Fosfomycin sodium composition and preparation method thereof

Abstract

The invention provides a fosfomycin sodium composition and a preparation method thereof, and particularly relates to the field of medicines. Comprising freeze-dried powder prepared from fosfomycin sodium and metronidazole lipid microspheres, the mass of the freeze-dried powder containing fosfomycin sodium is 0.09-1.01 g, the mass of the metronidazole lipid microspheres is 145-155 mg, the mass of metronidazole contained in the metronidazole lipid microspheres is 50 mg, and the pH value of the freeze-dried powder dissolved in 5 ml of water at the temperature of 25-35 DEG C is 6.0-6.5. Different from traditional single-variety drug combination, metronidazole is lipid microspheres, so that the bioavailability of metronidazole can be improved; the medicine and fosfomycin sodium are jointly filled into the same penicillin bottle, so that clinical medication is facilitated.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a sodium fosfomycin composition and its preparation method. Background Technology

[0002] Fosfomycin sodium is an antibiotic. It is used for respiratory tract infections, urinary tract infections, and skin and soft tissue infections caused by susceptible bacteria. It can also be used in combination with other antibiotics to treat severe infections caused by susceptible bacteria, such as sepsis, peritonitis, and osteomyelitis.

[0003] Infections during clinical surgery are often mixed infections involving both anaerobic and aerobic bacteria, rather than single anaerobic or aerobic infections. Metronidazole is the first-line drug for treating anaerobic infections. Clinically, fosfomycin sodium is often used in combination with metronidazole to prevent surgical infections and treat complex infections involving anaerobic bacteria. Internationally, the safety and efficacy of fosfomycin combined with metronidazole for preventing colorectal surgery infections are considered equivalent to that of doxycycline combined with metronidazole. However, both injectable fosfomycin sodium and injectable metronidazole are single-drug formulations. When used separately, the dosage of metronidazole is very high, and metronidazole has strong toxic side effects. Normal therapeutic doses of metronidazole can cause gastrointestinal reactions, most commonly including nausea, vomiting, loss of appetite, abdominal cramps, and high neurotoxicity. Fosfomycin sodium has a broad antibacterial spectrum, but its bactericidal effect is relatively weak, and it has mild gastrointestinal adverse reactions.

[0004] In view of the current state of the technology, there is a need for a sodium fosfomycin and its preparation method, namely sodium fosfomycin combined with metronidazole lipid microspheres, to overcome the shortcomings of the existing technology. Summary of the Invention

[0005] The purpose of this invention is to provide a fosfomycin sodium composition that differs from traditional single-drug combination therapy. In this invention, metronidazole is in the form of lipid microspheres, which can improve the bioavailability of metronidazole. It is also packaged together with fosfomycin sodium in the same vial for convenient clinical use.

[0006] A sodium fosfomycin composition comprising a lyophilized powder made from sodium fosfomycin and metronidazole lipid microspheres, wherein the lyophilized powder contains 0.09-1.01 g of sodium fosfomycin and 145-155 mg of metronidazole lipid microspheres, wherein the metronidazole lipid microspheres contain 50 mg of metronidazole, and the pH of the lyophilized powder dissolved in 5 ml of water at 25-35°C is 6.0-6.5.

[0007] Preferably, the lyophilized powdered phosphatidylcholine comprises 1g of sodium phosphatidylcholine and 150mg of metronidazole lipid microspheres.

[0008] The preparation method is as follows:

[0009] Preparation of metronidazole lipid microspheres:

[0010] S1a. Dissolve 9-11g of lactic acid-glycolic acid polymer (PLGA) and 0.09g-1.01g of polyethylene glycol in water for injection, and stir in a constant temperature water bath magnetic stirrer at 80°C until completely dissolved to prepare mixture A. The amount of water for injection is sufficient to fully dissolve the lactic acid-glycolic acid polymer (PLGA) and polyethylene glycol.

[0011] S2a. Add 0.03-0.05g of oleic acid to an oil phase consisting of 2.9-3.1g of soybean oil and 0.09g-1.01g of medium-chain fatty acid glycerides to form a mixed oil phase.

[0012] S3a. Add 0.4-0.6g of lecithin and 50mg of metronidazole to 200ml of anhydrous ethanol. Stir at 80℃ until the lecithin and metronidazole are completely dissolved. Then evaporate the anhydrous ethanol under reduced pressure. Add the mixed oil phase and stir evenly to prepare mixture B.

[0013] S4a. Add mixture A to mixture B and place it in a high-speed tissue homogenizer and stir 3 times at 8000r / min, 3 min each time;

[0014] S5a, adjust the pH to 6.5-6.8, add water for injection to a final volume of 1000ml, add to a high-pressure homogenizer, and homogenize 8 times at 70MPa;

[0015] S6a. Bottle, cap, sterilize at 100℃ for 30 min, and cool rapidly in an ice water bath to obtain metronidazole lipid microspheres.

[0016] Preparation of lyophilized powder:

[0017] S1b. Add the metronidazole lipid microspheres directly to the prescribed amount of water for injection, ensuring that the amount of water for injection is sufficient to completely dissolve the metronidazole lipid microspheres.

[0018] S2b, after stirring and dissolving, adjust the pH of the solution to the range of 6.5-6.8;

[0019] S3b. After sterilization filtration and sampling inspection, the solution is dispensed into stainless steel trays and placed in a freeze-drying chamber for freeze-drying to obtain metronidazole lipid microspheres aseptic freeze-dried powder, which is then pulverized and sieved.

[0020] S4b. Mix the pulverized and sieved metronidazole lipid microsphere lyophilized powder and fosfomycin sodium sterile powder according to the prescription amount to obtain the required powder injection.

[0021] Preferably, in step S1a, 10g of lactic acid-glycolic acid polymer (PLGA) and 1g of polyethylene glycol are dissolved in water for injection.

[0022] Preferably, in step S2a, 0.04g of oleic acid is added to an oil phase consisting of 3g of soybean oil and 1g of medium-chain fatty acid glycerides to form a mixed oil phase.

[0023] Preferably, in step S3a, 0.5g of lecithin and 50mg of metronidazole are added to 200ml of anhydrous ethanol.

[0024] Preferably, in step S4b, 150 mg of lyophilized metronidazole lipid microspheres after pulverization and sieving and 1 g of sodium fosfomycin are mixed to obtain the desired powder for injection.

[0025] The beneficial effects of this invention are:

[0026] Unlike traditional single-drug combination therapy, the metronidazole of this invention is in the form of lipid microspheres, which can improve the bioavailability of metronidazole; it is also packaged together with fosfomycin sodium in the same vial for convenient clinical use. Detailed Implementation

[0027] Example 1

[0028] A sodium fosfomycin composition comprising a lyophilized powder made from sodium fosfomycin and metronidazole lipid microspheres, wherein the lyophilized powder contains 0.09 g of sodium fosfomycin and 145 mg of metronidazole lipid microspheres, wherein the metronidazole lipid microspheres contain 50 mg of metronidazole, and the pH of the lyophilized powder when dissolved in 5 ml of water at 25°C is 6.0.

[0029] The preparation method is as follows:

[0030] Preparation of metronidazole lipid microspheres:

[0031] S1a. Dissolve 9g of lactic acid-glycolic acid polymer (PLGA) and 0.09g of polyethylene glycol in water for injection, and stir at 80°C in a constant temperature water bath with a magnetic stirrer until completely dissolved to prepare mixture A. The amount of water for injection should be sufficient to fully dissolve the lactic acid-glycolic acid polymer (PLGA) and polyethylene glycol. S2a. Add 0.03g of oleic acid to the oil phase composed of 2.9g of soybean oil and 0.09g of medium-chain triglycerides to form a mixed oil phase. S3a. Add 0.4g of lecithin and 50mg of metronidazole to anhydrous ethylene glycol. In 200 ml of ethanol, stir at 80 °C until lecithin and metronidazole are completely dissolved. Then, evaporate the anhydrous ethanol under reduced pressure and add the mixed oil phase. Stir until homogeneous to prepare mixture B. S4a: Add mixture A to mixture B and place in a high-speed tissue homogenizer and stir 3 times at 8000 r / min for 3 min each time. S5a: Adjust the pH to 6.5, add water for injection to a final volume of 1000 ml, and add to a high-pressure homogenizer. Homogenize 8 times at 70 MPa. S6a: Bottle, cap, sterilize at 100 °C for 30 min, and rapidly cool in an ice-water bath to obtain metronidazole lipid microspheres.

[0032] Preparation of lyophilized powder:

[0033] S1b: Add metronidazole lipid microspheres directly to the prescribed amount of water for injection, ensuring the water is sufficient to completely dissolve the microspheres; S2b: After stirring and dissolving, adjust the pH of the solution to within the range of 6.5; S3b: Perform sterile filtration, and after sampling and testing to ensure compliance with requirements, dispense the solution into stainless steel trays, place them in a freeze-drying chamber, and freeze-dry to obtain sterile freeze-dried powder of metronidazole lipid microspheres, which is then pulverized and sieved; S4b: Mix 145 mg of pulverized and sieved freeze-dried powder of metronidazole lipid microspheres with 0.09 g of sterile sodium fosfomycin powder to obtain the desired powder injection composition.

[0034] Example 2

[0035] A sodium fosfomycin composition comprising a lyophilized powder made from sodium fosfomycin and metronidazole lipid microspheres, wherein the lyophilized powder contains 1 g of sodium fosfomycin and 150 mg of metronidazole lipid microspheres, wherein the metronidazole lipid microspheres contain 50 mg of metronidazole, and the pH of the lyophilized powder when dissolved in 5 ml of water at 30°C is 6.2.

[0036] The preparation method is as follows:

[0037] Preparation of metronidazole lipid microspheres:

[0038] S1a. Dissolve 10g of lactic acid-glycolic acid polymer (PLGA) and 1g of polyethylene glycol in water for injection, and stir at 80°C in a constant temperature water bath with a magnetic stirrer until completely dissolved to prepare mixture A. The amount of water for injection should be sufficient to fully dissolve the lactic acid-glycolic acid polymer (PLGA) and polyethylene glycol. S2a. Add 0.04g of oleic acid to the oil phase composed of 3g of soybean oil and 1g of medium-chain triglycerides to form a mixed oil phase. S3a. Add 0.5g of lecithin and 50mg of metronidazole to 200ml of anhydrous ethanol. In ml, stir at 80℃ until lecithin and metronidazole are completely dissolved, then evaporate anhydrous ethanol under reduced pressure, and then add the mixed oil phase and stir evenly to prepare mixture B; S4a, add mixture A to mixture B, place in a high-speed tissue homogenizer and stir 3 times at 8000 r / min, 3 min each time; S5a, adjust the pH to 6.6, make up to 1000 ml with water for injection, add to a high-pressure homogenizer and homogenize 8 times at 70 MPa; S6a, bottle, cap, sterilize at 100℃ for 30 min, and cool rapidly in an ice water bath to obtain metronidazole lipid microspheres;

[0039] Preparation of lyophilized powder:

[0040] S1b: Add metronidazole lipid microspheres directly to the prescribed amount of water for injection, ensuring the water is sufficient to completely dissolve the microspheres; S2b: After stirring and dissolving, adjust the pH of the solution to within the range of 6.6; S3b: Perform sterile filtration, and after sampling and testing to ensure compliance with requirements, dispense the solution into stainless steel trays, place them in a freeze-drying chamber, and freeze-dry to obtain sterile freeze-dried powder of metronidazole lipid microspheres, which is then pulverized and sieved; S4b: Mix 150 mg of pulverized and sieved freeze-dried powder of metronidazole lipid microspheres with 1 g of sterile sodium fosfomycin powder to obtain the desired powder injection composition.

[0041] Example 3

[0042] A sodium fosfomycin composition comprising a lyophilized powder made from sodium fosfomycin and metronidazole lipid microspheres, wherein the lyophilized powder comprises 1.01 g of sodium fosfomycin and 155 mg of metronidazole lipid microspheres, wherein the metronidazole lipid microspheres contain 50 mg of metronidazole, and the pH of the lyophilized powder when dissolved in 5 ml of water at 35°C is 6.5.

[0043] The preparation method is as follows:

[0044] Preparation of metronidazole lipid microspheres:

[0045] S1a. Dissolve 11g of lactic acid-glycolic acid polymer (PLGA) and 1.01g of polyethylene glycol in water for injection, and stir at 80°C in a constant temperature water bath with a magnetic stirrer until completely dissolved to prepare mixture A. The amount of water for injection should be sufficient to fully dissolve the lactic acid-glycolic acid polymer (PLGA) and polyethylene glycol. S2a. Add 0.05g of oleic acid to the oil phase composed of 3.1g of soybean oil and 1.01g of medium-chain fatty acid glycerides to form a mixed oil phase. S3a. Add 0.6g of lecithin and 50mg of metronidazole to anhydrous ethylene glycol. In 200 ml of ethanol, stir at 80 °C until lecithin and metronidazole are completely dissolved. Then, evaporate the anhydrous ethanol under reduced pressure and add the mixed oil phase. Stir until homogeneous to prepare mixture B. S4a: Add mixture A to mixture B and place in a high-speed tissue homogenizer. Stir three times at 8000 r / min, 3 min each time. S5a: Adjust the pH to 6.8, add water for injection to a final volume of 1000 ml, and add to a high-pressure homogenizer. Homogenize at 70 MPa eight times. S6a: Bottle, cap, sterilize at 100 °C for 30 min, and rapidly cool in an ice-water bath to obtain metronidazole lipid microspheres.

[0046] Preparation of lyophilized powder:

[0047] S1b: Add metronidazole lipid microspheres directly to the prescribed amount of water for injection, ensuring the water is sufficient to completely dissolve the microspheres; S2b: After stirring and dissolving, adjust the pH of the solution to within the range of 6.8; S3b: Perform sterile filtration, and after sampling and testing to ensure compliance with requirements, dispense the solution into stainless steel trays, place them in a freeze-drying chamber, and freeze-dry to obtain sterile freeze-dried powder of metronidazole lipid microspheres, which is then pulverized and sieved; S4b: Mix 155 mg of pulverized and sieved freeze-dried powder of metronidazole lipid microspheres with 1.01 g of sterile sodium fosfomycin powder to obtain the desired powder injection composition.

[0048] Experimental data:

[0049] The products prepared in Examples 1 to 3 were designated as Example 1, Example 2, and Example 3, respectively. The pH of the solution was controlled at 6.0-6.5 when dissolved in 5 ml of water according to the prescribed dosage. Specific data are as follows:

[0050]

[0051] The prescription-sized samples prepared in Examples 1-3 were subjected to accelerated testing for bacterial endotoxins and sterility at the end of 6 months. The specific results are as follows:

[0052]

[0053] The data above shows that the samples prepared in Examples 1-3 have basically unchanged properties, pH value, diol content and metronidazole content, indicating good drug stability.

[0054] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A sodium fosfomycin composition, characterized in that: The product comprises a lyophilized powder made from sodium fosfomycin and metronidazole lipid microspheres, wherein the lyophilized powder contains 0.09-1.01 g of sodium fosfomycin and 145-155 mg of metronidazole lipid microspheres, wherein the metronidazole lipid microspheres contain 50 mg of metronidazole, and the pH of the lyophilized powder dissolved in 5 ml of water at 25-35°C is 6.0-6.

5.

2. The sodium fosfomycin composition according to claim 1, characterized in that: The lyophilized powdered phosphoam contains 1g of sodium oxytetracycline and 150mg of metronidazole lipid microspheres.

3. The method for preparing a sodium fosfomycin composition according to claim 1, characterized in that: Preparation of metronidazole lipid microspheres: S1a. Dissolve 9-11g of lactic acid-glycolic acid polymer (PLGA) and 0.09g-1.01g of polyethylene glycol in water for injection, and stir in a constant temperature water bath magnetic stirrer at 80°C until completely dissolved to prepare mixture A. The amount of water for injection is sufficient to fully dissolve the lactic acid-glycolic acid polymer (PLGA) and polyethylene glycol. S2a. Add 0.03-0.05g of oleic acid to an oil phase consisting of 2.9-3.1g of soybean oil and 0.09g-1.01g of medium-chain fatty acid glycerides to form a mixed oil phase. S3a. Add 0.4-0.6g of lecithin and 50mg of metronidazole to 200ml of anhydrous ethanol. Stir at 80℃ until the lecithin and metronidazole are completely dissolved. Then evaporate the anhydrous ethanol under reduced pressure. Add the mixed oil phase and stir evenly to prepare mixture B. S4a. Add mixture A to mixture B and place it in a high-speed tissue homogenizer and stir 3 times at 8000r / min, 3 min each time; S5a, adjust the pH to 6.5-6.8, add water for injection to a final volume of 1000ml, add to a high-pressure homogenizer, and homogenize 8 times at 70MPa; S6a. Bottle, cap, sterilize at 100℃ for 30 min, and cool rapidly in an ice water bath to obtain metronidazole lipid microspheres. Preparation of lyophilized powder: S1b. Add the metronidazole lipid microspheres directly to the prescribed amount of water for injection, ensuring that the amount of water for injection is sufficient to completely dissolve the metronidazole lipid microspheres. S2b, after stirring and dissolving, adjust the pH of the solution to the range of 6.5-6.8; S3b. After sterilization filtration and sampling inspection, the solution is dispensed into stainless steel trays and placed in a freeze-drying chamber for freeze-drying to obtain metronidazole lipid microspheres aseptic freeze-dried powder, which is then pulverized and sieved. S4b. Mix the pulverized and sieved metronidazole lipid microsphere lyophilized powder and fosfomycin sodium sterile powder according to the prescription amount to obtain the required powder injection.

4. The method for preparing a sodium fosfomycin composition according to claim 3, characterized in that: in step S1a, 10g of lactic acid-glycolic acid polymer (PLGA) and 1g of polyethylene glycol are dissolved in water for injection.

5. The method for preparing a sodium fosfomycin composition according to claim 3, characterized in that: in step S2a, 0.04g of oleic acid is added to an oil phase composed of 3g of soybean oil and 1g of medium-chain fatty acid glycerides to form a mixed oil phase.

6. The method for preparing a sodium fosfomycin composition according to claim 3, characterized in that: in step S3a, 0.5g of lecithin and 50mg of metronidazole are added to 200ml of anhydrous ethanol.

7. The method for preparing a sodium fosfomycin composition according to claim 3, characterized in that: in step S4b, 150 mg of lyophilized metronidazole lipid microspheres after pulverization and sieving and 1 g of sodium fosfomycin are mixed to obtain the desired powder for injection.

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