Isoniazide injection and preparation method thereof

Abstract

The invention relates to an isoniazide injection and a preparation method thereof, every 1000 ml of the isoniazide injection contains 50 g of isoniazide, anhydrous disodium hydrogen phosphate and methionine, every 1000 ml of the isoniazide injection contains 3.5-4.0 g of anhydrous disodium hydrogen phosphate and 10.2-12.6 g of methionine, so that the isoniazide injection has good stability, the preparation method is simple, and the isoniazide injection is suitable for industrial production. And complicated processes such as nitrogen charging and oxygen content control are not needed.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an isoniazid injection and its preparation method. Background Technology

[0002] Isoniazid, chemically known as 4-pyridinecarboxylhydrazine, is an anti-tuberculosis drug. Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis, with pulmonary tuberculosis being the most common form and ranking first among various infectious diseases.

[0003] Isoniazid remains a first-line drug for the treatment of tuberculosis. As an alternative to oral therapy, isoniazid injection still has important clinical significance for patients who cannot take oral medication.

[0004] Isoniazid can degrade into genotoxic impurities, such as free hydrazine, under oxidative and hydrolytic conditions. Currently, the preparation process of isoniazid injection often requires the addition of metal chelating agents and antioxidants, as well as strict control of residual oxygen levels through nitrogen purging. The process is rigorous, complicated, and demanding. Furthermore, the stability of isoniazid injection prepared by existing methods is poor. These shortcomings limit the safe use of isoniazid injection.

[0005] Through extensive and long-term research on isoniazid injection, the inventors have obtained an isoniazid injection and its preparation method. The preparation method is simple, does not require nitrogen flushing, and controls oxygen content. The isoniazid injection prepared by this method has extremely high quality stability, increases the safety of medication, and is significantly superior to existing technologies. Summary of the Invention

[0006] The purpose of this invention is to provide an isoniazid injection and its preparation method. The injection has good stability, the preparation method is simple, and it does not require complex processes such as nitrogen flushing and oxygen content control.

[0007] The technical solution provided by this invention is: an isoniazid injection, each 1000ml of which contains 50g of isoniazid, as well as anhydrous disodium hydrogen phosphate and methionine.

[0008] Preferably, each 1000ml of injection solution contains 3.5g to 4.0g of anhydrous disodium hydrogen phosphate and 10.2g to 12.6g of methionine.

[0009] Preferably, each 1000ml of injection solution contains 3.8g of anhydrous disodium hydrogen phosphate and 11.3g of methionine.

[0010] Preferably, the isoniazid injection solution is in the specification of 2ml:100mg.

[0011] Its preparation method includes the following steps: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 45-50°C; (2) Lower the water temperature and keep it at 30-35℃. Add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve. Add water for injection to 850ml. Adjust the pH to 6.0-6.5 with hydrochloric acid solution or sodium hydroxide solution. (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0012] Preferably, step (2) adjusts the pH to 6.1.

[0013] This invention uses anhydrous disodium hydrogen phosphate and methionine as excipients for isoniazid injection. The combined use of these two excipients helps increase the stability of isoniazid injection, simplifies the preparation process, and achieves unexpected results. Adding 3.5g–4.0g of anhydrous disodium hydrogen phosphate and 10.2g–12.6g of methionine per 1000ml yields good results, especially with 3.8g of anhydrous disodium hydrogen phosphate and 11.3g of methionine per 1000ml of injection. Unexpectedly, adjusting the pH of the isoniazid injection to 6.1 based on this ratio significantly reduces the amount of insoluble particles in the injection, improving its safety. Detailed Implementation

[0014] Example 1: Preparation of isoniazid injection (2ml: 100mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.5g Methionine: 10.2g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 45°C; (2) Lower the water temperature to 30°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.0 with hydrochloric acid solution or sodium hydroxide solution. (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0015] Example 2: Preparation of isoniazid injection (2ml: 100mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 4.0g Methionine: 12.6g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 50°C; (2) Lower the water temperature and keep it at 35°C. Add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve. Add water for injection to 850ml. Adjust the pH to 6.5 with hydrochloric acid solution or sodium hydroxide solution. (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0016] Example 3: Preparation of isoniazid injection (2ml: 100mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.8g Methionine: 11.3g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.3 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0017] Example 4: Preparation of isoniazid injection (2ml: 100mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.8g Methionine: 11.3g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0018] Example 5: Preparation of isoniazid injection (2ml: 100mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.8g Methionine: 11.3g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.5 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0019] Comparative Example 1: Preparation of isoniazid injection (2 ml: 100 mg) prescription: Isoniazid: 50g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of isoniazid in 700 ml of water for injection at 33°C; (2) Lower the water temperature to maintain the temperature at 33°C, add water for injection to 850 ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0020] Comparative Example 2: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Methionine: 11.3g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of methionine and isoniazid in 700 ml of water for injection at 33°C; (2) Keep the water temperature at 33℃, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0021] Comparative Example 3: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.8g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0022] Comparative Example 4: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.0g Methionine: 11.3g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0023] Comparative Example 5: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.8g Methionine: 9.5g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0024] Comparative Example 6: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.0g Methionine: 9.5g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0025] Comparative Example 7: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 4.5g Methionine: 13.0g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0026] Comparative Example 8: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 3.8g Methionine: 13.0g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0027] Comparative Example 9: Preparation of Isoniazid Injection (2 ml: 100 mg) prescription: Isoniazid: 50g Anhydrous disodium hydrogen phosphate: 4.5g Methionine: 11.3g Add water for injection to 1000ml Make 500 pieces Preparation method: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 48°C; (2) Lower the water temperature to maintain the temperature at 33°C, add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve, add water for injection to 850ml, and adjust the pH to 6.1 with hydrochloric acid solution or sodium hydroxide solution; (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

[0028] This invention provides the following experimental and comparative results: Example 1: The isoniazid injection solutions prepared in the examples and comparative examples were simulated for market packaging and subjected to accelerated stability testing. The test conditions were: placed at (40±2)℃ and RH (75±5)% for 6 months, and samples were taken at the end of the 0th, 3rd and 6th months for evaluation. The results are shown in Table 1-14.

[0029] Table 1. Accelerated test stability results of Example 1

[0030] Table 2. Accelerated test stability results of Example 2

[0031] Table 3. Accelerated test stability results of Example 3

[0032] Table 4. Accelerated test stability results of Example 4

[0033] Table 5. Accelerated test stability results of Example 5

[0034] Table 6. Accelerated test stability results of Comparative Example 1

[0035] Table 7. Accelerated test stability results for Comparative Example 2

[0036] Table 8. Accelerated test stability results for Comparative Example 3

[0037] Table 9. Accelerated test stability results for Comparative Example 4

[0038] Table 10. Accelerated test stability results for Comparative Example 5

[0039] Table 11 Accelerated test stability results of Comparative Example 6

[0040] Table 12 Accelerated test stability results for Comparative Example 7

[0042] Table 13 Accelerated test stability results for Comparative Example 8

[0043] Table 14 Accelerated test stability results for Comparative Example 9

[0044] As can be seen from the results in Tables 1-14, the isoniazid injection prepared by the formulation and process of this invention maintains extremely high stability. Anhydrous disodium hydrogen phosphate and methionine, as excipients for isoniazid injection, can ensure the stability of isoniazid injection during the preparation process without nitrogen flushing or controlling oxygen content. However, changing the proportion of anhydrous disodium hydrogen phosphate and methionine in the formulation of this invention will produce significant changes.

[0045] Example 2: The samples from the example were subjected to insoluble particle detection on day 0 (referring to the method for detecting insoluble particles in Part IV of the 2020 edition of the Chinese Pharmacopoeia) and influencing factor tests. They were placed at 60℃ for 10 days, and samples were taken on the 10th day for testing. The results were compared with those from day 0 to examine the stability of the samples. The results are shown in Table 15. Table 15 Test Results of Factors Affecting Insoluble Particulate Matter

[0046] As can be seen from the results in Table 15, adjusting the pH of isoniazid injection to 6.1 by adding 3.8g of anhydrous disodium hydrogen phosphate and 11.3g of methionine per 1000ml of isoniazid injection can significantly reduce the insoluble particles in the injection.

[0047] The above description is merely a preferred embodiment of the present invention, and should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. An isoniazid injection solution, characterized in that, Each 1000ml of injection solution contains 50g of isoniazid, as well as anhydrous disodium hydrogen phosphate and methionine.

2. The isoniazid injection solution as described in claim 1, characterized in that, Each 1000ml of injection solution contains 3.5g to 4.0g of anhydrous disodium hydrogen phosphate and 10.2g to 12.6g of methionine.

3. The isoniazid injection solution as described in claim 2, characterized in that, Each 1000ml of injection contains 3.8g of anhydrous disodium hydrogen phosphate and 11.3g of methionine.

4. The isoniazid injection solution as described in claim 1, 2, or 3, characterized in that, The isoniazid injection solution has the following specifications: 2ml:100mg.

5. A method for preparing isoniazid injection, characterized in that, Includes the following steps: (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 700 ml of water for injection at 45-50°C; (2) Lower the water temperature and keep it at 30-35℃. Add the prescribed amount of methionine and isoniazid in sequence and stir to dissolve. Add water for injection to 850ml. Adjust the pH to 6.0-6.5 with hydrochloric acid solution or sodium hydroxide solution. (3) Add water for injection to 1000ml, determine the pH and content of the solution, filter with a 0.22µm filter membrane, fill into ampoules according to specifications, and then sterilize at 121℃ for 25 minutes to obtain isoniazid injection.

6. The method for preparing isoniazid injection as described in claim 5, characterized in that, Step (2) Adjust the pH to 6.1.

Images