Levofloxacin sodium chloride injection and preparation method thereof

Abstract

The invention discloses a levofloxacin sodium chloride injection and a preparation method thereof. The injection contains levofloxacin, curcumin, disodium lauryl sulfosuccinate, sodium chloride and hydrochloric acid. The preparation method comprises the steps of metal container pretreatment, liquid medicine preparation, liquid medicine filtration, liquid medicine sterilization and liquid medicine filling. According to the present invention, the curcumin is adopted as the light absorption agent so as to effectively avoid the degradation of the levofloxacin under the illumination condition, such that the stability of the preparation is improved, and the tetrasodium glutamate diacetate is adopted as the metal ion chelating agent to pre-treat the metal container in the preparation process; the stability of the levofloxacin sodium chloride injection preserved in a metal container for a long time can be improved.

Description

Technical Field

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

[0002] Levofloxacin is the L-isomer of the racemic ofloxacin, an optically active L-isomer of the racemic ofloxacin. It belongs to the quinolone antibacterial drug class, and its antibacterial activity in vitro is about twice that of ofloxacin. Its mechanism of action is to inhibit DNA gyrase activity, and it has the characteristics of a broad antibacterial spectrum and strong antibacterial effect. At present, levofloxacin sodium chloride injection is one of the commonly used dosage forms in clinical practice, and is suitable for the treatment of the following mild, moderate and severe infections caused by sensitive strains of bacteria in adults (≥18 years old).

[0003] Levofloxacin is prone to degradation when exposed to strong light for a long time. The current solution adopted in the production and marketing process is to avoid light, which undoubtedly increases the production difficulty and production cost of this product, especially the commercially available finished products, which usually use light-shielding aluminum-plastic bags to improve the light stability of the product, increase the medication burden on patients and waste resources.

[0004] Chinese patent CN 102342910 A and Japanese patent JP 2009209069 A achieve the preparation of a product that is stable under light conditions by adding vitamin B6, a light-degradable substance. However, vitamin B6 is extremely unstable in the pH range of 4.3-5.3, and the impurities produced by its decomposition under light conditions have color, which will eventually cause the color of levofloxacin sodium chloride injection to change, affecting product quality.

[0004] In the actual production process of levofloxacin sodium chloride injection, due to basic production cost considerations, large quantities of liquid medicine have to be in contact with metal containers for a long time, and the halogen Cl in the liquid medicine — Elements will "corrode" metal containers, especially in high temperature environments, the "corrosion" rate will be faster, and metal ions (Fe, Cu, Al, etc.) will react with levofloxacin, which belongs to the quinolone drugs, causing changes in the key quality attributes of the product and directly affecting the product quality.

[0005] Chinese patent CN102961328A discloses the use of EDTA-Na as a chelating agent for levofloxacin injection to make the drug solution more stable. However, the chelating ability of EDTA-Na in the injection is limited. For drug solutions with strong metal "corrosion" ability, it usually shows insufficient chelating ability for free metal ions, and cannot ensure that the quality of the drug solution does not change after being stored in a metal container for a long time. This will directly affect the stability of levofloxacin. Moreover, EDTA-Na is added to large-volume injection solutions as a prescription ingredient, and long-term use will also cause certain harm to the safety of human medication.

[0006] Therefore, how to ensure the stability of levofloxacin sodium chloride injection during long-term storage in metal containers, and how to ensure the light stability of the product without causing changes in product quality such as color, has become a technical difficulty. Summary of the invention

[0007] The object of the present invention is to provide a levofloxacin sodium chloride injection which can be stored for a long time in a metal container, has stable quality, and is stable to light without causing the color of the liquid to change.

[0008] Another object of the present invention is to provide a method for preparing the levofloxacin sodium chloride injection.

[0009] The inventor screened multiple excipients and combinations, and accidentally discovered during the experiment that curcumin can be used as a light absorber to protect levofloxacin, and its color is basically the same as levofloxacin in the pH range of 4.3-5.3; in addition, tetrasodium glutamate diacetate has a high efficiency of metal ion chelating ability, and the inventor accidentally discovered that the chelating agent can be used to pretreat the metal container, and the stability of levofloxacin stored in the metal container for a long time is guaranteed without introducing additional metal ion chelating agents into the liquid medicine. Therefore, the prescription and preparation process of this product can solve the problems of instability of levofloxacin stored in metal containers for a long time and the light stability of the product in the prior art.

[0010] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 4.5-5.5g of levofloxacin, 8-10g of sodium chloride, 0.05-0.1g of curcumin, and 0.1g-0.2g of disodium lauryl sulfosuccinate.

[0011] The levofloxacin sodium chloride injection is characterized in that the levofloxacin raw material is levofloxacin hemihydrate.

[0012] The levofloxacin sodium chloride injection is characterized in that the concentration ratio of curcumin to disodium lauryl sulfosuccinate is 25% to 50%.

[0013] The preparation method of levofloxacin sodium chloride injection comprises:

[0014] (1) Add an appropriate amount of water for injection into a metal container, add tetrasodium glutamate diacetate at a water temperature of 60-80° C. and fully dissolve, then stir at the temperature for 1-3 hours, pre-treat the metal container, completely drain the liquid, and wash the metal container with water for injection and then dry it;

[0015] (2) Add 800 ml of water for injection at a temperature of 50-70°C into a metal container, and add the prescribed amount of sodium chloride, disodium lauryl sulfosuccinate, and levofloxacin to fully dissolve;

[0016] (3) After cooling the drug solution to 15-30°C, add an appropriate amount of hydrochloric acid to adjust the pH to 4.3-5.3, and then use water for injection to make the volume of the drug solution to 1000 ml;

[0017] (4) Add the prescribed amount of curcumin under stirring until it is completely dissolved;

[0018] (5) The drug solution is filtered, filled and sterilized using a 0.22 μm filter membrane.

[0019] The method for preparing levofloxacin sodium chloride injection is characterized in that the concentration of tetrasodium glutamate diacetate in step (1) is 0.1%-0.5% (w / v).

[0020] The preparation method of levofloxacin sodium chloride injection is characterized in that: the particle size requirement of curcumin powder in step (4) is: D 90 ≤30μm.

[0021] The method for preparing levofloxacin sodium chloride injection is characterized in that the filter membrane in step (5) is made of polyethersulfone (PES) or polytetrafluoroethylene (PVDF).

[0022] The method for preparing levofloxacin sodium chloride injection is characterized in that the filling volume in step (5) is 50 ml, 100 ml or 150 ml.

[0023] The method for preparing levofloxacin sodium chloride injection is characterized in that the sterilization condition in step (5) is 121° C. and the sterilization time is 8 min, 12 min, or 15 min.

[0024] The present invention has at least one of the following beneficial effects:

[0025] (1) The levofloxacin sodium chloride injection and preparation method of the present invention can ensure that the levofloxacin sodium chloride injection is stable under light conditions and the color does not change. (2) The levofloxacin sodium chloride injection and preparation method of the present invention can ensure that the quality of the levofloxacin sodium chloride injection is stable after long-term contact with a metal container. DETAILED DESCRIPTION

[0026] The present invention is further explained or illustrated by the following examples, but the examples provided should not be construed as limiting the scope of protection of the present invention.

[0027] Property detection method: visual

[0028] pH value detection method: Take this product and check it according to the law (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0631)

[0029] Color detection method: Take an appropriate amount of this product, add water to quantitatively dilute it to make a solution containing approximately 2 mg of levofloxacin per 1 ml, and measure the absorbance at a wavelength of 450 nm according to the UV-visible spectrophotometry (General Rules 0401 of Part IV of the Chinese Pharmacopoeia 2020 Edition). The absorbance shall not exceed 0.03.

[0030] Related substance detection method: accurately measure an appropriate amount of this product, quantitatively dilute it with 0.1mol / L hydrochloric acid solution to make a solution containing about 1.0mg of levofloxacin in 1ml, as the test solution; accurately measure an appropriate amount of the test solution, quantitatively dilute it with 0.1mol / L hydrochloric acid solution to make a solution containing 2μg of levofloxacin in 1ml, as the control solution. Use octadecylsilane bonded silica gel as the filler (Sapphire 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 4.0 with phosphoric acid)-acetonitrile (85:15) as mobile phase A, and use ethanol as mobile phase B, and perform gradient elution; the flow rate is 1ml per minute, the column temperature is 40℃, the detection wavelength is 294nm and 238nm, and the injection volume is 10μl.

[0031] Example 1

[0032] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.05g of curcumin, 0.1g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0033] Preparation method: (1) Add an appropriate amount of water for injection into a 316L stainless steel container, add tetrasodium glutamate diacetate (concentration of 0.1%) at a water temperature of 70°C to fully dissolve, maintain the temperature and stir for 2 hours, pre-treat the metal container and completely discharge the liquid, and use water for injection to clean the metal container and then drain it; (2) Add 800ml of water for injection into the metal container at a temperature of 60°C, add sodium chloride, disodium lauryl sulfosuccinate, and levofloxacin to fully dissolve; (3) After cooling the drug solution to 25°C, add an appropriate amount of hydrochloric acid to adjust the pH to 4.8, and then use water for injection to make the drug solution 1000ml; (4) Under stirring, add the prescribed amount of curcumin until it is completely dissolved; (5) Filter the drug solution with a 0.22μm filter membrane, the filling volume is 50ml, and the sterilization conditions are 121°C / 15min.

[0034] Example 2

[0035] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.1g of curcumin, 0.2g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0036] Preparation method: Same as Example 1.

[0037] Example 3

[0038] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.05g of curcumin, 0.2g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0039] Preparation method: in step (1), tetrasodium glutamate diacetate (concentration is 0.5%), and the rest is the same as in Example 1.

[0040] Example 4

[0041] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.08g of curcumin, 0.2g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0042] Preparation method: Step (1) The water temperature is 60°C, tetrasodium glutamate diacetate is added, and stirring is maintained at the temperature for 1 hour. The rest is the same as in Example 1.

[0043] Comparative Example 1

[0044] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.1g of curcumin, 0.1g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0045] Preparation method: Except that the concentration ratio of curcumin to disodium lauryl sulfosuccinate is 100%, the other steps are the same as those in Example 1.

[0046] Comparative Example 2

[0047] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.04g of curcumin, 0.2g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0048] Preparation method: Except that the concentration ratio of curcumin to disodium lauryl sulfosuccinate is 20%, the remaining steps are the same as those in Example 1.

[0049] Comparative Example 3

[0050] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.5g of curcumin, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0051] Preparation method: Except for adding curcumin, the remaining steps are the same as Example 1.

[0052] Comparative Example 4

[0053] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.2g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0054] Preparation method: Except that curcumin is not added and only disodium lauryl sulfosuccinate is added, the remaining steps are the same as those in Example 1.

[0055] Comparative Example 5

[0056] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.05g of curcumin, 0.1g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0057] Preparation method: In addition to adding curcumin, the particle size D 90 Except for the above, the remaining steps are the same as those in Example 1.

[0058] Comparative Example 6

[0059] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.05g of curcumin, 0.1g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0060] Preparation method: Except for not carrying out step (1), the remaining steps are the same as those in Example 1.

[0061] Comparative Example 7

[0062] A levofloxacin sodium chloride injection, characterized in that each liter of the injection contains 5g of levofloxacin, 9g of sodium chloride, 0.05g of curcumin, 0.1g of disodium lauryl sulfosuccinate, an appropriate amount of hydrochloric acid, and the rest is water for injection.

[0063] Preparation method: Except that the concentration of tetrasodium glutamate diacetate in step (1) is 0.6% (w / v), the remaining steps are the same as those in Example 1.

[0064] The above Examples 1-4 and Comparative Examples 1-5 were subjected to light stability testing, and the results are shown in Table 1.

[0065] Table 1 - Color investigation results of light stability (light intensity ≥ 1000lx) Test example project limit Light 0h Light 10h Light 24h Light 48h Lighting 120h Example 1 color ≤0.03 0.013 0.011 0.010 0.011 0.015 Example 2 color ≤0.03 0.011 0.014 0.011 0.009 0.014 Example 3 color ≤0.03 0.012 0.008 0.012 0.010 0.013 Example 4 color ≤0.03 0.009 0.010 0.011 0.011 0.014 Comparative Example 1 color ≤0.03 0.009 0.012 0.015 0.018 0.032 Comparative Example 2 color ≤0.03 0.010 0.014 0.021 0.033 0.042 Comparative Example 3 color ≤0.03 0.011 0.021 0.030 0.041 0.092 Comparative Example 4 color ≤0.03 0.009 0.018 0.025 0.037 0.097 Comparative Example 5 color ≤0.03 0.010 0.024 0.031 0.043 0.082

[0066] Conclusion: If only curcumin is added to the prescription of this product without disodium lauryl sulfosuccinate, the color of the solution of levofloxacin sodium chloride injection prepared according to the process of this product will be unqualified under long-term light conditions; if the concentration ratio of curcumin to disodium lauryl sulfosuccinate added in the prescription is not 25%-50%, the color of the solution will be unqualified under long-term light conditions; in the prescription of this product, curcumin and disodium lauryl sulfosuccinate are added according to the appropriate concentration ratio, but when the curcumin particle size D 90 When it exceeds 30μm, the color of the solution will be unqualified. In short, only when the levofloxacin sodium chloride injection is prepared according to the prescription and process of this product in the claims, the color can be guaranteed to be qualified and the color can remain stable under long-term light conditions. Therefore, the light stability of the product can be significantly improved.

[0067] The above Examples 1-4 and Comparative Examples 6-7 were placed in a sealed metal container and the key quality attributes (properties, pH, color, related substances, content) of the products were examined at 60°C. The results are shown in Table 2

[0068] Table 2 - Study on the stability of drug solution in long-term contact with metal container

[0069] Conclusion: According to the prescription of the present invention, if tetrasodium glutamate diacetate is not added according to the process requirements, the properties, pH, color, and related substances of levofloxacin sodium chloride injection in a metal container will change significantly, until it is unqualified; and when the concentration range of tetrasodium glutamate diacetate added exceeds 0.1% to 0.5%, the unknown impurities in the related substances of levofloxacin sodium chloride injection prepared according to this process will increase significantly. Therefore, according to the prescription and process of the claims of this product, the stability of levofloxacin sodium chloride injection after long-term storage in a metal container can be effectively improved, and the product quality can be guaranteed.

[0070] The above contents are further detailed descriptions of the present invention in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention.

Claims

1. A levofloxacin sodium chloride injection, characterized in that: Each liter of injection contains 4.5-5.5g of levofloxacin, 8-10g of sodium chloride, 0.05-0.1g of curcumin, and 0.1g-0.2g of disodium lauryl sulfosuccinate.

2. The levofloxacin sodium chloride injection according to claim 1, characterized in that: The raw material of levofloxacin is levofloxacin hemihydrate.

3. The levofloxacin sodium chloride injection according to claim 1, characterized in that: The concentration ratio of curcumin to disodium lauryl sulfosuccinate is 25% to 50%.

4. The method for preparing the levofloxacin sodium chloride injection according to claim 1, characterized in that The following steps are involved: (1) Add an appropriate amount of water for injection into a metal container, add tetrasodium glutamate diacetate at a water temperature of 60-80° C. and fully dissolve, then stir at the temperature for 1-3 hours, pre-treat the metal container, completely drain the liquid, and wash the metal container with water for injection and then dry it; (2) Add 800 ml of water for injection at a temperature of 50-70°C into a metal container, and add the prescribed amount of sodium chloride, disodium lauryl sulfosuccinate, and levofloxacin to fully dissolve; (3) After cooling the drug solution to 15-30°C, add an appropriate amount of hydrochloric acid to adjust the pH to 4.3-5.3, and then use water for injection to make the volume of the drug solution to 1000 ml; (4) Add the prescribed amount of curcumin under stirring until it is completely dissolved; (5) The drug solution is filtered, filled and sterilized using a 0.22 μm filter membrane.

5. The method for preparing levofloxacin sodium chloride injection according to claim 4, characterized in that: The concentration of tetrasodium glutamate diacetate in step (1) is 0.1%-0.5% (w / v).

6. The method for preparing levofloxacin sodium chloride injection according to claim 4, characterized in that: The curcumin powder particle size requirement in step (4) is: D 90 ≤30μm.

7. The method of claim 4, wherein: The filter membrane material in step (5) is polyethersulfone (PES) or polytetrafluoroethylene (PVDF).

8. The method of claim 4, wherein: The filling volumes in step (5) are 50 ml, 100 ml, and 150 ml.

9. The method of claim 4, wherein: In the step (5), the sterilization condition is 121° C., and the sterilization time is 8 min, 12 min, and 15 min.

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