A pharmaceutical composition for H2 receptor antagonists and its preparation method

Abstract

The application discloses a H2 receptor antagonist pharmaceutical composition which comprises an active ingredient famotidine, vitamin C, nicotinamide, phosphoric acid, tromethamine, sodium hydroxide and water for injection. The composition is prepared by mixing famotidine, vitamin C and nicotinamide, adjusting the pH to 6.0-6.2 by using tromethamine, further adjusting the pH to 6.5-8.0 by using sodium hydroxide, and finally adjusting the volume. The application solves the problems of poor stability of famotidine in the composition and easy precipitation at low temperature. The H2 receptor antagonist pharmaceutical composition disclosed by the application has the advantages of good stability, high safety, simple process, controllable quality and the like.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical formulations, specifically relating to an H2 receptor antagonist pharmaceutical composition and its preparation method. Background Technology

[0002] The H2 receptor antagonist of this invention is famotidine, with the molecular formula: C8H 15 N7O2S3, molecular weight: 337.45, chemical name: 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]-N-aminosulfonylpropanediamine. Famotidine is a potent histamine H2 receptor antagonist widely used for the treatment and prevention of peptic ulcers. As a third-generation H2 receptor antagonist, its ability to inhibit gastric acid secretion is 7 to 40 times higher than other tidine H2 receptor antagonists, and its efficacy in treating peptic ulcers and upper gastrointestinal bleeding is superior to ranitidine and cimetidine.

[0003] Numerous literature reports that famotidine is a chemically unstable compound, highly unstable under acidic, oxidative, and high-temperature conditions, and easily degraded, making it unsuitable for high-temperature sterilization in the preparation of injectable solutions. Furthermore, famotidine exhibits a distinct characteristic: it is readily soluble in acidic aqueous solutions but unstable in them, while remaining relatively stable in alkaline aqueous solutions but with poor solubility.

[0004] Therefore, the original manufacturer of famotidine injection (LTL Farm Corporation, Japan) added vitamin C as an antioxidant, lactic acid to provide an acidic environment to facilitate famotidine dissolution, and a large amount of nicotinamide as a solubilizer. However, famotidine is extremely unstable under acidic conditions, while it is relatively stable in alkaline aqueous solutions but its solubility is poor. Therefore, sodium hydroxide was added to the formulation to adjust the pH of the solution to a weakly acidic environment of around 6.0. If the pH is further increased, famotidine is prone to precipitation in the range of 15–25°C, making it impossible to further improve stability by increasing the pH.

[0005] Several issues need to be addressed regarding the original manufacturer's famotidine injection. First, impurities increase significantly when stored at room temperature (10–30°C), indicating that its stability under normal conditions remains unresolved. Second, the attempt to maximize stability by adjusting the pH to a weakly acidic environment of around 6.0 leads to decreased solubility and precipitation of famotidine below 15°C, making further temperature-controlled storage (e.g., 2–8°C or 10–15°C) unsuitable for improved stability. Third, while the addition of lactic acid to provide an acidic environment facilitates famotidine dissolution, the high proportion of polylactic acid (PLA) in the lactic acid solution causes it to hydrolyze into lactic acid during storage, resulting in a decrease in pH over time and further deterioration of stability. Fourth, the formulation contains a large amount of nicotinamide (50 mg / ml), and high doses of nicotinamide can increase liver toxicity, posing a potential safety risk.

[0006] Therefore, existing technologies are all focused on researching one of the aforementioned problems, hoping to find a way to solve the problems associated with famotidine injection.

[0007] Patent CN113143859A discloses a famotidine injection and its preparation method. This famotidine injection is composed of famotidine, ethanol, glycerol, acid, and mannitol. It utilizes an ethanol-glycerol-acid compound system to synergistically increase the solubility, pH tolerance, and stability of famotidine, thereby improving the safety of the formulation. However, after storage at 25±2℃ for 6 months, the total impurities still reach 1.2-2.3%, indicating that the stability issue of the famotidine injection remains unresolved.

[0008] Patent CN102225050B discloses a method for preparing famotidine sodium chloride injection and its product using an encapsulation method. The method involves encapsulating the drug solution with sulfobutyl ether-β-cyclodextrin before dissolving it in water, thereby improving the solubility and stability of famotidine. However, this patented method is complex, and studies have shown that its product still suffers from poor stability and is prone to precipitation during storage.

[0009] Therefore, the famotidine injection prepared by the existing technology still has problems such as poor stability, easy precipitation at low temperature storage, and high impurity content. In view of this, it is necessary to provide a new famotidine injection to solve the above technical problems.

[0010] The inventors were surprised to discover during their long-term research on famotidine injection that, under conditions where the pH of the solution system was kept close to neutral (less irritating) at 6.5-8 using tromethorphan and sodium hydroxide, famotidine could not precipitate and was exceptionally stable, and the amount of nicotinamide required was greatly reduced, thus completing this invention. Summary of the Invention

[0011] In order to overcome the shortcomings of the existing technology, the main objective of this invention is to provide a famotidine injection and its preparation method, which has a simple composition, good product stability, is not prone to precipitation during low-temperature storage, and has high safety.

[0012] The technical solution of this invention is as follows:

[0013] An H2 receptor antagonist pharmaceutical composition comprising famotidine, vitamin C, nicotinamide, phosphoric acid, tromethamine, sodium hydroxide, and water for injection.

[0014] Specifically, the H2 receptor antagonist drug composition, by mass-volume ratio, comprises famotidine 10 mg / ml, vitamin C 1.2 mg / ml, nicotinamide 5 mg / ml, phosphate 2 mg / ml, appropriate amounts of tromethorphan, appropriate amounts of sodium hydroxide, and the balance being water for injection.

[0015] Furthermore, phosphoric acid was added in the form of a 10% (w / w) phosphoric acid solution.

[0016] Furthermore, sodium hydroxide was added in the form of a 0.1M sodium hydroxide solution.

[0017] Further, the pH value of the pharmaceutical composition is 6.5-8.0, preferably 7.0-8.0.

[0018] This invention also provides a method for preparing an H2 receptor antagonist pharmaceutical composition, comprising the following steps:

[0019] Step 1: Take 80% of the prescribed amount of water for injection, add the prescribed amounts of vitamin C and nicotinamide, and stir well;

[0020] Step 2: Add the prescribed amount of 10% (w / w) phosphoric acid solution to lower the pH of the solution, then add the prescribed amount of famotidine and stir until completely dissolved;

[0021] Step 3: First, add an appropriate amount of tromethamine to adjust the pH to 6.0-6.2, then add 0.1M sodium hydroxide solution to adjust the pH to 6.5-8;

[0022] Step 4: Use the remaining water for injection to bring the volume up to the required level. Then, filter the solution through a sterile filter membrane and fill the ampoules to obtain famotidine injection.

[0023] Furthermore, the temperature of the water for injection in step 1 is 40°C.

[0024] Further, in step 2, 10% (w / w) of the prescribed amount of phosphoric acid solution is added to lower the pH of the solution to 3-4.

[0025] Furthermore, the sterilization filtration in step 4 uses a 0.22μm filter membrane.

[0026] Compared with the prior art, the beneficial effects of this application are as follows:

[0027] (1) During the research process, this application unexpectedly discovered that when adjusting the pH of a pharmaceutical composition containing famotidine, adding tromethorphan, a pharmaceutically and medically acceptable organic base, to adjust the pH to 6.0-6.2, and then further increasing the pH to 6.5-8.0 using sodium hydroxide, surprisingly, famotidine did not precipitate due to the continued increase in pH. This also solved the problems of poor stability and easy precipitation of famotidine at low temperatures. Furthermore, it significantly reduced the amount of nicotinamide in the formulation, improving safety.

[0028] (2) This application also uses phosphoric acid as a solvent to promote the dissolution of famotidine. It can form a phosphate buffer with sodium hydroxide, which can replace mannitol used to adjust the osmotic pressure of the injection solution in the original product, thereby reducing vascular irritation during injection. At the same time, the prescription ingredients are simplified, further increasing the safety of the product. Detailed Implementation

[0029] The present application is further illustrated below with specific embodiments. It should be understood that the embodiments of the present application are merely illustrative and not intended to limit the scope of the application. Experimental methods in the following embodiments without specified conditions are generally performed under conventional conditions or as recommended by the manufacturer. Raw materials and excipients in the following embodiments without specified sources are generally commercially available conventional products. Any simple improvements to the present application or equivalent substitutions of conventional methods or components based on the technical solutions of the present application are within the scope of protection of this application.

[0030] Example 1

[0031] prescription:

[0032]

[0033]

[0034] Preparation method:

[0035] Step 1: Take 800mL of water for injection (40℃), add 1.2g of vitamin C and 5g of nicotinamide, and stir well;

[0036] Step 2: Add 20g of 10% (w / w) phosphoric acid solution to lower the pH of the solution to 3.5, then add 10g of famotidine and stir until completely dissolved;

[0037] Step 3: First, add 3.6g of tromethamine to adjust the pH to 6.0, then add an appropriate amount of 0.1M sodium hydroxide solution to adjust the pH to 7.5;

[0038] Step 4: Use the remaining water for injection to bring the volume to the maximum. Then, filter the solution through a 0.22μm filter membrane for sterilization and fill the ampoule to obtain famotidine injection.

[0039] Example 2

[0040] This embodiment is basically the same as Example 1, except that an appropriate amount of 0.1M sodium hydroxide solution is added to the prescription, and the pH is adjusted to 6.5 in step 3.

[0041] Example 3

[0042] The examples are basically the same as Example 1, except that an appropriate amount of 0.1M sodium hydroxide solution is added to the prescription, and the pH is adjusted to 7.0 in step 3.

[0043] Example 4

[0044] The examples are basically the same as Example 1, except that an appropriate amount of 0.1M sodium hydroxide solution is added to the prescription, and the pH is adjusted to 8.0 in step 3.

[0045] Comparative Example 1

[0046] This comparative example is basically the same as Example 1, except that an appropriate amount of 0.1M sodium hydroxide solution is added to the formulation, and the pH is adjusted to 6.1 in step 3.

[0047] Comparative Example 2

[0048] This comparative example is basically the same as Example 1, except that an appropriate amount of 0.1M sodium hydroxide solution is added to the formulation, and the pH is adjusted to 8.3 in step 3.

[0049] Comparative Example 3

[0050] This comparative example is basically the same as Example 1, except that the 0.1M sodium hydroxide solution in the formulation is 0, and in step 3, only tromethamine is used to adjust the pH to 7.5.

[0051] Comparative Example 4

[0052] This comparative example is basically the same as Example 1, except that the amount of tromethorphan in the formulation is 0g, and in step 3, only an appropriate amount of 0.1M sodium hydroxide solution is used to adjust the pH to 7.5.

[0053] Comparative Example 5

[0054] This comparative example is basically the same as Example 1, except that in step 3, the pH is first adjusted to 5.5 with an appropriate amount of tromethamine, and then adjusted to 7.5 with an appropriate amount of 0.1M sodium hydroxide solution.

[0055] Comparative Example 6

[0056] This comparative example is basically the same as Example 1, except that in step 3, the pH is first adjusted to 6.5 with an appropriate amount of tromethamine, and then adjusted to 7.5 with 0.1M sodium hydroxide.

[0057] Comparative Example 7

[0058] This comparative example is basically the same as Example 1, except that the 20g 10% (w / w) phosphoric acid solution in the formulation is replaced with 1M hydrochloric acid solution, and 1M hydrochloric acid is used in step 2 to lower the pH of the solution to 3.5.

[0059] Comparative Example 8

[0060] This comparative example is basically the same as Example 1, except that the 20g 10% (w / w) phosphoric acid solution in the formulation is replaced with 1M acetic acid solution, and 1M acetic acid is used in step 2 to lower the pH of the solution to 3.5.

[0061] Comparative Example 9

[0062] Using the original formulation as control example 9, the information of the original formulation (trade name Gaster Injection 20mg; licensee LTL Fama Co., Ltd.) is shown in Table 1.

[0063] Table 1 Original Reagent Information

[0064] Prescription composition Prescription dosage Famotidine 20mg Niacinamide 100mg lactic acid 9.8mg Mannitol 40mg Vitamin C 2mg Sodium hydroxide Appropriate amount Water for Injection 2ml pH 5.8-6.2

[0065] Comparative Example 10

[0066] This comparative example is basically the same as Comparative Example 9 (original formulation), except that the nicotinamide content in the formulation is reduced from 100mg to 10mg, that is, the nicotinamide concentration is reduced from 50mg / ml to 5mg / ml.

[0067] Comparative Example 11

[0068] The sample prepared according to the formulation and preparation method of Example 1 in CN113143859A is Comparative Example 11.

[0069] Comparative Example 12

[0070] The sample prepared according to the formulation and preparation method of Example 1 in CN102225050B is Comparative Example 12.

[0071] Experimental Example 1: Investigating the effect of different pH values ​​on the quality and stability of the product.

[0072] Famotidine is easily hydrolyzed and unstable at lower pH solutions, while it is more stable but prone to precipitation at higher pH solutions. This application compares the stability of the prepared injection samples with Examples 1-4, Comparative Examples 1-2, and Comparative Examples 9-10. The low-temperature test method involved placing the sample at 2-8°C for 2 days, followed by placing it at 40°C for 2 days, repeated three times. The results are shown in Table 2.

[0073] Table 2 Results of product quality and stability in Experiment Example 1

[0074]

[0075] As shown in Table 2, regarding impurity content, the total impurity content of Examples 1-4 was relatively low. The impurity content of Comparative Example 1 was significantly higher than that of Examples 1-4. The impurity content of Comparative Example 2 was slightly lower than that of Example 2, but higher than that of Examples 1, 3, and 4. The impurity content of Comparative Examples 9-10 was significantly higher than that of Examples 1-4 and Examples 1-2. This indicates that a higher pH does not necessarily mean a more stable product. Regarding the issue of crystal precipitation at low temperatures, no crystals precipitated in Examples 1-4 and Comparative Example 1 under low-temperature conditions, while crystals precipitated in Comparative Examples 2 and 9-10. Comparative Example 10, compared to Comparative Example 9, reduced the nicotinamide concentration from 50 mg / ml to 5 mg / ml, indicating that reducing the amount of nicotinamide made crystal precipitation easier at low temperatures. This shows that the formulation of the present invention not only exhibits slow growth of related substances within the pH range of 6.5-8.0, but also, even with a reduced nicotinamide content (5 mg / ml), no crystals precipitated in the low-temperature experimental solution.

[0076] Experimental Example 2: Investigating the effects of different pH adjusters on product quality and stability

[0077] This application compares the prepared injectable products with Examples 1 and 3-6 to test their quality and stability. The low-temperature test method involves placing the product at 2-8°C for 2 days, followed by placing it at 40°C for 2 days, and repeating this cycle 3 times. The results are shown in Table 3.

[0078] Table 3 Results of product quality and stability in Experiment Example 2

[0079]

[0080] As shown in Table 3, when adjusted to the same final pH of 7.5, compared with Comparative Examples 4-5, Comparative Examples 4-5 showed crystal precipitation under low temperature conditions; compared with Comparative Examples 3 and 6, Comparative Examples 3 and 6 had higher impurities than Example 1.

[0081] Experimental Example 3: Investigating the effects of different buffering systems on vascular irritation

[0082] The original formulation (Comparative Example 9) uses mannitol as an osmotic pressure regulator to reduce vascular irritation during injection. Famotidine injection requires the addition of an acidic substance to lower the pH during preparation to promote famotidine dissolution, followed by the addition of an alkaline substance to raise the pH and maintain product stability. Based on the idea that acids and bases can form a buffer system to regulate osmotic pressure, this application investigated different buffer systems, conducting vascular irritation tests on the products of Examples 1-4 and Comparative Examples 7-8. The results are shown in Table 4.

[0083] Vascular stimulation experiment: Thirty-six rabbits were randomly divided into 6 groups, with half males and half females in each group. Experimental group: Rabbits were injected with drugs from Examples 1-4 via the left marginal ear vein; Control group: Rabbits were injected with drugs from Comparative Examples 7-8 via the left marginal ear vein; Blank group: Rabbits were injected with an equal volume of physiological saline via the left marginal ear vein. All groups were administered the drugs once daily for 5 consecutive days. The injection site and surrounding tissues were visually observed for signs of redness, swelling, congestion, or other irritation.

[0084] Table 4 shows the results of vascular irritation tests on the products of Examples 1-4 and Comparative Examples 7-8.

[0085]

[0086] As shown in Table 4, Examples 1-4 of this application have lower vascular irritation than Comparative Examples 7-8.

[0087] Test Example 4: Long-term stability study of the product

[0088] According to the General Chapter 9001 of the 2020 edition of the Chinese Pharmacopoeia, the stability test (accelerated and long-term test) of the sample prepared by Example 1 with the optimal combination was carried out, and Comparative Example 9 (original formulation), Comparative Example 11 (Example 1 in CN113143859A), and Comparative Example 12 (Example 1 in CN102225050B) were used for comparison.

[0089] Accelerated testing: Four batches of samples from Example 1, Comparative Example 9, Comparative Example 11 and Example 12 were taken and placed at 40℃±2 and RH75%±5% for 3 months. Samples were taken at 1 and 3 months respectively, and the stability was checked according to the key test items. The results were compared with the test results at 0 months.

[0090] Long-term test: Four batches of samples from Example 1, Comparative Example 9, Comparative Example 11, and Comparative Example 12 were taken and placed in their packaging for 6 months under the conditions of 25℃±2 and RH 60%±5%. Samples were taken at 6 months and tested according to the key stability test items. The results were compared with those of the 0-month test. The results of the accelerated test are summarized in Table 5, and the results of the long-term test are summarized in Table 6.

[0091] Table 5 Summary of Accelerated Experiment Results

[0092]

[0093]

[0094] Table 6 Summary of Long-Term Experiment Results

[0095]

[0096] Comparing accelerated testing (40℃) for 3 months and long-term testing (25℃) for 6 months with 0 days, Comparative Examples 9-12 showed a decrease in content and a significant increase in total impurities under both accelerated testing and long-term storage conditions. The quality change trend of the self-made product under the preferred formulation (Example 1) was significantly slower, the increase trend of related impurities was more gradual, and the pH value showed almost no change. All quality parameters met the requirements, demonstrating that the famotidine injection prepared by the technical solution of this invention has stable and controllable quality.

[0097] The above specific embodiments are only used to illustrate the technical solutions of this application and are not intended to limit it. Although this application has been described in detail with reference to examples, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of this application without departing from the scope of the technical solutions of this application, and all such modifications or substitutions should be covered within the scope of the claims of this application.

Claims

1. A method for preparing an H2 receptor antagonist injection solution, characterized in that, The injection solution comprises, by weight-volume ratio: famotidine 10 mg / ml, vitamin C 1.2 mg / ml, nicotinamide 5 mg / ml, phosphate 2 mg / ml, appropriate amounts of tromethorphan, appropriate amounts of sodium hydroxide, and the balance being water for injection. Its preparation method includes the following steps: Step 1: Take 80% of the prescribed amount of water for injection, add the prescribed amounts of vitamin C and nicotinamide, and stir well; Step 2: Add 10% w / w phosphate solution to lower the pH of the solution, then add the prescribed amount of famotidine and stir until completely dissolved; Step 3: First, add an appropriate amount of tromethamine to adjust the pH to 6.0-6.2, then add 0.1M sodium hydroxide solution to adjust the pH to 6.5-8.0; Step 4: Use the remaining water for injection to bring the volume to the required level. Then, filter the solution through a sterile filter membrane and fill the ampoule to obtain famotidine injection.

2. The method for preparing the H2 receptor antagonist injection solution according to claim 1, characterized in that, The temperature of the water for injection in step 1 is 40°C.

3. The method for preparing the H2 receptor antagonist injection solution according to claim 1, characterized in that, In step 2, 10% w / w of the prescribed amount of phosphoric acid solution is added to lower the pH of the solution to 3-4.

4. The method for preparing the H2 receptor antagonist injection solution according to claim 1, characterized in that, The sterilization filtration described in step 4 uses a 0.22μm filter membrane.

Images