A kind of butylphthalide sterilized injection and its preparation method and use

Abstract

The present invention relates to a sterile injection of butylphthalide and a preparation method and use thereof, belonging to the technical field of pharmaceutical preparations, and mainly solves the problem that the impurity content increases after terminal sterilization when a butylphthalide raw material drug containing no organic acid impurities is dissolved by inclusion with hydroxypropyl beta-cyclodextrin to prepare an aqueous solution. The sterile injection of butylphthalide of the present invention comprises, by mass percentage, 0.02-0.03% butylphthalide, 0.5-0.8% cosolvent, 0.9% osmotic pressure regulator, an appropriate amount of pH regulator and an appropriate amount of solvent, wherein: the butylphthalide is butylphthalide prepared by a chemical synthesis method, the content of the butylphthalide is greater than 99.0%, and the butylphthalide does not contain organic acid impurities, the acid value is less than 0.5, and the pH of the butylphthalide injection is 4.5-5.5, preferably, the pH is 5.0-5.3, and more preferably, the pH is 5.1-5.2.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a butylphthalide sterilized injection and a preparation method and application thereof. Background Art

[0002] Butylphthalide is a drug independently researched and developed in my country for the treatment of mild and moderate acute ischemic stroke. The structural formula of Butylphthalide is Butylphthalide is a synthetic racemic n-butylphthalide, which has the same structure as the natural L-butylphthalide. Clinical research results show that butylphthalide improves the damage of central nervous system function in patients with acute ischemic stroke and can promote the improvement of neurological deficits. Chinese patents CN98125618.X, CN03137457.3, CN200310100222.2 and CN200410001748.X respectively disclose the use of butylphthalide in anti-thrombosis and anti-platelet aggregation, and L-butylphthalide in the prevention and treatment of dementia, cerebral infarction and cerebral ischemia.

[0003] Butylphthalide is an oily liquid and is insoluble in water. At present, the marketed products of butylphthalide include soft capsules and infusions. The marketed infusions use cyclodextrin inclusion technology to solve the problem of poor water solubility of butylphthalide (see CN1166693C), which can basically meet the clinical drug demand. There are also methods for preparing butylphthalide injections using other solubilization technologies such as Chinese patent CN103505409B. However, the marketed butylphthalide raw material is limited by the refining process, and in fact, there are impurities such as o-pentylbenzoic acid in the product, and the presence of these impurities may lead to potential drug safety issues. In response to this problem, the applicant has optimized the preparation and purification process of butylphthalide raw material to produce a high-purity butylphthalide raw material with a purity greater than 99.0% and free of organic acid impurities such as n-pentylbenzoic acid and o-pentylbenzoic acid. The pH value of the butylphthalide injection made with this raw material using traditional technology is about 6.0. However, the applicant subsequently discovered a new problem. Although the purity of this butylphthalide raw material is higher, after the solution prepared using the butylphthalide raw material is terminally sterilized, the butylphthalide is hydrolyzed at high temperature to generate butylphthalide hydrolysis ring-opening impurities, which in turn leads to an increase in impurities in the finished product.

[0004] In order to reduce the impurity level of butylphthalide injection, on the one hand, we should start with the raw material drug, improve the quality of the raw material drug and reduce the impurity level by improving the synthesis process; on the other hand, we need to start with the injection formulation process to control the generation of new impurities in the injection preparation process. However, there is no report on the method for controlling the impurities of butylphthalide injection in the prior art.

[0005] The invention aims at the problem that the production process of injection leads to increased impurities after the quality of butylphthalide raw material is improved, and proposes a new solution to effectively control the impurity level in butylphthalide injection. Summary of the invention

[0006] In order to solve the above technical problems, the applicant has implemented the present invention through the following technical solutions:

[0007] In a first aspect, the present invention provides a sterile injection of butylphthalide, which comprises, by mass percentage, 0.02-0.03% butylphthalide, 0.5-0.8% cosolvent, 0.9% osmotic pressure regulator, an appropriate amount of pH regulator and an appropriate amount of solvent.

[0008] Wherein: the butylphthalide is prepared by a chemical synthesis method, the content of the butylphthalide is greater than 99.0%, and the butylphthalide does not contain organic acid impurities, and the acid value is less than 0.5,

[0009] The cosolvent is hydroxypropyl beta-cyclodextrin,

[0010] The osmotic pressure regulator is sodium chloride,

[0011] The pH regulator is selected from one or more of hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, ascorbic acid, EDTA, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, sodium carbonate, and sodium bicarbonate.

[0012] The solvent is water for injection, and

[0013] The pH of the butylphthalide injection is 4.5-5.5, or the pH of the butylphthalide injection is 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5, or a pH range with any two of the above values ​​as endpoints.

[0014] In a preferred embodiment, the injection comprises, by mass percentage: 0.025% butylphthalide, 0.6-0.7% cosolvent, 0.9% osmotic pressure regulator, an appropriate amount of pH regulator and an appropriate amount of solvent.

[0015] The purity of the butylphthalide is greater than 99.5%, and the butylphthalide does not contain organic acid impurities such as n-pentyl acid and o-pentylbenzoic acid, and

[0016] The pH of the butylphthalide injection is 5.0-5.3.

[0017] In a more preferred embodiment, the pH adjuster is selected from hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, and citric acid, and the pH of the butylphthalide injection is 5.1-5.2.

[0018] In another preferred embodiment, the method for preparing the sterile injection comprises the following steps:

[0019] (1) Liquid preparation: Dissolve the prescribed amount of cosolvent in water for injection to prepare a solution, slowly add the prescribed amount of butylphthalide into the solution, and stir vigorously until it is completely dissolved;

[0020] (2) volume determination: using high performance liquid chromatography (HPLC) to determine the content of butylphthalide in the solution, and adding water for injection to determine the final concentration of the solution according to the content determination result;

[0021] (3) pH adjustment: adjusting the pH of the solution with a pH adjuster;

[0022] (4) Packaging: The solution is filtered through a 0.22 μm filter membrane and then dispensed into injection containers, with rubber stoppers and aluminum-plastic composite caps; and

[0023] (5) Sterilization: The filled injection is transferred to a sterilization cabinet and sterilized at 121° C. for 15 minutes.

[0024] Preferably, in step (4), the filter membrane material is selected from polytetrafluoroethylene, polyethersulfone or polyvinylidene fluoride.

[0025] It is preferably selected from polytetrafluoroethylene.

[0026] In a second aspect, the present invention provides a method for preparing the butylphthalide injection described in the first aspect, characterized in that the preparation method comprises the following steps:

[0027] (1) Liquid preparation: Dissolve the prescribed amount of cosolvent in water for injection to prepare a solution, slowly add the prescribed amount of butylphthalide into the solution, and stir vigorously until it is completely dissolved;

[0028] (2) volume determination: using high performance liquid chromatography (HPLC) to determine the content of butylphthalide in the solution, and adding water for injection to determine the final concentration of the solution according to the content determination result;

[0029] (3) pH adjustment: adjusting the pH of the solution with a pH adjuster;

[0030] (4) Packaging: The solution is filtered through a 0.22 μm filter membrane and then dispensed into injection containers, with rubber stoppers and aluminum-plastic composite caps; and

[0031] (5) Sterilization: The filled injection is transferred to a sterilization cabinet and sterilized at 121° C. for 15 minutes.

[0032] Preferably, in step (3), the pH is 4.5-5.5, preferably, the pH is 5.0-5.3, more preferably, the pH is 5.1-5.2, or the pH of the butylphthalide injection is 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5, or a pH range with any two of the above values ​​as endpoints.

[0033] More preferably, in step (4), the filter membrane material is selected from polytetrafluoroethylene, polyethersulfone or polyvinylidene fluoride.

[0034] Preferably selected from polytetrafluoroethylene.

[0035] In a third aspect, the present invention provides use of the sterile injection described in the first aspect in the preparation of a medicament for preventing or treating stroke.

[0036] In a fourth aspect, the present invention provides a method for reducing the high-temperature hydrolysis impurities of butylphthalide that appear in the preparation process of the sterile injection described in the first aspect, characterized in that: the method comprises: after removing the organic acid impurities from the butylphthalide raw material, the acid value of the butylphthalide is reduced from more than 3.0 to less than 0.5, and the pH of the solution is also increased accordingly, and the pH of the solution is controlled at 4.5-5.5 by adding a pH regulator suitable for human body, and the high-temperature hydrolysis impurities of butylphthalide after sterilization are reduced from more than 0.5% by mass to less than 0.05%. Preferably, the organic acid impurities include n-pentyl acid and o-pentylbenzoic acid. Preferably, the pH regulator is selected from one or more of hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, ascorbic acid, EDTA, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, sodium carbonate, and sodium bicarbonate. Preferably, the pH is 5.0-5.3, and more preferably, the pH is 5.1-5.2.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] (1) The pH adjuster used in the present invention controls the pH value of the solution within a specified range, and can significantly inhibit the generation of hydrolysis impurities in the butylphthalide injection.

[0039] (2) The total impurity content of the butylphthalide injection in the present invention is significantly reduced.

[0040] (3) The butylphthalide injection of the present invention has good stability.

[0041] (4) The polytetrafluoroethylene filter membrane is used in the production process of the butylphthalide injection of the present invention, which can reduce the adsorption of the butylphthalide component by the filter membrane.

[0042] (5) The preparation process of the butylphthalide injection of the present invention is simple and easy to achieve stable production.

[0043] (6) The present invention provides a method for preparing a sterile injection of a high-purity butylphthalide raw material drug from which organic acid impurities have been removed. DETAILED DESCRIPTION

[0044] The present invention will be further described with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of the present invention.

[0045] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0046] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0047] Example:

[0048] 1. Analysis of impurities in sterile injection of butylphthalide

[0049] At present, the marketed products of butylphthalide include soft capsules and infusions. The marketed infusions use cyclodextrin inclusion technology to solve the problem of poor water solubility of butylphthalide, which meets the clinical drug demand very well. However, the applicant has analyzed and found that due to the limitations of the refining process of the marketed butylphthalide raw material, the product contains some organic acid impurities.

[0050] The highly purified butylphthalide API has been freed of organic acid impurities such as o-pentylbenzoic acid, and its acid value has been reduced from more than 3.0 before purification to less than 0.5 after purification. The pH value of the butylphthalide injection made from this raw material is about 6.0. After the solution is terminally sterilized, butylphthalide is hydrolyzed at high temperature to generate butylphthalide hydrolysis ring-opening impurities (impurity 1), which leads to an increase in impurities in the finished product.

[0051] The preparation method of the sodium chloride butylphthalide injection is as follows:

[0052] Prescription: 25 mg of butylphthalide, 700 mg of hydroxypropyl beta-cyclodextrin, 900 mg of sodium chloride, and water for injection to 100 mL.

[0053] Preparation: Dissolve the prescribed amount of cosolvent in water for injection to make a solution, slowly add the prescribed amount of butylphthalide to the solution, stir until it is completely dissolved, then add the prescribed amount of sodium chloride, stir until it is completely dissolved.

[0054] Make up the volume: Use HPLC method to determine the content of butylphthalide in the above solution. According to the determination result, add water for injection to make up the solution to the final concentration.

[0055] Packaging: The solution is filtered through a 0.22μm filter membrane and then dispensed into glass injection bottles for injection, with rubber stoppers and aluminum-plastic composite caps.

[0056] Sterilization: Transfer the filled preparation into a sterilizer and sterilize at 121°C for 15 minutes.

[0057] By comparing with the commercially available sodium chloride butylphthalide injection, it was found that the pH of the commercial preparation was about 5.2, and the pH of the self-made preparation was about 6.0. After sterilization, the impurity 1 increased significantly, which was significantly higher than the commercial preparation. The experimental results are shown in Table 1 below:

[0058] Table 1 Comparison of impurities between homemade preparations and commercial preparations

[0059]

[0060] The inventor speculated on the structure of the impurity. The main structure of butylphthalide is benzopentyl lactone, and the pentyl lactone structure will hydrolyze under alkaline or acidic conditions to form the impurity 2-(1-hydroxypentyl)benzoic acid). Under acidic conditions, it will form an equilibrium, and under alkaline conditions, it will be completely hydrolyzed and form the corresponding salt, which is 2-(1-hydroxypentyl)benzoate sodium in this product. High temperature will accelerate the hydrolysis process in the presence of water, and condensation and dehydration will form butylphthalide under anhydrous conditions. The reaction equilibrium is shown below:

[0061]

[0062] The impurity reference substance was prepared according to the above reaction mechanism, and was compared with the impurity 1 in the injection by HPLC. The results showed that the retention time of the two was consistent. Combined with the fact that the formation principle of this impurity is the same as that of the hydrolysis impurity, it can be determined that the impurity generated by the injection after high-temperature sterilization is the hydrolysis ring-opening impurity of butylphthalide.

[0063] Subsequently, we analyzed the cause of the generation of impurity 1. The pH value of sodium chloride butylphthalide injection prepared with homemade butylphthalide API was about 5.8 before sterilization. The impurity was not seen before sterilization. After high-temperature sterilization, the impurity was generated, and as the pH value of the solution before sterilization decreased, the impurity content also decreased. The pH of the original solution was about 5.2, and the impurity did not increase significantly after re-sterilization.

[0064] After the homemade butylphthalide raw material is refined by the alkaline washing process, the acidic impurities (n-pentanoic acid, o-pentylbenzoic acid, etc.) remaining in the butylphthalide raw material can be removed, and the acid value is reduced from more than 3.0 to less than 0.5. Without alkaline washing, these acidic impurities (volatile) are difficult to remove in the subsequent distillation process, and the alkali used is a non-volatile substance and will not be introduced into the product after distillation. The raw materials used in the commercially available butylphthalide sodium chloride injection may contain a small amount of acidic impurities, which makes the pH value of the injection low, thereby inhibiting the generation of impurities after sterilization.

[0065] Using gas chromatography to test the commercially available butylphthalide soft capsules and injections, it was detected that they contained o-pentylbenzoic acid impurities, which confirmed our speculation.

[0066] Through the above research, the inventors first discovered that removing organic acid impurities such as o-pentylbenzoic acid from butylphthalide API unexpectedly leads to an increase in the impurity content of the sterile injection of high-purity butylphthalide. In addition, the inventors also discovered a method for ensuring that the impurity content of the final butylphthalide injection product is low in this case.

[0067] 2. Methods for reducing impurities in the preparation process of sterile injection of butylphthalide

[0068] 2.1 Study on the correlation between various formulation process parameters and the impurity content in sterile injection of butylphthalide

[0069] (1) Preparation method of sodium chloride butylphthalide injection:

[0070] Preparation: Dissolve the prescribed amount of cosolvent in water for injection to make a solution, slowly add the prescribed amount of butylphthalide to the solution, stir until it is completely dissolved, then add the prescribed amount of sodium chloride, stir until it is completely dissolved.

[0071] Make up the volume: Use HPLC method to determine the content of butylphthalide in the above solution. According to the determination result, add water for injection to make up the solution to the final concentration.

[0072] Packaging: The solution is filtered through a 0.22μm filter membrane and then dispensed into glass injection bottles, with rubber stoppers and aluminum-plastic composite caps.

[0073] Sterilization: Transfer the filled preparation into a sterilizer and sterilize at 121°C for 15 minutes.

[0074] (2) Using self-made butylphthalide API, we found that, according to the above preparation process, if the pH is not adjusted, butylphthalide sodium chloride injection produces hydrolysis impurities (impurity 1) after sterilization. However, using inert gas protection, lowering the sterilization temperature, changing the packaging material and other methods failed to significantly change the generation of impurity 1. The research results are shown in Table 2 below:

[0075] Table 2 Comparison of impurities in homemade preparations treated by different methods

[0076]

[0077] (3) According to the above preparation process, the solution was fixed to volume and the pH value of the solution was adjusted to 5.0, 5.1, 5.2, and 5.3 with hydrochloric acid, and sterilized under the same conditions. The impurity levels before and after sterilization were compared. The results are shown in Table 3 below:

[0078] Table 3 Comparison of impurities in homemade preparations with different solution pH

[0079] pH before sterilization 5.01 5.10 5.22 5.31 pH after sterilization 5.14 5.16 5.35 5.42 Impurity 1(%) 0.02 0.03 0.05 0.07

[0080] The results show that after terminal sterilization, the growth of impurity 1 in the solution with reduced pH value is reduced to varying degrees. The higher the pH value, the higher the content of impurity 1 after sterilization, which proves that the stability of the feed liquid is closely related to its pH value. The lower the pH value, the more stable the feed liquid. When the pH value of the solution is controlled at 5.0-5.2, the level of impurity 1 is optimally controlled.

[0081] (4) We used common pH adjusters such as hydrochloric acid, acetic acid, phosphoric acid, etc. to adjust the pH of the solution to between 5.0 and 5.2, and then sterilized it. After sterilization, the level of impurity 1 in the solution was basically the same. The results are shown in Table 4 below:

[0082] Table 4 Comparison of impurities in homemade preparations using different acids to control the pH value of the solution

[0083] pH Adjusters hydrochloric acid acetic acid Phosphoric acid pH before sterilization 5.10 5.12 5.12 pH after sterilization 5.16 5.16 5.15 Impurity 1(%) 0.03 0.02 0.03

[0084] (5) We used unpurified butylphthalide API (acid value above 3.0) and prepared butylphthalide sodium chloride injection according to the same preparation process. The pH value of the solution was not adjusted. The results are shown in Table 5 below:

[0085] Table 5 Comparison of impurities in homemade preparations using unpurified butylphthalide API

[0086] batch number 200409 200411 pH before sterilization 5.17 5.19 pH after sterilization 5.20 5.21 Impurity 1(%) 0.02 0.03

[0087] The results showed that the unpurified butylphthalide raw material was used to make butylphthalide sodium chloride injection, and the pH of the solution was low, which could inhibit the formation of impurity 1 after sterilization.

[0088] (6) We used filter membranes of different materials to filter the solution prepared by the present prescription process, and compared the butylphthalide content before and after filtration. The results are shown in Table 6 below:

[0089] Table 6 Adsorption of butylphthalide in preparation solution by filter membranes of different materials

[0090]

[0091] The results showed that the PTFE membrane had the smallest adsorption capacity, while the PES and PVDF membranes had slightly higher adsorption rates.

[0092] 2.2 Preparation method and stability study of sterile injection of butylphthalide with low impurity content

[0093] (1) We used the patented recipe process to prepare multiple batches of samples, and the preparation process was as follows:

[0094] Preparation: Dissolve the prescribed amount of cosolvent in water for injection to make a solution, slowly add the prescribed amount of butylphthalide to the solution, stir until it is completely dissolved, then add the prescribed amount of sodium chloride, stir until it is completely dissolved.

[0095] Make up the volume: Use HPLC method to determine the content of butylphthalide in the above solution. According to the determination result, add water for injection to make up the solution to the final concentration.

[0096] pH adjustment: Use a pH adjuster to adjust the pH value of the solution to 5.00-5.30.

[0097] Packaging: The solution is filtered through a 0.22μm filter membrane and then dispensed into glass injection bottles, with rubber stoppers and aluminum-plastic composite caps.

[0098] Sterilization: Transfer the filled preparation into a sterilizer and sterilize at 121°C for 15 minutes.

[0099] The test results of impurities in the relevant batches of samples are shown in Table 7 below:

[0100] Table 7 Test results of multiple batches of homemade preparations

[0101]

[0102]

[0103] The results show that: for the samples prepared by the prescription process of the present invention, the impurity 1 can be controlled below 0.05% before and after sterilization, other impurities remain basically unchanged, and there are no new impurities, indicating that the prescription process of the present invention can ensure the stability of the feed liquid.

[0104] (2) The stability of the above three batches of samples was investigated, and the results are shown in Tables 8 and 9 below:

[0105] Table 8 Research results on factors affecting homemade preparations

[0106]

[0107] Through the investigation of influencing factors, the impurity spectrum under various conditions was basically consistent with that at 0 month. The quality of the sample was stable when placed under high temperature of 60°C and light conditions for 30 days.

[0108] Table 9 Results of stability study of homemade preparations

[0109]

[0110] After being placed at 25°C for 9 months, the impurity spectrum of the relevant substances detected at each time point was basically consistent with that at 0 months, with no obvious new impurities, indicating that the sample was stable under long-term conditions.

[0111] In summary, the present invention first discovered that the removal of organic acid impurities such as o-pentylbenzoic acid from butylphthalide raw materials unexpectedly led to an increase in the impurity content of the sterile injection of butylphthalide. In addition, in response to this problem, the inventors proposed that the impurity level in the sterile injection of butylphthalide can be effectively controlled by strictly controlling the pH of the injection within a specific range, and the operation method is simple.

[0112] The method of the present invention is used to prepare butylphthalide injection, which not only takes into account the high quality of the butylphthalide raw material, reduces the drug safety risk caused by impurities, but also ensures that the butylphthalide injection with low impurity content and quality that meets the requirements of relevant regulations can be produced.

[0113] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A sterile injection of butylphthalide, characterized in that: The injection comprises, by mass percentage, 0.02-0.03% butylphthalide, 0.5-0.8% cosolvent, 0.9% osmotic pressure regulator, an appropriate amount of pH regulator and an appropriate amount of solvent. Wherein: the butylphthalide is prepared by a chemical synthesis method, the content of the butylphthalide is greater than 99.0%, and the butylphthalide does not contain organic acid impurities such as n-pentanoic acid and o-pentylbenzoic acid, and the acid value is less than 0.5, The cosolvent is hydroxypropyl beta-cyclodextrin, The osmotic pressure regulator is sodium chloride, The pH regulator is selected from one or more of hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, ascorbic acid, EDTA, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, sodium carbonate, and sodium bicarbonate. The solvent is water for injection, and The pH of the butylphthalide injection is 5.1-5.

3.

2. The sterile injection according to claim 1, characterized in that: The injection comprises, by mass percentage, 0.025% of butylphthalide, 0.6-0.7% of a cosolvent, 0.9% of an osmotic pressure regulator, a proper amount of a pH regulator and a proper amount of a solvent, and the purity of the butylphthalide is greater than 99.5%.

3. The sterile injection according to claim 1, characterized in that: The pH adjuster is selected from hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid or citric acid.

4. The sterile injection according to claim 1, characterized in that: The preparation method of the sterile injection comprises the following steps: (1) Liquid preparation: Dissolve the prescribed amount of cosolvent in water for injection to prepare a solution, slowly add the prescribed amount of butylphthalide into the solution, and stir vigorously until it is completely dissolved; (2) volume determination: using high performance liquid chromatography (HPLC) to determine the content of butylphthalide in the solution, and adding water for injection to determine the final concentration of the solution according to the content determination result; (3) pH adjustment: adjusting the pH of the solution with a pH adjuster; (4) Packaging: The solution is filtered through a 0.22 μm filter membrane and then dispensed into injection containers, with rubber stoppers and aluminum-plastic composite caps; and (5) Sterilization: The filled injection is transferred to a sterilization cabinet and sterilized at 121° C. for 15 minutes.

5. The sterile injection according to claim 4, characterized in that: In step (4), the filter membrane material is selected from polytetrafluoroethylene, polyethersulfone or polyvinylidene fluoride.

6. The sterile injection according to claim 5, characterized in that: The filter membrane material is selected from polytetrafluoroethylene.

7. The method for preparing the butylphthalide injection according to any one of claims 1 to 6, characterized in that: The preparation method comprises the following steps: (1) Liquid preparation: Dissolve the prescribed amount of cosolvent in water for injection to prepare a solution, slowly add the prescribed amount of butylphthalide into the solution, and stir vigorously until it is completely dissolved; (2) volume determination: using high performance liquid chromatography (HPLC) to determine the content of butylphthalide in the solution, and adding water for injection to determine the final concentration of the solution according to the content determination result; (3) pH adjustment: adjusting the pH of the solution with a pH adjuster; (4) Packaging: The solution is filtered through a 0.22 μm filter membrane and then dispensed into injection containers, with rubber stoppers and aluminum-plastic composite caps; and (5) Sterilization: The filled injection is transferred to a sterilization cabinet and sterilized at 121° C. for 15 minutes.

8. The preparation method according to claim 7, characterized in that: In step (3), the pH is 5.1-5.

2.

9. The preparation method according to claim 7, characterized in that: In step (4), the filter membrane material is selected from polytetrafluoroethylene, polyethersulfone or polyvinylidene fluoride.

10. The preparation method according to claim 9, characterized in that: The filter membrane material is selected from polytetrafluoroethylene.

11. Use of the sterile injection according to any one of claims 1 to 6 in the preparation of a medicament for preventing or treating cerebral stroke.

12. A method for reducing the high temperature hydrolysis impurities of butylphthalide in the preparation process of the sterile injection according to any one of claims 1 to 6, characterized in that: The method comprises: after removing organic acid impurities from the butylphthalide raw material, the acid value of the butylphthalide is reduced from more than 3.0 to less than 0.5, and the pH value of the solution is correspondingly increased; by adding a pH regulator suitable for human body, the pH value of the solution is controlled at 5.1-5.3; after sterilization, the impurities of the butylphthalide hydrolysis at high temperature are reduced from more than 0.5% by mass to less than 0.05%, and the organic acid impurities include n-pentanoic acid and o-pentylbenzoic acid.

13. The method according to claim 12, characterized in that: The pH regulator is selected from one or more of hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, ascorbic acid, EDTA, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, sodium carbonate, and sodium bicarbonate.

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