Preparation method of ertapenem sodium for injection

Abstract

The invention relates to the technical field of medical, dental or dressing preparations, in particular to a preparation method of ertapenem sodium for injection. The preparation method comprises the following steps: S1, adding a prescription amount of sodium bicarbonate into water, cooling and stirring to obtain a sodium bicarbonate solution; and S2, adding half of the prescription amount of ertapenem sodium into water, stirring at low temperature for dissolving, then adding a sodium bicarbonate solution, then adding the rest of ertapenem sodium, adjusting the pH value with the sodium hydroxide solution, then adding the modified magnolol, adding water to a certain amount, and then carrying out sterile filtration, subpackaging and freeze drying to obtain the ertapenem sodium injection. The preparation with better stability is obtained through the method, so that the stability of the preparation in the preparation process, transportation and long-term storage can be ensured.

Description

Technical Field

[0001] The invention relates to the technical field of medical, dental or cosmetic preparations, and in particular to a preparation method of ertapenem sodium for injection. Background Art

[0002] Ertapenem sodium is a carbapenem antibiotic, and its chemical name is (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]thio-6-(1R-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt. In the molecular structure of ertapenem, the methyl group at the C-1 position of the mother nucleus has strong resistance to renal dehydropeptidase-I (DHP-I); the trans-hydroxyethyl group at the C-6 position has strong resistance to lactamase; the benzoic acid group on the C-2 side chain has a strong electron-withdrawing ability, which makes it have a wide range of protein binding and prolongs the half-life of the drug. Due to these structural characteristics, ertapenem exhibits good broad-spectrum antibacterial activity and pharmacokinetic properties, a long half-life, and does not need to be used in combination with drugs that resist DHP-I enzymes. It has a wide range of antibacterial activity, including Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria. Its main mechanism of action is to inhibit the synthesis of bacterial cell walls and bind to penicillin-binding proteins (PBPs) to exert a bactericidal effect. Ertapenem is stable to a variety of β-lactamases, but can be hydrolyzed by metallo-β-lactamases. The indications of ertapenem sodium include the treatment of moderate to severe infections caused by sensitive strains, such as secondary abdominal infections, complicated skin and appendage infections, community-acquired pneumonia, complicated urinary tract infections (including pyelonephritis), acute pelvic infections, and bacteremia.

[0003] CN109134469A relates to a solid pharmaceutical composition of ertapenem sodium and a preparation method thereof, wherein the pharmaceutical composition contains ertapenem sodium as shown in formula 1, and a compound as shown in formula 2 or its sodium salt, hydrate or solvate, and pharmaceutically acceptable excipients. The proportion of the compound of formula 2 or its pharmaceutically acceptable salt, hydrate or solvate in the solid pharmaceutical composition of ertapenem sodium provided by the invention is as high as more than 80%, which greatly improves the stability of the final preparation of ertapenem sodium.

[0004] CN116196272A relates to an ertapenem preparation and a preparation method thereof, which comprises the following steps: 1) dissolving sodium bicarbonate in water to obtain a sodium bicarbonate solution; 2) mixing i) the sodium bicarbonate solution obtained in step 1), ii) ertapenem sodium or its solution and iii) sodium hydroxide or its solution at a temperature of 0 to 5°C, preparing a solution, controlling the pH of the solution to be 7.0 to 7.5, and obtaining an ertapenem solution; 3) adjusting the pH of the ertapenem solution obtained in step 2) to be 7.5 to 8.0 using a sodium hydroxide solution; 4) obtaining an ertapenem preparation. The ertapenem preparation obtained by improving the formulation and preparation process has significantly reduced degradation of the raw material ertapenem sodium, significantly reduced impurity content, and improved stability; the ertapenem freeze-dried preparation prepared by further improving the freeze-drying process has uniform crystal nucleus size, good properties, and significantly improved preparation stability.

[0005] Ensuring the stability of ertapenem sodium is a challenge because it is easily decomposed under acid, alkali, high temperature, oxidation, and hydrolysis conditions, and its main decomposition products include open-ring compounds and dimers. During the formulation process, the stability of this compound may be affected by factors such as temperature, addition order, and pH adjustment, leading to increased impurity levels. In addition, the entire chain from production to pre-use, including transportation and storage, as well as during actual use, the formulation may be at risk of degradation, which may lead to a further increase in impurity content. In order to improve the quality and stability of ertapenem sodium formulations, improvements need to be made to the existing preparation methods to reduce factors that may affect product quality throughout the supply chain. This includes optimizing the production process, improving transportation and storage conditions, and ensuring stability during use. Through these measures, degradation and impurity formation can be minimized, thereby ensuring the safety and effectiveness of the formulation. Summary of the invention

[0006] In view of the above-mentioned defects of the prior art, the technical problem to be solved by the present invention is to provide a method for preparing ertapenem sodium for injection.

[0007] Studies have shown that ertapenem sodium is unstable under conditions such as acid, alkali, oxidation, high temperature, and illumination, and the main degradation product is an open-loop degradation product, and it is also unstable after being prepared into an aqueous solution. With the increase of the placement time, the impurity content of the open-loop degradation product and the polymer increases significantly, and the main component content decreases significantly. Therefore, the present invention provides an antioxidant-magnolia phenol is one of the main active ingredients of magnolia bark, magnolia phenol has significant antioxidant capacity, can inhibit various intermediates produced by the oxidative stress process, and can also capture peroxy radicals. The phenolic hydroxyl group in its molecular structure can provide hydrogen atoms to free radicals, thereby neutralizing free radicals and reducing oxidative stress. Therefore, magnolia phenol and its derivatives have a wide range of application prospects in the field of medicine and health products, especially in terms of anti-oxidation, as a natural antioxidant, it is also safer than other commonly used antioxidants. However, magnolia phenol is insoluble in water, so its effectiveness is greatly limited in water. In the present invention, magnolol is modified and a nitrogen heterocycle is grafted onto the magnolol. Since the nitrogen atom on the nitrogen heterocycle has a lone pair of electrons and can form a hydrogen bond with a water molecule, the magnolol has good hydrophilicity. After grafting, the water solubility of magnolol can be improved. The modified magnolol is added to ertapenem sodium for injection to play an antioxidant role, thereby reducing the oxidative degradation of ertapenem sodium and enhancing the stability of the preparation.

[0008] To achieve the above object, the present invention provides a method for preparing ertapenem sodium for injection, comprising the following steps:

[0009] S1. Add the prescribed amount of sodium bicarbonate to water and cool it to 0-5°C to obtain a sodium bicarbonate solution;

[0010] S2. Add half of the prescribed amount of ertapenem sodium into water, stir to dissolve at 0-5°C, then add sodium bicarbonate solution, then add the remaining ertapenem sodium, adjust the pH to 7.3-7.6 with sodium hydroxide solution, add modified magnolol, add water to a certain amount and stir evenly, filter aseptically, divide into packages, and freeze-dry to obtain ertapenem sodium for injection.

[0011] The preparation method of the modified magnolol comprises the following steps:

[0012] X1. Add 2-6 parts by weight of magnolol, 0.4-1 parts by weight of sodium hydroxide and 0.6-1.5 parts by weight of 37% formaldehyde solution to 20-50 parts by weight of ethanol, stir at room temperature for 20-30 hours, add ethyl acetate for extraction, separate the organic phase, wash with brine, dry, concentrate under reduced pressure to remove the solvent, purify by silica gel column, and dissolve in 10-30 parts by weight of dichloromethane, cool to 0-5°C, add 1-3 parts by weight of thionyl chloride dropwise, stir at room temperature for 0.5-1 hour after the addition is complete, wash with saturated sodium bicarbonate aqueous solution, dry, filter, concentrate under reduced pressure to remove the solvent, and then add to 8-25 parts by weight of acetonitrile, continue to add 0.6-2 parts by weight of 4-Boc-aminopiperidine, 1-3 parts by weight of cesium carbonate and 0.01-0.05 parts by weight of potassium iodide, heat and stir for 16-24 hours, cool to room temperature, dilute with water, extract with ethyl acetate, wash the combined organic phase with brine, dry, and purify by silica gel column for the next step;

[0013] X2. Dissolve 3-5 parts by weight of the product of the previous step in 10-30 parts by weight of dichloromethane, add 0.2-0.5 parts by weight of trifluoroacetic acid at 0-5°C, stir for 0.5-1h and remove the solvent to obtain a residue, add it to a saturated aqueous sodium bicarbonate solution and extract it with ethyl acetate, wash the organic phase with brine, dry it, concentrate it under reduced pressure to remove the solvent and purify it with a silica gel column to obtain modified magnolol.

[0014] Furthermore, the temperature range of the heating in step X1 is 70-80°C.

[0015] Furthermore, the prescription amount of the sodium bicarbonate is 185 to 200 g.

[0016] Furthermore, the prescription amount of ertapenem sodium is 1045-1155 g.

[0017] Furthermore, the concentration of the sodium hydroxide solution is 1 mol / L.

[0018] Furthermore, the added amount of the modified magnolol is 0.05-0.1 wt % of the total amount.

[0019] Furthermore, the final quantitative amount of the water is 11000 g.

[0020] Furthermore, the packaging is 11 g per bottle.

[0021] Furthermore, the sterilizing filtration membrane is 0.22 to 0.24 μm.

[0022] Beneficial effects of the present invention:

[0023] 1. Compared with the prior art, the present invention obtains a preparation with better stability by adding modified magnolol in the preparation of ertapenem sodium injection, thereby ensuring its stability during the preparation process, transportation and long-term storage.

[0024] 2. The present invention modifies magnolol and grafts a nitrogen heterocycle onto magnolol. Since the nitrogen atom on the nitrogen heterocycle has a lone pair of electrons, it can form hydrogen bonds with water molecules and thus has good hydrophilicity. After grafting, the water solubility of magnolol can be improved. The modified magnolol is added to ertapenem sodium for injection to play an antioxidant role, thereby reducing the oxidative degradation of ertapenem sodium and enhancing the stability of the preparation. DETAILED DESCRIPTION

[0025] Example 1

[0026] A method for preparing ertapenem sodium for injection comprises the following steps:

[0027] S1. Add 200 g of sodium bicarbonate to 1 L of water for injection and cool to 5° C. to obtain a sodium bicarbonate solution;

[0028] S2: Add 570 g of ertapenem sodium to 7 L of water for injection, stir and dissolve at 5 °C, then add sodium bicarbonate solution, then add 570 g of ertapenem sodium, adjust the pH to 7.5 with 1 mol / L sodium hydroxide solution, add modified magnolol in an amount of 0.05 wt%, add water to a quantitative amount of 11000 g, stir evenly, filter through a 0.22 μm filter membrane, and dispense into 11 g per bottle, and freeze-dry to obtain ertapenem sodium for injection.

[0029] The preparation method of the modified magnolol comprises the following steps:

[0030] X1, add 2.5g of magnolol, 0.4g of sodium hydroxide and 0.6g of 37% formaldehyde solution to 30g of ethanol, stir at room temperature for 24h, then add ethyl acetate for extraction, separate the organic phase, wash with brine, dry, concentrate under reduced pressure to remove the solvent, purify by silica gel column, and dissolve in 25g of dichloromethane, cool to 0°C, add 1g of thionyl chloride dropwise, stir at room temperature for 0.5h after the addition is complete, add saturated sodium bicarbonate aqueous solution for washing, dry, filter, concentrate under reduced pressure to remove the solvent, and then add to 20g of acetonitrile, continue to add 0.7g of 4-Boc-aminopiperidine, 1.4g of cesium carbonate and 0.01g of potassium iodide, heat to 75°C, stir for 18h, then cool to room temperature, dilute with water, extract with ethyl acetate, wash the combined organic phase with brine, dry, and purify by silica gel column for the next step;

[0031] X2. Dissolve 3 g of the product from the previous step in 30 g of dichloromethane, add 0.3 g of trifluoroacetic acid at 0°C, stir for 0.5 h, and remove the solvent to obtain a residue. Add it to a saturated aqueous sodium bicarbonate solution and extract it with ethyl acetate. The organic phase is washed with brine, dried, concentrated under reduced pressure to remove the solvent, and purified by silica gel column to obtain modified magnolol.

[0032] Example 2

[0033] The method is basically the same as Example 1, except that the amount of modified magnolol added is 0.06 wt %.

[0034] Example 3

[0035] The method is basically the same as Example 1, except that the amount of modified magnolol added is 0.08 wt %.

[0036] Example 4

[0037] The method is basically the same as Example 1, except that the amount of modified magnolol added is 0.1 wt %.

[0038] Comparative Example 1

[0039] A method for preparing ertapenem sodium for injection comprises the following steps:

[0040] S1. Add 200 g of sodium bicarbonate to 1 L of water for injection and cool to 5° C. to obtain a sodium bicarbonate solution;

[0041] S2 Add 570g of ertapenem sodium to 7L of water for injection, stir and dissolve at 5°C, then add sodium bicarbonate solution, then add 570g of ertapenem sodium, adjust the pH to 7.5 with 1mol / L sodium hydroxide solution, add water to a quantitative amount of 11000g and stir evenly, sterile filter through a 0.22μm filter membrane, divide into 11g per bottle, and freeze-dry to obtain ertapenem sodium for injection.

[0042] Comparative Example 2

[0043] A method for preparing ertapenem sodium for injection comprises the following steps:

[0044] S1. Add 200 g of sodium bicarbonate to 1 L of water for injection and cool to 5° C. to obtain a sodium bicarbonate solution;

[0045] S2: Add 570 g of ertapenem sodium to 7 L of water for injection, stir and dissolve at 5 °C, then add sodium bicarbonate solution, then add 570 g of ertapenem sodium, adjust the pH to 7.5 with 1 mol / L sodium hydroxide solution, add magnolol in an amount of 0.05 wt%, add water to a quantitative amount of 11000 g, stir evenly, filter aseptically through a 0.22 μm filter membrane, and package into 11 g per bottle, and freeze-dry to obtain ertapenem sodium for injection.

[0046] Test Example 1

[0047] The ertapenem sodium for injection prepared in the example and the control example was added to water for injection to prepare a 1 mg / mL solution. After preparation, the content of each effective substance was determined by HPLC. The content of the effective substance was also determined after being placed at room temperature for 1, 3, and 6 months. The test results are shown in Table 1.

[0048] Table 1 Stability test results of ertapenem sodium aqueous solution for injection

[0049]

[0050]

[0051] Studies have shown that ertapenem sodium is unstable under conditions such as acid, alkali, oxidation, high temperature, and illumination. The main degradation product is an open-loop degradation product, and it is also unstable after being prepared into an aqueous solution. From the data in Table 1, it can be seen that with the increase of the placement time, the impurity content of the open-loop degradation product and the polymer increases significantly, and the total impurity increases significantly. Compared with the comparative example 1, the embodiment can be found that the degradation of ertapenem sodium is significantly slowed down after adding modified magnolol as an antioxidant. This may be because magnolol has a significant antioxidant capacity, can inhibit various intermediates produced by the oxidative stress process, and can also capture peroxy radicals. The phenolic hydroxyl group in its molecular structure can provide hydrogen atoms to free radicals, thereby neutralizing free radicals and reducing oxidative stress. Therefore, the ertapenem sodium aqueous solution in the embodiment has better stability. Compared with the comparative example 2, the stability of the aqueous solution in the embodiment is also better. This may be because magnolol is insoluble in water, so it will greatly limit its effectiveness in the aqueous solution, resulting in its antioxidant properties being difficult to play in the aqueous solution. In the embodiment, the present invention modifies magnolol and grafts a nitrogen heterocycle onto magnolol. Since the nitrogen atom on the nitrogen heterocycle has a lone pair of electrons, it can form a hydrogen bond with a water molecule, so it has good hydrophilicity. After grafting, the water solubility of magnolol can be improved. Therefore, the modified magnolol has a stronger effect on enhancing the stability of the preparation. Compared with other embodiments, the stability difference of Example 1 is not significant. Therefore, considering the comprehensive cost and other aspects, the dosage in Example 1 is the best.

[0052] Test Example 2

[0053] The long-term toxicity test of ertapenem sodium for injection prepared by the embodiment and the control example was carried out. Healthy SD rats weighing (135±10)g were taken, 30 rats in each group, half of which were male and half were female. The experimental group was intravenously administered at a dose of 20mg / kg per day, and the blank control group was injected with an equal amount of normal saline. One week of observation before administration, the activities, eating, feces, etc. of the animals in each group were normal, and then the administration was started. The drug was administered once a day on time for 60 consecutive days, and the body weight was weighed once a week, and the dosage was adjusted according to the changes in body weight. General observations such as appearance signs, behavioral activities, fecal traits, food intake, and weight changes were performed. After the end of the medication, the eyeballs were removed and blood was taken for hemogram and blood biochemical examinations, and the five organs of the heart, liver, spleen, lung, and kidney were weighed to calculate the organ weight ratio.

[0054] The test results show that the ertapenem sodium injection preparation prepared by the present invention has no significant effect on the visual signs, behavioral activities, stool characteristics, food intake, and body weight of mice, and the blood picture, blood biochemistry, and various organs are all normal.

[0055] The preferred specific embodiments of the present invention are described in detail above. It should be understood that a person skilled in the art can make many modifications and changes based on the concept of the present invention without creative work. Therefore, any technical solution that can be obtained by a person skilled in the art through logical analysis, reasoning or limited experiments based on the concept of the present invention on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A method for preparing ertapenem sodium for injection, characterized in that: The steps include: S1. Add the prescribed amount of sodium bicarbonate to water and cool it to 0-5°C to obtain a sodium bicarbonate solution; S2. Add half of the prescribed amount of ertapenem sodium into water, stir to dissolve at 0-5°C, then add sodium bicarbonate solution, then add the remaining ertapenem sodium, adjust the pH to 7.3-7.6 with sodium hydroxide solution, add modified magnolol, add water to a certain amount and stir evenly, filter aseptically, divide into packages, and freeze-dry to obtain ertapenem sodium for injection.

2. The method for preparing the ertapenem sodium injection according to claim 1, characterized in that: The preparation method of the modified magnolol comprises the following steps: X1. Add 2-6 parts by weight of magnolol, 0.4-1 parts by weight of sodium hydroxide and 0.6-1.5 parts by weight of 37% formaldehyde solution to 20-50 parts by weight of ethanol, stir at room temperature for 20-30 hours, add ethyl acetate for extraction, separate the organic phase, wash with brine, dry, concentrate under reduced pressure to remove the solvent, purify by silica gel column, and dissolve in 10-30 parts by weight of dichloromethane, cool to 0-5°C, add 1-3 parts by weight of thionyl chloride dropwise, stir at room temperature for 0.5-1 hour after the addition is complete, wash with saturated sodium bicarbonate aqueous solution, dry, filter, concentrate under reduced pressure to remove the solvent, and then add to 8-25 parts by weight of acetonitrile, continue to add 0.6-2 parts by weight of 4-Boc-aminopiperidine, 1-3 parts by weight of cesium carbonate and 0.01-0.05 parts by weight of potassium iodide, heat and stir for 16-24 hours, cool to room temperature, dilute with water, extract with ethyl acetate, wash the combined organic phase with brine, dry, and purify by silica gel column for the next step; X2. Dissolve 3-5 parts by weight of the product of the previous step in 10-30 parts by weight of dichloromethane, add 0.2-0.5 parts by weight of trifluoroacetic acid at 0-5°C, stir for 0.5-1h and remove the solvent to obtain a residue, add it to a saturated aqueous sodium bicarbonate solution and extract it with ethyl acetate, wash the organic phase with brine, dry it, concentrate it under reduced pressure to remove the solvent and purify it with a silica gel column to obtain modified magnolol.

3. The method for preparing the ertapenem sodium injection according to claim 2, characterized in that: The temperature range of the heating in step X1 is 70-80°C.

4. The method for preparing the ertapenem sodium injection according to claim 1, characterized in that: The prescription amount of the sodium bicarbonate is 185-200g.

5. The method for preparing the ertapenem sodium injection according to claim 1, characterized in that: The prescription amount of ertapenem sodium is 1045-1155g.

6. The method for preparing the injection of ertapenem sodium according to claim 1, characterized in that: The concentration of the sodium hydroxide solution is 1 mol / L.

7. The method for preparing the ertapenem sodium injection according to claim 1, characterized in that: The modified magnolol is added in an amount of 0.05-0.1 wt % of the total amount.

8. The method for preparing the ertapenem sodium injection according to claim 1, characterized in that: The final quantitative amount of the water is 11000 g.

9. The method for preparing the injection of ertapenem sodium according to claim 1, characterized in that: The packaging is 11 g / bottle.

10. The method for preparing the ertapenem sodium injection according to claim 1, characterized in that: The sterilizing filtration membrane has a diameter of 0.22 to 0.24 μm.

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