), nylon (N6 / N66), or polyvinylidene fluoride (PVDF).

[0013] Preferably, the alkaline substance used in the above manufacturing method is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, and sodium bicarbonate.

[0014] Preferably, in the above manufacturing method, the concentration of the alkaline substance aqueous solution is 0.1 to 1.0 M.

[0015] Preferably, in the above manufacturing method, the pH value is adjusted to 8.0 to 10.0.

[0016] In the above manufacturing method, the inert gas is argon or nitrogen.

[0017] Preferably, in the above manufacturing method, sterilization filtration is performed within 16 hours after the specified volume.

[0018] Preferably, in the aforementioned production method, the mass-volume percentage concentration of the sulfaphenazole solution is 5~20 w / v%.

[0019] Preferably, in the aforementioned production method, freeze-drying is performed in a freeze dryer, comprising a pre-freezing stage, a temperature recovery stage, a re-cooling stage, a primary drying stage a, a primary drying stage b, and a desorption drying stage.

[0020] More preferably, in the aforementioned pre-freezing stage, the shelf temperature of the freeze dryer is lowered to -50~-30°C and maintained for 1~3 hours.

[0021] More preferably, in the aforementioned temperature recovery stage, the shelf temperature of the freeze dryer is raised to -5~5°C and maintained for 1~3 hours.

[0022] More preferably, in the aforementioned re-cooling stage, the shelf temperature of the freeze dryer is lowered to -50~-30°C and maintained for 1~3 hours.

[0023] More preferably, in the aforementioned primary drying stage a, the shelf temperature of the freeze dryer is raised to -30~-25°C and maintained for 10~30 hours, and the vacuum degree at this time is 5~20 Pa.

[0024] More preferably, in the aforementioned primary drying stage b, the shelf temperature of the freeze dryer is raised to 5~20°C and maintained for 10~30 hours, and the vacuum degree at this time is 5~20 Pa.

[0025] More preferably, in the desorption drying stage, the shelf temperature of the freeze dryer is raised to 10~40°C and maintained for 10~30 hours, and the vacuum degree at this time is 5~20 Pa.

[0026] Preferably, the aforementioned production method includes filling, caulking, capping, and / or packaging and the like.

[0027] Secondly, the present invention provides a sulfaphenazole freeze-dried powder for injection produced by the aforementioned production method.

[0028] Preferably, in the above-mentioned sulforapidil lyophilized powder for injection, sulforapidil is the only pharmacologically active ingredient.

[0029] Thirdly, the present invention provides the above-mentioned sulforapidil lyophilized powder for use in the manufacture of a medicament for the prevention and / or treatment of neurodegenerative diseases.

[0030] Preferably, the neurodegenerative disease is one or more selected from Huntington's disease, Alzheimer's disease, Pick's disease, Korsakoff's syndrome, cerebellar atrophy, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, glutaric acidemia, epilepsy, multi-infarct dementia, and encephalitis.

[0031] Fourthly, the present invention provides the use of the above-mentioned sulforapidil lyophilized powder for injection for the manufacture of a medicament for the prevention and / or treatment of cerebrovascular and nervous system diseases and conditions.

[0032] Preferably, the cerebrovascular and nervous system diseases and conditions are one or more selected from thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, cerebral aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia, and tissue hypoxia.

[0033] Fifthly, the present invention provides the use of the above-mentioned sulforapidil lyophilized powder for injection for the prevention and / or treatment of neurodegenerative diseases.

[0034] Preferably, the neurodegenerative disease is one or more selected from Huntington's disease, Alzheimer's disease, Pick's disease, Korsakoff's syndrome, cerebellar atrophy, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, glutaric acidemia, epilepsy, multi-infarct dementia, and encephalitis.

[0035] Sixthly, the present invention provides the use of the above-mentioned sulforapidil lyophilized powder for injection for the prevention and / or treatment of cerebrovascular and nervous system diseases.

[0036] Preferably, the cerebrovascular and nervous system diseases and symptoms should include one or more selected from thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, cerebral aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia, and tissue hypoxia.

[0037] Seventh, the present invention provides a method for the prevention and / or treatment of neurodegenerative diseases, comprising administering a prophylactic and / or therapeutically effective amount of sulfaprodyl lyophilized powder injection to an individual in need thereof.

[0038] Preferably, the neurodegenerative disease is one or more selected from Huntington's disease, Alzheimer's disease, Pick's disease, Korsakoff syndrome, cerebellar atrophy, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, glutaricemia, epilepsy, multiple infarct dementia, and encephalitis.

[0039] VIII. The present invention provides a method for the prevention and / or treatment of diseases and symptoms of the cerebrovascular and nervous system, comprising administering a preventive and / or therapeutically effective amount of sulfaprodyl lyophilized powder injection to an individual in need thereof.

[0040] Preferably, the cerebrovascular and nervous system diseases and symptoms are selected from one or more of the following: thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, cerebral aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia, and tissue hypoxia.

[0041] [Effects of the invention] The present invention has the following beneficial effects compared to the prior art.

[0042] (1) When a freeze-dried powder injection is produced by the method of the present invention, the solution before freeze-drying is clear and free of foreign matter visible to the naked eye.

[0043] (2) The freeze-dried powder injection of the present invention is a milky white powder with fine particles and a uniform structure.

[0044] (3) The freeze-dried powder injection of the present invention has excellent resolubility, and the solution after redissolution is pale yellow and has good transparency.

[0045] (4) The freeze-dried powder injection of the present invention has a low water content.

[0046] (5) The freeze-dried powder injection of the present invention does not increase in the content of impurities compared to the raw material and can be effectively controlled.

[0047] (6) The lyophilized powder injection of the present invention maintains virtually the same parameters before and after the 6-month accelerated test, demonstrating excellent stability.

[0048] [Modes for carrying out the invention] First, the present invention provides a novel method for producing a lyophilized sulfaprodyl powder injection.

[0049] Unless otherwise specified, the term "Salfaprodil" as used in this invention refers to one or more physical forms of potassium 2-hydroxyl-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoate, or a pharmaceutically acceptable salt, hydrate, or solvate.

[0050] Unless otherwise specified, the term "lyophilized powder injection" as used in this invention refers to a solid powder formulation produced by mixing one or more pharmacokinetic ingredients (or raw materials) with one or more excipients or dissolving them in a solvent (or solvent) in a sterile environment, and then undergoing certain processing (e.g., lyophilization).

[0051] Specifically, the above manufacturing method includes the following steps:

[0052] Sulfaplodyl is dissolved in sterile water for injection and then filtered. The pH of the filtrate is adjusted with an alkaline aqueous solution, sterile water for injection is added to the desired volume, and then the solution is filled with an inert gas for protection. After sterile filtration, the sulfaplodyl solution is obtained and freeze-dried.

[0053] Unless otherwise specified, "water for injection" as used in this invention means water that conforms to the relevant provisions for "water for injection" in the Chinese Pharmacopoeia (or the United States Pharmacopoeia, the European Pharmacopoeia, or the Japanese Pharmacopoeia).

[0054] Unless otherwise specified, the term "dissolution and purification" as used in this invention refers to the process or operation of dissolving a sample in a solvent until it becomes clear or free from any visible turbidity or precipitate.

[0055] Unless otherwise specified, the term "filtration" as used in this invention means the operation or process of separating two phases by passing a continuous phase (e.g., the liquid in a suspension or the gas in a solid particle aerosol) of a heterogeneous dispersion system containing solid particles (e.g., a suspension or a solid particle aerosol) through a specific separation medium (e.g., filter paper or a filter membrane) under the action of an external force, thereby capturing the dispersed phase (e.g., the solid particles in the heterogeneous dispersion system). When the multiple dispersion system is a suspension, the liquid continuous phase passing through the separation medium is the "filtrate," and the solid dispersed phase captured by the separation medium is the "filtration cake." Unless otherwise specified, the definitions of "filtrate" and "filtration cake" as used in this invention are as described above.

[0056] In some preferred implementations, the filtration of the manufacturing method is performed through a filtration membrane.

[0057] In some preferred methods, the pore size of the filtration membrane is 0.2 to 1.0 μm, preferably 0.2 to 0.5 μm, and more preferably 0.45 μm.

[0058] In some preferred implementations, the material of the filtration membrane is selected from one or more of PES, PTFE, N6 / N66, and PVDF.

[0059] In some preferred methods, the manufacturing method adjusts the pH of the filtrate using an aqueous solution of an alkaline substance.

[0060] In some more preferred embodiments, the alkaline substance of the manufacturing method is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, and sodium bicarbonate, preferably potassium hydroxide, potassium carbonate, potassium bicarbonate, and more preferably potassium hydroxide.

[0061] In some more preferred methods, the molar concentration of the alkaline aqueous solution is 0.1 to 1.0 mol / L, preferably 0.1 to 0.5 mol / L.

[0062] In some more preferred methods, the aqueous solution of the alkaline substance adjusts the pH of the filtrate to 8.0-10.0.

[0063] Unless otherwise specified, the term "constant volume" as used in this invention refers to the process of accurately and precisely adding a solvent to a measuring vessel (e.g., a volumetric flask) up to the marked line on the vessel when dissolving or diluting a substance to a certain concentration. In short, constant volume means adjusting to a fixed volume.

[0064] Unless otherwise specified, the terms "inert gas" or "chemically inert gas" used in this invention refer to gaseous substances that do not undergo chemical reactions under typical test conditions. These include helium (He), neon (Ne), argon (Ar), xenon (Xe), and radon (Rn), which belong to Group 0 of the periodic table and are commonly referred to as "inert gases," as well as nitrogen (N2) and carbon dioxide (CO2), which do not undergo chemical reactions under general conditions.

[0065] In some preferred embodiments, the inert gas protection step of the manufacturing method provides an inert atmosphere to a substance in a constant volume using an inert gas.

[0066] In some preferred implementations, the inert gas protection step of the manufacturing method provides an inert atmosphere to the substance in a constant volume using argon or nitrogen.

[0067] Unless otherwise specified, the terms "sterilization filtration" or "sterilization by filtration" as used in this invention refer to the operation or process of treating bacteria in a sample using a filtration method to achieve sterility. Typically, sterilization filtration requires the use of bacterial filtration devices with fine pore sizes, including thin-film bacterial filters (also called bacterial filtration membranes, or simply membranes; pore sizes mainly come in two types: 0.45 μm and 0.22 μm, with the latter offering superior sterilization), ceramic bacterial filters, asbestos bacterial filters, and sintered glass bacterial filters.

[0068] In some preferred implementations, the sterilization filtration of the manufacturing method is similarly carried out through a filtration membrane.

[0069] In some more desirable implementations, the pore size of the sterile filtration membrane is 0.20 to 0.22 μm.

[0070] In some more preferred implementations, the material of the sterile filtration membrane is similarly selected from one or more of PES, PTFE, N6 / N66, and PVDF.

[0071] In some more preferred methods, the sterilization filtration is performed within 16 hours after the completion of the volumetric process. Preferably, it is performed within 12 hours, and more preferably within 8 hours.

[0072] In some preferred methods, the sulfaprodyl solution of the manufacturing method maintains an appropriate mass-volume percentage concentration to ensure that the subsequent freeze-drying process proceeds smoothly.

[0073] Unless otherwise specified, the term "mass-volume percentage concentration" (or "mass concentration") used in this invention refers to a unit volume (e.g., 1 m³). 3It refers to the mass number of solute contained in a solution (e.g., 1 g or 1 mg), and the unit is usually g / m³. 3 Alternatively, it may be expressed in mg / L. Unless otherwise specified, the term "w / v%" as used in this invention means the number of grams of solute per 100 mL of solution, i.e., "g / 100 mL".

[0074] In some more desirable implementations, the appropriate mass-volume percentage concentration is 5–20 w / v%.

[0075] In some preferred implementations, the freeze-drying of the manufacturing method is performed in a freeze-dryer and includes pre-freezing, temperature recovery, re-cooling, primary drying (which is subdivided into stages a and b depending on the temperature change), and desorption drying.

[0076] Unless otherwise specified, the term "freeze-drying" as used in this invention refers to the process of freezing a water-containing substance (for example, a water-containing chemical solution, i.e., the sulfaprodyl solution of this invention) below its freezing point to convert the water into ice (solidify), converting the ice into water vapor (sublimation) under vacuum conditions, and then removing it. The substance may be pre-frozen in a freezing device and then dried in a drying device, or it may be directly frozen in a drying device through rapid vacuum and then dried. The water vapor generated during the sublimation process is removed by the condensation action of a condensing device, and the heat of vaporization required for the sublimation process is generally supplied by thermal radiation or thermal conduction.

[0077] Unless otherwise specified, the term "freeze dryer" as used in this invention refers to equipment or apparatus for performing freeze drying operations, and mainly consists of a sample storage device (including a rapid freezing chamber, drying chamber, optional post-processing chamber, etc.), a refrigeration device, a vacuum device, a heating device, and a control device. The operating principle of the freeze dryer is as follows: After pretreatment, the freeze-drying sample is transferred to the rapid freezing chamber for freezing, then transferred to the drying chamber for sublimation and dehydration, and finally transferred to the post-processing chamber for post-processing. The refrigeration device provides the necessary cooling capacity to the rapid freezing chamber, the vacuum device creates low-pressure conditions in the drying chamber, the heating device provides the sample with the latent heat of sublimation, and the control device is used to control commands such as running / interrupting / stopping the other devices.

[0078] In some more desirable implementations, when the freeze-drying process is carried out, the plate layer temperature of the freeze-dryer is lowered to -50 to -30°C during the pre-freezing stage and maintained for 1 to 3 hours.

[0079] In some more desirable implementations, during the freeze-drying process, the plate layer temperature of the freeze-dryer is raised to -5 to 5°C and maintained for 1 to 3 hours during the temperature recovery phase.

[0080] In some more desirable implementations, during the freeze-drying process, the plate layer temperature of the freeze-dryer is lowered to -50 to -30°C during the recooling stage and maintained for 1 to 3 hours.

[0081] In some more desirable implementations, when the freeze-drying process is carried out, the plate layer temperature of the freeze-dryer is raised to -30 to -25°C in the primary drying stage a and maintained for 10 to 30 hours, with a vacuum level of 5 to 20 Pa.

[0082] In some more desirable implementations, when the freeze-drying process is carried out, the plate layer temperature of the freeze-dryer is raised to 5-20°C and maintained for 10-30 hours during the primary drying b stage, and the vacuum level is 5-20 Pa.

[0083] In some more desirable implementations, when the freeze-drying process is carried out, the plate layer temperature of the freeze-dryer is raised to 10-40°C and maintained for 10-30 hours during the desorption-drying stage, with a vacuum level of 5-20 Pa.

[0084] Selectively, the method for producing sulfaprodyl lyophilized powder injection according to the present invention includes processes such as filling (or packaging), caulking, capping, and / or packaging. By incorporating one or more of filling (or packaging), caulking, capping, and / or packaging into the production method, a lyophilized powder injection in a specific container (e.g., ampoule or vial), specification, and packaging form can be obtained, which is convenient for subsequent storage and transport, sale, and use.

[0085] Furthermore, the present invention provides a lyophilized sulfaprodyl powder injection preparation manufactured by the above manufacturing method.

[0086] In some preferred methods of implementation, the lyophilized powder injection contains only one active ingredient, namely sulfaprodyl.

[0087] Furthermore, the present invention provides the sulfaprodyl lyophilized powder injection preparation for the manufacture of pharmaceuticals for the prevention and / or treatment of neurodegenerative diseases.

[0088] Unless otherwise specified, the term "neurodegenerative disease" as used in this invention refers to a complex disease that can progressively develop and induce disability and ultimately death. Characterized by the mass loss of specific neurons, it mainly includes amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD).

[0089] In some preferred implementations, the neurodegenerative disease is selected from one or more of the following: Huntington's disease (HD), Alzheimer's disease (AD), Pick's disease (PD), Korsakoff syndrome (KS), cerebellar degeneration, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Down syndrome (DS), glutaricemia, epilepsy, multiple infarct dementia, and encephalitis.

[0090] Furthermore, the present invention provides the sulfaprodyl lyophilized powder injection preparation for the manufacture of pharmaceuticals for the prevention and / or treatment of cerebrovascular and nervous system diseases and symptoms.

[0091] In some preferred implementation methods, the cerebrovascular and nervous system diseases and symptoms are selected from one or more of the following: thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, cerebral aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia, and tissue hypoxia.

[0092] Furthermore, the present invention provides the sulfaprodyl lyophilized powder injection preparation as a pharmaceutical product for the prevention and / or treatment of neurodegenerative diseases.

[0093] In some preferred implementations, the neurodegenerative disease is selected from one or more of the following: Huntington's disease, Alzheimer's disease, Pick's disease, Korsakoff syndrome, cerebellar degeneration, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, glutaricemia, epilepsy, polyinfarct dementia, and encephalitis.

[0094] Furthermore, the present invention provides the sulfaprodyl lyophilized powder injection preparation as a pharmaceutical product for the prevention and / or treatment of diseases and symptoms of the cerebrovascular and nervous systems.

[0095] In some preferred implementation methods, the cerebrovascular and nervous system diseases and symptoms are selected from one or more of the following: thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, cerebral aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia, and tissue hypoxia.

[0096] Furthermore, the present invention provides a method for the prevention and / or treatment of neurodegenerative diseases, comprising administering a prophylactic and / or therapeutically effective amount of lyophilized sulfaprodyl powder injection to an individual in need thereof.

[0097] In some preferred implementations, the neurodegenerative disease is selected from one or more of the following: Huntington's disease, Alzheimer's disease, Pick's disease, Korsakoff syndrome, cerebellar degeneration, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, glutaricemia, epilepsy, polyinfarct dementia, and encephalitis.

[0098] Finally, the present invention provides a method for the prevention and / or treatment of diseases and symptoms of the cerebrovascular and nervous system, comprising administering a prophylactic and / or therapeutically effective amount of sulfaprodyl lyophilized powder injection to an individual in need thereof.

[0099] In some preferred implementation methods, the cerebrovascular and nervous system diseases and symptoms are selected from one or more of the following: thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, cerebral aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia, and tissue hypoxia.

[0100] The present invention will be described in more detail below with reference to specific examples. The examples are provided to further illustrate the technical approach of the present invention, and those skilled in the art will understand that the present invention is not limited to these examples. Those skilled in the art can modify the present invention without departing from the spirit and scope of the invention, and such equivalent forms of modification are also within the scope of protection of the present invention. Unless otherwise specified, all pharmaceuticals, reagents, materials, and apparatus used in the following examples are available through ordinary commercial means.

[0101] [Example 1] Production of sulfaprodyl Potassium 2-hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoate is prepared according to the method disclosed in CN1309703C.

[0102] 5-aminosalicylic acid (102 g) and triethylamine (100 mL) were dissolved in dry DMF (8,000 mL) at room temperature under nitrogen protection, and 2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzyl bromide (123 g) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was removed under vacuum. The mixture was extracted with ethyl acetate / water, the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After removing the solvent by distillation, the residue was eluted with ether / n-hexane (1:10) and crystallized to obtain a white solid potassium 2-hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoate (160 g).

[0103] 100 g of potassium 2-hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoate is added to 500 mL of anhydrous ethanol, and the mixture is heated to 50°C under stirring conditions until completely dissolved. After cooling the solution to 10°C, the pH of the solution is adjusted to 6.8-7.0 with an anhydrous potassium hydroxide ethanol solution. The mixture is stirred at room temperature for 2 hours to precipitate crystals, which are then filtered and dried to obtain 102 g of milky white sulfaprodyl powder. HPLC testing shows a purity of 99.7% or higher.

[0104] [Example 2] Preparation of Sulfaprodyl Lyophilized Powder Injectable Solution Sulfaplodyl (3,000 g) is dissolved in sterile water for injection (30 L) and purified, then filtered through a PES material filter with a pore size of 0.45 μm. The pH of the filtrate is adjusted to 8.2 with a 0.1 mol / L potassium hydroxide aqueous solution, and sterile water for injection is added to bring the volume to 60 L. The solution is protected by filling it with argon gas, and within 8 hours, it is sterile filtered through a PES material filter with a pore size of 0.22 μm to obtain the sulfaplodyl solution.

[0105] Fill the vial with the sulfaprodyl solution and place the glass bottle in a freeze-dryer. Within 30 minutes, lower the plate layer temperature of the freeze-dryer to -50°C and maintain it for 1 hour, then raise the plate layer temperature to -5°C and maintain it for 1 hour. Lower the plate layer temperature again to -50°C and maintain it for 1 hour. After that, raise the plate layer temperature to -30°C and maintain a vacuum of 5 Pa for 10 hours. Next, raise the plate layer temperature to 10°C and maintain a vacuum of 5 Pa for 10 hours. Fill with nitrogen gas at 40 kPa, then caulk, cap, and package.

[0106] [Example 3] Preparation of Sulfaprodyl Lyophilized Powder Injectable Solution Sulfaplodyl (1,500 g) is dissolved in sterile water for injection (13 L) and purified, then filtered through a PVDF filter with a pore size of 0.45 μm. The pH of the filtrate is adjusted to 9.0 with a 0.5 mol / L potassium hydroxide aqueous solution, and sterile water for injection is added to bring the volume to 18 L. The solution is protected by filling it with argon gas, and within 4 hours, it is sterile filtered through a PVDF filter with a pore size of 0.22 μm to obtain the sulfaplodyl solution.

[0107] Fill the vial with the sulfaprodyl solution and place the glass bottle in a freeze-dryer. Within 60 minutes, lower the plate layer temperature of the freeze-dryer to -40°C and maintain it for 2 hours, then raise the plate layer temperature to 0°C and maintain it for 2 hours. Lower the plate layer temperature again to -40°C and maintain it for 2 hours. Next, raise the plate layer temperature to -25°C and maintain a vacuum of 10 Pa for 20 hours, then raise the plate layer temperature to 10°C and maintain a vacuum of 10 Pa for 20 hours. After that, raise the plate layer temperature to 25°C and maintain a vacuum of 10 Pa for 20 hours. Fill with nitrogen gas at 65 kPa, then caulk, cap, and package.

[0108] [Example 4] Preparation of Sulfaprodyl Lyophilized Powder Injectable Solution Sulfaplodyl (3,750 g) is dissolved in sterile water for injection (15 L) and purified, then filtered through a PTFE filter with a pore size of 0.45 μm. The pH of the filtrate is adjusted to 9.8 with a 0.8 mol / L potassium hydroxide aqueous solution, and sterile water for injection is added to bring the volume to 19 L. The solution is protected by filling it with argon gas, and within 2 hours, it is sterile filtered through a PTFE filter with a pore size of 0.22 μm to obtain the sulfaplodyl solution.

[0109] Fill the vial with the sulfaprodyl solution and place the glass bottle in a freeze-dryer. Within 90 minutes, lower the plate layer temperature of the freeze-dryer to -30°C and maintain it for 3 hours, then raise the plate layer temperature to 5°C and maintain it for 3 hours. Lower the plate layer temperature to -30°C again and maintain it for 3 hours. Next, raise the plate layer temperature to -20°C and maintain a vacuum of 20 Pa for 30 hours, then raise the plate layer temperature to 5°C and maintain a vacuum of 20 Pa for 30 hours. After that, raise the plate layer temperature to 40°C and maintain a vacuum of 20 Pa for 30 hours. Fill with nitrogen gas at 90 kPa, then caulk, cap, and package.

[0110] Table 1 shows the results of our investigation into the appearance of the lyophilized sulfaprodyl powder injection (General Rules of Part IV, 2015 Edition of the Chinese Pharmacopoeia), redissolution time, solution clarity and hue (Appendix IX B, 2015 Edition of the Chinese Pharmacopoeia), moisture content (General Rules 0832, Part IV, 2015 Edition of the Chinese Pharmacopoeia), related substances (General Rules 0512, Part IV, 2015 Edition of the Chinese Pharmacopoeia), and stability of the lyophilized sulfaprodyl powder injection in Examples 2 to 4.

[0111] [Table 1]

[0112] Through Examples 2-4, three lots of sulfaprodyl lyophilized powder injection according to the present invention were manufactured, and each lot of the product exhibited the following effects.

[0113] (1) When a lyophilized powder injection is produced by the method of the present invention, the solution before lyophilization is clear and free of foreign matter visible to the naked eye.

[0114] (2) The freeze-dried powder injection of the present invention is a milky white powder with fine particles and a uniform structure.

[0115] (3) The lyophilized powder injection of the present invention has excellent resolubility (resolving time within 10 seconds), and the solution after resolving is pale yellow and has good transparency.

[0116] (4) The freeze-dried powder injection of the present invention has a low moisture content (0.2% or less).

[0117] (5) The freeze-dried powder injection of the present invention does not increase in the content of impurities compared to the raw material and can be effectively controlled.

[0118] (6) The lyophilized powder injection of the present invention maintains virtually the same parameters before and after the 6-month accelerated test, demonstrating excellent stability.

Claims

1. A method for producing a lyophilized sulfaprodyl powder injection, The process includes the steps of adding sulfaporyl to sterile water for injection and dissolving it, filtering the solution, adjusting the pH of the filtrate to 8.0-10.0 using an alkaline aqueous solution, adding sterile water for injection to reach a fixed volume, filling the solution with an inert gas for protection, performing sterile filtration to obtain a sulfaporyl solution, and then freeze-drying the solution to obtain a freeze-dried sulfaporyl powder injection. The freeze-drying described above is carried out in a freeze-dryer and includes a pre-freezing stage, a temperature recovery stage, a re-cooling stage, a primary drying stage a, a primary drying stage b, and a desorption drying stage. In the aforementioned pre-freezing stage, the plate layer temperature of the freeze dryer is lowered to -50 to -30°C and maintained for 1 to 3 hours. During the temperature recovery stage, the plate layer temperature of the freeze dryer is raised to -5 to 5°C and maintained for 1 to 3 hours. In the aforementioned recooling stage, the plate layer temperature of the freeze dryer is lowered to -50 to -30°C and maintained for 1 to 3 hours. In the primary drying stage a, the plate layer temperature of the freeze dryer is raised to -30 to -25°C and maintained for 10 to 30 hours, and the vacuum level is set to 5 to 20 Pa. In the primary drying stage b, the plate layer temperature of the freeze dryer is raised to 5 to 20°C and maintained for 10 to 30 hours, and the vacuum level is set to 5 to 20 Pa. A method for producing a lyophilized sulfaprodyl powder injection, comprising the steps of increasing the plate layer temperature of the freeze dryer to 10 to 40°C and maintaining it for 10 to 30 hours, and maintaining a vacuum of 5 to 20 Pa during the desorption drying step.

2. The method for producing a sulfaprodyl freeze-dried powder injection according to claim 1, wherein the pore size of the filtration membrane used for the filtration and the sterile filtration is independently 0.2 to 1.0 μm.

3. The method for producing a sulfaprodyl freeze-dried powder injection according to claim 1, wherein the alkaline substance is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, and sodium bicarbonate.

4. The method for producing a sulfaprodyl lyophilized powder injection according to claim 1, wherein the sterilization filtration is performed within 16 hours after the specified volume.

5. The method for producing a sulfaprodyl lyophilized powder injection according to claim 1, wherein the mass-volume concentration of the sulfaprodyl solution is 5 to 20 w / v%.

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