Composition of beta-lactam inhibitor and cephalosporin medicine as well as preparation method and application of composition

Abstract

The invention provides a beta-lactam inhibitor and cephalosporin medicine composition as well as a preparation method and application thereof, and belongs to the technical field of pharmacy. The composition disclosed by the invention is prepared from the following components in parts by weight: 5 to 90 parts of beta-lactamase inhibitor and 0.01 to 50 parts of cephalosporin medicine. The antibacterial activity of the composition on gram-positive bacteria and gram-negative bacteria is remarkably improved, the antibacterial spectrum is expanded, and meanwhile the clinical application range is widened.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a composition of a beta-lactam inhibitor and a cephalosporin drug, and a preparation method and application thereof. Background Art

[0002] β-lactamase inhibitors are a new class of β-lactam drugs. β-lactamases are produced by plasmid transmission, which causes the β-lactam ring of some drugs to be hydrolyzed and inactivated. This is the main way for pathogens to become resistant to some common β-lactam cephalosporins (penicillins and cephalosporins).

[0003] Irreversible competitive β-lactamase inhibitors refer to inhibitors that inactivate the enzyme after an irreversible reaction with β-lactamase. The inhibitor itself is destroyed in the process of acting on the enzyme, so this type of enzyme inhibitor is called a "suicide enzyme inhibitor (SucideInhibitor)". Competitive β-lactamase inhibitors compete with substrates for the catalytic site of the enzyme, and by binding to certain points of the enzyme, the enzyme loses its function. β-lactamase inhibitors began to be developed in 1969. Through microbial screening and structural modification of enzyme inhibitors, a variety of β-lactamase inhibitors have been obtained. The drugs currently used in clinical practice are divided into two categories according to their chemical structure. Oxypenicillins, the representative drug is clavulanic acid. Penicillin sulfones, avibactam sodium, vilbobactam, relebactam, dulobactam sodium, enmetazobactam, etc.

[0004] The developed β-lactamase inhibitors include clavulanic acid, sulbactam and tazobactam. Clavulanic acid is the first β-lactamase inhibitor discovered and used clinically. When used alone, its antibacterial activity is very poor, but it is a strong inhibitor of β-lactamases of many bacteria, and its enzyme inhibitory activity is stronger than sulbactam. Clavulanic acid can inhibit broad-spectrum and ultra-broad-spectrum enzymes and form compound preparations of Ansitol and Timentin with amoxicillin and ticarcillin. Sulbactam is a semi-synthetic β-lactamase inhibitor. Its own antibacterial effect is very weak, but it has a strong and irreversible inhibitory effect on β-lactamases produced by Staphylococcus aureus and most Gram-negative bacteria. When used in combination with ampicillin, cefoperazone and amoxicillin, it can produce unexpected antibacterial effects. Tazobactam has a wider enzyme inhibition spectrum, strong tissue penetration and wide distribution. It forms a compound preparation Tazocillin with piperacillin, which has shown good clinical efficacy.

[0005] However, to date, no one has studied the combination of cefuroxime sodium or cefuroxime with avibactam sodium, lelibactam, or vaborbactam.

[0006] Therefore, it is very important to need a combination of cefuroxime sodium or cefuroxime or a pharmaceutically acceptable salt thereof and a β-lactamase inhibitor. Summary of the invention

[0007] The object of the present invention is to provide a composition of a β-lactam inhibitor and a cephalosporin drug, and a preparation method and application thereof, so as to solve the vacancy in the prior art of the combination of cefuroxime sodium or cefuroxime with a β-lactamase inhibitor.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a composition of a β-lactam inhibitor and a cephalosporin drug, which is composed of the following components in parts by weight:

[0010] 5 to 90 parts of β-lactamase inhibitor,

[0011] 0.01 to 50 parts of cephalosporins;

[0012] The β-lactamase inhibitors include one or more of avibactam sodium, ralelibactam, vaborbactam, relebactam, dulobactam sodium and enmetazobactam;

[0013] The cephalosporin drugs include one or more of cefuroxime, cefazolin sodium, latamoxef, ceftazidime, ceftriaxone sodium, cefuroxime, cefuroxime sodium, cefminox sodium, cefmetazole sodium, cefazolin sodium, cefodizime sodium and ceftriaxone sodium.

[0014] Furthermore, the dosage form of the composition is a lyophilized preparation or a powder injection preparation.

[0015] Furthermore, when the dosage form of the composition is a lyophilized preparation, the composition also includes pharmaceutically acceptable additives and solvents;

[0016] The additives include one or more of fillers, disintegrants, binders, wetting agents, lubricants, flavoring agents, pH regulators, isotonicity regulators, antioxidants and metal ion chelating agents.

[0017] Furthermore, when the dosage form of the composition is a powder injection preparation, the preparation method of the powder injection preparation is:

[0018] Mix the β-lactamase inhibitor and cephalosporin under sterile conditions and package them.

[0019] Furthermore, when the dosage form of the composition is a lyophilized preparation, the preparation method of the lyophilized preparation is:

[0020] Adding a β-lactamase inhibitor, a cephalosporin drug and an additive to a solvent having a mass fraction of 85 to 95% of the total mass of the composition, adjusting the pH, adding the remaining 5 to 15% of the solvent, and then filtering and filling to obtain a freeze-dried preparation intermediate solution;

[0021] The freeze-dried preparation intermediate solution is rapidly cooled at a cooling rate of ≥20°C / h, so that the temperature of the freeze-dried preparation solution drops to -50 to -25°C, maintained for 0.5 to 4h, and then sublimated under the conditions of vacuum degree ≤200Pa and temperature of -15 to 0°C for 0.5 to 12h, and the temperature is raised to 25 to 35°C for analytical drying for 1 to 5h. Finally, the prepared freeze-dried preparation is taken out of the box and capped.

[0022] The present invention also provides an application of the combination of the beta-lactam inhibitor and cephalosporin drugs in the preparation of antibacterial drugs.

[0023] Beneficial effects of the present invention:

[0024] The composition of the present invention not only significantly improves the antibacterial activity against Gram-positive bacteria and Gram-negative bacteria through the synergistic effect of the β-lactam inhibitor and the cephalosporin drug, but also expands the antibacterial spectrum and the scope of clinical application.

[0025] The compositions of the present invention can be used for bacterial infections in mammals. DETAILED DESCRIPTION

[0026] The present invention provides a composition of a β-lactam inhibitor and a cephalosporin drug, which is composed of the following components in parts by weight:

[0027] 5 to 90 parts of β-lactamase inhibitor,

[0028] 0.01~50 parts of cephalosporin drugs.

[0029] In the present invention, the content of the β-lactamase inhibitor is preferably 6 to 85 parts by weight, and more preferably 7 to 80 parts by weight.

[0030] In the present invention, the β-lactamase inhibitor includes one or more of avibactam sodium, ralelibactam, vaborbactam, relebactam, dulobactam sodium and emmetazobactam, preferably one or more of avibactam sodium, ralelibactam, vaborbactam, dulobactam sodium and emmetazobactam, further preferably one or more of avibactam sodium, ralelibactam, vaborbactam and dulobactam sodium.

[0031] In the present invention, the content of the cephalosporin drug is preferably 0.05 to 45 parts by weight, and more preferably 1 to 40 parts by weight.

[0032] In the present invention, the cephalosporin drugs include one or more of cefuroxime, ceftizoxime sodium, latamoxef, ceftazidime, ceftriaxone sodium, cefuroxime, cefoxime sodium, cefminox sodium, cefmetazole sodium, cefazolin sodium, cefdizime sodium and ceftriaxone sodium, preferably one or more of cefuroxime, ceftizoxime sodium, latamoxef, ceftriaxone sodium, cefuroxime, cefoxime sodium, cefminox sodium, cefmetazole sodium, cefazolin sodium, cefdizime sodium and ceftriaxone sodium, further preferably one or more of cefuroxime, ceftizoxime sodium, ceftriaxone sodium, ceftriaxone sodium, cefuroxime, cefoxime sodium, cefminox sodium, cefdizime sodium and ceftriaxone sodium.

[0033] In the present invention, the β-lactamase inhibitor is mainly penicillin sulfone, and the specific compounds are as follows:

[0034] 1) The chemical name of avibactam sodium is [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]sulfate monosodium salt, and the chemical structure is as follows:

[0035]

[0036] Avibactam sodium belongs to the diazabicyclooctanone compound, which itself has no significant antibacterial activity, but can inhibit type A (including ESBL and KPC) and type C β-lactamases;

[0037] 2) The chemical structure of lelibactam is as follows:

[0038]

[0039] The mechanism of action of ralibactam is similar to that of avibactam sodium, and it has enzyme inhibitory activity against KPC-producing bacteria, but unlike avibactam sodium, ralibactam has low activity against class D β-lactamases;

[0040] 3) The chemical name of faborbactam is (3R,6S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxaborane-6-acetic acid, and its structural formula is as follows:

[0041]

[0042] Faborbactam is mainly used to enhance the antibacterial effect of meropenem and other cephalosporins against drug-resistant bacteria by inhibiting the β-lactamase produced by bacteria and protecting meropenem from being degraded by these enzymes, thereby enhancing its antibacterial activity;

[0043] 4) The chemical name of dulobactam sodium is (2S,5R)-2-carboxamido-3-methyl-7-keto-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sodium sulfate, and the structural formula is as follows:

[0044]

[0045] Dulobactam sodium is a diazabicyclooctane, non-β-lactam β-lactamase inhibitor that protects sulbactam from degradation by β-lactamases;

[0046] 5) The chemical name of Enmetazobactam is (2S,3S,5R)-3-methyl-3-((3-methyl-1hydrogen-1,2,3-triazol-3-ium-1-yl)methyl)-7-keto-4-sulfone-1azabicyclo[3.2.0]heptane-2-carboxylate, and the structural formula is as follows:

[0047]

[0048] Enmetazobactam is a β-lactamase inhibitor that protects cephalosporins from degradation by certain serine β-lactamases.

[0049] In the present invention, cephalosporin drugs refer to a type of cephalosporin obtained by semi-synthetically modifying the side chain of natural cephalosporin C obtained by culturing Cephalosporin C as a raw material. There are about 30 commonly used cephalosporins, which are divided into the first, second, third, fourth and fifth generations according to their generation order and antibacterial properties. The specific compounds are as follows:

[0050] 1) The structural formula of cefuroxime is as follows:

[0051]

[0052] The bactericidal effect of cefuroxime originates from the inhibition of cell wall biosynthesis and is mediated by binding to penicillin-binding proteins (PBPs). Cefuroxime is an inhibitor of Pseudomonas aeruginosa PBPs (e.g., PBP1b, PBP1c, and PBP3) and Escherichia coli (e.g., PBP3).

[0053] 2) The chemical name of cefotaxime sodium is (6R,7R)-3-[(acetyloxy)methyl]-7-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, and the structural formula is as follows:

[0054]

[0055] Ceftriaxone sodium is a third-generation semi-synthetic cephalosporin. It is less effective than cefazolin against Gram-positive bacteria. Enterococci are resistant to this product. It is ineffective against penicillin-resistant pneumococci. It has strong bactericidal activity against Gram-negative bacteria. It has stronger antibacterial effects than cefoperazone against Escherichia coli, influenza bacilli, pneumonia bacilli, Proteus mirabilis, and Salmonella. It has weak effects or is resistant to Bacteroides fragilis. Pseudomonas aeruginosa and Enterobacter cloacae are not sensitive to this product.

[0056] 3) The chemical name of cefuroxime sodium is (6R, 7R)-7-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, and the structural formula is as follows:

[0057]

[0058] Cefuroxime sodium is a third-generation cephalosporin with a broad-spectrum antibacterial effect. It is stable against broad-spectrum β-lactamases (including penicillinase and cephalosporinase) produced by a variety of Gram-positive and Gram-negative bacteria. Cefuroxime sodium has a strong antibacterial effect on Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and other Enterobacteriaceae. Pseudomonas and Acinetobacter such as Pseudomonas aeruginosa are less sensitive to this product. Cefuroxime sodium has a good antibacterial effect on Haemophilus influenzae and Neisseria gonorrhoeae.

[0059] 4) The chemical name of cefuroxime is 3-carbamoyloxymethyl-7-[2-(2-furyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-1-ethiocefuroxime, and the structural formula is as follows:

[0060]

[0061] Cefuroxime is a bactericidal cephalosporin that is resistant to most β-lactamases and can be widely used against Gram-positive and Gram-negative bacteria. The bactericidal activity of cefuroxime in vivo comes from its parent compound cefuroxime. Cefuroxime is a well-characterized and effective antibacterial drug with a broad antibacterial spectrum and bactericidal activity against a wide range of common pathogens, including β-lactamase-producing bacteria. Cefuroxime has good stability against bacterial β-lactamases and is therefore effective against many strains resistant to ampicillin and amoxicillin. The bactericidal activity of cefuroxime comes from inhibiting cell wall synthesis by binding to key target proteins.

[0062] 5) The chemical name of cefoxitin sodium is sodium 3-carbamoyloxymethyl-7-methoxy-7-(2-thiopheneacetamido)-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and the structural formula is as follows:

[0063]

[0064] Cefuroxime sodium is a cephalosporin of the cephalosporin class. It is a cephalosporin produced by Streptomyces Lactamdurans. It is a new type of cephalosporin prepared by semi-synthesis. Its parent nucleus is similar to cephalosporin and has similar antibacterial properties. It is usually included in the second-generation cephalosporins. The antibacterial mechanism of cefuroxime sodium is to inhibit the cell wall synthesis of bacterial dividing active cells by binding to one or more penicillin binding proteins (PBPs) in bacterial cells, thereby exerting an antibacterial effect. The antibacterial action of cefuroxime sodium is characterized by its stability to β-lactamase produced by Gram-negative bacilli and its antibacterial activity against most Gram-positive cocci and Gram-negative bacilli.

[0065] 6) The structural formula of cefuroxime sodium is as follows:

[0066]

[0067] Cefuroxime sodium is a cephalosporin of the cephalomycin class. It is highly stable to β-lactamase and has a strong affinity with penicillin-binding protein, the action point of β-lactam cephalosporins. It can inhibit the biosynthesis of cell walls and bind to peptidoglycans, inhibiting the binding of peptidoglycans to lipoproteins and promoting bacteriolysis. Cefuroxime sodium can also bind to diaminopimelic acid of the outer membrane lipoproteins unique to Gram-negative bacteria, showing its strong dual bactericidal effect in a short period of time.

[0068] 7) The chemical name of cefmetazole sodium is (6R,7S)-7-[2-[(cyanomethyl)thio]acetylamino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, and the structural formula is as follows:

[0069]

[0070] Ceftriaxone sodium is a semi-synthetic cephalosporin derivative with antibacterial activity similar to that of the second-generation cephalosporins. Ceftriaxone sodium also has good antibacterial activity against some cephalosporin-resistant strains, and has strong antibacterial activity against Staphylococcus aureus, Escherichia coli, Klebsiella, indole-negative or -positive Proteus, Bacteroides fragilis, Peptococcus (including Peptostreptococcus), etc.

[0071] 8) The chemical name of cefazolin sodium is (6R, 7R)-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]tetrazol-1-yl>acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, and the structural formula is as follows:

[0072]

[0073] The antibacterial spectrum of cefazolin sodium is similar to that of cephalexin, and it has antibacterial effects on Staphylococci (including enzyme-producing strains), Streptococci (except enterococci), Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Haemophilus influenzae, and Enterobacter aerogenes. The characteristics of cefazolin sodium are that it has a stronger effect on Gram-positive bacteria and weaker resistance to β-lactamase of Staphylococci.

[0074] 9) The chemical name of cefodizime sodium is (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetylamino]-3-[(5-carboxymethyl-4-methylthiazol-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt, and the structural formula is as follows:

[0075]

[0076] Cefdizime sodium is a third-generation cephalosporin for parenteral use. Cefdizime sodium has a high affinity for proteins involved in cell wall synthesis in sensitive bacteria. Cefdizime sodium has a broad antibacterial spectrum, including most clinically relevant Gram-positive bacteria, Gram-negative bacteria, aerobic bacteria and anaerobic bacteria. Cefdizime sodium is insensitive to most β-lactamases.

[0077] 10) The chemical name of ceftriaxone sodium is (6R, 7R)-7-[[(2Z)-(2-aminothiazol-4-yl)(methoxyimino)acetyl]amino]-3-[[(2-methyl-6-hydroxy-5-oxo-2,5-dihydro-1,2,4-triazine-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt triphemihydrate, and the structural formula is as follows:

[0078]

[0079] Ceftriaxone sodium is a third-generation cephalosporin with strong activity against Enterobacteriaceae. The MIC90 for Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter fluorescens, indole-positive Proteus, Providencia and Serratia is between 0.12-0.25 mg / L. Enterobacter cloacae, Acinetobacter and Pseudomonas aeruginosa are less sensitive to this product. It has a strong antibacterial effect on Haemophilus influenzae, Neisseria gonorrhoeae and Neisseria meningitidis, and also has a good effect on hemolytic Streptococcus and Pneumococcus.

[0080] 11) The chemical name of ceftazidime is (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(1-hydroxy-2-methyl-1-oxopropane-2-yl)oxyiminoacetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and the structural formula is as follows:

[0081]

[0082] Ceftazidime is a third-generation cephalosporin developed by GlaxoSmithKline. It has a strong effect on both Gram-positive and Gram-negative bacteria, and has strong antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Klebsiella, Proteus, Enterococcus, Salmonella, Shigella, Neisseria gonorrhoeae, Neisseria meningitidis, Staphylococcus aureus, hemolytic Streptococcus, Pneumococcus and Clostridium difficile. Especially for Pseudomonas aeruginosa, ceftazidime is the most effective cephalosporin. Its medicinal injection is a sterile mixture of ceftazidime pentahydrate and sodium carbonate or arginine.

[0083] In the present invention, the combination of the β-lactam inhibitor and the cephalosporin drug comprises:

[0084] 1) A combination of avibactam sodium and cefuroxime, wherein the weight ratio of avibactam sodium to cefuroxime is 1 to 20:1, preferably 1:1, 1:2, 1:3, 1:4, 1:6, 1:7 or 20:1;

[0085] 2) A combination of lelibactam and cefuroxime sodium, wherein the weight ratio of lelibactam to cefuroxime sodium is 1 to 20:1, preferably 1:1, 1:2, 1:3, 1:4, 1:6, 1:7 or 20:1;

[0086] 3) A combination of vaborbactam and ceftizoxime sodium, wherein the weight ratio of vaborbactam to ceftizoxime sodium is 1 to 20:1, preferably 1:1, 1:2, 1:3, 1:4, 1:6, 1:7 or 20:1;

[0087] 4) A combination of Webobactam and Cefuroxime Sodium, wherein the weight ratio of Webobactam to Cefuroxime Sodium is 1 to 20:1, preferably 1:1, 1:2, 1:3, 1:4, 1:6, 1:7 or 20:1;

[0088] 5) A combination of dulobactam sodium and cefoxitin sodium, wherein the weight ratio of dulobactam sodium to cefoxitin sodium is 1 to 20:1, preferably 1:1, 1:2, 1:3, 1:4, 1:6, 1:7 or 20:1.

[0089] In the present invention, the dosage form of the composition is a lyophilized preparation or a powder injection preparation.

[0090] In the present invention, when the dosage form of the composition is a lyophilized preparation, the composition further comprises pharmaceutically acceptable additives and solvents;

[0091] The additives include one or more of fillers, disintegrants, binders, wetting agents, lubricants, flavoring agents, pH adjusters, isotonic adjusters, antioxidants and metal ion chelators, preferably one or more of fillers, disintegrants, binders, wetting agents, pH adjusters, isotonic adjusters, antioxidants and metal ion chelators, and further preferably one or more of fillers, disintegrants, wetting agents, pH adjusters, isotonic adjusters and metal ion chelators.

[0092] In the present invention, the pH adjuster includes one or more of sodium hydroxide, phosphoric acid, phosphate, citric acid, citrate, citric acid, citrate, acetic acid, acetate, glycine and lysine, preferably one or more of sodium hydroxide, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, glycine and lysine, and further preferably one or more of sodium hydroxide, phosphoric acid, phosphate, citric acid, citrate, glycine and lysine.

[0093] In the present invention, the isotonicity adjusting agent includes one or more of sodium chloride, glucose, glycerol, sorbitol, maltose, mannitol and propylene glycol, preferably one or more of sodium chloride, glucose, glycerol, sorbitol, mannitol and propylene glycol, and further preferably one or more of sodium chloride, glucose, sorbitol, mannitol and propylene glycol.

[0094] In the present invention, the antioxidant includes one or more of sodium sulfite, sodium bisulfite and sodium pyrosulfite, preferably sodium sulfite and / or sodium bisulfite, and more preferably sodium sulfite.

[0095] In the present invention, the metal chelating agent includes ethylenediaminetetraacetic acid and / or ethylenediaminetetraacetic acid sodium salt, preferably ethylenediaminetetraacetic acid.

[0096] In the present invention, the solvent is preferably water for injection.

[0097] In the present invention, when the dosage form of the composition is a powder injection preparation, the preparation method of the powder injection preparation is:

[0098] Mix the β-lactamase inhibitor and cephalosporin under sterile conditions and package them.

[0099] In the present invention, when the dosage form of the composition is a lyophilized preparation, the preparation method of the lyophilized preparation is:

[0100] Adding a β-lactamase inhibitor, a cephalosporin drug and an additive to a solvent having a mass fraction of 85 to 95% of the total mass of the composition, adjusting the pH, adding the remaining 5 to 15% of the solvent, and then filtering and filling to obtain a freeze-dried preparation intermediate solution;

[0101] The freeze-dried preparation intermediate solution is rapidly cooled at a cooling rate of ≥20°C / h, so that the temperature of the freeze-dried preparation solution drops to -50 to -25°C, maintained for 0.5 to 4h, and then sublimated under the conditions of vacuum degree ≤200Pa and temperature of -15 to 0°C for 0.5 to 12h, and the temperature is raised to 25 to 35°C for analytical drying for 1 to 5h. Finally, the prepared freeze-dried preparation is taken out of the box and capped.

[0102] Preferably, the preparation method of the lyophilized preparation is:

[0103] Adding a β-lactamase inhibitor, a cephalosporin drug and an additive to a solvent having a mass fraction of 87 to 92% of the total mass of the composition, adjusting the pH, adding the remaining 8 to 13% of the solvent, and then filtering and filling to obtain a lyophilized preparation solution;

[0104] The freeze-dried preparation solution is rapidly cooled at a cooling rate of ≥22°C / h, so that the temperature of the freeze-dried preparation solution drops to -45 to -20°C, maintained for 1 to 3.5 hours, and then sublimated under the conditions of vacuum degree ≤190Pa and temperature of -12 to -1°C for 1 to 10 hours, and the temperature is raised to 27 to 32°C for analytical drying for 1.5 to 4.5 hours. Finally, the prepared freeze-dried preparation is taken out of the box and capped.

[0105] Further preferably, the preparation method of the lyophilized preparation is:

[0106] Adding a β-lactamase inhibitor, a cephalosporin drug and an additive to a solvent having a mass fraction of 90% of the total mass of the composition, adjusting the pH, adding the remaining 10% of the solvent, and then filtering and filling to obtain a lyophilized preparation solution;

[0107] The freeze-dried preparation solution is rapidly cooled at a cooling rate of ≥25°C / h, so that the temperature of the freeze-dried preparation solution drops to -40 to -25°C, maintained for 2 to 3 hours, and then sublimated under the conditions of vacuum degree ≤180Pa and temperature of -10 to -3°C for 5 to 7 hours, and the temperature is raised to 30°C for analytical drying for 2 to 4 hours. Finally, the prepared freeze-dried preparation is taken out of the box and capped.

[0108] The present invention also provides an application of the combination of the beta-lactam inhibitor and cephalosporin drugs in the preparation of antibacterial drugs.

[0109] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0110] Example 1

[0111] The raw materials for preparing the combination of β-lactam inhibitor and cephalosporin are shown in Table 1.

[0112] Table 1 Raw material ratio of Example 1

[0113] raw material Dosage(g) Cefuroxime 100.0 Avibactam sodium 50

[0114] The preparation method of the combination of β-lactam inhibitor and cephalosporin is as follows:

[0115] According to the name, specification, batch number, quantity, manufacturer, and raw material inspection report of β-lactamase inhibitors and cephalosporins, after passing the review, remove the outer packaging, wipe the inner packaging with 75% ethanol, put it in the external cleaning for 30 minutes, irradiate with ultraviolet light for 30 minutes, and enter Class D. After wiping the inner packaging with 75% ethanol, put it in the transfer cabin of the material buffer room, and after hydrogen peroxide disinfection, enter Class B to obtain sterile raw powder, mark it, and set it aside;

[0116] After the sterile raw powder is mixed, the sample, sterile rubber stopper and sterile vial are all checked and qualified, and the filling volume and visible foreign matter are checked and qualified, and then the formal sub-packaging begins. The post-nitrogen filling system is used, and sterile raw powder is added to the hopper of the filling machine, and sterile rubber stopper is added to the oscillator. The whole sub-packaging and plugging process must be carried out in a Class A clean area;

[0117] According to the content of the original powder report, the theoretical filling volume is calculated and debugged. After the debugging filling volume is qualified, the vehicle speed is adjusted for formal filling. The powder level is kept stable during the filling process. The filling volume of 2 bottles / times / machine is checked every 15 minutes, weighed and recorded and printed in real time. The vials are directly used for filling of medicinal powder under the protection of Class A laminar flow, and the stoppers are pressed after filling.

[0118] The discarded vials, rubber stoppers and empty powder bags in the production process are first rinsed clean of dust inside and outside and on the surface with injection water, and then treated with 2% Na2CO3.

[0119] Example 2

[0120] The raw materials for preparing the combination of β-lactam inhibitor and cephalosporin are shown in Table 2.

[0121] Table 2 Raw material ratio of Example 2

[0122] raw material Dosage(g) Cefuroxime Sodium 50 Lelibatan 25

[0123] The preparation method of the combination of β-lactam inhibitor and cephalosporin is the same as that in Example 1.

[0124] Example 3

[0125] The raw materials for preparing the combination of β-lactam inhibitor and cephalosporin are shown in Table 3.

[0126] Table 3 Raw material ratio of Example 3

[0127] raw material Dosage(g) Cefuroxime Sodium 50 Faborbactam 50

[0128] The preparation method of the combination of β-lactam inhibitor and cephalosporin is the same as that in Example 1.

[0129] Example 4

[0130] The raw materials for preparing 100 vials of the combination of β-lactam inhibitor and cephalosporin are shown in Table 4.

[0131] Table 4 Raw material ratio of Example 4

[0132] Components Dosage Cefuroxime 100.0g Avibactam sodium 50g Mannitol 200g Sodium hydroxide Moderate Water for injection Moderate Made in total 1000mL

[0133] The preparation method of the combination of 100 β-lactam inhibitors and cephalosporins is as follows:

[0134] Add a β-lactamase inhibitor, a cephalosporin drug and mannitol to 90% of the total mass of the water for injection, adjust the pH to 2.5 with sodium hydroxide, add the remaining 10% of the water for injection to 1000 mL, filter with a 0.2 μm polyethersulfone filter membrane, and fill into 20 mL vials, with 10 mL per bottle; half-stopper the vial and place it in a freeze dryer for freeze drying to obtain a freeze-dried preparation intermediate solution;

[0135] The freeze-dried preparation intermediate solution is rapidly cooled at a rate of 25°C / h, so that the temperature of the freeze-dried preparation solution drops to -40°C and maintained for 4 hours. Then, the vacuum pump is turned on to evacuate the solution, and the solution is sublimated under the conditions of a vacuum degree of 180Pa and a temperature of -10°C for 10 hours until the water line disappears. Subsequently, the temperature is raised to 30°C for analytical drying, and the analytical drying time is 3 hours. The vacuum pump is turned off, and finally, the prepared freeze-dried preparation is taken out of the box and capped.

[0136] Example 5

[0137] The raw materials for preparing 100 vials of the combination of β-lactam inhibitor and cephalosporin are shown in Table 5.

[0138] Table 5 Raw material ratio of Example 5

[0139] Components Dosage Cefuroxime Sodium 50g Lelibatan 25g Mannitol 200g Sodium hydroxide Moderate Water for injection Moderate Made in total 1000mL

[0140] The preparation method of 100 tubes of the combination of β-lactam inhibitor and cephalosporin is the same as that of Example 4.

[0141] Example 6

[0142] The raw materials for preparing 100 tubes of the combination of β-lactam inhibitor and cephalosporin are shown in Table 6.

[0143] Table 6 Raw material ratio of Example 6

[0144]

[0145]

[0146] The preparation method of 100 tubes of the combination of β-lactam inhibitor and cephalosporin is the same as that of Example 4.

[0147] According to the guidance principles for stability testing of raw materials and preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, 9001, the preparations prepared in Examples 1 to 3 were subjected to influencing factors, long-term and accelerated stability tests.

[0148] The influencing factors examined the stability of the die under strong light, high temperature, and high humidity conditions. The specific conditions are: strong light (4500±500LX), high temperature (50°C), and high humidity (92.5%, 25°C);

[0149] The long-term test examined the stability of the tablets with packaging materials at a temperature of 25±2°C and a relative humidity of 60±5%;

[0150] The accelerated test examines the stability of the tablets with packaging materials at a temperature of 40±2°C and a relative humidity of 75±5%;

[0151] The items for stability investigation are: related substances, polymers, content, etc.

[0152] The content of cefuroxime or cefuroxime sodium can be determined according to the following HPLC conditions: chromatographic column: octadecylsilane bonded silica column (AgelaMP C18 (2) (4.6*250mm, 5μm); column temperature: 40°C; flow rate: 1.3mL / min; injection volume: 10μL; detector: UV detector (wavelength 254nm); mobile phase A: 3.6g / L disodium hydrogen phosphate and 1.4g / L potassium dihydrogen phosphate aqueous solution (adjusted to pH 3.4 with 10% phosphoric acid); mobile phase B: acetonitrile; gradient program is shown in Table 7:

[0153] Table 7

[0154] Time (min) Mobile phase A% Mobile phase B% 0 96 4 10 89 11 20 80 20 50 20 80 60 20 80 65 96 4 70 96 4

[0155] System suitability: The number of theoretical plates calculated based on the peak of cefuroxime sodium or cefuroxime is not less than 8000. In the present invention, unless otherwise specified, the amount or relative amount of cefuroxime sodium or cefuroxime in the composition or bulk drug is determined by the method under the above HPLC conditions.

[0156] The determination of the related substances of cefuroxime sodium or cefuroxime in Examples 1 to 3 can be carried out by referring to the same HPLC conditions as the above content determination, and the known impurities and unknown impurities in the composition or raw material drug are quantitatively calculated by the main component self-dilution control method.

[0157] The content of the cephalosporin polymer in Examples 1 to 3 can be determined by referring to the following HPLC conditions: using dextran gel G-10 (40 to 120 μm) as a filler; mobile phase A is 0.01 mol / L phosphate buffer containing 3.5% ammonium sulfate (taking 2.19 g of disodium hydrogen phosphate and 0.54 g of sodium dihydrogen phosphate, adding 1000 mL of water to dissolve, and adjusting the pH value to 7.0), and mobile phase B is 0.01% sodium dodecyl sulfate solution; the flow rate is 1 mL per minute; the detection wavelength is 254 nm. With mobile phase A as the mobile phase, 1 mg / mL blue dextran 2000 solution is injected with 200 μL for determination, the theoretical plate number should not be less than 900, the tailing factor is 0.75 to 1.5, the reference solution is with mobile phase B as the mobile phase, repeated injection of 200 μL, the relative standard deviation of the peak area value should be less than 5.0%.

[0158] The content of avibactam or lelibactam or vaborbactam in Example 1, Example 2 and Example 3 can be determined according to the following HPLC conditions: chromatographic column: octadecylsilane bonded silica column (Diamonisil C18 (4.6*250 mm, 5 μm); column temperature: 25° C.; flow rate: 1.0 mL / min; injection volume: 20 μL; detector: UV detector (wavelength 210 nm); mobile phase A: 100 mmol / L potassium dihydrogen phosphate aqueous solution, mobile phase B: acetonitrile; gradient program as shown in Table 8:

[0159] Table 8

[0160] Time (min) A phase% Phase B % 0 100 0 10 100 0 25 20 80 45 20 80 46 100 0 60 100 0

[0161] System applicability: The theoretical number of plates shall not be less than 5000.

[0162] The determination of the related substances of avibactam sodium or ralibactam or vaborbactam in Examples 1 to 3 can be carried out by referring to the same HPLC conditions as the above content determination, and the known impurities and unknown impurities in the composition or raw material drug are quantitatively calculated by the main component self-dilution control method.

[0163] The test results of the influencing factors of the preparations prepared in Examples 1 to 3 are shown in Table 9, and the test results of the long-term and accelerated stability tests are shown in Table 10.

[0164] Table 9 Test results of influencing factors of Examples 1 to 3

[0165]

[0166]

[0167] Table 10 Stability test results of Examples 1 to 3

[0168]

[0169]

[0170] From the above examples, it can be seen that the present invention provides a composition of a β-lactam inhibitor and a cephalosporin drug, and its preparation method and application. From Tables 9 to 10, it can be seen that under accelerated tests, long-term tests, and strong light, high temperature, and high humidity conditions, the quality attributes of the compound cefotaxime / avibactam sodium solid composition, cefotaxime sodium / ralibactam solid composition, and cefotaxime sodium / faborbactam solid composition provided by the present invention did not change significantly, and the stability was good, which can fully meet the production, transportation and storage requirements of drugs. It is particularly pointed out that the organic impurities and polymers did not increase significantly, and the organic impurities were all less than 0.5%, and the polymers were all less than 0.3%.

[0171] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A composition of a β-lactam inhibitor and a cephalosporin drug, characterized in that: It is composed of the following components in parts by weight: 5 to 90 parts of β-lactamase inhibitor, 0.01 to 50 parts of cephalosporins; The β-lactamase inhibitors include one or more of avibactam sodium, ralelibactam, vaborbactam, relebactam, dulobactam sodium and enmetazobactam; The cephalosporin drugs include one or more of cefuroxime, cefazolin sodium, latamoxef, ceftazidime, ceftriaxone sodium, cefuroxime, cefuroxime sodium, cefminox sodium, cefmetazole sodium, cefazolin sodium, cefodizime sodium and ceftriaxone sodium.

2. The composition of a β-lactam inhibitor and a cephalosporin according to claim 1, characterized in that: The dosage form of the composition is a freeze-dried preparation or a powder injection preparation.

3. The composition of a β-lactam inhibitor and a cephalosporin according to claim 2, characterized in that: When the dosage form of the composition is a lyophilized preparation, the composition further comprises pharmaceutically acceptable additives and solvents; The additives include one or more of fillers, disintegrants, binders, wetting agents, lubricants, flavoring agents, pH regulators, isotonicity regulators, antioxidants and metal ion chelating agents.

4. The composition of a β-lactam inhibitor and a cephalosporin according to claim 2, characterized in that: When the dosage form of the composition is a powder injection preparation, the preparation method of the powder injection preparation is: Mix the β-lactamase inhibitor and cephalosporin under sterile conditions and package them.

5. The composition of a β-lactam inhibitor and a cephalosporin according to claim 3, characterized in that: When the dosage form of the composition is a lyophilized preparation, the preparation method of the lyophilized preparation is: Adding a β-lactamase inhibitor, a cephalosporin drug and an additive to a solvent having a mass fraction of 85 to 95% of the total mass of the composition, adjusting the pH, adding the remaining 5 to 15% of the solvent, and then filtering and filling to obtain a freeze-dried preparation intermediate solution; The freeze-dried preparation intermediate solution is rapidly cooled at a cooling rate of ≥20°C / h, so that the temperature of the freeze-dried preparation solution drops to -50 to -25°C, maintained for 0.5 to 4h, and then sublimated under the conditions of vacuum degree ≤200Pa and temperature of -15 to 0°C for 0.5 to 12h, and the temperature is raised to 25 to 35°C for analytical drying for 1 to 5h. Finally, the prepared freeze-dried preparation is taken out of the box and capped.

6. Use of a combination of a β-lactam inhibitor according to any one of claims 1 to 5 and a cephalosporin drug in the preparation of an antibacterial drug.

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