Flurbiprofen injection and preparation method thereof

Abstract

The invention provides flurbiprofen injection and a preparation method thereof, and belongs to the technical field of biological medicine. The flurbiprofen arginine salt is prepared from the flurbiprofen, the solubility is remarkably improved, and the problem that the water solubility of the flurbiprofen is extremely poor is solved; meanwhile, nitrogen is filled to serve as a protective agent, the dissolved oxygen content of liquid medicine before filling is controlled to be not larger than 5 ppm, the headspace residual oxygen content in a bottle during filling is controlled to be not larger than 5%, the prepared flurbiprofen injection is stable in quality, the quality stability can be kept for 6 months in an acceleration test at the temperature of 40 DEG C, and the stability of the flurbiprofen injection is improved. The content of the generated oxidative degradation impurity 4-acetyl-2-fluorobiphenyl is obviously low (the total impurity content does not exceed 0.2%), and when the 4-acetyl-2-fluorobiphenyl is used in compatibility with a sodium chloride injection or a glucose injection, the clear and transparent liquid medicine can be ensured, and the clinical compatibility stability is good.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a flurbiprofen injection and a preparation method thereof. Background Art

[0002] Flurbiprofen, chemically known as (+)-2-(2-fluoro-4-biphenyl)-propionic acid, is a non-steroidal (NSAIDS) antipyretic, anti-inflammatory, and analgesic drug. Its mechanism of action is to inhibit prostaglandin cyclonitrogenase and block the biosynthesis of prostaglandins, thereby exerting its therapeutic effect. Its anti-inflammatory and analgesic ability is stronger than aspirin, and it has fewer side effects and good tolerance. It is widely used to treat rheumatoid arthritis and other rheumatic diseases.

[0003] NSAIDS are a class of non-steroidal drugs that can relieve pain, swelling, stiffness and inflammation. NSAIDS are commonly used for painful diseases in a variety of situations: including but not limited to arthritis, bursitis, tendinitis, gout, menstrual cramps, sprains, strains and other injuries. NSAIDS can also be used to treat mild pain that does not require narcotic analgesics after surgery, or as an alternative treatment for acute pain in patients who cannot accept narcotic analgesics, or as a follow-up treatment after treatment with strong analgesics, or to assist addictive strong analgesics to reduce the dosage of the former. NSAIDs are divided into various chemical types, but can generally be divided into non-selective and cyclooxygenase-2 (COX-2) selective drugs, including celecoxib and rofecoxib.

[0004] Due to the fact that flurbiprofen is almost insoluble in water and there is no flurbiprofen intravenous preparation on the market, flurbiprofen axetil, a prodrug of flurbiprofen, is prepared as a lipid-free emulsion injection for intravenous injection and is clinically used for postoperative and cancer analgesia.

[0005] Prior art Haresh Damor (Formulation and evaluation of flurbiprofen aqueous injection. Open access Journal of science. 2017; 1 (2): 37-42) uses a variety of cosolvents such as sodium benzoate, sodium acetate, propylene glycol, PEG and ethanol, etc., alone or in various proportions to obtain flurbiprofen aqueous injection. When propylene glycol 25% + PEG 10% + S5% and sodium benzoate 5% + PEG 25% + S5% (S refers to a solvent system containing the same concentration of PEG 200, PEG 400, glycerol and propylene glycol) are used as cosolvent combinations, the solubility of flurbiprofen in water and the stability of the product can be improved. However, a large amount of additives are added to the above prescription as solubilizers, which will cause high safety risks when used in clinical use.

[0006] Chinese patent CN103301101A discloses a novel pharmaceutical composition of 2-(2-fluoro-4-biphenyl)-propionic acid, which combines flurbiprofen with basic amino acids arginine or lysine to form a pharmaceutical composition solution with simple ingredients. However, its stability is relatively poor, and the total impurities of the sample in the 6-month accelerated stability test are close to 0.4%, which poses a great hidden danger to the safety of medication.

[0007] Chinese patent CN111494308A discloses a stable flurbiprofen injection, comprising flurbiprofen, amino polyols and water for injection. The flurbiprofen injection provided by the invention can maintain stability for 6 months at 40°C, and the content of degradation impurities (2-fluorobiphenyl-4-carboxylic acid) produced is low. However, it only examines the compatibility stability with propofol injection (fat emulsion), and it is impossible to observe whether the properties are turbid, and it does not examine 0.9% sodium chloride injection, 5% glucose injection, etc. for compatibility stability tests, which has great limitations.

[0008] Chinese patent CN111494307A discloses a flurbiprofen injection, the formula of which includes flurbiprofen, phosphate and water for injection, the molar ratio of phosphate to flurbiprofen is 0.1:1-10:1, and the phosphate is disodium hydrogen phosphate. As is well known, flurbiprofen is a substance that is extremely difficult to dissolve in water. Even if it is dissolved with 10 times the amount of disodium hydrogen phosphate of flurbiprofen, problems such as turbidity and crystallization will occur later, which poses a great hidden danger to the safety of medication.

[0009] Therefore, it is necessary to provide a flurbiprofen intravenous injection preparation with higher safety and stability. Summary of the invention

[0010] The object of the present invention is to provide a flurbiprofen injection and a preparation method thereof. The flurbiprofen injection has stable quality and high safety.

[0011] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0012] The present invention provides a method for preparing flurbiprofen injection, comprising the following steps:

[0013] 1) heating and mixing arginine and water for injection to obtain an arginine aqueous solution;

[0014] 2) mixing the arginine aqueous solution with flurbiprofen, and after dissolving, removing oxygen and filling nitrogen from the resulting liquid until the dissolved oxygen content of the liquid is ≤5 ppm;

[0015] 3) filtering the liquid medicine obtained in step 2) and filling it into bottles, and filling the bottles with nitrogen until the residual oxygen content in the headspace is ≤5%;

[0016] 4) performing terminal sterilization to obtain flurbiprofen injection.

[0017] Preferably, the molar ratio of arginine to flurbiprofen is 0.8 to 2:1.

[0018] Preferably, the molar ratio of arginine to flurbiprofen is 1.0-1.5:1.

[0019] Preferably, the temperature of the heating and mixing is 78-82°C.

[0020] Preferably, the mass concentration of flurbiprofen in the flurbiprofen injection is 0.5-5%.

[0021] Preferably, the filtration is performed using a filter membrane with a pore size of 0.22 μm.

[0022] Preferably, the sterilization temperature is 121° C. and the time is 15 min.

[0023] The present invention provides a flurbiprofen injection prepared by the preparation method described in the above technical scheme.

[0024] The invention provides a method for preparing flurbiprofen injection. The method adopts arginine to prepare flurbiprofen into flurbiprofen arginine salt. The guanidine group in the arginine contains three amino groups, which is conducive to forming an organic salt with a carboxyl group of flurbiprofen and dissolving in water. The solubility of flurbiprofen is significantly improved, thereby overcoming the problem of extremely poor water solubility of flurbiprofen. At the same time, the method uses nitrogen as a protective agent, controls the dissolved oxygen content of the drug solution before filling to be no more than 5ppm, and the residual oxygen content in the headspace of the bottle during filling to be no more than 5%. The prepared flurbiprofen injection has stable quality, can maintain quality stability for 6 months in an accelerated test at 40°C, has significantly lower content of 4-acetyl-2-fluorobiphenyl as an oxidative degradation impurity (total impurities do not exceed 0.2%), and has high safety. When used in combination with sodium chloride injection or glucose injection, the drug solution can be ensured to be clear and transparent, and has good clinical compatibility stability.

[0025] The concentration of flurbiprofen in the flurbiprofen injection prepared by the present invention is any value between 1.0 and 5.0% (w / v), and can be developed into a preparation for clinical use, and the specific specifications are determined by technical personnel.

[0026] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0027] 1. The flurbiprofen injection prepared by the method is a colorless clear liquid, which has higher safety while ensuring the stability of flurbiprofen and can greatly improve its bioavailability.

[0028] 2. The present invention uses oxygen removal and nitrogen filling technology to control the dissolved oxygen content of the drug solution and the residual oxygen content in the headspace of the bottle, which can effectively reduce oxidative degradation impurities and control the quality research of the preparation at the molecular level.

[0029] 3. The present invention reasonably controls the molar ratio of arginine to flurbiprofen, thereby ensuring the solubility of flurbiprofen and having good clinical compatibility stability.

[0030] 4 The flurbiprofen injection of the present invention can be terminally sterilized, and the sterility assurance level is improved, which is safer than the sterilization filtration process used in freeze-dried preparations.

[0031] 5 The preparation method of the present invention has a simple process, is suitable for industrial production, has a low preparation cost, and has guiding significance for industrial application. DETAILED DESCRIPTION

[0032] In the present invention, unless otherwise specified, the raw materials or reagents used are commercially available products well known in the art.

[0033] The present invention provides a method for preparing flurbiprofen injection, comprising the following steps:

[0034] 1) heating and mixing arginine and water for injection to obtain an arginine aqueous solution;

[0035] 2) mixing the arginine aqueous solution with flurbiprofen, and after dissolving, removing oxygen and filling nitrogen from the resulting liquid until the dissolved oxygen content of the liquid is ≤5 ppm;

[0036] 3) filtering the liquid medicine obtained in step 2) and filling it into bottles, and filling the bottles with nitrogen until the residual oxygen content in the headspace is ≤5%;

[0037] 4) performing terminal sterilization to obtain flurbiprofen injection.

[0038] In the present invention, the molar ratio of arginine to flurbiprofen is preferably 0.8 to 2:1, more preferably 1.0 to 1.5:1.

[0039] The arginine of the present invention is of injection grade (produced by Avituo (Shanghai) Pharmaceutical Technology Co., Ltd.), and the dosage does not exceed the maximum dosage for the same route of administration in the "FDA Inactive Ingredient Database", which can ensure clinical drug safety.

[0040] In the present invention, the temperature of the heating and mixing is preferably 78-82°C, more preferably 80°C.

[0041] The present invention preferably adds arginine to part of the water for injection, and heats to dissolve with magnetic stirring; adds flurbiprofen, continues stirring until completely dissolved, and adds the remaining water for injection; passes nitrogen to the bottom of the container through a stainless steel conduit, and performs oxygen removal and nitrogen filling under stirring (online monitoring of dissolved oxygen content of the medicinal liquid); the medicinal liquid is filtered through a 0.22 μm filter membrane (PES), filled under nitrogen filling, and sterilized to obtain flurbiprofen injection. The present invention has no special limitation on the ratio of the part of the water for injection and the remaining water for injection, and can be adjusted according to actual needs.

[0042] In the present invention, the mass concentration of flurbiprofen in the flurbiprofen injection is preferably 0.5-5%, more preferably 1-2.5%.

[0043] In the present invention, the dissolved oxygen content of the drug solution in step 2) is preferably 2.2 to 3.8 ppm, more preferably 3.0 to 3.2 ppm.

[0044] In the present invention, the filtration is preferably performed using a filter membrane with a pore size of 0.22 μm.

[0045] In the present invention, the sterilization temperature is preferably 121° C. and the sterilization time is preferably 15 min.

[0046] The present invention provides a flurbiprofen injection prepared by the preparation method described in the above technical scheme.

[0047] In addition, flurbiprofen is easily oxidized, and the degradation impurity 4-acetyl-2-fluorobiphenyl (British Pharmacopoeia, impurity D, CAS No. 42771-79-9) will be produced during terminal sterilization and accelerated testing:

[0048]

[0049] The content of 4-acetyl-2-fluorobiphenyl, an oxidative degradation impurity, generated by the flurbiprofen injection of the present invention is significantly lower (the total impurity does not exceed 0.2%), and the safety is high.

[0050] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0051] Example 1

[0052] This embodiment provides 2440 mL of flurbiprofen injection (concentration of 1%, w / v), which is prepared from the following ingredients:

[0053] Flurbiprofen 24.4g (0.1mol)

[0054] Arginine 17.4g (0.1mol)

[0055] Water for injection, add until the total amount of all raw materials is 2.44kg

[0056] Preparation method:

[0057] Weigh 17.4 g of arginine and add it to 900 g of water for injection. Heat to 80°C with magnetic stirring until dissolved. Add 24.4 g of flurbiprofen and continue stirring until completely dissolved. Add more water for injection to 2.44 kg.

[0058] The nitrogen was passed to the bottom of the container through a stainless steel pipe, and the obtained liquid medicine was deoxygenated and nitrogen filled for 3 minutes under stirring, and the dissolved oxygen content of the liquid medicine was monitored online at 3.2ppm;

[0059] The drug solution was filtered through a 0.22 μm filter membrane (PES), filled into a vial under nitrogen filling, with a filling volume of 5 mL, and sterilized at 120° C. for 15 min to obtain flurbiprofen injection.

[0060] The flurbiprofen injection is a colorless clear liquid with a pH value of 7.1, no impurity D detected, total impurities of 0.05%, and residual oxygen in the headspace of 2.3%.

[0061] Example 2

[0062] This embodiment provides 2440 mL of flurbiprofen injection (concentration of 5%, w / v), which is prepared from the following ingredients:

[0063] Flurbiprofen 122.0g (0.5mol)

[0064] Arginine 174g (1.0mol)

[0065] Water for injection, add until the total amount of all raw materials is 2.44kg

[0066] Preparation method:

[0067] Weigh 174 g of arginine and add it to 900 g of water for injection. Heat it to 80°C with magnetic stirring until it dissolves. Add 122.0 g of flurbiprofen and continue stirring until it is completely dissolved. Add more water for injection to 2.44 kg.

[0068] The nitrogen was passed to the bottom of the container through a stainless steel pipe, and the obtained liquid was deoxygenated and nitrogen filled for 8 minutes under stirring, and the dissolved oxygen content was monitored online at 2.2ppm;

[0069] The drug solution was filtered through a 0.22 μm filter membrane (PES), filled into vials under nitrogen filling, with each vial containing 1 mL, and sterilized at 120° C. for 15 min to obtain flurbiprofen injection.

[0070] The flurbiprofen injection is a colorless clear liquid with a pH value of 7.5, a total impurity content of 0.06%, and a headspace residual oxygen content of 1.9%.

[0071] Example 3

[0072] This embodiment provides 2440 mL of flurbiprofen injection (concentration of 5%, w / v), which is prepared from the following ingredients:

[0073] Flurbiprofen 122.0g (0.5mol)

[0074] Arginine 69.6g (0.4mol)

[0075] Water for injection, add until the total amount of all raw materials is 2.44kg

[0076] Preparation method:

[0077] Weigh 69.6 g of arginine and add it to 900 g of water for injection. Heat to 80°C with magnetic stirring until dissolved. Add 122.0 g of flurbiprofen and continue stirring until completely dissolved. Add more water for injection to 2.44 kg.

[0078] The nitrogen was passed to the bottom of the container through a stainless steel conduit, and the obtained liquid was deoxygenated and nitrogen filled for 5 minutes under stirring, and the dissolved oxygen content was monitored online at 3.0 ppm;

[0079] The drug solution was filtered through a 0.22 μm filter membrane (PES), filled into vials under nitrogen filling, with each vial containing 1 mL, and sterilized at 120° C. for 15 min to obtain flurbiprofen injection.

[0080] The flurbiprofen injection is a colorless clear liquid with a pH value of 7.6, a total impurity content of 0.05%, and a headspace residual oxygen content of 1.8%.

[0081] Example 4

[0082] This embodiment provides 2440 mL of flurbiprofen injection (concentration of 2.5%, w / v), which is prepared from the following ingredients:

[0083] Flurbiprofen 61.0g (0.25mol)

[0084] Arginine 87.0g (0.5mol)

[0085] Water for injection, add until the total amount of all raw materials is 2.44kg

[0086] Preparation method:

[0087] Weigh 87.0 g of arginine and add it to 900 g of water for injection. Heat it to 80°C with magnetic stirring until it dissolves. Add 61.0 g of flurbiprofen and continue stirring until it is completely dissolved. Add more water for injection to 2.44 kg.

[0088] The nitrogen was passed through a conduit to the bottom of the stainless steel container, and the obtained liquid was deoxygenated and nitrogen filled for 5 minutes under stirring, and the dissolved oxygen content was monitored online at 3.8 ppm;

[0089] The drug solution was filtered through a 0.22 μm filter membrane (PES), filled into a vial under nitrogen filling, with a filling volume of 2 mL, and sterilized at 120° C. for 15 min to obtain flurbiprofen injection.

[0090] The flurbiprofen injection is a colorless clear liquid with a pH value of 8.2, a total impurity content of 0.06%, and a headspace residual oxygen content of 2.8%.

[0091] Comparative Example 1

[0092] This embodiment provides 2440 mL of flurbiprofen injection (concentration of 5%, w / v), which is prepared from the following ingredients:

[0093] Flurbiprofen 122.0g (0.5mol)

[0094] Arginine 52g (0.3mol)

[0095] Water for injection up to 2.44kg

[0096] Preparation method:

[0097] Weigh 52g of arginine and add it to 900g of water for injection, and heat it to 80°C with magnetic stirring until it dissolves; add 122.0g of flurbiprofen and continue stirring until it is completely dissolved; add more water for injection to 2.44kg;

[0098] The drug solution was filtered through a 0.22 μm filter membrane (PES), filled into vials without nitrogen filling, with each vial containing 1 mL, and sterilized at 120° C. for 15 min to obtain flurbiprofen injection.

[0099] The flurbiprofen injection is a colorless clear liquid with a pH value of 6.8, an impurity D content of 0.05%, a total impurity content of 0.08%, and a headspace residual oxygen content of 19.2%.

[0100] Test Case

[0101] Stability test of flurbiprofen injection

[0102] The drug stability of flurbiprofen injection (using the flurbiprofen injection samples of Example 1 and Comparative Example 1) was investigated by the accelerated test method, and the prepared flurbiprofen injection was placed in a stability test box at a temperature of 40°C ± 2°C, and samples were taken once at 0th month, 1st month, 2nd month, 3rd month and 6th month, respectively, and the properties, pH value, related substances and content of the test sample were checked on schedule. Among them, the impurity content test was carried out according to the titration method in the Chinese Pharmacopoeia 2020 Edition Part II-Flurbiprofen Content Detection Method.

[0103] The results are shown in Tables 1 and 3.

[0104] Table 1 Accelerated stability test results of samples in Example 1

[0105] time Characteristics pH content Impurity D Total Miscellaneous 0 month Colorless clear liquid 7.1 99.2％ Not detected 0.05％ January Colorless clear liquid 7.3 100.2％ 0.01％ 0.06％ February Colorless clear liquid 7.0 99.8％ 0.01％ 0.08％ March Colorless clear liquid 7.3 99.9％ 0.03％ 0.08％ June Colorless clear liquid 7.3 100.3％ 0.05％ 0.16％

[0106] The results of Table 1 show that the flurbiprofen injection in Example 1 of the present invention was subjected to an accelerated stability test at a temperature of 40°C ± 2°C. The external properties of the 6-month sample were good, and the pH value, related substances and content determination results were relatively stable, meeting the quality control requirements.

[0107] The flurbiprofen injection sample of Example 1 of the present invention was mixed with 0.9% sodium chloride injection and 5% glucose injection in a volume ratio of 1:1, and left at room temperature for 6 hours to perform a compatibility test. The results are shown in Table 2.

[0108] Table 2 Compatibility test results of samples in Example 1

[0109]

[0110]

[0111] The test results in Table 2 show that the mixed solution of the flurbiprofen injection sample in Example 1 after being matched with 0.9% sodium chloride injection or 5% glucose injection is a clear liquid without turbidity.

[0112] Table 3 Comparative Example 1 Sample Accelerated Stability Test Results

[0113] time Characteristics pH content Impurity D Total Miscellaneous 0 month Colorless clear liquid 6.8 99.3％ 0.05％ 0.08％ January Colorless clear liquid 6.6 99.2％ 0.08％ 0.11％ February Colorless clear liquid 6.8 99.8％ 0.12％ 0.18％ March Light yellow clear liquid 6.7 99.9％ 0.13％ 0.28％ June Light yellow clear liquid 6.6 98.8％ 0.21％ 0.42％

[0114] The results in Table 3 show that the sample of Comparative Example 1 (low arginine content, no nitrogen protection) was subjected to accelerated stability test at a temperature of 40°C ± 2°C. The sample was a light yellow liquid after 6 months, with high levels of related substances, and relatively stable pH and content determination results.

[0115] The flurbiprofen injection sample of comparative example 1 was mixed with 0.9% sodium chloride injection and 5% glucose injection in a volume ratio of 1:1, respectively, and left at room temperature for 6 hours for a compatibility test. The results are shown in Table 4.

[0116] Table 4 Comparative Example 1 Sample Compatibility Test Results

[0117]

[0118] The test results in Table 4 show that the mixed solution of the flurbiprofen injection sample in Comparative Example 1 with 0.9% sodium chloride injection or 5% glucose injection becomes turbid because the amount of arginine is insufficient and a small amount of flurbiprofen is released from the arginine salt, resulting in turbidity.

[0119] The above results show that the flurbiprofen injection provided by the present invention has good stability, can be stored at room temperature, and has a shelf life of up to 2 years.

[0120] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing flurbiprofen injection, characterized in that: The following steps are involved: 1) heating and mixing arginine and water for injection to obtain an arginine aqueous solution; 2) mixing the arginine aqueous solution with flurbiprofen, and after dissolving, removing oxygen and filling nitrogen from the resulting liquid until the dissolved oxygen content of the liquid is ≤5 ppm; 3) filtering the liquid medicine obtained in step 2) and filling it into bottles, and filling the bottles with nitrogen until the residual oxygen content in the headspace is ≤5%; 4) performing terminal sterilization to obtain flurbiprofen injection.

2. The preparation method according to claim 1, characterized in that: The molar ratio of arginine to flurbiprofen is 0.8-2:

1.

3. The preparation method according to claim 2, characterized in that: The molar ratio of arginine to flurbiprofen is 1.0-1.5:

1.

4. The preparation method according to claim 3, characterized in that: The temperature of the heating and mixing is 78-82°C.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The mass concentration of flurbiprofen in the flurbiprofen injection is 0.5-5%.

6. The preparation method according to claim 1, characterized in that: The filtration is performed using a filter membrane with a pore size of 0.22 μm.

7. The preparation method according to claim 1, characterized in that: The sterilization temperature is 121° C. and the time is 15 min.

8. Flurbiprofen injection prepared by the preparation method according to any one of claims 1 to 7.

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