Levofloxacin lactate sodium chloride injection and preparation method thereof

Abstract

The invention discloses a levofloxacin lactate sodium chloride injection, each 1000 ml of the injection contains 2 g of levofloxacin lactate, 3-4 g of aminopropyl-betaine, 2-4 g of propylene glycol, 9 g of sodium chloride, 0.2-0.4 g of ethanolamine, 0.7 ml of 10% lactic acid and the balance of water for injection, impurities can be reduced, and the stability of the injection can be improved.

Description

Technical Field

[0001] The invention relates to the field of chemical pharmacy, and in particular to a levofloxacin sodium lactate injection and a preparation method thereof. Background Art

[0002] Levofloxacin lactate, chemical name: (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid lactate hemihydrate, molecular weight: 460.41. Calculated as anhydrous, contains C 18 H 20 FN3O4 shall not be less than 78.9%. Levofloxacin is the left-handed isoform of ofloxacin and is a quinolone antibiotic with a broad antibacterial spectrum. It can inhibit the activity of bacterial DNA helicase, prevent bacterial DNA synthesis and replication, and lead to bacterial death.

[0003] At present, the injection of levofloxacin lactate injection has been approved for marketing, but there are problems with clarity and high impurity content after long-term storage, and the solution color turns yellow, which does not meet the quality standard requirements, seriously affecting the safety of clinical use. The impurities in drugs are mainly closely related to their production process and prescription. At present, the impurities of levofloxacin lactate sodium chloride injection in China mainly include levofloxacin diamine and demethyl levofloxacin, with the structural formulas as follows Ⅰ and Ⅱ respectively.

[0004]

[0005] CN109431993B discloses a lactic acid levofloxacin injection, which contains lactic acid levofloxacin 5-8g, long-chain triglyceride 3-4g, Tween 2-4g, sodium chloride 5-6g, ferrous gluconate 0.2-0.4g, citric acid-sodium citrate buffer solution 400-600g per liter of injection, and the surplus is water for injection. The lactic acid levofloxacin injection overcomes the defects of poor solubility and poor stability, and has the characteristics of good solubility and stability after long-term placement, color does not turn yellow, clarity meets regulations, pH decline is not obvious and stable content, etc. Moreover, the preparation method is simple, easy to control, and has higher application value. However, long-chain triglyceride is not soluble in water, and impurities are not measured, so there is no operational feasibility.

[0006] CN112957322B discloses a levofloxacin lactate sodium chloride injection and a preparation method thereof, which belongs to the field of medicine, contains 0.5w / v% of levofloxacin lactate and 0.86w / v% of sodium chloride as solute, and the solvent is water for injection, or a mixture of lactic acid and water for injection. The preparation method comprises dissolving levofloxacin lactate and sodium chloride in water for injection, adding lactic acid to adjust the pH, continuing to add water for injection to the configured amount for constant volume, filtering, and obtaining levofloxacin lactate sodium chloride injection. The present invention dissolves levofloxacin lactate and sodium chloride in water for injection at 42°C; dissolves levofloxacin lactate and sodium chloride specifically in a humidity environment of 40-60%RH; and sequentially filters through a polypropylene filter element and a polyethersulfone filter element for secondary filtration, wherein the filtration aperture of the polypropylene filter element is larger than that of the polyethersulfone filter element, the process is complicated, and no impurities are measured. Summary of the invention

[0007] In view of the deficiencies in the prior art, the object of the present invention is to provide a levofloxacin lactate sodium chloride injection and a preparation method thereof.

[0008] The technical scheme of the present invention is as follows: a levofloxacin lactate sodium chloride injection, wherein each 1000 ml injection contains 2 g of levofloxacin lactate, 3-4 g of aminopropyl-betaine, 2-4 g of propylene glycol, 9 g of sodium chloride, 0.2-0.4 g of ethanolamine, 0.7 ml of 10% lactic acid, and the remainder is water for injection.

[0009] The pH value of the lactated levofloxacin sodium chloride injection is 4.0-5.0.

[0010] In the levofloxacin lactate sodium chloride injection, the aminopropyl-betaine is one or more of lauryl amide propyl-, cocamidopropyl-, linoleyl amide propyl-, myristyl amide propyl-, palmitamidopropyl-, or isostearyl amide propyl-betaine.

[0011] The preparation method of the levofloxacin lactate sodium chloride injection comprises the following steps: taking sodium chloride and putting it into injection water with a weight of 5 times that of the sodium chloride, ultrasonically dispersing it, adding 0.1 g of activated carbon for injection, stirring and mixing, boiling at 100° C. for 15 minutes, cooling it slightly, circulating it internally for 10 minutes, filtering it under pressure with a titanium rod filter, adding 750 ml of injection water, adding 2 g of levofloxacin lactate, and mixing it with C 18 H 20According to FN3O4, aminopropyl-betaine, propylene glycol, sodium chloride, and ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir and reflux for 15 minutes, adjust the pH value to 4.0-5.0 with 10% lactic acid, cool to 40-50℃, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, and filter with a 0.22μm membrane filter element at the end. After homogenization, the injection solution is divided into bottles, filled with nitrogen, sealed, and sterilized.

[0012] The ultrasonic dispersion process of the levofloxacin lactate sodium chloride injection is as follows: 500-600W ultrasonic oscillation treatment for 30-40 minutes.

[0013] The process conditions for the two stirrings of the levofloxacin lactate sodium chloride injection are: 300-400 r / min, stirring for 40-50 minutes.

[0014] The present invention creatively discovered a levofloxacin lactate sodium chloride injection and a preparation method thereof, which has the characteristics of not changing yellow in color after being placed for a long time, clarity meeting the requirements, low and stable impurity content, good preparation process stability, simple process, high production efficiency, and is suitable for industrial mass production. DETAILED DESCRIPTION

[0015] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, but these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0016] Embodiment 1:

[0017] Preparation method: Sodium chloride is added to water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 550W ultrasonic oscillation treatment for 35 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 350r / min, stirring for 45 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, and filtering under pressure with a titanium rod filter. 750ml of water for injection is added, and 2g of levofloxacin lactate is added. 18 H 20According to FN3O4, palmitamide propyl-betaine, propylene glycol, sodium chloride, and ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, and stir. The stirring process conditions are: 350r / min, stirring for 45 minutes, refluxing for 15 minutes, adjusting the pH value to 4.5 with 10% lactic acid, cooling to 45°C, and pressurized filtering with a titanium rod filter and a 0.22μm membrane filter element, and finally filtering with a 0.22μm membrane filter element. After homogenization, the injection solution is divided into bottles, filled with nitrogen, sealed, and sterilized.

[0018] Embodiment 2:

[0019] Preparation method: Sodium chloride is added to water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 500W ultrasonic oscillation treatment for 40 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 300r / min, stirring for 50 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, filtering under pressure with a titanium rod filter, adding 750ml of water for injection, adding 2g of levofloxacin lactate, and mixing at C 18 H 20 FN3O4, lauramide propyl betaine, propylene glycol, sodium chloride, ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir, the stirring process conditions are: 300r / min, stirring for 50 minutes, reflux for 15 minutes, adjust the pH value to 4.0 with 10% lactic acid, cool to 50℃, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, filter with a 0.22μm membrane filter element at the end, and divide the injection into bottles after homogenization, fill with nitrogen, seal and sterilize.

[0020] Embodiment 3:

[0021]

[0022] Preparation method: Sodium chloride is put into water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 600W ultrasonic oscillation treatment for 30 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 400r / min, stirring for 40 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, filtering under pressure with a titanium rod filter, adding 750ml of water for injection, adding 2g of levofloxacin lactate, and mixing at C 18 H 20FN3O4, cocamidopropyl betaine, propylene glycol, sodium chloride, ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir, the stirring process conditions are: 400r / min, stirring for 40 minutes, reflux for 15 minutes, adjust the pH value to 5.0 with 10% lactic acid, cool to 40℃, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, filter with a 0.22μm membrane filter element at the terminal, and divide the injection into bottles after homogenization, fill with nitrogen, seal and sterilize.

[0023] Embodiment 4:

[0024] Preparation method: Sodium chloride is put into water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 600W ultrasonic oscillation treatment for 30 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 400r / min, stirring for 40 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, filtering under pressure with a titanium rod filter, adding 750ml of water for injection, adding 2g of levofloxacin lactate, and mixing at C 18 H 20 According to FN3O4, linoleamidopropyl-betaine, propylene glycol, sodium chloride, and ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, and stir. The stirring process conditions are: 400r / min, stirring for 40 minutes, refluxing for 15 minutes, adjusting the pH value to 5.0 with 10% lactic acid, cooling to 40°C, and filtering under pressure with a titanium rod filter and a 0.22μm membrane filter element. Filter with a 0.22μm membrane filter element at the terminal. After homogenization, the injection solution is divided into bottles, filled with nitrogen, sealed, and sterilized.

[0025] Embodiment 5:

[0026] Preparation method: Sodium chloride is added to water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 550W ultrasonic oscillation treatment for 35 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 350r / min, stirring for 45 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, and filtering under pressure with a titanium rod filter. 750ml of water for injection is added, and 2g of levofloxacin lactate is added. 18 H 20According to FN3O4, myristamide propyl betaine, propylene glycol, sodium chloride, and ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir, and the stirring process conditions are: 350r / min, stirring for 45 minutes, reflux for 15 minutes, adjust the pH value to 4.5 with 10% lactic acid, cool to 45°C, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, and filter with a 0.22μm membrane filter element at the end. After homogenization, the injection solution is divided into bottles, filled with nitrogen, sealed, and sterilized.

[0027] Comparative Example 1:

[0028]

[0029] Preparation method: Take 9g of sodium chloride and put it into 45ml of water for injection, stir to dissolve, add 0.1g of activated carbon for injection, stir to mix, boil at 100℃ for 15 minutes, cool slightly, circulate internally for 10 minutes, filter under pressure with a titanium rod filter, add 750ml of water for injection, add levofloxacin lactate (C 18 H 20 FN3O4) 2g, add 0.1g activated carbon for injection, add water for injection to the full amount, stir and reflux for 15 minutes, adjust the pH value to 4.5 with 10% lactic acid, cool to 45°C, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, and filter at the terminal with a 0.22μm membrane filter element. After homogenization, the injection solution is packaged in bottles, filled with nitrogen, sealed and sterilized.

[0030] Comparative Example 2:

[0031] Preparation method: Sodium chloride is added to water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 550W ultrasonic oscillation treatment for 35 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 350r / min, stirring for 45 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, and filtering under pressure with a titanium rod filter. 750ml of water for injection is added, and 2g of levofloxacin lactate is added. 18 H 20 FN3O4, propylene glycol, sodium chloride, ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir, the stirring process conditions are: 350r / min, stirring for 45 minutes, reflux for 15 minutes, adjust the pH value to 4.5 with 10% lactic acid, cool to 45℃, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, filter with a 0.22μm membrane filter element at the end, and divide the injection into bottles after homogenization, fill with nitrogen, seal and sterilize.

[0032] Comparative Example 3:

[0033]

[0034] Preparation method: Sodium chloride is added to water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 550W ultrasonic oscillation treatment for 35 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 350r / min, stirring for 45 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, and filtering under pressure with a titanium rod filter. 750ml of water for injection is added, and 2g of levofloxacin lactate is added. 18 H 20 FN3O4, lauramide propyl-betaine, sodium chloride, ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir, the stirring process conditions are: 350r / min, stirring for 45 minutes, reflux for 15 minutes, adjust the pH value to 4.5 with 10% lactic acid, cool to 40-50℃, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, filter with a 0.22μm membrane filter element at the end, and divide the injection into bottles after homogenization, fill with nitrogen, seal and sterilize.

[0035] Comparative Example 4:

[0036] Preparation method: Sodium chloride is added to water for injection with a weight of 5 times that of sodium chloride, and ultrasonic dispersion is performed. The process conditions for ultrasonic dispersion are: 550W ultrasonic oscillation treatment for 35 minutes, 0.1g of activated carbon for injection is added, and stirring is performed. The stirring process conditions are: 350r / min, stirring for 45 minutes, boiling at 100℃ for 15 minutes, cooling slightly, circulating internally for 10 minutes, and filtering under pressure with a titanium rod filter. 750ml of water for injection is added, and 2g of levofloxacin lactate is added. 18 H 20 FN3O4, aminopropyl-betaine, propylene glycol, sodium chloride, ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir, the stirring process conditions are: 350r / min, stirring for 45 minutes, reflux for 15 minutes, adjust the pH value to 4.5 with 10% lactic acid, cool to 45℃, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, filter with a 0.22μm membrane filter element at the end, and divide the injection into bottles after homogenization, fill with nitrogen, seal and sterilize.

[0037] Example 6: The levofloxacin lactate sodium chloride injections obtained in Examples 1 to 5 and Comparative Examples 1 to 4 were subjected to accelerated tests (temperature 40°C, humidity 75%). The inspection items included: clarity and color of the solution, impurity content, and main drug content. The results are shown in Table 1.

[0038] Impurity content determination method: Referring to the determination method of related substances of levofloxacin in Part II of the Chinese Pharmacopoeia (2015 edition), the related substances and impurity spectrum of levofloxacin lactate sodium chloride injection were studied. Chromatographic conditions: The chromatographic column is Welch C18 (4.6mm×250mm, 5μm), ammonium acetate sodium perchlorate solution (take 4.0g of ammonium acetate and 7.0g of sodium perchlorate, add 1300mL of water to dissolve, and adjust the pH value to 2.2 with phosphoric acid)-acetonitrile (85:15) as mobile phase A, acetonitrile as mobile phase B, and linear gradient elution is performed according to Table 1; the flow rate is 1mL·min -1 , column temperature was 40°C; detection wavelengths were 238 nm and 294 nm; injection volume was 10 μL.

[0039] Table 1 Gradient elution method of levofloxacin lactate sodium chloride injection

[0040] Time / min Mobile phase A / % Mobile phase B / % 0 100 0 18 100 0 25 70 30 39 70 30 40 100 0 50 100 0

[0041] Content determination method: high performance liquid chromatograph (Shimadzu Corporation, Japan); SPD-10AVP ultraviolet detector; N2000 chromatography workstation, chromatographic column: C18 column (150mm×4·6mm, 5μm); mobile phase: 0.05mol / L citric acid solution-1mol / L ammonium acetate solution-acetonitrile (77:1:14); detection wavelength is 293nm; flow rate is 1.0ml / min; injection volume: 10μl.

[0042] Table 2 Accelerated test of levofloxacin lactate sodium chloride injection

[0043]

[0044]

[0045] As shown in Table 2, the levofloxacin lactate sodium chloride injection obtained in Examples 1 to 5 has excellent stability. Comparative Example 1 is a preparation method of a conventional levofloxacin lactate sodium chloride injection, the levofloxacin lactate sodium chloride injection prescription of Comparative Example 2 omits aminopropyl-betaine, the levofloxacin lactate sodium chloride injection of Comparative Example 3 omits propylene glycol, and the levofloxacin lactate sodium chloride injection prescription of Comparative Example 4 omits ethanolamine. In these three cases, the stability of the injection is significantly deteriorated, indicating that the composition of the surfactant aminopropyl-betaine, propylene glycol, and the acid-base regulator ethanolamine in a specific ratio in the levofloxacin lactate sodium chloride injection can reduce impurities and improve the stability of the injection.

[0046] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A levofloxacin lactate sodium chloride injection, characterized in that: Each 1000ml injection contains 2g of levofloxacin lactate, 3-4g of aminopropyl betaine, 2-4g of propylene glycol, 9g of sodium chloride, 0.2-0.4g of ethanolamine, 0.7ml of 10% lactic acid, and the remainder is water for injection.

2. The levofloxacin lactate sodium chloride injection according to claim 1, characterized in that: The pH of levofloxacin lactate sodium chloride injection is 4.0-5.

0.

3. The levofloxacin lactate sodium chloride injection according to claim 1, characterized in that: The aminopropyl-betaine is one or more of lauryl amide propyl-, cocoamide propyl-, linoleamide propyl-, myristamide propyl-, palmitamide propyl-, or isostearamidopropyl-betaine.

4. The levofloxacin lactate sodium chloride injection according to claim 1, 2 or 3, characterized in that: The preparation method comprises the following steps: putting sodium chloride into water for injection with a weight of 5 times the weight of sodium chloride, dispersing by ultrasonic, adding 0.1 g of activated carbon for injection, stirring and mixing, boiling at 100°C for 15 minutes, cooling slightly, circulating internally for 10 minutes, filtering under pressure with a titanium rod filter, adding 750 ml of water for injection, adding 2 g of levofloxacin lactate, and mixing at C 18 H 20 According to FN3O4, aminopropyl-betaine, propylene glycol, sodium chloride, and ethanolamine, add 0.1g of activated carbon for injection, add water for injection to the full amount, stir and reflux for 15 minutes, adjust the pH value to 4.0-5.0 with 10% lactic acid, cool to 40-50℃, filter under pressure with a titanium rod filter and a 0.22μm membrane filter element, and filter with a 0.22μm membrane filter element at the end. After homogenization, the injection solution is divided into bottles, filled with nitrogen, sealed, and sterilized.

5. The levofloxacin lactate sodium chloride injection according to claim 4, characterized in that: The process conditions of ultrasonic dispersion are: 500-600W ultrasonic oscillation treatment for 30-40 minutes.

6. The levofloxacin lactate sodium chloride injection according to claim 5, characterized in that: The process conditions for the two stirrings are: 300-400r / min, stirring for 40-50 minutes.

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