Preparation method of acetylcysteine injection

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a preparation method of an acetylcysteine injection for terminal sterilization, which is characterized in that the oxygen content and hydrogen sulfide content in liquid medicine are reduced by vacuumizing and nitrogen charging, and the appropriate pH is adjusted to make related substances meet the requirements, so that the sterilized acetylcysteine injection with high quality and stability is prepared. The method solves the problem that hydrogen sulfide and related substances in the acetylcysteine injection exceed the standard.

Description

Technical Field

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

[0002] Acetylcysteine ​​has a chemical formula of C5H9NO3S. It is an organic compound and an amino acid drug. It is mainly used for the early treatment of patients with liver failure. It can reduce bilirubin and increase prothrombin activity. Acetylcysteine ​​is a precursor of reduced glutathione (GSH) and is an oxygen free radical scavenger in the body. The mechanism of its liver protection is not very clear, but it may be related to maintaining or restoring glutathione levels. In addition, acetylcysteine ​​may also play a liver protection role by improving hemodynamics and oxygen transport capacity and expanding microcirculation.

[0003] Acetylcysteine ​​is unstable in aqueous solution and is sensitive to oxygen and temperature. Therefore, most of the current preparation processes for acetylcysteine ​​injection use filtration and sterilization processes. Even with non-terminal sterilization processes, many domestic manufacturers are still found to have unqualified hydrogen sulfide. Hydrogen sulfide is an impurity generated after the degradation of acetylcysteine, and it is seriously harmful to human health. Hydrogen sulfide is an acute and highly toxic substance. It inhibits the oxidative phosphorylation of cells, hinders the respiration of cells, and causes cell death. Hydrogen sulfide is irritating to the eyes, respiratory system, and nervous system. Exposure to low concentrations may cause eye irritation, headache, cough, and difficulty breathing. Inhaling a small amount of high-concentration hydrogen sulfide can be fatal in a short period of time. It is soluble in water. At 0°C, 1 mole of water can dissolve about 2.6 moles of hydrogen sulfide. The aqueous solution of hydrogen sulfide is called hydrosulfuric acid, which is a weak acid. When it is heated, hydrogen sulfide escapes from the water.

[0004] According to the "Guidelines for Research and Validation of Sterilization and Aseptic Processes for Chemical Injections" issued by CDE on August 3, 2020, if terminal sterilization can be used according to the sterilization decision tree, terminal sterilization process should be given priority. Currently, producing acetylcysteine ​​injections of qualified quality that can be terminally sterilized is a challenge facing the pharmaceutical industry. Summary of the invention

[0005] The present invention aims at the problems existing in the prior art and provides a novel preparation method of acetylcysteine ​​injection. By optimizing the preparation process, an injection with content, related substances, hydrogen sulfide and the like meeting the requirements and high quality is obtained. The preparation method comprises the following steps.

[0006] Add about 60% of the total prescription amount of injection water cooled to room temperature into the liquid preparation tank, start stirring, open the nitrogen valve, and fill nitrogen below the liquid surface for 10-30 minutes (the dissolved oxygen content should be ≤1000ppb). When the temperature of the injection water drops to 15℃~20℃, add the materials; Add the prescribed amount of disodium edetate to the preparation tank and stir for 5 minutes; Add 50% sodium hydroxide solution to the preparation tank, rinse the container twice with injection water, add it to the preparation tank, and stir for 5 minutes; Keep nitrogen gas under the liquid surface for at least 10 minutes, and when the temperature drops to 15℃~20℃, slowly add the prescribed amount of acetylcysteine, control the temperature at 15℃~25℃, stir until completely dissolved, and take a sample to test the pH value; Use 2% sodium hydroxide solution or 0.5 mol / L hydrochloric acid solution to adjust the pH value to 6.3-6.7; Stop stirring and close the nitrogen valve, add cooled water for injection (temperature below 25°C) to fix the weight, stir for 20 minutes; evacuate and fill with nitrogen, and repeat three times; The drug solution is filtered and sealed into ampoules, and the residual oxygen in the headspace is controlled below 1.0%; After sterilization at 121℃ for 15min and passing the light inspection and leak detection, the product can be packaged and obtained.

[0007] The technical effects achieved by the present invention are: Disodium edetate chelates metal ions and weakens the catalytic oxidation effect of metal ions; Sodium hydroxide is added in the form of 50% before the API to avoid the effect of the large amount of heat released by the dissolution of sodium hydroxide on acetylcysteine; Remove oxygen and hydrogen sulfide from the liquid medicine by vacuuming and filling with nitrogen; By regulating the dissolved oxygen content and residual oxygen content, the oxidation of acetylcysteine ​​is reduced at the source. DETAILED DESCRIPTION

[0008] The present application is further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present application and are not used to limit the scope of protection of the present application.

[0009] Example 1 The prescription of acetylcysteine ​​injection of the present embodiment is as follows: The preparation method of the acetylcysteine ​​injection preparation of this embodiment is: (1) Add about 60% of the total prescription amount of water for injection cooled to room temperature into the liquid preparation tank, start stirring, open the nitrogen valve, and fill nitrogen below the liquid surface for 10 to 30 minutes (the dissolved oxygen content should be ≤1000ppb). When the temperature of the water for injection drops to 15℃~20℃, add the materials; (2) Add the prescribed amount of disodium edetate to the dispensing tank and stir for 5 minutes; (3) Add 50% sodium hydroxide solution to the liquid preparation tank, rinse the container twice with injection water, add it to the liquid preparation tank, and stir for 5 minutes; (4) Continue to fill the liquid with nitrogen for at least 10 minutes, and when the temperature drops to 15°C~20°C, slowly add the prescribed amount of acetylcysteine, control the temperature at 15°C~25°C, stir until completely dissolved, and take a sample to test the pH value; (5) Use 2% sodium hydroxide solution or 0.5 mol / L hydrochloric acid solution to adjust the pH value to 6.3-6.7; (6) Stop stirring and close the nitrogen valve, add cooled water for injection (temperature below 25°C) to adjust the weight, stir for 20 minutes; evacuate and fill with nitrogen, and repeat three times; (7) Filter the drug solution and fill it into an ampoule, and control the residual oxygen in the headspace to below 1.0%; (8) After sterilization at 121°C for 15 minutes and passing the light inspection for leaks, the product can be packaged and obtained.

[0010] Example 2 The prescription of acetylcysteine ​​injection of the present embodiment is as follows: The preparation method of the acetylcysteine ​​injection preparation of this embodiment is: Add about 60% of the total prescription amount of injection water cooled to room temperature into the liquid preparation tank, start stirring, open the nitrogen valve, and fill nitrogen below the liquid surface for 10-30 minutes (the dissolved oxygen content should be ≤1000ppb). When the temperature of the injection water drops to 15℃~20℃, add the materials; Add 50% sodium hydroxide solution to the preparation tank, rinse the container twice with injection water, add it to the preparation tank, and stir for 5 minutes; Keep nitrogen gas under the liquid surface for at least 10 minutes, and when the temperature drops to 15℃~20℃, slowly add the prescribed amount of acetylcysteine, control the temperature at 15℃~25℃, stir until completely dissolved, and take a sample to test the pH value; Use 2% sodium hydroxide solution or 0.5 mol / L hydrochloric acid solution to adjust the pH value to 6.3-6.7; Stop stirring and close the nitrogen valve, add cooled water for injection (temperature below 25°C) to fix the weight, stir for 20 minutes; evacuate and fill with nitrogen, and repeat three times; The drug solution is filtered and sealed into ampoules, and the residual oxygen in the headspace is controlled below 1.0%; After sterilization at 121℃ for 15min and passing the light inspection and leak detection, the product can be packaged and obtained.

[0011] Comparative Example 1 The preparation was carried out according to the preparation method of Example 1, except that the vacuum operation was not performed.

[0012] The acetylcysteine ​​injection obtained in Examples 1-2 and Comparative Example 1 was tested according to the relevant requirements and standards of the Chinese Pharmacopoeia. The results are shown in Table 1 below. Table 1 The stability data of the acetylcysteine ​​injection obtained in Example 1 are shown in Table 2 below.

[0013] Table 2 By comparing the test results of the embodiment and the comparative example, the product quality is significantly improved after adding disodium edetate to the acetylcysteine ​​injection; the vacuum and nitrogen filling operation significantly improves the quality of the liquid medicine, reduces related substances, and effectively controls hydrogen sulfide. The acetylcysteine ​​injection prepared by the present invention has good stability under the intended storage conditions (normal temperature, protected from light).

[0014] The above embodiments are merely illustrative of the present invention, and the present invention may also be implemented in other specific ways or other specific forms without departing from the gist or essential features of the present invention. Therefore, the described embodiments should be considered illustrative rather than restrictive in any respect. The scope of the present invention should be described by the appended claims, and any changes equivalent to the intent and scope of the claims should also be included within the scope of the present invention.

Claims

1. A method for preparing acetylcysteine ​​injection, the prescription composition comprising acetylcysteine, sodium hydroxide, hydrochloric acid, and disodium edetate.

2. The method for preparing acetylcysteine ​​injection according to claim 1, characterized in that The solution preparation temperature is 0℃~30℃.

3. The preparation method of acetylcysteine ​​injection according to claim 1, characterized in that The pH adjusters are sodium hydroxide and hydrochloric acid.

4. The pH adjusting agent according to claim 3, wherein the pH range of the pH adjusting agent is 5.5 to 7.

5.

5. The method for preparing acetylcysteine ​​injection according to claim 1, characterized in that Vacuuming and nitrogen filling operations are performed during the liquid preparation process.

6. The method for preparing acetylcysteine ​​injection according to claim 1, characterized in that Perform terminal sterilization.

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