Acetylcysteine Injection and Its Preparation Method

Abstract

The present invention relates to the field of pharmaceutical chemicals, in particular to the synthetic method of acetylcysteine injection, comprising the steps of: 1) adding water for injection into a stainless steel preparation tank, continuing to pass through nitrogen to displace the air in the preparation tank, then adding disodium edetate at 50 55 DEG C, stirring, and obtaining a disodium edetate aqueous solution; 2) adding water for injection into another stainless steel preparation tank, continuing to pass through nitrogen to displace the air in the preparation tank, adding acetylcysteine, stirring and dissolving, using basic amino acid to adjust pH to 7.0 7.3, obtaining the acetylcysteine aqueous solution; 3) continuing to pass through nitrogen into the stainless steel preparation tank equipped with disodium edetate, the acetylcysteine aqueous solution obtained is added into the disodium edetate aqueous solution, stirring and dissolving, using basic amino acid to adjust pH to 7.0 7.3, filtering, sterilizing after canning, obtaining acetylcysteine injection. The present invention uses basic amino acid to adjust pH so that the impurities such as hydrogen sulfide in the system are significantly reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical and chemical engineering, and in particular to a method for preparing acetylcysteine injection. Background Art

[0002] N-acetylcysteine (NAC), an acetyl derivative of cysteine, is widely recognized as an antidote for acetaminophen overdose and can act through actions on glutamatergic and dopaminergic neurotransmission, oxidative stress, neurogenesis, mitochondrial dysfunction, and inflammatory pathways.

[0003] N-acetyl-L-cysteine has a molecular formula of C5H9NO3S and a molecular weight of 163.20. It is a white or off-white crystalline powder. Contact with metals such as iron and copper, rubber, oxygen, and oxides can cause irreversible binding and render it ineffective. Avoid contact with these metals. In China, its injection is used for the early treatment of liver failure to lower bilirubin and increase prothrombin activity; however, infusion can cause nausea, vomiting, rash, bronchospasm, headache, dizziness, fever, and allergic reactions.

[0004] Harrison et al. reported that acetylcysteine exhibits beneficial hemodynamic activity in acute liver failure by increasing levels of the endogenous vasodilator nitric oxide and enhancing the activity of the soluble guanylate cyclase system. Nagasaki et al. reported that acetylcysteine can protect against liver damage caused by GSH deficiency and maintain liver integrity during ischemia / reperfusion injury.

[0005] In the prior art, after adding a prescribed amount of acetylcysteine and stirring to dissolve it, sodium hydroxide is usually added to adjust the pH value. The addition of sodium hydroxide will cause hydrogen sulfide and impurities such as cysteine, N,N'-diacetylcysteine, and N,S-diacetylcysteine to be generated in the system, resulting in an increased probability of side effects of the acetylcysteine solution. Summary of the Invention

[0006] To address the problems of the prior art, the present invention utilizes basic amino acids to adjust the pH of the acetylcysteine aqueous solution, significantly reducing impurities such as hydrogen sulfide in the reaction system, thereby reducing the probability of side effects of the acetylcysteine solution.

[0007] In one aspect, the present invention provides a method for preparing acetylcysteine injection, comprising the following steps:

[0008] 1) Adding water for injection to a stainless steel preparation tank, continuously introducing nitrogen to replace the air in the preparation tank, then adding the prescribed amount of the metal chelator disodium edetate at 50-55° C. and stirring uniformly to obtain a disodium edetate aqueous solution;

[0009] 2) Adding water for injection to another stainless steel preparation tank, continuously introducing nitrogen to displace the air in the preparation tank, adding the prescribed amount of acetylcysteine, stirring thoroughly to dissolve, and adjusting the pH to 7.0-7.3 with a basic amino acid to obtain an acetylcysteine aqueous solution;

[0010] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring thoroughly to dissolve, adjusting the pH to 7.0-7.3 with a basic amino acid, filtering using a 0.45 μm filter, and then filling with nitrogen, canning, and sterilizing to obtain acetylcysteine injection;

[0011] In some embodiments, the basic amino acid used in step 2) and step 3) can be selected from L-lysine, L-arginine and L-histidine; compared with the prior art, the preparation method of acetylcysteine injection provided by the present invention selects basic amino acids as buffers to adjust the pH, which can avoid the increase of impurity content in the drug solution during the preparation process.

[0012] In some embodiments, an appropriate amount of cysteine may be added to the basic amino acid so that the molar ratio of the basic amino acid to cysteine is 1:0.2.

[0013] In some embodiments, each 1 ml of acetylcysteine injection includes about 100 mg of acetylcysteine and about 1 mg of edetate disodium, with a pH of 7.0-7.3, which stabilizes the pH of the liquid, thereby improving the stability of product quality. The specific pH value can avoid the degradation of acetylcysteine, thereby reducing the content of impurities generated by the decomposition products and other changes of acetylcysteine.

[0014] In some embodiments, step 3) further includes filtering with a 0.45 μm filter cartridge, measuring the pH value of the solution to ensure that the pH value is within the range of 7.0-7.3, and measuring the content of acetylcysteine and edetate disodium to ensure that each 1 ml of acetylcysteine injection contains approximately 100 mg of acetylcysteine and approximately 1 mg of edetate disodium; after the pH value and the content of acetylcysteine and edetate disodium are tested and qualified, filling is performed.

[0015] In some embodiments, the sterilization method is to sterilize the drug by moist heat sterilization after filling.

[0016] In some embodiments, the moist heat sterilization condition is sterilization at 120° C. for 30 min.

[0017] In some embodiments, during the nitrogen filling, the filling temperature is 18° C.-26° C., the filling speed is 80-85 bottles / minute, and the nitrogen filling pressure is 0.3 MPa-0.5 MPa.

[0018] In some embodiments, a leak detection step is further included after sterilization, wherein the leak detection adopts a high-voltage discharge leak detection method, and the leak detection conditions are: the discharge voltage is 18KV, and the threshold value is ≤5.

[0019] In some embodiments, the total impurity content in the acetylcysteine injection does not exceed 2%, and the related substances are impurities generated by decomposition products and other changes of acetylcysteine.

[0020] In another aspect, the present invention provides an acetylcysteine injection, wherein each 1 ml of the acetylcysteine injection comprises about 100 mg of acetylcysteine and about 1 mg of edetate disodium, and has a pH of 7.0-7.3.

[0021] In some embodiments, the content of related substances in the acetylcysteine injection does not exceed 2%, and the related substances are impurities generated by the decomposition products and other changes of acetylcysteine. DETAILED DESCRIPTION

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0023] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail. In addition, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

[0024] The terms "about" and "approximately," when used in connection with a numerical variable, generally mean that the value of the variable and all values of the variable are within measurement or experimental error (e.g., a 95% confidence interval for the mean) or within the broader range of the specified value (e.g., ±5% or ±10%).

[0025] The term "comprise" or its variations such as "contains," "has," and "includes" means including the stated steps or elements but not excluding any other steps or elements. "Consisting of" means excluding unrecited steps or elements. "Consisting essentially of" means not excluding steps or elements that do not materially affect the basic and novel characteristics of the claimed invention. The term "comprising" specific steps or elements and its variations also include "consisting of" and "consisting essentially of" specific steps or elements.

[0026] When a numerical range is mentioned, it should be considered that the specific values of its upper and lower limits are specifically disclosed, as well as all intermediate ranges included therein, such as intermediate ranges between its upper or lower limit and any intermediate value, or intermediate ranges between any two intermediate values. In addition, any intermediate ranges, subranges and all individual values described in the numerical range can be excluded from the numerical range.

[0027] The term "and / or" should be understood to refer to any one element or any combination of several elements connected by this term.

[0028] In some embodiments, the prescribed amount of the metal chelator edetate disodium is added to a stainless steel preparation tank at 50-55°C, for example, edetate disodium can be added at 50°C, 51°C, 52°C, 53°C, 54°C, or 55°C.

[0029] In some embodiments, the pH of the aqueous acetylcysteine solution is adjusted to 7.0-7.3, eg, 7.0, 7.1, 7.2, 7.3, using a basic amino acid.

[0030] In some embodiments, the basic amino acid can be selected from L-lysine, L-arginine and L-histidine. In some embodiments, an appropriate amount of cysteine can be added to the basic amino acid so that the molar ratio of the basic amino acid to cysteine is 1:0.2.

[0031] In some embodiments, each 1 ml of acetylcysteine injection includes 100 mg of acetylcysteine and 1 mg of edetate disodium.

[0032] In some embodiments, when filling with nitrogen, the filling temperature is 18°C-26°C, for example, 18°C, 19°C, 20°C, 21°C, 22°C, 24°C, 26°C, and the value is not limited to the specific values listed.

[0033] In some embodiments, the filling speed is 80-85 bottles / minute, for example, 80 bottles / minute, 81 bottles / minute, 82 bottles / minute, 83 bottles / minute, 84 bottles / minute, 85 bottles / minute.

[0034] In some embodiments, the pressure of nitrogen filling is 0.3 MPa-0.5 MPa, such as 0.3 MPa, 0.4 MPa, or 0.5 MPa.

[0035] After sterilization, a leak detection step is also included, using a high-voltage discharge leak detection method. The leak detection conditions are: discharge voltage is 18KV, threshold value ≤5, for example, the threshold values are 5, 4, 3, 2, and 1.

[0036] The term "related substances" used in this specification has the same definition as the "related substances" in the drug stability test guidelines recorded in Appendix XI X of Part II of the 2020 edition of the Chinese Pharmacopoeia, and refers to the decomposition products of acetylcysteine and substances produced by other changes.

[0037] Determination of acetylcysteine content: Determine according to the high performance liquid chromatography method described in Appendix VD of Part II of the 2020 edition of the Chinese Pharmacopoeia.

[0038] Chromatography test conditions:

[0039] Octadecylsilane bonded silica gel was used as filler, methanol-0.02 mol / L sodium pentanesulfonate 0.5% ammonium sulfate solution (1:9) and adjusted to pH 2.0 with 2 mol / L hydrochloric acid solution was used as mobile phase; the detection wavelength was 205 nm.

[0040] Determination method:

[0041] Accurately measure an appropriate amount of acetylcysteine, add the mobile phase to make a solution containing 80 μg of acetylcysteine per 1 ml, shake well, filter, and take the filtrate as the test solution. Accurately measure 20 μl of the above solution, inject it into the liquid chromatograph, and record the chromatogram; accurately weigh the acetylcysteine reference substance that has been dried to a constant weight under reduced pressure, and determine it in the same way. Calculate the acetylcysteine content by peak area according to the external standard method.

[0042] Related substances:

[0043] Take an appropriate amount of acetylcysteine and dilute it with mobile phase to prepare a solution containing 2 mg of acetylcysteine per 1 ml (1). Weigh an appropriate amount of acetylcysteine separately and add it to mobile phase to prepare a solution containing 2 mg per 1 ml (2). Let solution (2) stand at room temperature for 2 hours to form solution (3). Then take 20 mg of L-cysteine and 20 mg of L-cystine and dissolve them in 10 ml of 1 mol / L hydrochloric acid solution. Add 40 mg of acetylcysteine and dissolve it, then immediately dilute it with mobile phase to prepare a solution containing 10 μg of L-cysteine, 10 μg of L-cystine, and 20 μg of acetylcysteine per 1 ml (4). Except for solution (3), which should be left at room temperature for 2 hours, all other solutions should be prepared temporarily before analysis.

[0044] According to the high performance liquid chromatography method in Appendix VD of Part II of the 2020 edition of the Chinese Pharmacopoeia, octadecylsilane bonded silica gel was used as the filler, methanol-0.02 mol / L sodium pentanesulfonate 0.5% ammonium sulfate solution (1:9) and the pH value was adjusted to 2.0 with 2 mol / L hydrochloric acid solution as the mobile phase; the detection wavelength was 205 nm.

[0045] Take 20 μl of each of the above solutions (2) and (3) and inject them separately. The peak area of diacetylcysteine displayed by solution (3) should be larger than the corresponding peak on the chromatogram of solution (2). Take 20 μl of solution (4) and inject it into the liquid chromatograph. Adjust the detection sensitivity so that the peak height of the acetylcysteine chromatographic peak is about 20% of the full scale of the recorder, and the height of the valley between the L-cysteine and L-cystine chromatographic peaks should be less than 1 / 4 of the acetylcysteine peak height. Then accurately measure 20 μl of each of solutions (1) and (4) and inject them separately. Record the chromatogram until it reaches 3 times the retention time of the main component peak of acetylcysteine.

[0046] The present invention is further described by the following examples, which should not be construed as limiting the present invention.

[0047] Unless otherwise specified, all reagents used in the following examples are commercially available products.

[0048] Example 1

[0049] 1) Add 450 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0050] 2) Add 450 ml of water for injection to another stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, and after complete dissolution, divide the solution into three parts, and adjust the pH to 7.0 using an aqueous solution of L-lysine, an aqueous solution of L-arginine, and an aqueous solution of L-histidine, respectively, to obtain an aqueous solution of acetylcysteine;

[0051] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, then adding water for injection to make up the volume, adjusting the pH to 7.0 using an L-lysine aqueous solution, an L-arginine aqueous solution, and an L-histidine aqueous solution when the volume is close to 10 L, respectively, filtering using a 0.45 μm filter element, and then filling with nitrogen at 26° C., filling at a speed of 80 bottles / minute, and a nitrogen filling pressure of 0.3 MPa. After canning, the tank is sterilized with wet heat at 120° C. for 30 min, and after sterilization, discharge leak detection is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5 to obtain acetylcysteine injection.

[0052] Example 2

[0053] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0054] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, then add water for injection to make up to volume. When the volume is close to 10 L, adjust the pH to 7.3 with L-arginine aqueous solution to obtain an acetylcysteine aqueous solution;

[0055] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 7.3 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 26° C. at a filling rate of 80 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After filling, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5 to obtain acetylcysteine injection.

[0056] Example 3

[0057] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 55° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0058] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, then add water for injection to make up to volume. When the volume is close to 10 L, adjust the pH to 7.0 with L-arginine aqueous solution to obtain an acetylcysteine aqueous solution;

[0059] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 7.0 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 24° C. at a filling rate of 85 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After filling, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 3 to obtain acetylcysteine injection.

[0060] Example 4

[0061] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 55° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0062] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, then add water for injection to make up to volume. When the volume is close to 10 L, adjust the pH to 7.0 with an aqueous solution of L-arginine to obtain an aqueous solution of acetylcysteine;

[0063] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 7.0 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 18° C. at a filling rate of 85 bottles / minute and a nitrogen filling pressure of 0.5 MPa. After canning, moist heat sterilization is performed at 120° C. for 30 minutes. After sterilization, discharge leakage detection is performed under conditions of a discharge voltage of 18 kV and a threshold value of 3 to obtain acetylcysteine injection.

[0064] Example 5

[0065] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0066] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, then add water for injection to make up to volume. When the volume is close to 10 L, adjust the pH to 7.5 with L-arginine aqueous solution to obtain an acetylcysteine aqueous solution;

[0067] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 7.5 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 26° C. at a filling rate of 80 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After canning, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5 to obtain acetylcysteine injection.

[0068] Example 6

[0069] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0070] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, then add water for injection to make up to volume. When the volume is close to 10 L, adjust the pH to 6.8 with L-arginine aqueous solution to obtain an acetylcysteine aqueous solution;

[0071] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 6.8 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 32° C. at a filling rate of 80 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After canning, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5 to obtain acetylcysteine injection.

[0072] Example 7

[0073] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0074] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, then add water for injection to make up to volume. When the volume is close to 10 L, adjust the pH to 6.8 with L-arginine aqueous solution to obtain an acetylcysteine aqueous solution;

[0075] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 6.8 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 32° C. at a filling rate of 80 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After canning, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5 to obtain acetylcysteine injection.

[0076] Example 8

[0077] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0078] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1.5 kg of acetylcysteine, stir thoroughly to dissolve, then add water for injection to make up to volume. When the volume is close to 10 L, adjust the pH to 6.8 with L-arginine aqueous solution to obtain an acetylcysteine aqueous solution;

[0079] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 6.8 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 26° C. at a filling rate of 80 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After filling, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5 to obtain acetylcysteine injection.

[0080] Example 9

[0081] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 10 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0082] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir and dissolve thoroughly, then add water for injection to make up to volume, and when it approaches 10 L, adjust the pH to 6.8 using a mixed aqueous solution of L-arginine and cysteine, wherein the molar ratio of L-arginine to cysteine is 1:0.2, to obtain an acetylcysteine aqueous solution;

[0083] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 7.0 with an L-arginine aqueous solution, filtering using a 0.45 μm filter element, and then filling with nitrogen at 26° C. at a filling rate of 80 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After canning, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5 to obtain acetylcysteine injection.

[0084] Example 10

[0085] The stability of the acetylcysteine injections obtained in Examples 1-9 was tested. The specific steps were as follows: the acetylcysteine injections obtained in Examples 1-9 were placed in a container. Two groups of samples were set up for each example, one group was exposed to light, and the other group was subjected to high-temperature treatment. The illumination conditions were: 4500Lx±500Lx, and the high-temperature treatment conditions were: 60°C. The stability of the products was measured. The results are shown in Table 1.

[0086] Table 1: Stability test results of acetylcysteine injection of Examples 1-9

[0087]

[0088]

[0089] Example 11

[0090] 1) The acetylcysteine injection obtained in Example 1-9 was subjected to quality testing; the testing conditions were: chromatographic column: C18 column, specifications: C18 21.2*250mm; mobile phase: 0.01mol / L phosphate buffer-methanol (95:5); detection wavelength: 210nm; injection volume: 20μL; flow rate: 1.5mL / min; column temperature: 20°C. The peak elution time of cysteine was 5-6min, the peak elution time of N,N'-diacetylcysteine was 10-11min, and the peak elution time of N,S-diacetylcysteine was 13-15min. The test results are shown in Table 2 below:

[0091] Table 2: Quality test results of acetylcysteine injection of Examples 1-9

[0092]

[0093]

[0094] 2) Samples after light treatment and samples after high temperature treatment were extracted from Examples 1-9 and quality tested again. The test results are shown in Table 3 below:

[0095] Table 3: Stability test results of acetylcysteine injections extracted from Examples 1-9

[0096]

[0097] Example 12

[0098] The hydrogen sulfide content of the acetylcysteine injections obtained in Examples 1-9 and Comparative Example 1 was tested using a hydrogen sulfide sensor (manufacturer: Alphasense). Based on the electrochemical amperometric principle, the hydrogen sulfide sensor can rapidly analyze dissolved hydrogen sulfide in water on-site. Hydrogen sulfide diffuses into the sensor through a permeable membrane, then undergoes an oxidation-reduction reaction on the surface of the working electrode within the sensor. Quantitative analysis is performed by recording the current signal related to the hydrogen sulfide content. The hydrogen sulfide content test results of the acetylcysteine injections obtained in Examples 1-9 and Comparative Example 1 are shown in Table 4 below:

[0099] Table 4: Hydrogen sulfide content test results of acetylcysteine injection obtained in Examples 1-9 and Comparative Example 1

[0100]

[0101] Comparative Example 1

[0102] 1) Add 300 ml of water for injection to a stainless steel preparation tank, continuously introduce nitrogen to displace the air in the preparation tank, then add 1 g of the metal chelator disodium edetate at 50° C. and stir evenly to obtain an aqueous solution of disodium edetate;

[0103] 2) Add 300 ml of water for injection to another stainless steel preparation tank, continue to introduce nitrogen to replace the air in the preparation tank, add 1 kg of acetylcysteine, stir thoroughly to dissolve, and adjust the pH to 7.0 with sodium hydroxide to obtain an acetylcysteine aqueous solution;

[0104] 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 7.0 with sodium hydroxide, filtering using a 0.45 μm filter element, and then filling with nitrogen at 26° C. at a filling rate of 80 bottles / minute and a nitrogen filling pressure of 0.3 MPa. After canning, the tank is sterilized with wet heat at 120° C. for 30 minutes. After sterilization, a discharge leak test is performed under the conditions of a discharge voltage of 18 kV and a threshold of 5. Finally, water for injection is added to 1 L to obtain acetylcysteine injection.

[0105] 4) The acetylcysteine injection obtained in step 3) was subjected to stability tests according to the conditions of Example 10. The test results are shown in Table 4 below. It can be seen that when sodium hydroxide is used as a pH adjuster, the solution gradually changes from neutral to acidic after light exposure and high temperature treatment;

[0106] Table: 5: Comparative Example 1 Stability Test Results

[0107]

[0108]

[0109] 5) The acetylcysteine injection obtained in step 3) was tested for content according to the conditions of Example 11. The test results are shown in Table 5 below:

[0110] Table 6: Stability test results of acetylcysteine injection of Comparative Example 1

[0111]

[0112] The embodiments of the present invention are not limited to the above embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and details, and these are all considered to fall within the scope of protection of the present invention.

Claims

1. A method for preparing acetylcysteine injection, characterized in that, The steps include: 1) Adding water for injection to a stainless steel preparation tank, continuously introducing nitrogen to replace the air in the preparation tank, then adding the prescribed amount of the metal chelator disodium edetate at 50-55° C. and stirring uniformly to obtain a disodium edetate aqueous solution; 2) Adding water for injection to another stainless steel preparation tank, continuously introducing nitrogen to displace the air in the preparation tank, adding the prescribed amount of acetylcysteine, stirring thoroughly to dissolve, and adjusting the pH to 7.0-7.3 with a basic amino acid to obtain an acetylcysteine aqueous solution; 3) continuously introducing nitrogen into a stainless steel preparation tank containing edetate disodium, adding the acetylcysteine aqueous solution obtained in step 2) to the edetate disodium aqueous solution, stirring and dissolving, adjusting the pH to 7-7.3 with a basic amino acid, filtering with a 0.45 μm filter cartridge, and then nitrogen-filling and canning followed by sterilization to obtain acetylcysteine injection; during the nitrogen-filling canning, the filling temperature is 18° C.-26° C., the filling speed is 80-85 bottles / minute, and the nitrogen filling pressure is 0.3 MPa-0.5 MPa; Wherein, in step 2) and step 3), the basic amino acid is L-arginine; Each 1 ml of acetylcysteine injection contains about 100 mg of acetylcysteine and about 1 mg of edetate disodium, with a pH of 7.0-7.

3.

2. The preparation method according to claim 1, wherein: Step 3) further includes filtering with a 0.45 μm filter cartridge, measuring the pH value of the solution to ensure that the pH value is within the range of 7.0-7.3, and measuring the content of acetylcysteine and edetate disodium to ensure that each 1 ml of acetylcysteine injection contains approximately 100 mg of acetylcysteine and approximately 1 mg of edetate disodium; after the pH and the content of the acetylcysteine and edetate disodium are tested, filling is performed.

3. The preparation method of acetylcysteine injection according to claim 2, wherein: The sterilization method is to sterilize the medicine by moist heat sterilization after filling the medicine, and the moist heat sterilization condition is sterilization at 120°C for 30 minutes.

4. The preparation method according to claim 1, wherein: After sterilization, a leak detection step is also included. The leak detection adopts a high-voltage discharge leak detection method. The leak detection conditions are: the discharge voltage is 18KV and the threshold value is ≤5.

5. The preparation method according to claim 4, characterized in that The content of related substances in the acetylcysteine injection does not exceed 2%.

6. The acetylcysteine injection obtained by the preparation method according to any one of claims 1 to 5, wherein Each 1 ml of acetylcysteine injection contains approximately 100 mg of acetylcysteine and approximately 1 mg of edetate disodium, with a pH of 7.0-7.

3.

7. The acetylcysteine injection according to claim 6, characterized in that The content of related substances in the acetylcysteine injection does not exceed 2%.

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