Acetylcysteine injection and preparation method thereof

Abstract

The invention provides an acetylcysteine injection and a preparation method thereof. The acetylcysteine injection comprises the following components in percentage by weight: 5-15% of acetylcysteine, 0.5-1.5% of an antioxidant, a pH regulator and the balance of water for injection, the antioxidant is edetate disodium and sodium pyrosulfite, and the pH value of the injection is 6.5-7.5. The acetylcysteine injection prepared by the invention is simple in prescription, good in stability and long in preservation time.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to an acetylcysteine ​​injection and a preparation method thereof. Background Art

[0002] Acetylcysteine ​​is a precursor of reduced glutathione, which can remove oxygen free radicals in the body and protect liver cells. Acetylcysteine ​​injection is a liver-protecting drug, mainly used for the early treatment of liver failure, which can reduce bilirubin and increase prothrombin activity.

[0003] The preparation process of acetylcysteine ​​injection in the prior art generally has the following problems: multiple steps of pH adjustment (such as acidic dissolution followed by alkaline neutralization) are required, which is complicated to operate; multiple stabilizers (such as EDTA, excessive antioxidants) need to be added, which increases the risk of impurities; the sterilization process is harsh (such as high temperature and long-term sterilization), which easily leads to drug degradation. Therefore, developing an acetylcysteine ​​injection with a simple prescription and easy preparation process is of great significance to reducing manufacturing costs, controlling quality, and improving patient medication safety. Summary of the invention

[0004] In order to solve the problems in the prior art, the present invention provides an acetylcysteine ​​injection and a preparation method thereof. The obtained acetylcysteine ​​injection has a simple prescription, good stability and a long storage time.

[0005] The present invention solves the technical problem by adopting the following technical solutions:

[0006] The first object of the present invention is to provide an acetylcysteine ​​injection, comprising the following components in weight percentage: 5% to 15% of acetylcysteine, 0.5% to 1.5% of an antioxidant and a pH regulator, and the rest is water for injection; the antioxidant is disodium edetate and sodium pyrosulfite, and the pH value of the injection is 6.5 to 7.5.

[0007] Furthermore, the acetylcysteine ​​injection comprises the following components in weight percentage: 8% to 12% acetylcysteine, 0.8% to 1.2% antioxidant, and pH regulator, and the rest is water for injection, and the pH value of the injection is 6.5 to 7.5.

[0008] Furthermore, the water for injection is oxygen-free water for injection.

[0009] The present invention uses oxygen-free water for injection as a solvent, which reduces the contact between acetylcysteine ​​and oxygen from the source, reduces the risk of acetylcysteine ​​being oxidized during the preparation process, and improves the effectiveness of the drug. At the same time, with the full nitrogen environment, the stability is better.

[0010] Furthermore, the content of disodium edetate is 0.7-1.1%, and the content of sodium pyrosulfite is 0.1%.

[0011] Furthermore, the content of disodium edetate is 1.0%, and the content of sodium pyrosulfite is 0.1%.

[0012] Furthermore, the pH adjuster is sodium hydroxide or a solution thereof.

[0013] Disodium edetate has strong antioxidant properties and can preferentially combine with metal ions and oxygen to help improve the stability of acetylcysteine ​​and prevent it from being oxidized during storage. The present invention selects disodium edetate and sodium pyrosulfite as antioxidants, and the simultaneous use of the two has a synergistic effect, further improves the stability of acetylcysteine, reduces the content of impurities in the injection, and is more conducive to the preservation of the injection.

[0014] The second object of the present invention is to provide a method for preparing acetylcysteine ​​injection, comprising the following steps:

[0015] S1. Passivate the container with disodium edetate solution and then clean it;

[0016] S2. Add oxygen-free water for injection into the container, then continue to fill with nitrogen, add disodium edetate and sodium metabisulfite, stir until dissolved, and obtain a solution;

[0017] S3, adding acetylcysteine ​​to the solution, stirring until completely dissolved, to obtain an acetylcysteine ​​solution;

[0018] S4, add sodium hydroxide solution, adjust the solution pH to 6.5-7.5, stir and mix, and make up to volume;

[0019] S5, filtering, packaging, and sterilizing the solution by high-pressure steam to obtain the acetylcysteine ​​injection.

[0020] Furthermore, in step S5, filtration is performed using a PTFE filter membrane, and the pore size of the filter membrane is less than or equal to 0.22 μm.

[0021] The present invention selects PTFE filter membrane for filtration, which has good compatibility with acetylcysteine ​​injection, controls the generation of impurities, and reduces the load of microorganisms.

[0022] Furthermore, in step S5, the sterilization conditions are 121° C., 12 min, and F0≥12.

[0023] Furthermore, before adding acetylcysteine, ensure that edetate disodium and sodium metabisulfite are completely dissolved.

[0024] Furthermore, nitrogen needs to be filled during the packaging process in step S5, and nitrogen is filled at the end of packaging so that the injection solution can be sealed and stored in a nitrogen environment.

[0025] Furthermore, the sodium hydroxide solution is a sodium hydroxide solution with a mass concentration of 10%.

[0026] Compared with the prior art, the beneficial technical effects of the present invention are:

[0027] The present invention selects disodium edetate and sodium pyrosulfite as antioxidants, improves the stability of acetylcysteine, reduces the content of impurities in the injection, reduces the degradation caused during the storage process and the increase of the impurity content, is more conducive to the preservation of the injection, and prolongs the storage time of the injection. The whole process of preparation is operated in a nitrogen environment, which reduces the participation of oxygen from the source and improves the stability of the injection. The preparation method of the present invention is simple and easy to operate.

[0028] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention, it can be implemented according to the contents of the specification. In order to make the above and other purposes, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are listed below. DETAILED DESCRIPTION

[0029] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0030] In addition, unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0031] Example 1

[0032] An acetylcysteine ​​injection comprises the following components in percentage by weight:

[0033] Acetylcysteine ​​10%, disodium edetate 1.1%, sodium metabisulfite 0.1%, and the rest is water for injection. The pH of the solution is 6.8.

[0034] A preparation method of acetylcysteine ​​injection:

[0035] S1. Passivate the container with disodium edetate solution and then clean it;

[0036] S2. Under normal temperature conditions, add oxygen-free water for injection into the container, then continue to fill with nitrogen, add disodium edetate and sodium metabisulfite, and stir until dissolved to obtain a solution;

[0037] S3. Under a nitrogen environment, add acetylcysteine ​​to the above solution and stir until completely dissolved to obtain an acetylcysteine ​​solution;

[0038] S4. Under nitrogen environment, add 10% sodium hydroxide solution to adjust the pH of the solution to 6.8, stir and mix, and make up to volume;

[0039] S5. Filter the solution through a 0.22 μm PTFE filter membrane, then package it, and sterilize it with high-pressure steam at 121° C. for 12 min to obtain the acetylcysteine ​​injection.

[0040] Example 2

[0041] An acetylcysteine ​​injection comprises the following components in percentage by weight:

[0042] Acetylcysteine ​​10%, disodium edetate 1.0%, sodium metabisulfite 0.1%, and the rest is water for injection. The pH of the solution is 7.0.

[0043] A preparation method of acetylcysteine ​​injection:

[0044] S1. Passivate the container with disodium edetate solution and then clean it;

[0045] S2. Under normal temperature conditions, add oxygen-free water for injection into the container, then continue to fill with nitrogen, add disodium edetate and sodium metabisulfite, and stir until dissolved to obtain a solution;

[0046] S3. Under a nitrogen environment, add acetylcysteine ​​to the above solution and stir until completely dissolved to obtain an acetylcysteine ​​solution;

[0047] S4. Under nitrogen environment, add 10% sodium hydroxide solution to adjust the pH of the solution to 7.0, stir and mix, and make up to volume;

[0048] S5. Filter the solution through a 0.22 μm PTFE filter membrane, then package it, and sterilize it with high-pressure steam at 121° C. for 12 min to obtain the acetylcysteine ​​injection.

[0049] Example 3

[0050] An acetylcysteine ​​injection comprises the following components in percentage by weight:

[0051] Acetylcysteine ​​10%, disodium edetate 0.8%, sodium metabisulfite 0.1%, and the rest is water for injection. The solution pH is 7.2.

[0052] A preparation method of acetylcysteine ​​injection:

[0053] S1. Passivate the container with disodium edetate solution and then clean it;

[0054] S2. Under normal temperature conditions, add oxygen-free water for injection into the container, then continue to fill with nitrogen, add disodium edetate and sodium metabisulfite, and stir until dissolved to obtain a solution;

[0055] S3. Under a nitrogen environment, add acetylcysteine ​​to the above solution and stir until completely dissolved to obtain an acetylcysteine ​​solution;

[0056] S4. Under nitrogen environment, add 10% sodium hydroxide solution to adjust the pH of the solution to 7.2, stir and mix, and make up to volume;

[0057] S5. Filter the solution through a 0.22 μm PTFE filter membrane, then package it, and sterilize it with high-pressure steam at 121° C. for 12 min to obtain the acetylcysteine ​​injection.

[0058] Comparative Example 1

[0059] The difference from Example 2 is the addition ratio of disodium edetate.

[0060] An acetylcysteine ​​injection comprises the following components in percentage by weight:

[0061] Acetylcysteine ​​10%, edetate disodium 0.5%, sodium metabisulfite 0.1%, and the rest is water for injection.

[0062] Comparative Example 2

[0063] The difference from Example 2 is that the pH value of the solution is adjusted to 5.8 using a 10% sodium hydroxide solution in this comparative example.

[0064] Comparative Example 3

[0065] The difference from Example 2 is that nitrogen is not charged during the preparation process.

[0066] A preparation method of acetylcysteine ​​injection:

[0067] S1. Passivate the container with disodium edetate solution and then clean it;

[0068] S2. Under normal temperature, add oxygen-free water for injection into a container, add disodium edetate and sodium metabisulfite, and stir until dissolved to obtain a solution;

[0069] S3, adding acetylcysteine ​​to the above solution, stirring until completely dissolved, to obtain an acetylcysteine ​​solution;

[0070] S4, add 10% sodium hydroxide solution, adjust the solution pH to 7.0, stir and mix, and make up to volume;

[0071] S5. Filter the solution through a 0.22 μm PTFE filter membrane, then package it, and sterilize it with high-pressure steam at 121° C. for 12 minutes to obtain acetylcysteine ​​injection.

[0072] Comparative Example 4

[0073] The difference from Example 2 is that only disodium edetate is used as the antioxidant in the raw materials, and the preparation process is the same.

[0074] An acetylcysteine ​​injection comprises the following components in percentage by weight:

[0075] Acetylcysteine ​​10%, disodium edetate 1.0%, the rest is water for injection. The pH of the solution is 7.0.

[0076] Experimental example

[0077] The acetylcysteine ​​injection obtained in Example 1-3 and Comparative Example 1-2 was sealed and placed in a high temperature environment of 60° C. for 10 days, and the changes were observed. The impurity content was detected by liquid chromatography. The results are shown in Table 1.

[0078] Table 1

[0079]

[0080] As can be seen from Table 1, when the content of disodium edetate is low, after 10 days at 60°C, the impurity C increases significantly. When the content of disodium edetate is lower than 1.0%, as the content of disodium edetate decreases, the growth rate of impurity C changes rapidly over time. The optimal content of disodium edetate is 1.0%.

[0081] When the pH value of the solution was reduced to 5.8, the content of each impurity in the solution was significantly higher than that in the embodiment of the present invention, and the content of multiple impurities exceeded the standard. Moreover, as the storage time increased, after 10 days in a high temperature environment of 60°C, the content of impurity B increased significantly, far exceeding the limit requirement.

[0082] The acetylcysteine ​​injections obtained in Example 2 and Comparative Example 3 were sealed and placed at room temperature for 24 to 28 hours, and their changes were observed. The impurity content was detected by liquid chromatography. The results are shown in Table 2.

[0083] Table 2

[0084]

[0085] As can be seen from Table 2, Comparative Example 3 was not nitrogen-filled during the preparation process, and the content of impurity C in the obtained acetylcysteine ​​injection increased rapidly after being stored for 24 hours. It can be seen that acetylcysteine ​​injection is sensitive to oxygen and needs to be in a nitrogen environment during the preparation and storage process.

[0086] The acetylcysteine ​​injections obtained in Example 2 and Comparative Example 4 were sealed and placed in a high temperature environment of 60° C. for 10 days, and the changes were observed. The impurity content was detected by liquid chromatography. The results are shown in Table 3.

[0087] Table 3

[0088]

[0089] As can be seen from Table 3, in Comparative Example 4, only disodium edetate is used as an antioxidant. Compared with the embodiment of the present invention, disodium edetate and sodium pyrosulfite are used as antioxidants together, the content of each impurity in the just prepared product is not much different, but with the increase of storage time, the growth rate of each impurity content in Comparative Example 4 is faster, especially impurity B and impurity C, which grow faster. It can be seen that the embodiment of the present invention uses disodium edetate and sodium pyrosulfite as antioxidants to further improve the stability of acetylcysteine, which is more conducive to the preservation of the injection and has a longer storage time.

[0090] It should be noted that the impurity A detected by liquid chromatography in the present invention is L-cystine (C6H 12 N2O4S2), impurity B is L-cysteine ​​(C3H7NO2S), and impurity G is N,N'-diacetyl-L-lanthionine (C 10 H 16 N2O6S), impurity C is N,N'-diacetyl-L-cystine (C 10 H 16 N2O6S2), impurity D is N,S-diacetyl-L-cysteine ​​(C7H 11 NO4S). The structural formula of each impurity is as follows:

[0091]

[0092] The serial numbers of the above embodiments of the present invention are only for description and do not represent the advantages or disadvantages of the embodiments.

[0093] The embodiments of the present invention are described above, but the present invention is not limited to the above-mentioned specific implementation modes. The above-mentioned specific implementation modes are merely illustrative and not restrictive. Under the guidance of the present invention, ordinary technicians in this field can also make many forms without departing from the scope of protection of the purpose of the present invention and the claims, which are all within the protection of the present invention.

Claims

1. An acetylcysteine ​​injection, characterized in that: The invention comprises the following components in weight percentage: 5%-15% acetylcysteine, 0.5%-1.5% antioxidant and pH regulator, and the rest is water for injection; the antioxidant is disodium edetate and sodium pyrosulfite, and the pH value of the injection is 6.5-7.

5.

2. An acetylcysteine ​​injection as claimed in claim 1, characterized in that: The acetylcysteine ​​injection comprises the following components in weight percentage: 8% to 12% acetylcysteine, 0.8% to 1.2% antioxidant, and pH regulator, and the rest is injection water. The pH value of the injection is 6.5 to 7.

5.

3. An acetylcysteine ​​injection as claimed in claim 1 or 2, characterized in that: The content of the disodium edetate is 0.7-1.1%, and the content of the sodium pyrosulfite is 0.1%.

4. An acetylcysteine ​​injection as claimed in claim 3, characterized in that: The content of the disodium edetate is 1.0%, and the content of the sodium pyrosulfite is 0.1%.

5. A method for preparing the acetylcysteine ​​injection according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1. Passivate the container with disodium edetate solution and then clean it; S2. Add oxygen-free water for injection into the container, then continue to fill with nitrogen, add disodium edetate and sodium metabisulfite, stir until dissolved, and obtain a solution; S3, adding acetylcysteine ​​to the solution, stirring until completely dissolved, to obtain an acetylcysteine ​​solution; S4, add sodium hydroxide solution, adjust the solution pH to 6.5-7.5, stir and mix, and make up to volume; S5, filtering, packaging, and sterilizing the solution by high-pressure steam to obtain the acetylcysteine ​​injection.

6. A method for preparing acetylcysteine ​​injection as claimed in claim 5, characterized in that: In step S5, filtration is performed using a PTFE filter membrane, and the pore size of the filter membrane is less than or equal to 0.22 μm.

7. A method for preparing acetylcysteine ​​injection as claimed in claim 5, characterized in that: The sterilization conditions in step S5 are 121° C., 12 min, and F0 ≥ 12.

8. A method for preparing acetylcysteine ​​injection as claimed in claim 5, characterized in that: Ensure that edetate disodium and sodium metabisulfite are completely dissolved before adding acetylcysteine.

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