Compound sulfamethoxazole injection and preparation method thereof

Abstract

The present invention provides a compound sulfamethoxazole injection and a preparation method thereof. The compound sulfamethoxazole injection provided by the present invention has stable properties, does not precipitate the raw material drug, has excellent comprehensive performance in the pH range of 9.0-10.0, and the finished product properties meet the regulations and remain unchanged after sterilization. The preparation method provided by the present invention strictly regulates the order of mixing the raw and auxiliary materials, can effectively control the growth of related substances, and ensures the content of the raw material drug.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a compound sulfamethoxazole injection and a preparation method thereof. Background Art

[0002] This product is mainly used to treat Pneumocystis jiroveci pneumonia or opportunistic infections caused by sensitive strains in immunocompromised patients in adults and children over 6 weeks of age.

[0003] As early as 1973, Roche AB developed sulfamethoxazole tablets, which were approved by the FDA for marketing. Later, the injection was launched in the EU, the United States and Japan. Currently, the product is launched in many EU member states, including: it was launched in France on March 2, 1982, with the license holder being Eumedica Pharmaceuticals GmbH; it was launched in Italy in August 1992, with the license holder being Eumedica Pharmaceuticals GmbH. The product names listed in the above countries are The specifications are all 5ml, sulfamethoxazole 80mg / ml, trimethoprim 16mg / ml. In October 2018, Japan's Sun Pharmaceutical Industries purchased the ownership of this product in the Japanese and US markets from Roche Pharma, and successfully launched it in Japan and the US, but it has now been withdrawn from the US market. The original formulation has not yet been launched in China.

[0004] At present, many domestic companies including Jinling Pharmaceutical (approval number: National Medicine Standard H32025719) have launched compound sulfamethoxazole injection, all with the specifications of 2ml: sulfamethoxazole 0.4g, trimethoprim 80mg. The National Drug Administration has clarified the reference preparation information of this product in the "Catalogue of Reference Preparations for Generic Chemical Drugs (45th Batch)", namely, compound sulfamethoxazole injection launched in the EU by Roche SpA / Eumedica Pharmaceuticals GmbH with serial number 35-21, specifications: 5ml, sulfamethoxazole 80mg / ml, trimethoprim 16mg / ml.

[0005] Sulfamethoxazole is a white crystalline powder, odorless, almost insoluble in water, but easily soluble in dilute hydrochloric acid, sodium hydroxide solution or ammonia solution. Its chemical name is: 4N-(5-methyl-3-isoxazolyl)-4-aminobenzenesulfonamide, and its structural formula is as follows:

[0006]

[0007] Trimethoprim is a white or off-white crystalline powder; odorless. It is slightly soluble in ethanol or acetone, almost insoluble in water; and easily soluble in glacial acetic acid. Its chemical name is: 5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine, and its structural formula is shown below7:

[0008] Summary of the invention

[0009] In view of the shortcomings of the prior art, patent CN202111345729.9 uses a large amount of ethanolamine solution, and excessive ethanolamine can damage the human central nervous system, respiratory system, and digestive system, and the product of the embodiment of CN202111345729.9 is a slightly yellow clear liquid, while the present invention is a colorless clear liquid. The object of the present invention is to provide a compound sulfamethoxazole injection and a preparation method thereof.

[0010] The technical scheme of the present invention is as follows: A compound sulfamethoxazole injection preparation comprises the following components: sulfamethoxazole, trimethoprim, sodium hydroxide, propylene glycol, anhydrous ethanol, a pH regulator and water

[0011] In some embodiments, the pH adjuster is selected from one or more of ethanolamine, diethanol, and triethanolamine; preferably ethanolamine.

[0012] In some embodiments, the compound sulfamethoxazole injection preparation includes the following components by weight: 33-45 parts of sulfamethoxazole, 6.5-9 parts of trimethoprim, 4.9-6.6 parts of sodium hydroxide, 170-228 parts of propylene glycol, 41-56 parts of anhydrous ethanol, 10.4-11 parts of ethanolamine, and 4160-5560 parts of water.

[0013] In some embodiments, the compound sulfamethoxazole injection preparation includes the following components by weight: 40 parts of sulfamethoxazole, 8 parts of trimethoprim, 5.9 parts of sodium hydroxide, 205 parts of propylene glycol, 50 parts of anhydrous ethanol, 10.4 parts of ethanolamine, and 4800 parts of water.

[0014] The present invention also provides a method for preparing the compound sulfamethoxazole injection, comprising the following steps:

[0015] 1) Under nitrogen protection throughout the process, weigh an appropriate amount of purified water, add it to the prescribed amount of propylene glycol, stir, and heat to 70-85°C;

[0016] 2) Add the prescribed amount of trimethoprim and stir to dissolve, then add the prescribed amount of anhydrous ethanol and stir evenly;

[0017] 3) Take an appropriate amount of purified water and add the prescribed amount of sodium hydroxide, stir to dissolve, then add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve, and control the temperature in the range of 25-45° C. during the dissolution process;

[0018] 4) Combine the dissolved and cooled trimethoprim solution and sulfamethoxazole solution, and stir evenly to obtain the mixture.

[0019] Preferably, the amount of purified water used in step 1) is 50-68% of the prescribed amount, preferably 68% of the prescribed amount.

[0020] Preferably, the amount of purified water used in step 1) is 9.5%-22% of the prescribed amount, preferably 9.5% of the prescribed amount.

[0021] In some typical embodiments, the preparation method of compound sulfamethoxazole injection comprises the following steps:

[0022] 1) Under nitrogen protection throughout the process, weigh 68% of the prescribed amount of purified water, add it to the prescribed amount of propylene glycol, stir, and heat to 70-85°C;

[0023] 2) Add the prescribed amount of trimethoprim and stir to dissolve, then add the prescribed amount of anhydrous ethanol and stir evenly;

[0024] 3) Take 9.5% of the prescription amount of purified water and add the prescription amount of sodium hydroxide, stir to dissolve, then add the prescription amount of ethanolamine, stir evenly, add the prescription amount of sulfamethoxazole and stir to dissolve;

[0025] 4) Combine the dissolved and cooled trimethoprim solution and sulfamethoxazole solution, and stir evenly to obtain the mixture.

[0026] Beneficial effects of the present invention:

[0027] (1) The production process is simple and has good reproducibility, and can be produced using common preparation processes and equipment.

[0028] (2) The properties of the finished product meet the requirements and remain unchanged after sterilization.

[0029] (3) The overall performance is excellent in the pH range of 9.0-10.0.

[0030] (4) The order of mixing raw and auxiliary materials is strictly regulated. The method of the present invention can effectively control the growth of related substances and ensure the content of the raw material.

[0031] (5) The proportions of the prescription ingredients are precisely determined, especially for ethanolamine. When the dosage is within the range of 10.4 to 11 parts, the solution is stable. If the dosage exceeds this range, the API will precipitate.

[0032] (6) During the stirring and dissolving process of sulfamethoxazole, the temperature is controlled within the range of 25-45°C, otherwise the compound will become unstable.

[0033] The present invention creatively discovers a new method for preparing sulfamethoxazole injection, which has the advantages of good stability and less precipitation, while the properties are stable and the yield is improved. At the same time, the preparation process has good stability, simple process, high production efficiency, and is suitable for industrial mass production.

[0034] Instruction Manual

[0035] Figure 1 Typical chromatogram for detection of sulfamethoxazole-related substances.

[0036] Figure 2 Typical chromatogram for detection of trimethoprim-related substances. DETAILED DESCRIPTION

[0037] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0038] The specific material ratios, process conditions and results described in the present invention are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0039] Detection method of related substances in sulfamethoxazole injection:

[0040] 1.1 Chromatographic conditions

[0041]

[0042] Gradient elution was as follows:

[0043]

[0044] 1.2 Preparation of test solution: Accurately measure 2.5 ml of the product (equivalent to about 0.2 g of sulfamethoxazole) and place it in a 200 ml volumetric flask, dilute to the scale with solvent, and shake well.

[0045] 1.3 Typical chromatogram: Figure 1 and Figure 2 shown.

[0046] Example 1

[0047] Prescription composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Ethanolamine 10.4 Purified water Add to 5ml

[0048] Note: The volume of propylene glycol, anhydrous ethanol and ethanolamine is approximately 0.2 ml, so the following prescription volume of purified water is calculated as 4.8 ml.

[0049] Preparation process:

[0050] Under nitrogen protection throughout the process, weigh 68% of purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir to dissolve, then add the prescribed amount of anhydrous ethanol and stir evenly; take 9.5% purified water, add the prescribed amount of sodium hydroxide, stir to dissolve, then add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, add purified water to make up to volume, stir evenly to obtain. Each vial is 5ml.

[0051] Example 2

[0052]

[0053]

[0054] The alkaline regulator of the injection solution is diethanolamine, and the other prescription compositions and preparation process are the same as those in Example 1.

[0055] Example 3

[0056] Prescription composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Triethanolamine 10.4 Purified water Add to 5ml

[0057] The injection alkaline regulator is triethanolamine, and the other prescription compositions and preparation process are the same as those in Example 1.

[0058] Example 4

[0059] Prescription composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Ethanolamine 10.4 Purified water Add to 5ml

[0060] Preparation process

[0061] Under nitrogen protection, weigh 68% purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir to dissolve, add the prescribed amount of anhydrous ethanol and stir evenly; take 22% purified water, add the prescribed amount of sodium hydroxide, stir to dissolve, add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, mix to volume, stir evenly. Each vial is 5ml.

[0062] Example 5

[0063]

[0064]

[0065] Preparation process

[0066] Under nitrogen protection, weigh 68% purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir to dissolve, add the prescribed amount of anhydrous ethanol and stir evenly; take 15% purified water, add the prescribed amount of sodium hydroxide, stir to dissolve, add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, mix to volume, stir evenly. Each vial is 5ml.

[0067] Example 6

[0068] Prescription composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Ethanolamine 10.4 Purified water Add to 5ml

[0069] Preparation process

[0070] Under nitrogen protection, weigh 68% purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir to dissolve, add the prescribed amount of anhydrous ethanol and stir evenly; take 18% purified water, add the prescribed amount of sodium hydroxide, stir to dissolve, add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, mix to volume, stir evenly. Each vial is 5ml.

[0071] Example 7

[0072]

[0073]

[0074] Preparation process

[0075] Under nitrogen protection, weigh 50% of purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir to dissolve, add the prescribed amount of anhydrous ethanol and stir evenly; take 9.5% purified water, add the prescribed amount of sodium hydroxide, stir to dissolve, add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, mix to volume, stir evenly. Each vial is 5ml.

[0076] Example 8

[0077] Prescription composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Ethanolamine 10.4 Purified water Add to 5ml

[0078] Preparation process

[0079] Under nitrogen protection, weigh 60% of purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir to dissolve, add the prescribed amount of anhydrous ethanol and stir evenly; take 9.5% purified water, add the prescribed amount of sodium hydroxide, stir to dissolve, add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, mix to volume, stir evenly. Each vial is 5ml.

[0080] Example 9

[0081]

[0082]

[0083] The dosage of ethanolamine, an alkaline regulator of the oral liquid, is adjusted to 10.5, 10.6, 10.8 or 11 mg / vial. The other prescription compositions and preparation process are the same as those in Example 1.

[0084] Comparative Example 1

[0085] Prescription composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Ethanolamine 10.4 Purified water Add to 5ml

[0086] Preparation process:

[0087] Under nitrogen protection throughout the process, weigh 75% purified water, add the prescribed amount of propylene glycol and trimethoprim, stir at 55-80℃ to dissolve for 20 minutes, maintain the temperature at 55℃, add the prescribed amount of anhydrous ethanol, sulfamethoxazole, add alkali solution (add 5.91kg of sodium hydroxide to 15% cooled purified water, stir to dissolve, and add to the liquid preparation tank); add the prescribed amount of ethanolamine, adjust the pH to 9.2-10.0. Add purified water to the full amount, stir evenly.

[0088] Comparative Example 2

[0089] Comparative Example 2 Prescription Composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Ethanolamine 10.4 Purified water Add to 5ml

[0090] Preparation process:

[0091] Under nitrogen protection throughout the process, weigh 60% of purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir and dissolve; take 9.5% purified water, add the prescribed amount of sodium hydroxide, stir and dissolve, then add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole, stir and dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, add the prescribed amount of anhydrous ethanol to make up the volume, stir evenly to obtain. Each vial is 5ml.

[0092] Comparative Example 3

[0093] Comparative Example 2 Prescription Composition Prescription quantity (mg / vial) Sulfamethoxazole 40 Trimethoprim 8 Sodium hydroxide 5.9 Propylene glycol 205 Anhydrous ethanol 50 Ethanolamine 10.0 / 11.4 Purified water Add to 5ml

[0094] Preparation process:

[0095] Under nitrogen protection, weigh 60% of purified water, add it to the prescribed amount of propylene glycol, stir, heat to 70-85℃, add the prescribed amount of trimethoprim, stir to dissolve, add the prescribed amount of anhydrous ethanol and stir evenly; take 9.5% purified water, add the prescribed amount of sodium hydroxide, stir to dissolve, add the prescribed amount of ethanolamine, stir evenly, add the prescribed amount of sulfamethoxazole and stir to dissolve; cool the dissolved trimethoprim solution and sulfamethoxazole solution, mix to volume, stir evenly. Each vial is 5ml.

[0096] Test Example 1: Comparison between Comparative Example 1 and Example 1

[0097] The results show (Table 1): Different preparation methods have a significant impact on sample-related substances.

[0098] Table 1 Summary of related substances in samples prepared in different ways

[0099]

[0100] Test Example 2: Comparison between Comparative Example 1 and Examples 1 / 9

[0101] The results show (Table 2) that the separated preparations and the use of ethanolamine at an amount of 10.4 gave the best results for the detection of related substances.

[0102] Table 2 Summary of results of related substances at different dosages of ethanolamine

[0103]

[0104] Test Example 3: Comparison between Comparative Example 1 and Examples 1, 2, and 3

[0105] The results show (3) that ethanolamine is better than diethanolamine and triethanolamine as alkaline regulator, and both are better than the control samples.

[0106] Table 3 Summary of results of related substances of different alkaline regulators

[0107]

[0108]

[0109] Test Example 4: Comparison of Comparative Example 1 and Examples 1, 4, 5, 6, 7, and 8

[0110] The results show (Table 4), comparing the effects of using different amounts of solvents to dissolve trimethoprim and different amounts of solvents to dissolve sulfamethoxazole on the related substances of the product:

[0111] Trimethoprim is dissolved in purified water within the range of 50%-68% of the prescribed amount. The use of purified water at 68% of the prescribed amount has the lowest impurity content and the best effect.

[0112] Sulfadimethoxazole is dissolved in purified water within the range of 9.5% to 22% of the prescribed amount. The impurity content of sulfadimethoxazole dissolved in purified water at a prescribed amount of 9.5% is the lowest and the effect is the best.

[0113] Table 4 Summary of results of related substances at different solvent dosages

[0114]

[0115]

[0116] Test Example 5: The comparison results of Comparative Example 2 and Example 1 show that the trimethoprim solution in Comparative Example 2 is unstable and easily precipitates before being combined with the sulfamethoxazole solution.

[0117] Table 5 Summary of related substances in samples prepared in different ways

[0118]

[0119] Table 5 Summary of sample content results in different preparation methods

[0120]

[0121]

[0122] Test Example 6: Comparison between Comparative Example 3 and Example 1

[0123] The results show that in comparative example 3, when the amount of ethanolamine is less than 10.4, sulfamethoxazole cannot be completely dissolved; when the amount of ethanolamine is higher than 11, after the trimethoprim solution and the sulfamethoxazole solution are combined and fixed to volume, they are easy to precipitate after being left standing.

[0124] Table 5 Summary of related substances in samples prepared in different ways

[0125]

[0126] Table 5 Summary of sample content results in different preparation methods

[0127]

Claims

1. A method for preparing a compound sulfamethoxazole injection preparation, wherein the compound sulfamethoxazole injection preparation comprises the following components by weight: 40 parts of sulfamethoxazole, 8 parts of trimethoprim, 5.9 parts of sodium hydroxide, 205 parts of propylene glycol, 50 parts of anhydrous ethanol, 10.4 parts of ethanolamine, and 4800 parts of purified water. The following steps are involved: 1) Under nitrogen protection throughout the process, weigh 68% of the prescribed amount of purified water, add it to the prescribed amount of propylene glycol, stir, and heat to 70-85°C; add the prescribed amount of trimethoprim, stir to dissolve, and then add the prescribed amount of anhydrous ethanol and stir evenly; 2) Take 9.5% of the prescription amount of purified water and add the prescription amount of sodium hydroxide, stir to dissolve, then add the prescription amount of ethanolamine, stir evenly, add the prescription amount of sulfamethoxazole and stir to dissolve, and control the temperature in the range of 25-45° C. during the dissolution process; 3) Combine the dissolved and cooled trimethoprim solution and sulfamethoxazole solution, and stir evenly to obtain the product.

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