Preparation method of famotidine injection

Abstract

The invention discloses a preparation method of a famotidine injection. The preparation method of the famotidine injection provided by the invention comprises the following steps: injecting water for injection into a liquid preparation tank, and then sequentially adding nicotinamide, lactic acid hydrolysate, famotidine, mannitol and vitamin C according to a prescription dosage to obtain a feed liquid; adjusting the pH value of the feed liquid to 5.8-6.2, and fixing the volume; sterilizing, filtering and encapsulating the feed liquid; the preparation method is carried out under full-scale nitrogen charging protection, and in the liquid preparation process, the headspace residual oxygen content is controlled to be smaller than or equal to 0.5%, the liquid preparation temperature is controlled to be smaller than or equal to 25 DEG C, the dissolved oxygen content of liquid medicine is controlled to be smaller than or equal to 0.6 mg / L, and the headspace residual oxygen content of a finished product is controlled to be smaller than or equal to 1.2%. Under the condition of adopting the same raw and auxiliary materials and proportion as the original research medicine preparation, by strictly controlling the operation conditions in the large-scale preparation process, the content of related substances in the injection can be remarkably reduced, the impurity level can be reduced, and meanwhile, the long-term stability of the injection can be remarkably improved.

Description

Technical Field

[0001] The invention belongs to the technical field of injection production technology, and particularly relates to a large-scale production method for famotidine injection. Background Art

[0002] Famotidine injection is a drug that inhibits gastric acid secretion. The active ingredient, famotidine, is a histamine H2 receptor blocker that has a significant inhibitory effect on gastric acid, can inhibit the secretion of pepsin, and has a protective effect on experimental gastric ulcers. Famotidine is a third-generation H2 receptor blocker after cimetidine and ranitidine. Its inhibitory effect on gastric acid secretion caused by histamine lasts longer than cimetidine, and its maximum efficacy is about 40 times stronger. It is clinically used for gastric ulcers, duodenal ulcers, etc., with an effective rate of more than 90%, obvious anti-ulcer effect, and few side effects. It is an ideal anti-ulcer drug.

[0003] Famotidine is an alkaline compound with a pKa value of about 7.1. It is water-soluble in the acidic region but has poor stability. It has high stability in the neutral region but extremely low solubility and is extremely difficult to dissolve in water. The original drug preparation-related patent CN100438871C describes a method for preparing famotidine injection, which uses nicotinamide and acidic substances (vitamin C, lactic acid) to assist dissolution, adds mannitol to increase absorption, and adopts sterilization filtration and nitrogen filling operation methods to achieve the purpose of not exceeding the standard of related substances, thereby improving the stability of the injection.

[0004] However, experiments have found that the famotidine injection prepared by using commercially available raw materials and excipients according to the original drug formulation and the patented method has a large pH change under long-term storage conditions, resulting in an increase in the content of related substances, affecting the stability of the injection and increasing the risk of clinical medication. In addition, according to existing research data, even if the pH stability of famotidine injection is improved, famotidine will still cause a continuous increase in related substances due to its own degradation, and the product has a short shelf life. Especially under high temperature accelerated conditions, the increase in related substances is particularly obvious and it is easy to exceed the upper limit.

[0005] To this end, CN116059163A proposes a method for preparing famotidine injection, which uses commercially available raw materials and auxiliary materials according to the prescription of the original drug preparation, improves the pH stability of famotidine injection by increasing the lactic acid monomer content of the lactic acid hydrolyzate during the preparation process, and reduces the content of related substances and their increase rate, and the content of related substances in the injection meets the requirement of total impurities ≤ 5%. However, the content of related substances in the 0-day product prepared by this method is still high, indicating that the stability of the drug solution cannot be guaranteed during the production process of the product, resulting in a significant increase in related substances, affecting the control level of related substances in the drug 0-day.

[0006] In addition, during the commercial large-scale production trial of the injection, it was found that the main ingredients of famotidine injection were still prone to degradation during the preparation and storage processes, and the antioxidant vitamin C was also easily decomposed, affecting the initial levels of related substances in the product and increasing the risk of clinical use.

[0007] In view of this, the present invention is proposed. Summary of the invention

[0008] The object of the present invention is to provide a large-scale production method of famotidine injection, which significantly improves the shelf life stability of the injection and the control level of drug 0-day related substances without adding additional economic burden to the production enterprise. Therefore, the method is more suitable for large-scale production and has better application prospects.

[0009] In order to achieve the above object, the present invention adopts the following technical solutions: In a first aspect, the present invention provides a method for preparing famotidine injection, comprising the following steps: before initial water collection, subjecting a liquid preparation tank to a vacuum nitrogen replacement process to control the headspace residual oxygen content to ≤0.5%; under nitrogen protection, adding raw materials to the liquid preparation tank for mixing and liquid preparation, adjusting pH, constant volume, sterilizing and filtering, and potting; during the liquid preparation process, the dissolved oxygen content of the drug solution is ≤0.6 mg / L.

[0010] The present invention adopts the original drug preparation prescription and commercially available raw and auxiliary materials, and optimizes and improves the oxygen control process conditions of the above-mentioned different processes, thereby improving the shelf life stability of the injection, the control level of the injection's 0-day related substances and the stability of vitamin C. The method is highly operable and more practical.

[0011] In the present invention, during the liquid preparation process, the nitrogen ventilation rate is 48-52NL / min, such as 50NL / min.

[0012] In the present invention, the liquid preparation is carried out according to the following operation: nitrogen is introduced into the liquid preparation tank and vacuum is drawn, and a circulation operation is performed, while water for injection is injected, and nitrogen is introduced underwater, a stirring device is turned on, and nicotinamide, lactic acid hydrolyzate, famotidine, mannitol, and vitamin C in prescribed amounts are added in sequence, and mixed to obtain a feed liquid.

[0013] In the present invention, the mass fraction of lactic acid monomer in the lactic acid hydrolyzate is ≥95%, preferably ≥96%. The lactic acid hydrolyzate is obtained by heat treating a lactic acid solution at 121° C. for 90 minutes.

[0014] In the present invention, the pH is 5.8-6.2. The pH is adjusted using a sodium hydroxide solution; the concentration of the sodium hydroxide solution is 1 mol / L.

[0015] In the present invention, the volume setting is performed according to the following operation: first stop nitrogen filling, replenish the prescribed amount of water for injection, then restart nitrogen filling below the liquid surface, and start stirring.

[0016] In the present invention, the sterilization filtration is performed twice. The sterilization filtration is performed according to the following operation: Primary sterilization filtration: Use a 5-inch polyethersulfone (PES) hydrophilic filter element with a pore size of 0.22µm to filter the prepared liquid from the preparation tank through the primary sterilization filter element to the sterile filtrate storage tank, and continuously fill nitrogen below the liquid surface with a nitrogen flow rate of 15-50NL / min and a dissolved oxygen content of ≤0.6mg / L. During the sterilization filtration process, the pressure difference before and after the filter is controlled to be ≤0.2MPa.

[0017] Secondary sterilization filtration: Use a 5-inch polyethersulfone (PES) hydrophilic material filter element with a pore size of 0.22µm and nitrogen pressure filtration to transfer the drug solution in the sterile filtrate storage tank to the buffer tank through the secondary sterilization filter element. Continuously fill the buffer tank with nitrogen at a nitrogen flow rate of 25NL / min.

[0018] In the present invention, during the potting process, the residual oxygen content in the headspace of the product is controlled to be ≤1.2%.

[0019] In the present invention, the nitrogen filling requirements for potting are: nitrogen filling at the station before filling, nitrogen filling at the station after filling, nitrogen filling at the preheating station, and nitrogen filling at the wire drawing and sealing station. The specific nitrogen filling is carried out according to the following operations: nitrogen filling at the station before filling with a nitrogen flow rate of 40NL / min, nitrogen filling at the station after filling with a nitrogen flow rate of 25NL / min, nitrogen filling at the preheating station with a nitrogen flow rate of 90% (full scale 100%: 65NL / min), and nitrogen filling at the wire drawing and sealing station with a nitrogen flow rate of 65% (full scale 100%: 65NL / min).

[0020] In the present invention, nitrogen is used as a power to hydraulically deliver the material to a buffer tank of a filling and sealing machine; the filled ampoules are stored after leak detection, light inspection and packaging.

[0021] In a second aspect, the present invention also provides famotidine injection obtained by the above preparation method.

[0022] Compared with the prior art, the present invention has the following beneficial effects: The present invention optimizes the oxygen control process conditions of the liquid preparation, solution temporary storage and filling processes through a large number of exploratory experiments, significantly reduces the content of related substances in the preparation process, avoids the destruction of vitamin C in large quantities, thereby improving the purity of the product, and also improving the long-term stability of the product. Moreover, the oxygen control operation method provided by the present invention is highly feasible, the residual oxygen level of the product is significantly reduced, the yield of the product is greatly improved, and it is easy to be widely used. DETAILED DESCRIPTION

[0023] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0024] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0025] The lactic acid, water for injection, nicotinamide, famotidine, mannitol, vitamin C and sodium hydroxide used in the present invention are all pharmaceutical grade commercially available products.

[0026] Example 1: Preparation of Famotidine Injection (Controlling the Preparation Temperature and Filling with Nitrogen Throughout the Process) Here are the steps: Step 1, heat-treating lactic acid at 121° C. for 90 min to hydrolyze to obtain a lactic acid hydrolyzate containing 95% lactic acid monomer; Step 2, fill the liquid preparation tank with nitrogen and evacuate, circulate the operation, and at the same time inject 80% of the prescribed amount of water for injection into the liquid preparation tank, pass nitrogen under the liquid surface and turn on the stirring device of the liquid preparation tank; during this process, the nitrogen introduction flow rate is 50NL / min, and the temperature in the liquid preparation tank is controlled to be 25°C; after nitrogen filling, evacuation and stirring, the residual oxygen content in the headspace of the liquid preparation tank is 0.5%, and the dissolved oxygen content in the water is 0.6mg / L.

[0027] Step 3, controlling the temperature in the liquid preparation tank to be no higher than 25° C., and sequentially adding the prescribed amount of nicotinamide, the lactic acid hydrolyzate obtained in step 1, famotidine, mannitol, and vitamin C into the liquid preparation tank; Step 4: Take samples, detect the pH value of the solution, and add an appropriate amount of 1 mol / L sodium hydroxide solution to adjust the pH value of the solution to 5.8-6.2; Step 5, stop nitrogen filling, replenish the prescribed amount of water for injection, restart nitrogen filling below the liquid surface and start the stirring device; Step 6, the liquid obtained in the liquid preparation tank is subjected to secondary sterilization filtration, and then the nitrogen pressure is used as the power to press the liquid in the liquid preparation tank into the buffer tank of the filling machine, and the filling is carried out under the protection of nitrogen; at the same time, the nitrogen filling flow rate of the pre-filling station is controlled to be 40NL / min, the nitrogen filling flow rate of the post-filling station is controlled to be 25NL / min, the nitrogen filling flow rate of the preheating station is controlled to be 90% (full scale 100%: 65NL / min), the nitrogen flow rate of the wire drawing and sealing station is controlled to be 65% (full scale 100%: 65NL / min), and the headspace residual oxygen content of the preparation bottle is controlled to be 1.2%; Step 7: After filling, the ampoules are leak tested, light inspected and packaged before being put into storage.

[0028] Example 2: Preparation of Famotidine Injection (Controlling the Preparation Temperature and Filling with Nitrogen Throughout the Process) Compared with Example 1, the difference is that in step 2, the temperature in the liquid preparation tank is controlled to be 23° C.; after nitrogen filling, evacuation and stirring, the headspace residual oxygen content in the liquid preparation tank is 0.4%, and the dissolved oxygen content in water is 0.5 mg / L; in step 6, the headspace residual oxygen content of the preparation bottle is controlled to be 1.0%.

[0029] Comparative Example 1 Compared with the embodiment, the only difference is that the residual oxygen content in the headspace in step 2 is higher, which is 0.7%.

[0030] Comparative Example 2 Compared with the embodiment, the only difference is that the dissolved oxygen content in step 2 is higher, which is 0.8 mg / L.

[0031] Comparative Example 3 Compared with the embodiment, the only difference is that the temperature inside the tank is not controlled in step 2, and the actual measured temperature inside the tank reaches 35°C.

[0032] Comparative Example 4 Compared with the embodiment, the only difference is that the residual oxygen content in the headspace in step 6 is higher, which is 1.4%.

[0033] The samples obtained in Comparative Examples 1 to 4 were tested according to the above method, and the results showed that after being left for 5 and 10 days without influencing factors, the content of vitamin C in the samples was lower than that in the examples, and the content of related substances was higher than that in the examples.

[0034] Test example: Testing of injection product quality Under high temperature (40°C) conditions, the properties, pH, solution color, impurity B content, impurity C content, impurity D content, impurity K content, other single impurities (impurity E, impurity F, impurity G, impurity H, impurity J), total impurity content, number of impurities and vitamin C content of the injection solution samples were tested.

[0035] in: The national standards for relevant substances and vitamin C content are: the content of impurity B, impurity C, impurity D and impurity K should not be greater than 0.5%; the largest single impurity should not be greater than 0.5%; the total impurities should not be greater than 5.0%; the vitamin C content should not be less than 0.70 mg / mL.

[0036] The above impurity structures are as follows: Table 1 Impurity types

[0037] Table 2 Test results

[0038] As can be seen from the data in Table 2, the single impurity and total impurity content in the initial injection products obtained in Example 1 and Example 2 are very low, and the total impurity content is only 0.21% and 0.19%, and the number of impurities is small, only 3, which shows that the initial product has high purity and good quality. At the same time, the vitamin C content in the initial injection product is as high as 1.01 mg / mL and 1.02 mg / mL, and after the accelerated experiment, its content still maintains a high level, indicating that its antioxidant effect is better, the degradation of famotidine is controlled during the preparation process, and the single impurity and total impurity content in the injection are low, indicating that the injection has excellent stability.

[0039] However, the initial products of the injections obtained in Comparative Examples 1-4 had a high content of total impurities and a low content of vitamin C. After the accelerated test, the total impurity content was even higher, the content of the main component and the content of vitamin C were significantly reduced, and the stability was poor.

[0040] This shows that the present invention can significantly improve the quality and stability of the initial injection product by strictly controlling the operating conditions of the preparation and filling process, including the temperature in the tank, the residual oxygen content in the headspace, the dissolved oxygen content of the drug solution, and the residual oxygen content in the headspace of the finished product.

[0041] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing famotidine injection, comprising the following steps: adding raw materials into a liquid preparation tank under nitrogen protection, mixing and preparing the liquid, adjusting pH, constant volume, sterilizing and filtering, and potting; During the liquid preparation process, the residual oxygen content in the headspace is controlled to be ≤0.5%, and the dissolved oxygen content in the liquid is controlled to be ≤0.6 mg / L.

2. The preparation method according to claim 1, characterized in that: During the liquid preparation process, the temperature in the liquid preparation tank is controlled to be ≤25°C.

3. The preparation method according to claim 1 or 2, characterized in that: During the liquid preparation process, the nitrogen ventilation rate is 48-52 NL / min.

4. The preparation method according to any one of claims 1 to 3, characterized in that The liquid preparation is carried out according to the following operation: nitrogen is introduced into the liquid preparation tank and vacuum is drawn, and a circulation operation is performed, while water for injection is injected, and nitrogen is introduced underwater, a stirring device is turned on, and nicotinamide, lactic acid hydrolyzate, famotidine, mannitol, and vitamin C in prescribed amounts are added in sequence, and mixed to obtain a feed liquid.

5. The preparation method according to claim 4, characterized in that: The mass fraction of lactic acid monomer in the lactic acid hydrolyzate is ≥95%.

6. The preparation method according to any one of claims 1 to 5, characterized in that The pH is 5.8~6.

2.

7. The preparation method according to any one of claims 1 to 6, characterized in that The sterilizing filtration is performed according to the following operation: Primary sterilization filtration: Use a 5-inch polyethersulfone hydrophilic filter element with a pore size of 0.22µm to filter the prepared liquid from the preparation tank through the primary sterilization filter element to the sterile filtrate storage tank, and continuously fill nitrogen below the liquid surface. The nitrogen flow rate is 15-50NL / min, and the dissolved oxygen content is ≤0.6mg / L. During the sterilization filtration process, the pressure difference before and after the filter is controlled to be ≤0.2MPa; Secondary sterilization filtration: Use a 5-inch polyethersulfone hydrophilic material filter element with a pore size of 0.22µm and nitrogen pressure filtration to transfer the drug solution in the sterile filtrate storage tank to the buffer tank through the secondary sterilization filter element. Continuously fill the buffer tank with nitrogen at a nitrogen flow rate of 25NL / min.

8. The preparation method according to any one of claims 1 to 7, characterized in that During the filling process, the residual oxygen content in the headspace of the product is controlled to be ≤1.2%.

9. The preparation method according to any one of claims 1 to 8, characterized in that The nitrogen filling requirements for the potting are: The nitrogen flow rate of the nitrogen filling station before filling is 40NL / min; The nitrogen flow rate of the nitrogen filling station after filling is 25NL / min; The nitrogen flow rate of the preheating station is 90% of the full scale, and the full scale is 100%: 65NL / min; The nitrogen flow rate at the wire drawing and sealing station is 65% of the full scale, and the full scale is 100%: 65NL / min.

10. The famotidine injection obtained by the preparation method according to any one of claims 1 to 9.

Images