WO2020259464A1 - Metronidazole and sodium chloride injection and preparation method therefor - Google Patents

Abstract

A metronidazole and sodium chloride injection and a preparation method therefor. Each 100ml injection comprises the following components: 350-700mg of metronidazole, 600-1100mg of sodium chloride, 35.0mg-69.0mg of anhydrous sodium hydrogen phosphate and 12.0mg-30.0mg of citri acid anhydrous, wherein the pH value is 5.4-6.3. The preparation method comprises: adding water for injection accounting for 25％-40％ of the total preparation volume into a concentrated solution tank, adding metronidazole, sodium chloride, anhydrous sodium hydrogen phosphate and citri acid anhydrous of the prescription dosages, stirring and dissolving, and filtering to a diluted solution tank; and supplementing water for injection to the volume, stirring and mixing uniformly, detecting contents and pH value, noting visible foreign particles, filtering after qualified, filling and sealing, and sterilizing for 12-15mins at 121℃. The prepared metronidazole and sodium chloride injection is stable in the contents of effective components and pH value and is low in related substance content. Product quality and stability are improved.

Description

Metronidazole and sodium chloride injection and preparation method thereof

This application claims the priority of the Chinese patent application CN201910579075.2 filed on June 28, 2019. The disclosure of the earlier application is incorporated into this application by reference in its entirety.

Technical field

This scheme relates to metronidazole sodium chloride injection and a preparation method thereof, and belongs to the field of medical injections.

Background technique

Metronidazole has a strong antibacterial effect on most anaerobic bacteria, but it has no effect on aerobes and facultative anaerobes. The antibacterial spectrum includes Bacteroides fragilis and other Bacteroides, Fusobacteria, and Clostridium aerobicans Bacillus, Eubacterium, Veillonella, Peptococcus and Peptostreptococcus, etc., Actinomyces, Lactobacillus, Propionibacterium are resistant to this product.

Metronidazole sodium chloride injection is mainly used for the treatment of anaerobic bacterial infections. In the existing preparation technology, the common operation is to add activated carbon in the concentration stage for preparation. The literature reports that activated carbon has a strong adsorption effect on metronidazole , The inspection of finished products often finds that the content of metronidazole is low. Therefore, the input amount of metronidazole is generally increased when the concentration is mixed. However, the content of the finished product is still high or low during the inspection, which affects the quality of the finished product. In addition, the conventional use of sodium hydroxide or hydrochloric acid to adjust the pH value in the dilute preparation stage is likely to cause a large change in the local pH of the dilute solution, resulting in an increase in related substances. Therefore, the quality of metronidazole sodium chloride injection prepared by the prior art And stability needs to be improved.

Summary of the invention

technical problem

In view of the poor quality and stability of the existing metronidazole sodium chloride injection, this solution provides a metronidazole sodium chloride injection and a preparation method thereof to improve the quality and stability of the injection.

The solution to the problem

Technical solutions

The first aspect of the application provides a metronidazole sodium chloride injection, which contains metronidazole, sodium chloride, anhydrous disodium hydrogen phosphate, and anhydrous citric acid. The content of each component is as follows:

Preferably, the metronidazole sodium chloride injection described in this scheme contains, based on the preparation of 100L, the content of each component is:

The above-mentioned metronidazole sodium chloride injection formulation is the dosage of 1000 bags of injection.

In the metronidazole sodium chloride injection described in this program, sodium chloride in the injection is used as an isotonic agent; anhydrous disodium hydrogen phosphate and anhydrous citric acid are used as pH buffers, making the injection suitable for Human injection and the pH value can be adjusted 5.4-6.3.

The second aspect of the application provides a method for preparing metronidazole sodium chloride injection, which includes the following steps:

①Concentration stage: Add 25%-40% of the total preparation volume of fresh water for injection into the concentration tank, and add the prescription amount of metronidazole, sodium chloride, anhydrous disodium hydrogen phosphate and anhydrous citric acid in sequence, and stir to dissolve After that, it is filtered to the rare distribution tank.

②Dilute formulation stage: add water for injection to make the volume constant, stir and mix evenly, check the content, pH value, and visible foreign matter, filter, fill, seal, and sterilize at 121°C for 12-15 minutes after passing the test.

In the preparation method of metronidazole sodium chloride injection in this scheme, the whole preparation process does not use medicinal activated carbon, and does not need to add acid and alkali to adjust the pH value.

Preferably, the pH of the metronidazole sodium chloride injection is 5.4-6.3.

As an embodiment of the present application, a polyethersulfone filter element with a pore size of 1.0 μm is used in the filtration step of the concentrated blending stage, and a two-stage polyethersulfone filter element with a pore size of 0.45 μm and 0.22 μm is used in the thin blending stage before filling.

The anhydrous disodium hydrogen phosphate and anhydrous citric acid added to the metronidazole sodium chloride injection in this program are used as pH buffers, which can keep the pH of the solution in a relatively stable state and effectively control impurities The product quality and stability have been improved due to the low content of related substances.

In this plan, there are no restrictions on supplier requirements for metronidazole, sodium chloride, anhydrous disodium hydrogen phosphate, and anhydrous citric acid, but because the production process does not use medicinal activated carbon, the production process further controls endotoxins and microorganisms And reduce its limit, strictly control the raw material production environment to ensure that the entire production environment meets GMP requirements; the production environment and production process of pharmaceutical packaging materials for production are strictly controlled and required to ensure that the entire production process meets GMP requirements and pharmaceutical product quality requirements , Strictly control bacterial endotoxin and microbial limits, and have real-time online monitoring facilities to ensure stable and uniform product quality throughout the production process.

The beneficial effects of the invention

Beneficial effect

Compared with the prior art, this solution has the following advantages:

(1) Activated carbon is not used in the entire preparation process of the formulation of this scheme, which avoids the adsorption of metronidazole by activated carbon, improves product quality, is simple to operate, reduces production costs, and also reduces pollution to clean production areas.

(2) The whole operation method is simple and easy to implement, and the efficiency is improved. Compared with the conventional preparation method that uses sodium hydroxide or hydrochloric acid to adjust the pH value in the dilution stage, the pH value of the product prepared by this scheme is easy to control and stable, and the content of related substances is low , Good stability, ensuring the effectiveness and safety of medication.

Implementation of this application

Example 1 (S1): The preparation amount is 100L

(1) Add 35L of freshly prepared water for injection into the concentrated tank, add 0.50kg of metronidazole, 0.80kg of sodium chloride, 45g of anhydrous disodium hydrogen phosphate and 20g of anhydrous citric acid in sequence, stir for 20 minutes and dissolve through the pore size The 1.0μm polyethersulfone filter element is filtered to the thinning tank.

(2) Add water for injection to a constant volume, stir for 15 minutes and mix evenly. After measuring the pH value, content, visible foreign matter and insoluble particles, it is filtered through a two-stage polyethersulfone filter with a pore size of 0.45μm and 0.22μm, filling and sealing. Sterilize at 121℃ for 15 minutes to make 1000 bags.

The quality of the metronidazole sodium chloride injections prepared in the above examples before and after sterilization were tested according to the pharmacopoeia standards. The results are shown in Table 1.

Table 1 Quality Test Results of Metronidazole Sodium Chloride Injection

It can be seen from the above table that the semi-finished product before sterilization and the finished product after sterilization of the metronidazole sodium chloride injection prepared in the above embodiment meet the quality standards.

Example 2 (S2): The preparation amount is 100L

(1) Add 40L of freshly prepared water for injection into the concentrated tank, add 0.60kg of metronidazole, 0.90kg of sodium chloride, 43g of anhydrous disodium hydrogen phosphate and 17g of anhydrous citric acid in sequence, stir for 15 minutes to dissolve, then pass through the aperture The 1.0μm polyethersulfone filter element is filtered to the thinning tank.

(2) Add water for injection to a constant volume, stir for 15 minutes and mix evenly, measure the pH value, content, properties, osmotic pressure, visible foreign matter, and filter through two-stage polyethersulfone filter with pore size of 0.45μm and 0.22μm. Pack, seal, and sterilize at 121℃ for 15 minutes to make 1000 bags.

The quality of the metronidazole sodium chloride injections prepared in the above examples before and after sterilization were tested according to the pharmacopoeia standards. The results are shown in Table 2.

Table 2 Quality test results of metronidazole and sodium chloride injection

It can be seen from the above table that the semi-finished product before sterilization and the finished product after sterilization of the metronidazole sodium chloride injection prepared in the above embodiment meet the quality standards.

Example 3 (S3): The preparation amount is 100L

(1) Add 25L of freshly prepared water for injection into the concentrated mixing tank, add 51g of anhydrous disodium hydrogen phosphate and 18g of anhydrous citric acid successively, stir for 10 minutes to dissolve, and then add 0.48kg of metronidazole and 0.85kg of sodium chloride. After stirring for 25 minutes to dissolve, it is filtered through a polyethersulfone filter element with a pore size of 1.0 μm to a thinning tank.

(2) Add water for injection to a constant volume, stir for 15 minutes and mix evenly, measure the pH value, content, properties, osmotic pressure, visible foreign matter, and filter through two-stage polyethersulfone filter with pore size of 0.45μm and 0.22μm. Pack, seal, and sterilize at 121℃ for 15 minutes to make 1000 bags.

The pre-sterilization and post-sterilization metronidazole sodium chloride injections prepared in the above examples were respectively tested for quality according to the pharmacopoeia standards. The results are shown in Table 3.

Table 3 Quality Test Results of Metronidazole Sodium Chloride Injection

It can be seen from the above table that the semi-finished product before sterilization and the finished product after sterilization of the metronidazole sodium chloride injection prepared in the above embodiment meet the quality standards.

Example 4 (S4): The preparation amount is 100L

(1) Add 29L of freshly prepared water for injection into the concentrated tank, add 0.40kg of metronidazole, 0.70kg of sodium chloride, 51g of anhydrous disodium hydrogen phosphate and 25g of anhydrous citric acid, stir for 15 minutes and dissolve through the pore size The 1.0μm polyethersulfone filter element is filtered to the thinning tank.

(2) Add water for injection to a constant volume, stir for 15 minutes and mix evenly, measure the pH value, content, properties, osmotic pressure, visible foreign matter, and filter through two-stage polyethersulfone filter with pore size of 0.45μm and 0.22μm. Pack, seal, and sterilize at 121℃ for 15 minutes to make 1000 bags.

The metronidazole sodium chloride injections before and after sterilization prepared in the above examples were respectively tested for quality according to the pharmacopoeia standards. The results are shown in Table 4.

Table 4 Quality test results of metronidazole sodium chloride injection

It can be seen from the above table that the semi-finished product before sterilization and the finished product after sterilization of the metronidazole sodium chloride injection prepared in the above embodiment meet the quality standards.

Example 5 (S5): The preparation amount is 100L

(1) Add 25L of fresh water for injection into the concentrated tank, add 0.35kg of metronidazole, 0.85kg of sodium chloride, 69g of anhydrous disodium hydrogen phosphate and 12g of anhydrous citric acid, and stir for 15 minutes. The 1.0μm polyethersulfone filter element is filtered to the thinning tank.

(2) Add water for injection to a constant volume, stir for 15 minutes and mix evenly, measure the pH value, content, properties, osmotic pressure, visible foreign matter, and filter through two-stage polyethersulfone filter with pore size of 0.45μm and 0.22μm. Pack, seal, and sterilize at 121℃ for 15 minutes to make 1000 bags.

The quality of the metronidazole sodium chloride injections prepared in the above examples before and after sterilization were tested according to the pharmacopoeia standards, and the results are shown in Table 5.

Table 5 Quality Test Results of Metronidazole Sodium Chloride Injection

It can be seen from the above table that the semi-finished product before sterilization and the finished product after sterilization of the metronidazole sodium chloride injection prepared in the above embodiment meet the quality standards.

Example 6 (S6): The preparation amount is 100L

(1) Add 40L of freshly prepared water for injection into the concentrated tank, add 0.70kg of metronidazole, 1.10kg of sodium chloride, 35g of anhydrous disodium hydrogen phosphate and 30g of anhydrous citric acid. The 1.0μm polyethersulfone filter element is filtered to the thinning tank.

(2) Add water for injection to a constant volume, stir for 15 minutes and mix evenly, measure the pH value, content, properties, osmotic pressure, visible foreign matter, and filter through two-stage polyethersulfone filter with pore size of 0.45μm and 0.22μm. Pack, seal, and sterilize at 121℃ for 15 minutes to make 1000 bags.

The pre-sterilization and post-sterilization metronidazole sodium chloride injections prepared in the above examples were respectively tested for quality according to the pharmacopoeia standards, and the results are shown in Table 6.

Table 6 Quality test results of metronidazole sodium chloride injection

Example 7 (S7): The preparation amount is 100L

(1) Add 30L of fresh water for injection into the concentrated tank, add metronidazole 0.68kg, sodium chloride 0.60kg, anhydrous disodium hydrogen phosphate 60g and anhydrous citric acid 15g and stir for 30 minutes. The 1.0μm polyethersulfone filter element is filtered to the thinning tank.

(2) Add water for injection to a constant volume, stir for 15 minutes and mix evenly, measure the pH value, content, properties, osmotic pressure, visible foreign matter, and filter through two-stage polyethersulfone filter with pore size of 0.45μm and 0.22μm. Pack, seal, and sterilize at 121℃ for 15 minutes to make 1000 bags.

The pre-sterilization and post-sterilization metronidazole sodium chloride injections prepared in the above examples were respectively tested for quality according to the pharmacopoeia standards. The results are shown in Table 7.

Table 7 Quality Test Results of Metronidazole Sodium Chloride Injection

It can be seen from the above table that the semi-finished product before sterilization and the finished product after sterilization of the metronidazole sodium chloride injection prepared in the above embodiment meet the quality standards.

Comparative example 1 (D1): the preparation volume is 100L

(1) Add 30L of fresh water for injection into the concentrated tank, add 0.50kg of metronidazole and 0.75kg of sodium chloride and stir for 15 minutes to dissolve, then put in 15g of activated carbon, stir for 20 minutes, and then pass through a 5.0μm titanium rod filter and The 1.0μm polyethersulfone filter element is filtered to the thinning tank.

(2) Add water for injection to a constant volume (adjust the pH value with 1M sodium hydroxide solution if necessary), stir for 15 minutes and mix well, measure the pH value, content, properties, osmotic pressure, visible foreign matter, and the pore size is 0.45 The μm and 0.22μm two-stage polyethersulfone filter cartridges are filtered, filled, sealed, and sterilized at 121°C for 15 minutes to make 1000 bags.

The metronidazole sodium chloride injections before and after sterilization prepared in the above examples were respectively tested for quality according to the pharmacopoeia standards, and the results are shown in Table 8.

Table 8 Quality test results of metronidazole and sodium chloride injection

It can be seen from the above table that the sodium chloride and metronidazole in the metronidazole sodium chloride injection prepared in Comparative Example 1 also meet the quality standards.

Stability test (accelerated test)

Place the metronidazole sodium chloride injection prepared in Examples 1-7 and Comparative Example 1 at 40°C±2°C and relative humidity (25±5%)% for 6 months. At the end of 6 months, samples were taken to test the stability of metronidazole in the injection to detect properties, content, and pH. The test results are shown in Table 9-11.

Table 9 Test results of accelerated test traits

[Table 1]

Table 10 Test results of accelerated test content

Table 11 pH test results of accelerated test

[Table 2]

It can be seen from the results in Table 9-11 that the properties, content, and pH test results of Metronidazole Sodium Chloride Injection prepared by the method of this scheme are in compliance with the requirements of the Pharmacopoeia of the People’s Republic of China (2015 Edition), and compared with the comparative example Compared with the prepared metronidazole sodium chloride injection, the metronidazole sodium chloride injection of this scheme has better stability, fewer insoluble particles, and higher product quality.

Claims (9)

1. A metronidazole sodium chloride injection, containing metronidazole, sodium chloride, anhydrous disodium hydrogen phosphate, and anhydrous citric acid, characterized in that, based on 100L, the content of each component is:

   
2. The metronidazole sodium chloride injection according to claim 1, characterized in that, based on 100L, the content of each component is:

   
3. The metronidazole sodium chloride injection according to claim 1 or 2, wherein sodium chloride is used as an isotonic agent; anhydrous disodium hydrogen phosphate and anhydrous citric acid are used as pH buffers .
4. The method for preparing metronidazole sodium chloride injection according to claim 1 or 2, wherein the steps are as follows:

   ①Concentration stage: Add 25%-40% of the total preparation volume of fresh water for injection into the concentration tank, add the prescription amount of metronidazole, sodium chloride, anhydrous disodium hydrogen phosphate and anhydrous citric acid, stir and dissolve , Filter to the rare distribution tank.

   ②Dilute formulation stage: add water for injection to make the volume constant, stir and mix evenly, check the content, pH value, and visible foreign matter, filter, fill, seal, and sterilize at 121°C for 12-15 minutes after passing the test.
5. The preparation method according to claim 4, characterized in that the anhydrous disodium hydrogen phosphate and anhydrous citric acid in step ① are used as pH buffers.
6. The preparation method of claim 5, wherein the pH of the metronidazole sodium chloride injection is 5.4-6.3.
7. The preparation method according to claim 4, characterized in that the whole preparation process does not use medicinal activated carbon.
8. The preparation method according to claim 4, characterized in that a polyethersulfone filter element with a pore size of 1.0 μm is used for the filtration in the concentration stage.
9. The preparation method according to claim 4, characterized in that the filtration before filling in the dilute mixing stage adopts a two-stage polyethersulfone filter element with a pore size of 0.45 μm and 0.22 μm in sequence.