Preparation process of marbofloxacin for vacuum freeze-drying injection

Abstract

The invention discloses a preparation process of marbofloxacin for vacuum freeze-drying injection, and relates to the technical field of pharmaceutical preparations. The preparation process comprises the following steps: S1, mixing marbofloxacin, mannitol and water for injection, and adding a pH regulator to regulate the pH to obtain a mixed solution A; s2, stirring the mixed solution A and modified activated carbon, and carrying out decarburization treatment to obtain filtrate; and S3, freeze-drying the filtrate to obtain the marbofloxacin for vacuum freeze-drying injection. The marbofloxacin prepared by the preparation process disclosed by the invention has the advantages of low impurity content and high redissolution speed.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a preparation process of vacuum freeze-dried marbofloxacin for injection. Background Art

[0002] The veterinary medicine industry has made great efforts to significantly improve the quality of livestock products. However, diseases caused by bacteria are very serious, and often occur and spread in the form of mixed bacterial infections. Bacterial resistance is becoming increasingly prominent, which not only causes huge economic losses to the breeding industry, but also poses potential public health and food safety problems. Quinolones have the characteristics of spectrum, high efficiency, and low toxicity, and have become commonly used drugs for the clinical treatment of various infectious diseases. Marbofloxacin is another third-generation quinolone antibacterial drug after enrofloxacin, danofloxacin, and difloxacin. It has the characteristics of a broad antibacterial spectrum, a long elimination half-life, and high bioavailability. Marbofloxacin has strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and mycoplasmas. The drug has strong tissue penetration, is rapidly and completely absorbed in the body, and is widely distributed. It has a long elimination half-life, high bioavailability, a wide range of safe doses, and no obvious reproductive and genetic toxicity.

[0003] In recent years, the main dosage form of marbofloxacin is injection. Water is the most commonly used solvent for injection and can be completely absorbed and metabolized in animals. However, marbofloxacin is slightly soluble in water and needs to be dissolved in acid and alkali to exist relatively stably. Injectable marbofloxacin is made into marbofloxacin lyophilized powder injection. During the lyophilization process, the water is directly sublimated without passing through the liquid state, so that the physical, chemical properties and shape of the dried substance remain basically unchanged, the loss of effective ingredients is small, the rehydration is good, and the sealed storage period is long. However, the existing preparation method is limited in controlling the degradation of marbofloxacin, which increases the content of ineffective ingredients in the product, resulting in the existence of a high content of impurities in the obtained product and unstable product quality. Summary of the invention

[0004] The object of the present invention is to provide a preparation process of vacuum freeze-dried marbofloxacin for injection to solve the following technical problems:

[0005] The existing preparation methods are limited in controlling the degradation of marbofloxacin, which increases the content of ineffective components in the product, resulting in the presence of higher levels of impurities in the obtained product and unstable product quality.

[0006] The purpose of the present invention can be achieved through the following technical solutions:

[0007] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0008] S1: Marbofloxacin, mannitol and water for injection are mixed, and a pH regulator is added to adjust the pH to obtain a mixed solution A;

[0009] S2: stirring and decarbonizing the mixed solution A and modified activated carbon to obtain a filtrate;

[0010] S3: freeze-drying the filtrate to obtain vacuum freeze-dried marbofloxacin for injection.

[0011] As a further embodiment of the present invention, the dosage ratio of marbofloxacin, mannitol and water for injection is 100 g: 20-40 g: 500-1000 mL.

[0012] As a further solution of the present invention: the specific steps of adjusting the pH value are: adding a pH adjuster to adjust the pH to 4.0-6.0, and the pH adjuster is lactic acid.

[0013] As a further embodiment of the present invention: the mass ratio of marbofloxacin to modified activated carbon is 1:0.1-0.3.

[0014] As a further scheme of the present invention: the specific steps of freeze drying are: controlling the vacuum degree at 10-40Pa, cooling to -40℃~-30℃ at a rate of 5-10℃ / h, freezing for 1h~6h; continuing to control the vacuum degree at 2-6Pa, heating to 40-50℃ at a rate of 1-10℃ / h, and drying for 3-6h.

[0015] As a further embodiment of the present invention: the preparation method of modified activated carbon comprises the following steps:

[0016] A1: Add activated carbon, alanine and deionized water into a reaction bottle, stir evenly, heat to 70-90°C, keep warm for 9-12 hours, filter, wash until neutral, and dry to obtain component 1;

[0017] A2: Add component 1, succinic anhydride and tetrahydrofuran into a reaction kettle, stir evenly, heat to 30-40°C, keep warm for 3-6 hours, filter and dry to obtain modified activated carbon.

[0018] As a further embodiment of the present invention, the mass ratio of activated carbon: alanine: deionized water is 100:7-15:100-500.

[0019] As a further solution of the present invention: the addition ratio of component 1: succinic anhydride: tetrahydrofuran is 100g: 10-15g: 500-1000mL.

[0020] Beneficial effects of the present invention:

[0021] The present application adds modified activated carbon during the preparation process, and the modified activated carbon is obtained by modifying activated carbon with alanine and succinic anhydride. The present application adds modified activated carbon during the preparation process of marbofloxacin, so that it reacts with marbofloxacin to form salts, thereby increasing the speed and solubility of marbofloxacin in subsequent water redissolution, and the modified activated carbon after use can be effectively filtered to reduce the impurity content in the finished marbofloxacin. The marbofloxacin prepared by the present invention has good solubility in water and is convenient for clinical medication; compared with marbofloxacin tablets, the absorption speed is fast and more complete, the apparent distribution volume is large, and the bioavailability is high. In the preparation process, water is also used as a solvent to avoid the use of organic solvents such as DMF, toluene, and dichloromethane, thereby reducing pollution to the environment; the process steps are simple, the cost is low, and the problem of marbofloxacin being insoluble in water is effectively solved. The prepared marbofloxacin for injection has a more stable content during storage, and the related substances are easier to control, which increases the administration route of marbofloxacin, facilitates clinical medication, and has a good application prospect. DETAILED DESCRIPTION

[0022] The following will be described clearly and completely in conjunction with the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0023] Example 1

[0024] The method for preparing activated carbon comprises the following steps:

[0025] A1: Add 100 g activated carbon, 7 g alanine and 100 mL deionized water into a reaction bottle, stir evenly, heat to 70°C, keep warm for 9 h, filter, wash to neutrality, and dry to obtain component 1;

[0026] A2: Add 100g of component 1, 10g of succinic anhydride and 500mL of tetrahydrofuran into a reaction kettle, stir evenly, heat to 30°C, keep warm for 3h, filter and dry to obtain modified activated carbon.

[0027] Example 2

[0028] The method for preparing activated carbon comprises the following steps:

[0029] A1: Add 100 g activated carbon, 10 g alanine and 300 mL deionized water into a reaction bottle, stir evenly, heat to 80°C, keep warm for 9 hours, filter, wash to neutrality, and dry to obtain component 1;

[0030] A2: Add 100g of component 1, 12g of succinic anhydride and 800mL of tetrahydrofuran into a reaction kettle, stir evenly, heat to 35°C, keep the temperature for 3h, filter and dry to obtain modified activated carbon.

[0031] Example 3

[0032] The method for preparing activated carbon comprises the following steps:

[0033] A1: Add 100 g activated carbon, 15 g alanine and 500 mL deionized water into a reaction bottle, stir evenly, heat to 90°C, keep warm for 12 h, filter, wash to neutrality, and dry to obtain component 1;

[0034] A2: Add 100g of component 1, 15g of succinic anhydride and 1000mL of tetrahydrofuran into a reaction kettle, stir evenly mechanically, heat to 40°C, keep the temperature for 6h, filter and dry to obtain modified activated carbon.

[0035] Example 4

[0036] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0037] S1: 100 g of marbofloxacin, 20 g of mannitol and 500 mL of water for injection were mixed, and lactic acid was added to adjust the pH to 5 to obtain a mixed solution A;

[0038] S2: stirring and decarbonizing the mixed solution A with 20 g of the modified activated carbon prepared in Example 1 to obtain a filtrate;

[0039] S3: freeze-dry the filtrate, control the vacuum degree at 10 Pa, cool it to -40 °C at a rate of 5 °C / h, and freeze it for 3 hours; continue to control the vacuum degree at 5 Pa, heat it to 45 °C at a rate of 5 °C / h, and dry it for 3 hours to obtain vacuum freeze-dried marbofloxacin for injection.

[0040] Example 5

[0041] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0042] S1: 100 g of marbofloxacin, 20 g of mannitol and 500 mL of water for injection were mixed, and lactic acid was added to adjust the pH to 5 to obtain a mixed solution A;

[0043] S2: Stirring and decarbonizing the mixed solution A with 20 g of the modified activated carbon prepared in Example 2 to obtain a filtrate;

[0044] S3: freeze-dry the filtrate, control the vacuum degree at 10 Pa, cool it to -40 °C at a rate of 5 °C / h, and freeze it for 3 hours; continue to control the vacuum degree at 5 Pa, heat it to 45 °C at a rate of 5 °C / h, and dry it for 3 hours to obtain vacuum freeze-dried marbofloxacin for injection.

[0045] Example 6

[0046] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0047] S1: 100 g of marbofloxacin, 20 g of mannitol and 500 mL of water for injection were mixed, and 0.1 mol / L sodium citrate solution was added to adjust the pH to 5 to obtain a mixed solution A;

[0048] S2: stirring and decarbonizing the mixed solution A with 20 g of the modified activated carbon prepared in Example 3 to obtain a filtrate;

[0049] S3: freeze-dry the filtrate, control the vacuum degree at 10 Pa, cool it to -40 °C at a rate of 5 °C / h, and freeze it for 3 hours; continue to control the vacuum degree at 5 Pa, heat it to 45 °C at a rate of 5 °C / h, and dry it for 3 hours to obtain vacuum freeze-dried marbofloxacin for injection.

[0050] Example 7

[0051] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0052] S1: 100 g of marbofloxacin, 30 g of mannitol and 500 mL of water for injection were mixed, and lactic acid was added to adjust the pH to 5 to obtain a mixed solution A;

[0053] S2: stirring and decarbonizing the mixed solution A with 20 g of the modified activated carbon prepared in Example 1 to obtain a filtrate;

[0054] S3: freeze-dry the filtrate, control the vacuum degree at 10 Pa, cool it to -40 °C at a rate of 5 °C / h, and freeze it for 3 hours; continue to control the vacuum degree at 5 Pa, heat it to 45 °C at a rate of 5 °C / h, and dry it for 3 hours to obtain vacuum freeze-dried marbofloxacin for injection.

[0055] Example 8

[0056] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0057] S1: 100 g of marbofloxacin, 40 g of mannitol and 500 mL of water for injection were mixed, and lactic acid was added to adjust the pH to 5 to obtain a mixed solution A;

[0058] S2: stirring and decarbonizing the mixed solution A with 20 g of the modified activated carbon prepared in Example 1 to obtain a filtrate;

[0059] S3: freeze-dry the filtrate, control the vacuum degree at 10 Pa, cool it to -40 °C at a rate of 5 °C / h, and freeze it for 3 hours; continue to control the vacuum degree at 5 Pa, heat it to 45 °C at a rate of 5 °C / h, and dry it for 3 hours to obtain vacuum freeze-dried marbofloxacin for injection.

[0060] Comparative Example 1

[0061] The method for preparing activated carbon comprises the following steps:

[0062] A1: Add 100 g activated carbon, 7 g alanine and 100 mL deionized water into a reaction bottle, stir evenly, heat to 70 ° C, keep warm for 9 hours, filter, wash to neutrality, and dry to obtain modified activated carbon.

[0063] Comparative Example 2

[0064] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0065] S1: 100 g of marbofloxacin, 20 g of mannitol and 500 mL of water for injection were mixed, and lactic acid was added to adjust the pH to 5 to obtain a mixed solution A;

[0066] S2: Stirring and decarbonizing the mixed solution A and 20 g of the modified activated carbon prepared in Comparative Example 1 to obtain a filtrate;

[0067] S3: freeze-dry the filtrate, control the vacuum degree at 10 Pa, cool it to -40 °C at a rate of 5 °C / h, and freeze it for 3 hours; continue to control the vacuum degree at 5 Pa, heat it to 45 °C at a rate of 5 °C / h, and dry it for 3 hours to obtain vacuum freeze-dried marbofloxacin for injection.

[0068] Comparative Example 3

[0069] A process for preparing vacuum freeze-dried marbofloxacin for injection comprises the following steps:

[0070] S1: 100 g of marbofloxacin, 20 g of mannitol and 500 mL of water for injection were mixed, and lactic acid was added to adjust the pH to 5 to obtain a mixed solution A;

[0071] S2: Stir the mixed solution A with 20 g of activated carbon and perform decarbonization treatment to obtain a filtrate;

[0072] S3: freeze-dry the filtrate, control the vacuum degree at 10 Pa, cool it to -40 °C at a rate of 5 °C / h, and freeze it for 3 hours; continue to control the vacuum degree at 5 Pa, heat it to 45 °C at a rate of 5 °C / h, and dry it for 3 hours to obtain vacuum freeze-dried marbofloxacin for injection.

[0073] The impurity content and reconstitution time of the vacuum freeze-dried marbofloxacin for injection prepared in Examples 4-8 and Comparative Examples 2-3 were tested, and the test results are shown in Table 1:

[0074] Table 1: Statistical table of Marbofloxacin performance test data for Examples 4-8 and Comparative Examples 2-3

[0075]

[0076]

[0077] As can be seen from Table 1, the marbofloxacin prepared in the present application has the advantages of low impurity content and fast re-dissolution rate.

[0078] The above is a detailed description of an embodiment of the present invention, but the content is only a preferred embodiment of the present invention and cannot be considered to limit the scope of implementation of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the scope of the patent coverage of the present invention.

Claims

1. A process for preparing vacuum freeze-dried marbofloxacin for injection, characterized in that: The steps include: S1: Marbofloxacin, mannitol and water for injection are mixed, and a pH regulator is added to adjust the pH to obtain a mixed solution A; S2: stirring and decarbonizing the mixed solution A and modified activated carbon to obtain a filtrate; S3: freeze-drying the filtrate to obtain vacuum freeze-dried marbofloxacin for injection.

2. The process for preparing the vacuum freeze-dried marbofloxacin for injection according to claim 1, characterized in that: The dosage ratio of marbofloxacin, mannitol and water for injection is 100g:20-40g:500-1000mL.

3. The process for preparing the vacuum freeze-dried marbofloxacin for injection according to claim 1, characterized in that: The specific steps of adjusting the pH value are: adding a pH adjuster to adjust the pH to 4.0-6.0, and the pH adjuster is lactic acid.

4. The process for preparing the vacuum freeze-dried marbofloxacin for injection according to claim 1, characterized in that: The mass ratio of marbofloxacin to modified activated carbon is 1:0.1-0.

3.

5. The process for preparing the vacuum freeze-dried marbofloxacin for injection according to claim 1, characterized in that: The specific steps of freeze drying are: control the vacuum degree at 10-40Pa, cool down to -40℃~-30℃ at a rate of 5-10℃ / h, freeze for 1-6h; continue to control the vacuum degree at 2-6Pa, heat up to 40-50℃ at a rate of 1-10℃ / h, and dry for 3-6h.

6. The process for preparing the vacuum freeze-dried marbofloxacin for injection according to claim 1, characterized in that: The preparation method of modified activated carbon comprises the following steps: A1: Add activated carbon, alanine and deionized water into a reaction bottle, stir evenly, heat to 70-90°C, keep warm for 9-12 hours, filter, wash until neutral, and dry to obtain component 1; A2: Add component 1, succinic anhydride and tetrahydrofuran into a reaction kettle, stir evenly, heat to 30-40°C, keep warm for 3-6 hours, filter and dry to obtain modified activated carbon.

7. The process for preparing the vacuum freeze-dried marbofloxacin for injection according to claim 6, characterized in that: The mass ratio of the activated carbon: alanine: deionized water is 100:7-15:100-500.

8. The process for preparing the vacuum freeze-dried marbofloxacin for injection according to claim 6, characterized in that: The addition ratio of the component 1: succinic anhydride: tetrahydrofuran is 100g: 10-15g: 500-1000mL.

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