A preparation method of sofadil lyophilized powder injection and its product and use

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and relates to a preparation method of a sofadil lyophilized powder injection, and its product and use. Specifically, the method of the present invention comprises the following steps: adding sofadil to water for injection, filtering after dissolving, adjusting the pH value of the filtrate with an alkaline aqueous solution, adding water for injection to make up the volume, filling with inert gas for protection, sterilizing and filtering to obtain a sofadil solution, and lyophilizing. The method of the present invention is easy to prepare the corresponding lyophilized powder injection, is simple to operate, has stable product quality and high controllability, and is suitable for large-scale commercial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a method for preparing a sofadil lyophilized powder injection, a sofadil lyophilized powder injection product prepared by the method, and medical uses of the product. Background Art

[0002] Sofadil (Salfaprodil), chemical name is potassium 2-hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoate, and its structural formula is shown below.

[0003]

[0004] Sofadil is a moderate-strength N-methyl-D-aspartate (NMDA) receptor antagonist and a powerful antioxidant with dual neuroprotective effects. It can simultaneously block NMDA receptor-mediated excitotoxicity and the body's oxidative stress response. Its effect of protecting nerve function can last for more than 28 days, providing a wide range of neuroprotective effects and expanding the treatment time window.

[0005] CN1309703C discloses that Sofadil can be used for treating conventional or pathological neurological diseases in cerebrovascular and nervous system diseases and symptoms. Specifically, Sofadil is used for preventing and treating thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, brain aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, anoxia and tissue hypoxia. Sofadil can also be effectively used to alleviate neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease, cerebellar degeneration, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, epilepsy, multi-infarct dementia and encephalitis.

[0006] Existing freeze-dried preparation process is of various types and is widely used in various powder injection drugs. However, when preparing injection sofadil by the process used by other varieties in the prior art (for example, the freeze-drying process of fludarabine phosphate in CN104771369B), due to the crystallization behavior of different pharmacological active ingredients when freezing, the product is not easy to form a uniform and meticulous crystalline form when freeze-dried. In addition, the product produces precipitation after redissolution, and there are defects such as poor stability and obvious stratification in appearance. Therefore, it is urgent to develop a freeze-dried preparation process suitable for injection sofadil. Summary of the invention

[0007] Problem that the invention aims to solve

[0008] In order to overcome the defects of using the existing freeze-drying technology to prepare sofadil for injection, the present invention provides a method for preparing sofadil for injection with good formability, clear appearance of the solution before freeze-drying, good resolubility of the freeze-dried product, good clarity after reconstitution, low impurity content, good stability, and controllable quality, as well as a product prepared by the method.

[0009] Solutions for solving problems

[0010] The present invention is achieved through the following scheme:

[0011] In a first aspect, the present invention provides a method for preparing a sofadil lyophilized powder injection, which comprises the following steps: adding sofadil to water for injection, filtering after dissolving, adjusting the pH value of the filtrate with an aqueous solution of an alkaline substance, adding water for injection to make up the volume, filling with an inert gas for protection, sterilizing and filtering to obtain a sofadil solution, and lyophilizing.

[0012] Preferably, in the above preparation method, the pore sizes of the filter membranes used for the filtration and the sterilizing filtration are each independently 0.2 to 1.0 μm.

[0013] More preferably, in the above preparation method, the materials of the filter membranes used for the filtration and the sterilization filtration are independently polyethersulfone (PES), polytetrafluoroethylene (PTFE), nylon (N6 / N66) or polyvinylidene fluoride (PVDF).

[0014] Preferably, in the above preparation method, the alkaline substance is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate and sodium bicarbonate.

[0015] Preferably, in the above preparation method, the concentration of the aqueous solution of the alkaline substance is 0.1-1.0M.

[0016] Preferably, in the above preparation method, the pH value is adjusted to 8.0-10.0.

[0017] Preferably, in the above preparation method, the inert gas is argon or nitrogen.

[0018] Preferably, in the above preparation method, the sterilizing filtration is performed within 16 hours after the volume fixing.

[0019] Preferably, in the above preparation method, the mass volume concentration of the sofadil solution is 5 to 20 w / v%.

[0020] Preferably, in the above preparation method, the freeze-drying is carried out in a freeze dryer and includes a pre-freezing stage, a warming stage, a cooling stage, a primary drying stage a, a primary drying stage b and a analytical drying stage.

[0021] More preferably, in the pre-freezing stage, the plate temperature of the freeze dryer is reduced to -50 to -30°C and kept warm for 1 to 3 hours.

[0022] More preferably, in the warming stage, the plate temperature of the freeze dryer is raised to -5 to 5°C and kept warm for 1 to 3 hours.

[0023] More preferably, in the second cooling stage, the plate temperature of the freeze dryer is reduced to -50 to -30°C and kept warm for 1 to 3 hours.

[0024] More preferably, in the primary drying stage a, the plate temperature of the freeze dryer is raised to -30 to -25°C, kept warm for 10 to 30 hours, and the vacuum degree is 5 to 20Pa.

[0025] More preferably, in the primary drying stage b, the plate temperature of the freeze dryer is raised to 5-20° C., kept warm for 10-30 hours, and the vacuum degree is 5-20 Pa.

[0026] More preferably, in the analytical drying stage, the plate temperature of the freeze dryer is raised to 10-40° C., kept warm for 10-30 hours, and the vacuum degree is 5-20 Pa.

[0027] Preferably, the above preparation method further comprises the steps of filling, plugging, capping and / or packaging.

[0028] In a second aspect, the present invention provides a sofadil lyophilized powder injection, which is prepared by the above-mentioned preparation method.

[0029] Preferably, in the above-mentioned sofadil lyophilized powder injection, sofadil is the only pharmacologically active ingredient.

[0030] In a third aspect, the present invention provides use of the above-mentioned sofadil lyophilized powder injection in the preparation of a medicament for preventing and / or treating neurodegenerative diseases.

[0031] Preferably, in the above use, the neurodegenerative disease is selected from one or more of Huntington's disease, Alzheimer's disease, Pick's disease, Korsakoff syndrome, cerebellar degeneration, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, glutaric acidemia, epilepsy, multi-infarct dementia and encephalitis.

[0032] In a fourth aspect, the present invention provides use of the above-mentioned sofadil lyophilized powder injection in the preparation of a medicament for preventing and / or treating cerebrovascular and nervous system diseases and symptoms.

[0033] Preferably, in the above-mentioned use, the cerebrovascular and nervous system diseases and symptoms are selected from one or more of thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, brain aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia and tissue hypoxia.

[0034] Effects of the Invention

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) When the freeze-dried powder injection is produced by the method of the present invention, the solution before freeze-drying is clear and free of visible foreign matter;

[0037] (2) The freeze-dried powder injection of the present invention is an off-white powder with fine powder and uniform structure;

[0038] (3) The freeze-dried powder injection of the present invention has good resolubility, and the solution after reconstitution is light yellow with good clarity;

[0039] (4) The freeze-dried powder injection of the present invention has a low moisture content;

[0040] (5) Compared with the raw material, the impurity content of the freeze-dried powder injection of the present invention does not increase and can be effectively controlled;

[0041] (6) The various parameters of the lyophilized powder injection of the present invention can remain roughly consistent before and after the 6-month accelerated test, and the stability performance is good. DETAILED DESCRIPTION

[0042] Firstly, the present invention provides a novel preparation method of sofadil lyophilized powder injection.

[0043] Unless otherwise specified, the term "sofadil" used in the present invention refers to potassium 2-hydroxyl-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoate or its pharmaceutically acceptable salt, hydrate or solvate in any one or more physical forms.

[0044] Unless otherwise specified, the term "lyophilized powder injection" used in the present invention refers to a solid powder preparation prepared by mixing one or more pharmaceutically active ingredients (or raw materials) into one or more excipients or dissolving them in one or more solvents (or vehicles) under a sterile environment and undergoing certain processing (for example, freeze drying).

[0045] Specifically, the above preparation method comprises the following steps:

[0046] Add sofadil to water for injection, filter after dissolving, adjust the pH value of the filtrate with an aqueous solution of alkaline substance, add water for injection to make up the volume, fill with inert gas for protection, sterilize and filter to obtain sofadil solution, and freeze-dry to obtain the product.

[0047] Unless otherwise specified, the term "water for injection" used in the present invention refers to water that complies with the relevant provisions under "Water for Injection" in the Chinese Pharmacopoeia (or as an alternative, the United States Pharmacopoeia, the European Pharmacopoeia or the Japanese Pharmacopoeia).

[0048] Unless otherwise specified, the term "dissolving and clarifying" (or its full name "dissolving and clarifying") used in the present invention refers to the operation or process of dissolving a sample to be dissolved in a solvent until it is clear or has no turbidity or precipitation visible to the naked eye.

[0049] Unless otherwise specified, the term "filtration" used in the present invention refers to an operation or process in which a continuous phase (e.g., liquid in a suspension or gas in a solid particle aerosol) in a multiphase dispersion system containing solid particles (e.g., a suspension or a solid particle aerosol) is allowed to pass through a specific separation medium (e.g., filter paper or filter membrane) under the action of an external force, while the dispersed phase (e.g., solid particles in the multiphase dispersion system) is retained, thereby separating the two phases. When the above-mentioned multiphase dispersion system is a suspension, the liquid continuous phase that passes through the separation medium is the "filtrate", and the solid dispersed phase retained by the separation medium is the "filter cake". Unless otherwise specified, the terms "filtrate" and "filter cake" used in the present invention have the same meanings as described above.

[0050] In some preferred embodiments, the filtration in the above preparation method is performed by a filter membrane.

[0051] In some more preferred embodiments, the pore size of the filter membrane is 0.2-1.0 μm, preferably 0.2-0.5 μm, and more preferably 0.45 μm.

[0052] In some more preferred embodiments, the material of the filter membrane is selected from any one or more of PES, PTFE, N6 / N66 and PVDF.

[0053] In some preferred embodiments, the preparation method uses an aqueous solution of an alkaline substance to adjust the pH value of the filtrate.

[0054] In some more preferred embodiments, the alkaline substance in the above preparation method is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate and sodium bicarbonate, preferably potassium hydroxide, potassium carbonate or potassium bicarbonate, more preferably potassium hydroxide.

[0055] In some more preferred embodiments, the molar concentration of the aqueous solution of the alkaline substance is 0.1 to 1.0 mol / L, preferably 0.1 to 0.5 mol / L.

[0056] In some more preferred embodiments, the alkaline aqueous solution adjusts the pH value of the filtrate to 8.0-10.0.

[0057] Unless otherwise specified, the term "volume setting" used in the present invention refers to the operation or process of accurately and precisely adding the solvent to the scale line of the container with the help of a liquid transfer device (e.g., a dropper or a pipette) when using a fixed-capacity container (e.g., a volumetric flask) to dissolve or dilute a substance to a certain concentration; in short, volume setting means adjusting to a fixed capacity.

[0058] Unless otherwise specified, the term "inert gas" or "chemically inert gas" used in the present invention refers to a gaseous substance that is chemically inert under conventional experimental conditions, including helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe) and radon (Rn), which are located in Group 0 of the periodic table and are collectively referred to as "rare gases", as well as nitrogen (N2) and carbon dioxide (CO2), which do not exhibit chemical reactivity under normal conditions.

[0059] In some preferred embodiments, the inert gas protection step in the above preparation method uses an inert gas to provide an inert atmosphere for the material after volume adjustment.

[0060] In some more preferred embodiments, the inert gas protection step in the above preparation method uses argon or nitrogen to provide an inert atmosphere for the material after volume adjustment.

[0061] Unless otherwise specified, the term "sterile filtration" or "filtration sterilization" used in the present invention refers to the operation or process of removing bacteria from the sample to be treated by filtering to achieve the purpose of sterilization. Generally, sterile filtration requires the use of a bacterial filter device with a micropore size, including a membrane filter (also known as a bacterial filter membrane, sometimes also referred to as a filter membrane, with pore sizes of 0.45 μm and 0.22 μm, and the latter has a better sterilization effect), a ceramic filter, an asbestos filter, a sintered glass filter, etc.

[0062] In some preferred embodiments, the sterilization filtration in the above preparation method is also completed by a filter membrane.

[0063] In some more preferred embodiments, the pore size of the filter membrane for sterilization filtration is 0.20 to 0.22 μm.

[0064] In some more preferred embodiments, the material of the filter membrane for sterilization filtration is also selected from any one or more of PES, PTFE, N6 / N66 and PVDF.

[0065] In some more preferred embodiments, the above-mentioned sterilization filtration is carried out within 16 hours after the volume fixing step is completed, preferably within 12 hours, and more preferably within 8 hours.

[0066] In some preferred embodiments, the sofadil solution in the above preparation method has an appropriate mass volume concentration so as to smoothly carry out the subsequent freeze-drying step.

[0067] Unless otherwise specified, the term "mass volume concentration" (or its abbreviation "mass concentration") used in the present invention refers to the concentration per unit volume (e.g., 1 m 3 The mass of solute contained in a solution of 1 liter (e.g., 1 g or 1 mg), usually expressed in g / m 3 Unless otherwise specified, the term "w / v%" used in the present invention means the number of grams of solute contained in 100 ml of solution, that is, "g / 100 mL".

[0068] In some more preferred embodiments, the above suitable mass volume concentration is 5 to 20 w / v%.

[0069] In some preferred embodiments, the freeze-drying in the above preparation method is carried out in a freeze dryer and includes a pre-freezing stage, a warming stage, a cooling stage, a primary drying (in the primary drying, it is subdivided into stage a and stage b according to temperature changes) and a analytical drying stage.

[0070] Unless otherwise specified, the term "freeze drying" (or its full name "freeze drying") used in the present invention refers to a drying operation or process in which a water-containing material (e.g., a water-containing liquid medicine, i.e., the sofadil solution in the present invention) is first frozen to below the freezing point to convert the water into ice (solidification), and then, under vacuum conditions, the ice is converted into water vapor (sublimation) and removed. Not only can the material be frozen in a freezing device in advance and then transferred to a drying device for drying, but the material can also be directly frozen in the drying device by rapid vacuumization and then dried. The water vapor generated during the sublimation process is removed by the condensation action of a condensing device, and the vaporization heat required for the sublimation process is generally supplied by thermal radiation or heat conduction.

[0071] Unless otherwise specified, the term "freeze dryer" (or its full name "freeze dryer") used in the present invention refers to an instrument or device used to perform freeze-drying operations, which is mainly composed of a sample holding device (including a quick-freezing chamber, a drying chamber, and an optional post-processing chamber, etc.), a refrigeration device, a vacuum device, a heating device, and a control device. The working principle of the freeze dryer is as follows: after the freeze-dried sample is pre-treated, it is first sent to the quick-freezing chamber for freezing, then sent to the drying chamber for sublimation dehydration, and finally sent to the post-processing chamber for post-processing. The refrigeration device provides the required cooling capacity for the quick-freezing chamber, the vacuum device establishes low pressure conditions for the drying chamber, the heating device provides sublimation latent heat for the sample, and the control device is used to control other devices to execute / interrupt / stop a certain instruction.

[0072] In some more preferred embodiments, during the freeze-drying step, the plate temperature of the freeze-dryer in the pre-freezing stage is reduced to -50 to -30°C and kept warm for 1 to 3 hours.

[0073] In some more preferred embodiments, when the freeze-drying step is performed, the plate temperature of the freeze-drying machine in the warming stage is raised to -5 to 5°C and kept warm for 1 to 3 hours.

[0074] In some more preferred embodiments, when the freeze-drying step is performed, the plate temperature of the freeze-drying machine in the second cooling stage is reduced to -50 to -30°C and kept warm for 1 to 3 hours.

[0075] In some more preferred embodiments, during the freeze-drying step, the plate temperature of the freeze dryer in the primary drying stage a is raised to -30 to -25°C and kept warm for 10 to 30 hours with a vacuum degree of 5 to 20 Pa.

[0076] In some more preferred embodiments, during the freeze-drying step, the plate temperature of the freeze dryer in the primary drying stage b is raised to 5-20°C and kept warm for 10-30 hours with a vacuum degree of 5-20Pa.

[0077] In some more preferred embodiments, during the freeze-drying step, the plate temperature of the freeze dryer in the analytical drying stage is raised to 10-40°C, kept warm for 10-30 hours, and the vacuum degree is 5-20Pa.

[0078] Optionally, the preparation method of the sofadil lyophilized powder injection of the present invention further comprises the steps of filling (or subpackaging), plugging, capping and / or packaging. By introducing one or more of the steps of filling (or subpackaging), plugging, capping and / or packaging into the method, a lyophilized powder injection in a specific container (e.g., ampoule or vial), specification and packaging form can be finally obtained, which is convenient for subsequent storage, transportation, sale and use.

[0079] Secondly, the present invention also provides a sofadil lyophilized powder injection prepared by the above preparation method.

[0080] In some preferred embodiments, the above-mentioned lyophilized powder injection contains only one pharmacologically active ingredient, namely, sofadil.

[0081] Again, the present invention also provides the use of the above-mentioned sofadil lyophilized powder injection in the preparation of drugs for preventing and / or treating neurodegenerative diseases.

[0082] Unless otherwise specified, the term "neurodegenerative disease" (or "neurodegenerative disease") used in the present invention refers to a class of complex diseases that are progressive and can cause disability or even death, characterized by the massive loss of specific neurons, mainly including amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), etc.

[0083] In some preferred embodiments, the neurodegenerative disease in the above use is selected from one or more of Huntington's Disease (HD), Alzheimer's Disease (AD), Pick's Disease (PD), Korsakov's Syndrome (KS), olivopontocerebellar degeneration, amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), Down's Syndrome (DS), glutaric acidaemia, epilepsy, multi-infarct dementia and encephalitis.

[0084] Finally, the present invention provides the use of the above-mentioned sofadil lyophilized powder injection in the preparation of drugs for preventing and / or treating cerebrovascular and nervous system diseases and symptoms.

[0085] In some preferred embodiments, the cerebrovascular and nervous system diseases and symptoms in the above-mentioned uses are selected from one or more of thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, brain aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, hypoxia and tissue hypoxia.

[0086] The present invention will be further described below in conjunction with specific embodiments. The following specific embodiments are for a better understanding of the technical solutions of the present invention, but those skilled in the art should recognize that the present invention is not limited to these embodiments. Those skilled in the art may make various modifications to the present invention without departing from the spirit and scope of the present invention, and these equivalent modifications also fall within the scope of protection of the present invention. Unless otherwise specified, the drugs, reagents, materials and instruments used in the following examples can be obtained by conventional commercial means.

[0087] Example 1: Preparation of Sofadil.

[0088] According to the method described in CN1309703C, 2-hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoic acid was prepared:

[0089] At room temperature and under nitrogen protection, 5-aminosalicylic acid (102 g) and triethylamine (100 mL) were dissolved in dry DMF (8000 mL), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl 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. It was extracted with ethyl acetate / water, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was dissolved and crystallized in ether / n-hexane (1:10) to obtain 2-hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoic acid (160 g) as a white solid.

[0090] 2-Hydroxy-5-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzylamino]benzoic acid (100 g) was added to anhydrous ethanol (500 mL), and the temperature was raised to 50° C. under stirring until it was completely dissolved. The resulting solution was cooled to 10° C., and the pH value of the above solution was adjusted to 6.8-7.0 with anhydrous ethanol solution of potassium hydroxide. The solution was stirred at room temperature for 2 hours, and crystals were precipitated. The crystals were filtered and dried to obtain off-white powder sofadil (102 g). The purity was ≥99.7% as determined by HPLC.

[0091] Example 2: Preparation of Sofadil lyophilized powder injection.

[0092] Sofadil (3000 g) was dissolved in water for injection (30 L), the solution was clarified and filtered with a PES filter membrane with a pore size of 0.45 μm. The pH value of the filtrate was adjusted to 8.2 with a 0.1 mol / L potassium hydroxide aqueous solution, and then water for injection was added to make up to 60 L. The solution was protected by argon gas and sterilized and filtered with a PES filter membrane with a pore size of 0.22 μm within 8 hours to obtain a sofadil solution.

[0093] Fill the above-mentioned sofadil solution into a vial. After filling, place the glass bottle into a freeze dryer. Reduce the plate temperature of the freeze dryer to -50°C within 30 minutes and keep it warm for 1 hour; then increase the plate temperature to -5°C and keep it warm for 1 hour; then reduce the plate temperature to -50°C and keep it warm for 1 hour. Next, increase the plate temperature to -30°C, maintain the vacuum degree at 5Pa, and keep it warm for 10 hours; then increase the plate temperature to 5°C, maintain the vacuum degree at 5Pa, and keep it warm for 10 hours; continue to increase the plate temperature to 10°C, maintain the vacuum degree at 5Pa, and keep it warm for 10 hours. Fill with nitrogen to 40kPa, press the plug, roll the cap, and package.

[0094] Example 3: Preparation of Sofadil lyophilized powder injection.

[0095] Sofadil (1500 g) was dissolved in water for injection (13 L), the solution was clarified and filtered through a PVDF filter membrane with a pore size of 0.45 μm. The pH value of the filtrate was adjusted to 9.0 with a 0.5 mol / L potassium hydroxide aqueous solution, and then water for injection was added to make the volume to 18 L. The solution was protected by argon gas and sterilized and filtered through a PVDF filter membrane with a pore size of 0.22 μm within 4 hours to obtain a sofadil solution.

[0096] The above-mentioned sofadil solution is filled into a vial. After filling, the glass bottle is placed in a freeze dryer. The plate temperature of the freeze dryer is reduced to -40°C within 60 minutes and kept warm for 2 hours; then the plate temperature is raised to 0°C and kept warm for 2 hours; then the plate temperature is reduced to -40°C and kept warm for 2 hours. Next, the plate temperature is raised to -25°C, the vacuum degree is maintained at 10Pa, and kept warm for 20 hours; then the plate temperature is raised to 10°C, the vacuum degree is maintained at 10Pa, and kept warm for 20 hours; then the plate temperature is raised to 25°C, the vacuum degree is maintained at 10Pa, and kept warm for 20 hours. Inflate with nitrogen to 65kPa, press the plug, roll the cap, and package.

[0097] Example 4: Preparation of Sofadil lyophilized powder injection.

[0098] Sofadil (3750 g) was dissolved in water for injection (15 L), the solution was clarified and filtered through a PTFE filter membrane with a pore size of 0.45 μm. The pH value of the filtrate was adjusted to 9.8 with a 0.8 mol / L potassium hydroxide aqueous solution, and then water for injection was added to make the volume to 19 L. The solution was protected by nitrogen gas and sterilized and filtered through a PTFE filter membrane with a pore size of 0.22 μm within 2 hours to obtain a sofadil solution.

[0099] The above-mentioned sofadil solution is filled into a glass bottle. After filling, the glass bottle is placed in a freeze dryer. Within 90 minutes, the plate temperature of the freeze dryer is reduced to -30°C and kept warm for 3 hours; then the plate temperature is raised to 5°C and kept warm for 3 hours; then the plate temperature is reduced to -30°C and kept warm for 3 hours. Next, the plate temperature is raised to -20°C, the vacuum degree is maintained at 20Pa, and kept warm for 30 hours; then the plate temperature is raised to 5°C, the vacuum degree is maintained at 20Pa, and kept warm for 30 hours; then the plate temperature is raised to 40°C, the vacuum degree is maintained at 20Pa, and kept warm for 30 hours. Inflate with nitrogen to 90kPa, press the plug, roll the cap, and package.

[0100] The appearance (General Rules of Part Four of the 2015 Edition of the Chinese Pharmacopoeia), reconstitution time, clarity and color of the solution (Appendix IX B of the 2015 Edition of the Chinese Pharmacopoeia), water content (General Rules of Part Four of the 2015 Edition of the Chinese Pharmacopoeia 0832), related substances (General Rules of Part Four of the 2015 Edition of the Chinese Pharmacopoeia 0512), stability and other items of the sofadil lyophilized powder injection in Examples 2 to 4 were investigated, and the results are shown in Table 1.

[0101] Table 1. Results of investigation on properties of Sofadil lyophilized powder injection

[0102]

[0103] Through the above-mentioned Examples 2 to 4, the present invention prepared three different batches of sofadil lyophilized powder injections, and all batches of products can achieve the following effects:

[0104] (1) When the freeze-dried powder injection is produced by the method of the present invention, the solution before freeze-drying is clear and free of visible foreign matter;

[0105] (2) The freeze-dried powder injection of the present invention is an off-white powder with fine powder and uniform structure;

[0106] (3) The freeze-dried powder injection of the present invention has good resolubility (resolubility time is within 10 seconds), and the solution after resolubility is light yellow with good clarity;

[0107] (4) The moisture content of the freeze-dried powder injection of the present invention is low (less than 0.2%);

[0108] (5) Compared with the raw material, the impurity content of the freeze-dried powder injection of the present invention does not increase and can be effectively controlled;

[0109] (6) The various parameters of the lyophilized powder injection of the present invention can remain roughly consistent before and after the 6-month accelerated test, and the stability performance is good.

Claims

1. A method for preparing a sofadil lyophilized powder injection, comprising the following steps: Add sofadil to water for injection, filter after dissolving, adjust the pH value of the filtrate with an alkaline aqueous solution, add water for injection to make up the volume, fill with inert gas for protection, sterilize and filter to obtain a sofadil solution, and freeze-dry to obtain; The pH value is adjusted to 8.0-10.0; The mass volume concentration of the sofadil solution is 5-20 w / v; The freeze drying is carried out in a freeze dryer and includes a pre-freezing stage, a warming stage, a cooling stage, a primary drying stage a, a primary drying stage b and an analytical drying stage; In the pre-freezing stage, the plate temperature of the freeze dryer is reduced to -50 to -30°C and kept warm for 1 to 3 hours; In the warming stage, the plate temperature of the freeze dryer is raised to -5~5°C and kept warm for 1~3 hours; In the second cooling stage, the plate temperature of the freeze dryer is reduced to -50 to -30°C and kept warm for 1 to 3 hours; In the primary drying stage a, the plate temperature of the freeze dryer is raised to -30 to -25°C, kept warm for 10 to 30 hours, and the vacuum degree is 5 to 20 Pa; In the primary drying stage b, the plate temperature of the freeze dryer is raised to 5-20°C, kept warm for 10-30 hours, and the vacuum degree is 5-20 Pa; In the analytical drying stage, the plate temperature of the freeze dryer is raised to 10-40° C., kept warm for 10-30 hours, and the vacuum degree is 5-20 Pa.

2. The preparation method according to claim 1, characterized in that: The pore sizes of the filter membranes used for the filtration and the sterilizing filtration are independently 0.2-1.0 μm.

3. The preparation method according to claim 1, characterized in that: The pore size of the filter membrane used in the filtration is 0.2-0.5 μm.

4. The preparation method according to claim 1, characterized in that: The pore size of the filter membrane used in the filtration is 0.45 μm.

5. The preparation method according to claim 1, characterized in that: The pore size of the filter membrane used in the sterilization filtration is 0.20-0.22 μm.

6. The preparation method according to claim 1, characterized in that: The alkaline substance is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate and sodium bicarbonate.

7. The preparation method according to claim 1, characterized in that: The alkaline substance is potassium hydroxide, potassium carbonate or potassium bicarbonate.

8. The preparation method according to claim 1, characterized in that: The alkaline substance is potassium hydroxide.

9. The preparation method according to claim 1, characterized in that: The sterilizing filtration is performed within 16 hours after the volume is fixed.

10. The preparation method according to claim 1, characterized in that: The sterilizing filtration is performed within 12 hours after the volume is fixed.

11. The preparation method according to claim 1, characterized in that: The sterilizing filtration is performed within 8 hours after the volume is fixed.

12. A sofadil lyophilized powder injection, prepared by the preparation method according to any one of claims 1 to 11.

13. Use of the sofadil lyophilized powder injection according to claim 12 in the preparation of a medicament for preventing and / or treating a neurodegenerative disease, wherein the neurodegenerative disease is selected from one or more of Huntington's disease, Alzheimer's disease, cerebellar degeneration, amyotrophic lateral sclerosis, Parkinson's disease, Down syndrome, epilepsy, multi-infarct dementia and encephalitis.

14. Use of the sofadil lyophilized powder injection according to claim 12 in the preparation of a medicament for preventing and / or treating cerebrovascular and nervous system diseases and symptoms, wherein the cerebrovascular and nervous system diseases and symptoms are selected from one or more of thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral vasospasm, brain aging, traumatic brain injury, traumatic spinal cord injury, cardiac arrest, arterial hypotension, hypoglycemia, anoxia and tissue hypoxia.

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