Famotidine injection and preparation method thereof

Abstract

The invention discloses a famotidine injection and a preparation method thereof, the famotidine injection comprises the following components: famotidine, N-methyl-D-glucosamine, histidine, L-methionine, mannitol and water for injection, the preparation process comprises the following steps: under the protection of nitrogen, firstly adding the N-methyl-D-glucosamine into the water for injection, stirring and dissolving until the solution is clarified, then adding the histidine, the L-methionine, mannitol and the water for injection; and finally, sequentially adding the histidine, the L-methionine and the mannitol, stirring and dissolving, supplementing the water for injection to the total amount, filtering, filling, carrying out nitrogen-filled heat sealing, and sterilizing, so as to obtain the famotidine injection. The famotidine injection prepared by the invention has the characteristics of good stability, simple preparation process, high sterility guarantee and the like.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a famotidine injection and a preparation method thereof. Background Art

[0002] Famotidine is a third-generation H2 receptor antagonist, following cimetidine and ranitidine. Its inhibitory effect on histamine-induced gastric acid secretion lasts longer than cimetidine, with a maximum efficacy approximately 40 times stronger. It is clinically used for gastric and duodenal ulcers, with an efficacy rate exceeding 90%. Its significant anti-ulcer effect and minimal side effects make it an ideal anti-ulcer drug.

[0003] In China, famotidine is listed in both the Essential Medicines Catalog and the National Medical Insurance Category A Catalog. Numerous approved famotidine dosage forms exist, including sustained-release tablets, dispersible tablets, chewable tablets, capsules, granules, injections, and powders. Injections are the most popular form, accounting for over 98% of the market. However, due to famotidine's poor stability in acidic conditions, poor solubility in alkaline conditions, and susceptibility to degradation at high temperatures, most existing famotidine injections in China are freeze-dried preparations or cold-stored aqueous solutions, making clinical use cumbersome and posing high storage and transportation costs.

[0004] Japan LTL Pharmaceutical Co., Ltd. has released a famotidine injection that can be stored at room temperature. However, the production process of this injection is a sterile production process, and the sterility guarantee is relatively poor. The prescription published a method for preparing famotidine injection with a pH value in the range of 5.8 to 6.2. Lactic acid is used as a pH regulator and volume expander in the prescription. The preparation process requires heat treatment of the lactic acid solution to remove polymers contained in the lactic acid. The production process is complicated. At the same time, since the pH value of the product is still acidic, the product cannot withstand high-temperature sterilization, and the sterility properties cannot be effectively guaranteed. There are certain risks in the clinical use process. Summary of the Invention

[0005] The purpose of the present invention is to develop a famotidine injection with good stability, simple preparation process and high sterility guarantee.

[0006] To solve the above problems, the inventors found through a large number of research and experiment attempts that the use of N-methyl-D-glucamine can effectively improve the solubility of famotidine under slightly neutral conditions, and the use of N-methyl-D-glucamine as a solubilizer can still ensure good solubility when the pH value of the product is in the range of 6.4-6.8. With the increase of the pH value of the product, the thermal stability of the product is greatly improved. Meanwhile, it is found in the sterilization process research and experiment that the related substances (impurities A, C and D) of famotidine are more affected by the sterilization time. Under the premise of ensuring the sterilization effect (F0 value≥12 min), the sterilization time can be reduced by increasing the sterilization temperature to reduce the degradation of famotidine. In addition, through the screening of a large number of antioxidants, it is found that the use of L-methionine as an antioxidant can effectively alleviate the oxidative degradation of famotidine, and at the same time, it will not appear the situation that the product property changes due to the oxidation and yellowing of antioxidants such as vitamin C.

[0007] The specific technical solutions are as follows:

[0008] 1. A famotidine injection solution, which is composed of famotidine, N-methyl-D-glucamine, histidine, L-methionine, mannitol and water for injection.

[0009] 2. The famotidine injection solution, wherein the concentrations of the components are as follows:

[0010] 3. The famotidine injection solution, wherein the concentrations of the components are preferably as follows:

[0011] 4. A preparation method of a famotidine injection solution, comprising the following steps:

[0012] (1) Solution preparation: under the protection of nitrogen, N-methyl-D-glucamine is dissolved in 80% water for injection, stirred until clear, then famotidine is added and stirred to dissolve, and then histidine, L-methionine and mannitol are added and stirred to dissolve, the pH value is adjusted to 6.4-6.8, and water for injection is added to constant volume;

[0013] (2) Filtration and filling: the constant volume solution is filtered through a 0.22 μm filter membrane, filled into ampoule bottles, and nitrogen sealed;

[0014] (3) Sterilization: the sealed product is subjected to 131℃ moist heat sterilization for 2-3 min to obtain the product.

[0015] 5. The preparation method, wherein the solution preparation temperature in step (1) should be controlled in the range of 10-45℃.

[0016] 6. In the preparation method, the pH value after dissolving in step (1) is preferably adjusted to a range of 6.5 to 6.6.

[0017] 7. In the preparation method, in step (2) of nitrogen sealing, the residual oxygen content in the headspace should be controlled to be ≤3%.

[0018] 8. In the preparation method, the sterilization time in step (3) is preferably 2 minutes.

[0019] Beneficial effects

[0020] The famotidine injection of the present invention improves the quality and stability of the preparation product, reduces the storage and transportation costs of the product, and can withstand high-temperature sterilization, with high sterility assurance, greatly reducing the risk of clinical medication. In addition, the preparation method of the present invention is simple and suitable for large-scale industrial production. DETAILED DESCRIPTION

[0021] The present invention will be further described below with reference to specific examples so that those skilled in the art can better understand the present invention and implement it, but the examples are not intended to limit the present invention.

[0022] Example 1 Famotidine injection and preparation method thereof

[0023] 1. Prescription

[0024] 2. Preparation process:

[0025] (1) Solution preparation: Under nitrogen protection, dissolve N-methyl-D-glucamine in 80% water for injection, stir until clear, and control the temperature of the solution to 10-45°C. Add famotidine and stir to dissolve. Then, add histidine, L-methionine, and mannitol in sequence and stir to dissolve. Adjust the pH to 6.6 and dilute to the full volume with water for injection.

[0026] (2) Filtration and filling: Filter the fixed volume solution through a 0.22 μm filter membrane, fill into ampoules, fill with nitrogen and seal, and control the residual oxygen in the headspace to ≤3%;

[0027] (3) Sterilization: Sterilize the sealed product by moist heat sterilization at 131°C for 2 minutes.

[0028] Example 2 Famotidine injection and preparation method thereof

[0029] 1. Prescription

[0030] 2. Preparation process: same as Example 1

[0031] Example 3 Famotidine injection and its preparation method

[0032] 1. Prescription

[0033] 2. Preparation process: same as Example 1

[0034] Example 4 Famotidine injection and its preparation method

[0035] 1. Prescription

[0036] 2. Preparation process:

[0037] (1) Solution preparation: Under nitrogen protection, dissolve N-methyl-D-glucamine in 80% water for injection, stir until clear, and control the temperature of the solution to 10-45°C. Add famotidine and stir to dissolve. Then, add histidine, L-methionine, and mannitol in sequence and stir to dissolve. Adjust the pH to 6.4 and dilute to the full volume with water for injection.

[0038] (2) Filtration and filling: Filter the fixed volume solution through a 0.22 μm filter membrane, fill into ampoules, fill with nitrogen and seal, and control the residual oxygen in the headspace to ≤3%;

[0039] (3) Sterilization: Sterilize the sealed product by moist heat sterilization at 131°C for 2 minutes.

[0040] Example 5 Famotidine injection and its preparation method

[0041] 1. Prescription

[0042] 2. Preparation process:

[0043] (1) Solution preparation: Under nitrogen protection, dissolve N-methyl-D-glucamine in 80% water for injection, stir until clear, and control the temperature of the solution to 10-45°C. Add famotidine and stir to dissolve. Then, add histidine, L-methionine, and mannitol in sequence and stir to dissolve. Adjust the pH to 6.8 and dilute to the full volume with water for injection.

[0044] (2) Filtration and filling: Filter the fixed volume solution through a 0.22 μm filter membrane, fill into ampoules, fill with nitrogen and seal, and control the residual oxygen in the headspace to ≤3%;

[0045] (3) Sterilization: Sterilize the sealed product by moist heat sterilization at 131°C for 2 minutes.

[0046] Comparative Example 1 Famotidine injection and preparation method thereof

[0047] 1. Prescription

[0048] 2. Preparation process: same as Example 1

[0049] Comparative Example 2 Famotidine injection and preparation method thereof

[0050] 1. Prescription

[0051] 2. Preparation process:

[0052] (1) Solution preparation: Under nitrogen protection, dissolve N-methyl-D-glucamine in 80% water for injection, stir until clear, and control the temperature of the solution to 10-45°C. Add famotidine and stir to dissolve. Then, add histidine, L-methionine, and mannitol in sequence and stir to dissolve. Adjust the pH to 6.0 and dilute to the full volume with water for injection.

[0053] (2) Filtration and filling: Filter the fixed volume solution through a 0.22 μm filter membrane, fill into ampoules, fill with nitrogen and seal, and control the residual oxygen in the headspace to ≤3%;

[0054] (3) Sterilization: Sterilize the sealed product by moist heat sterilization at 131°C for 2 minutes.

[0055] Comparative Example 3 Famotidine injection and preparation method thereof

[0056] 1. Prescription

[0057] 2. Preparation process:

[0058] (1) Solution preparation: Under nitrogen protection, dissolve N-methyl-D-glucamine in 80% water for injection, stir until clear, and control the temperature of the solution to 10-45°C. Add famotidine and stir to dissolve. Then, add histidine, L-methionine, and mannitol in sequence and stir to dissolve. Adjust the pH to 6.6 and dilute to the full volume with water for injection.

[0059] (2) Filtration and filling: Filter the fixed volume solution through a 0.22 μm filter membrane, fill into ampoules, fill with nitrogen and seal, and control the residual oxygen in the headspace to ≤3%;

[0060] (3) Sterilization: Sterilize the sealed product by moist heat sterilization at 121°C for 12 minutes.

[0061] Test Example 1

[0062] Take the famotidine injection prepared in Examples 1 to 5 and Comparative Examples 1 to 3 and the famotidine injection produced by Japan LTL Phama Co., Ltd. After sterilization at 131℃ for 2min The samples were subjected to accelerated (40°C) stability study. According to the JP18 famotidine injection quality standard, the product solution color, pH value, related substances and content were tested. The results are shown in Table 1.

[0063] Table 1 Test results of famotidine injection under accelerated conditions (40°C)

[0064] in conclusion:

[0065] (1) In the formulation of Comparative Example 1, N-methyl-D-glucosamine was not used as a bulking agent, and the product showed precipitation, which did not meet the requirements for injections;

[0066] (2) The pH value of the product in Comparative Example 2 was not within the range of 6.4 to 6.8, the related substances in the product were high and the content was low. During the accelerated test, the growth rate of the related substances was fast and the content showed a clear downward trend. In the sixth month of the accelerated test, the related substances in the product exceeded the limit standard of 5.0%;

[0067] (3) The product in Comparative Example 3 was sterilized at 121°C for 12 minutes. The content of related substances in the product was high, and there was a possibility that the related substances exceeded the limit during storage.

[0068] (4) Take the famotidine injection that is already on the market from Japan LTL Pharmaceutical Co., Ltd. Comparing the quality of the famotidine injection of the present invention with that of Examples 1 to 5, it can be found that the initial solution color, related substances and content of the famotidine injection of the present invention are the same as those of the The products of the present invention adopt terminal sterilization technology (F0>12), and the sterility level of the products is significantly better than those produced by aseptic production technology. And experiments have confirmed Unable to withstand high temperature sterilization process;

[0069] (5) By comparison Compared with the changes in solution color under the accelerated experimental conditions of Examples 1 to 5, it can be seen that the use of L-methionine as an antioxidant in the formulation can effectively reduce the changes in product properties caused by oxidation of the product or the antioxidant.

[0070] In summary, the present invention effectively addresses the low solubility of famotidine at higher pH values ​​by using N-methyl-D-glucamine as a bulking agent in the formulation, thereby enabling the product to have a higher pH value and better stability. Furthermore, by optimizing the sterilization process, product degradation caused by the sterilization process is minimized while ensuring good sterility. Furthermore, the use of L-methionine can effectively improve the problem of changes in product properties.

[0071] Test Example 2

[0072] The product of Example 1 and The long-term (30°C) stability was investigated, and the test results of the product of Example 1 after 24 months met the standard requirements, and the quality was obviously superior to The results are shown in Table 2.

[0073] Table 2 Test results of famotidine injection under long-term conditions (30°C)

[0074] Conclusion: According to the prescription and preparation method of the present application, the key quality attributes of the obtained product can meet the requirements, the stability is obviously superior to the marketed product, and the product is safer for clinical use.

[0075] The above is a further detailed description of the present application in combination with specific embodiments, and the specific implementation of the present application cannot be limited to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, a number of simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A famotidine injection, characterized in that, It is composed of famotidine, N-methyl-D-glucamine, histidine, L-methionine, mannitol and water for injection.

2. Famotidine injection according to claim 1, is characterized in that The concentration of each component is:

3. Famotidine injection according to claim 2, is characterized in that The concentration of each component is preferably:

4. A preparation method of famotidine injection, characterized in that The steps include: (1) Solution preparation: Under nitrogen protection, dissolve N-methyl-D-glucamine in 80% water for injection, stir until clear, add famotidine and stir to dissolve, then add histidine, L-methionine, and mannitol in sequence and stir to dissolve, adjust the pH to 6.4-6.8, and dilute to the full volume with water for injection; (2) Filtration and filling: The fixed volume solution is filtered through a 0.22 μm filter membrane, filled into ampoules, and sealed with nitrogen; (3) Sterilization: Sterilize the sealed product by moist heat sterilization at 131°C for 2 to 3 minutes.

5. The preparation method according to claim 4, wherein the solution preparation temperature in step (1) should be controlled within the range of 10-45°C.

6. The preparation method according to claim 4, wherein the pH value after dissolving in step (1) is preferably adjusted to a range of 6.5 to 6.

6.

7. The preparation method according to claim 4, wherein the nitrogen filling and sealing in step (2) should control the residual oxygen content in the headspace to be ≤3%.

8. The preparation method according to claim 4, wherein the sterilization time in step (3) is preferably 2 minutes.

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