A pharmaceutical composition containing cefotaxime / sulbactam or cefotaxime / tazobactam with stable quality and high antibacterial activity.

Abstract

This invention relates to a pharmaceutical composition with stable quality and high antibacterial activity. The sulbactam or tazobactam pharmaceutical composition of this invention exhibits excellent stability, and when used to further prepare cefotaxime-containing compound antibiotics, the resulting cefotaxime-sulbactam or cefotaxime-tazobactam compound antibiotics show even higher antibacterial activity.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and to pharmaceutical compositions of sulbactam or tazobactam, and pharmaceutical compositions containing cefotaxime sulbactam or cefotaxime tazobactam. Background Technology

[0002] In the 1940s, it was discovered that bacteria can develop antibiotic resistance by producing β-lactamases. Inhibiting β-lactamases can reduce bacterial resistance and thus increase antibiotic activity. To this day, β-lactamases remain the primary cause of bacterial resistance. Through continuous research, various β-lactamase inhibitors have been discovered, from the initial oleic acid and clavulanic acid, to later sulbactam and tazobactam, and more recently, avibactam and faborbactam.

[0003] β-lactamase inhibitors generally have very weak antibacterial activity, and even when they do exhibit antibacterial activity, their antibacterial spectrum is very narrow. They are primarily used in combination with antibiotics, either as a combination therapy or in the form of compound preparations. Examples include ampicillin-sulbactam, piperacillin-tazobactam, cefoperazone-sulbactam, ceftazidime-avibactam, and meropenem-borbactam. In these compound preparations, a larger proportion of the antibiotic is typically used to provide antibacterial activity, while a smaller proportion of the β-lactamase inhibitor is used to provide β-lactamase inhibition. The mechanism by which β-lactamase inhibitors inhibit β-lactamase is known as "suicide inactivation," meaning that upon binding to β-lactamase, the inhibitor's own chemical structure is destroyed along with the enzyme's inactivation.

[0004] One major reason why β-lactamase inhibitors protect antibiotics from β-lactamase attack is that their affinity for the enzyme is generally higher than that of the antibiotics. However, this often leads to poor stability of their chemical structure. For example, clavulanic acid is particularly sensitive to humid heat; sulbactam and tazobactam have improved stability through structural modifications based on clavulanic acid, but they still retain strong hygroscopicity. Increased moisture content in materials can accelerate degradation reactions, potentially leading to substandard product quality. Furthermore, when these β-lactamase inhibitors are formulated with antibiotics in combination, the stability of the combination formulation is also at risk. Therefore, it is necessary to investigate methods to improve the stability of β-lactamase inhibitors. Summary of the Invention

[0005] The embodiments of the present invention aim to at least solve one of the technical problems existing in the prior art to a certain extent.

[0006] Therefore, the first object of the present invention is to provide a pharmaceutical composition.

[0007] A second object of the present invention is to provide the use of the above-described pharmaceutical composition.

[0008] A third objective of this invention is to provide a method for preventing or treating bacterial infections.

[0009] The technical solution of the present invention is as follows.

[0010] A first aspect of the present invention provides a pharmaceutical composition comprising cefotaxime and a β-lactamase inhibitor, wherein the weight ratio of cefotaxime to the β-lactamase inhibitor is less than or equal to 1:15. Preferably, the weight ratio of cefotaxime to the β-lactamase inhibitor is 1:15 to 1:2000; for example, weight ratios of 1:15, 1:20, 1:50, 1:80, 1:100, 1:500, 1:1000, 1:1500, or 1:2000. Preferably, the weight ratio of cefotaxime to the β-lactamase inhibitor is 1:15 to 1:1000; for example, the weight ratios are 1:15, 1:20, 1:50, 1:80, 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, and 1:1000.

[0011] According to some embodiments of the present invention, the β-lactamase inhibitor is selected from clavulanic acid, sulbactam, or tazobactam, or any combination thereof. Preferably, the β-lactamase inhibitor is sulbactam and / or tazobactam.

[0012] According to some embodiments of the present invention, the cefotaxime and the β-lactamase inhibitor are present together in the pharmaceutical composition (e.g., as a mixture).

[0013] According to some embodiments of the present invention, the pharmaceutical composition further includes a β-lactam antibiotic, which is not cefotaxime.

[0014] According to some embodiments of the present invention, the β-lactam antibiotics include at least one of penicillin antibiotics, penicillene antibiotics, carbapenem antibiotics, cephalosporin antibiotics, cephamycin antibiotics, oxycephalosporin antibiotics, and monocyclic β-lactam antibiotics.

[0015] According to some embodiments of the present invention, the β-lactam antibiotics are selected from amoxicillin, ampicillin, apucillin, aducillin, azlocillin, bamocillin, carbenicillin, carinicillin, cloxacillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, metancillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin, fenescillin, mecillin, penicillin, penicillin G, penicillin V, phenoxymethylpenicillin, piperacillin, and pimecrolimus. Medicinal fungi, licorice, sulfamethoxazole, phthalimide, temoxicillin, ticarcillin, pimecrolimus, benzathine penicillin, benzathine penicillin G, benzathine penicillin V, benzathine penicillin, cefotaxime, cefoxitin, cefotaxime, cefotaxime, cefonicid, cefodizine, cefpirome, cefpirome, cefazolin, cefpodoxime, cefoperazone, cefadroxil, cefepime, cefotaxime, ceftazidime, cefotoxin, ceftriaxone Cefadroxil, Cefalothin, Cefazolin, Cefepime, Cefotiazole, Cefamandole, Cefamandole ester, Cefotiam, Cefuroxime, Cefuroxime axetil, Cefazolin oxime, Cefsulfuron-methyl, Cefmetazole, Cefminox, Cefalexin, Cefadroxil, Cefaclor, Cefprozil, Cefuroxime oxetil, Cefixime, Cefbufen, Cefdinir, Cefoxitin, Ceftracin, Cefosadine, Cefotetan, Carbazocephalosporin, Cefradine, Fluoxetine, Latamoxef, Cefpodoxime, Cefbiproxetil At least one of the following: (ceftobiprolemedocaril), ceftarolinefosamil, cefiderocol, ceftolozane, cefotaxime, cefotobiprolemedocaril, meropenem, ertapenem, doripenem, biapenem, panipenem, telbipenem, thiopenem, imipenem, aztreonam, carumonem, faropenem, and telbipenemedocaril.

[0016] According to some embodiments of the present invention, the β-lactam antibiotic is selected from at least one of ceftazidime, cefoperazone, cefotaxime, and ceftriaxone.

[0017] According to some embodiments of the present invention, in the pharmaceutical composition, the weight ratio of the β-lactamase inhibitor to the β-lactam antibiotic is 1:1 to 1:10, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

[0018] According to some embodiments of the present invention, the β-lactam antibiotic in the pharmaceutical composition may be present as a separate component or together with other components (e.g., as a mixture). When present as a separate component, it may be administered simultaneously with other components or separately. "Simultaneously" means within approximately the same time period, and "separately" means within different time periods.

[0019] According to some embodiments of the present invention, the pharmaceutical composition further includes pharmaceutically acceptable excipients.

[0020] According to some embodiments of the present invention, the pharmaceutically acceptable excipient may be selected from any pharmaceutically acceptable excipient known in the art, depending on actual needs. In some examples, the pharmaceutically acceptable excipient is selected from at least one of fillers, binders, matrices, disintegrants, lubricants, solvents, solubilizers, flavoring agents, colorants, flavor masking agents, pH adjusters, isotonic agents, suspending agents, thickeners, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, propellants, absorption enhancers, absorption delaying agents, and coating materials.

[0021] According to some embodiments of the present invention, the pharmaceutical composition is a pharmaceutical preparation or an intermediate of a pharmaceutical preparation.

[0022] According to some embodiments of the present invention, the pharmaceutical composition is in solid form, such as powder.

[0023] According to some embodiments of the present invention, the pharmaceutical composition can be formulated into various dosage forms, such as oral dosage forms, injectable dosage forms, inhaled dosage forms, and transdermal dosage forms. Typical non-limiting examples of dosage forms include solid, semi-solid, liquid, and aerosol dosage forms; such as tablets, capsules, powders, injections, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs, etc.

[0024] According to some embodiments of the present invention, the pharmaceutical composition can be administered by any suitable method for delivering the composition or its components or the active ingredient to a desired site. The method of administration can vary depending on several factors, such as the nature of the components or active ingredient of the pharmaceutical composition, the site of possible or actual infection, the microorganisms involved (e.g., bacteria), the severity of the infection, the age and physical condition of the subject, etc. Some non-limiting examples of methods for administering the composition to a subject according to embodiments of the present invention include gastrointestinal administration, intravenous administration, subcutaneous administration, intramuscular administration, sublingual administration, skin administration, ocular administration, oral inhalation administration, and nasal inhalation administration.

[0025] The second aspect of the invention also provides the use of the pharmaceutical composition described in any embodiment of the first aspect of the invention in the preparation of a medicament for the prevention or treatment of bacterial infections.

[0026] According to some embodiments of the present invention, the bacteria are β-lactamase-producing bacteria.

[0027] According to some embodiments of the present invention, some non-limiting examples of the bacteria include streptococci, Neisseria, Haemophilus influenzae, Salmonella, Moraxella catarrhalis, Acinetobacter, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococci, anaerobic cocci, Enterobacter, Bacteroides, anaerobic cocci, Proteus vulgaris, Proteus mirabilis, Klebsiella, Citrobacter, etc.

[0028] According to some embodiments of the present invention, the bacterial infection includes bacterial infectious diseases.

[0029] According to some embodiments of the present invention, non-limiting examples of bacterial infections include: skin and soft tissue infection (SSTI), bone and / or joint infection, urogenital system infection, intra-abdominal infection (IAI), respiratory system infection, bacteremia, meningitis, and surgical site infection (SSI), etc.

[0030] A third aspect of the present invention provides a method for preventing or treating bacterial infections, comprising administering a therapeutically effective amount of a pharmaceutical composition of any of the first aspects of the present invention to a subject in need of such treatment.

[0031] According to some embodiments of the present invention, the bacteria are β-lactamase-producing bacteria.

[0032] According to some embodiments of the present invention, some non-limiting examples of the bacteria include streptococci, Neisseria, Haemophilus influenzae, Salmonella, Moraxella catarrhalis, Acinetobacter, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococci, anaerobic cocci, Enterobacter, Bacteroides, anaerobic cocci, Proteus vulgaris, Proteus mirabilis, Klebsiella, Citrobacter, etc.

[0033] According to some embodiments of the present invention, non-limiting examples of bacterial infections include: skin and soft tissue infections, bone and / or joint infections, genitourinary system infections, intra-abdominal infections, respiratory system infections, bacteremia, meningitis, or surgical site infections, etc.

[0034] According to some embodiments of the present invention, the pharmaceutical composition can be administered by any suitable method for delivering the composition or its components or the active ingredient to a desired site. The method of administration can vary depending on several factors, such as the nature of the components or active ingredient of the pharmaceutical composition, the site of possible or actual infection, the microorganisms involved (e.g., bacteria), the severity of the infection, the age and physical condition of the subject, etc. Some non-limiting examples of methods for administering the pharmaceutical composition to a subject according to embodiments of the present invention include gastrointestinal administration, intravenous administration, subcutaneous administration, intramuscular administration, sublingual administration, skin administration, ocular administration, oral inhalation administration, and nasal inhalation administration.

[0035] The specific dosage of the pharmaceutical composition described in the embodiments of the present invention may need to be adjusted due to various factors, including but not limited to: the severity of the subject's condition, the subject's age, gender, weight, route of administration, and drug dosage form.

[0036] definition

[0037] As used herein, the term "cefotaxime" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salt of any chemical purity, polymorph, solvate, and hydrate, but excludes the ester of the compound. In some specific embodiments, cefotaxime in the present invention can be cefotaxime acid ((6R,7R)-7-[[[(2Z)-2-(2-amino-1,3-thiazo-4-yl)-2-methoxyiminoacetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid, CAS No.: 65052-63-3) or cefotaxime sodium ((6R,7R)-7-((Z)-2-(2-aminothiazo-4-yl)-2-(methoxyimino)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid sodium, CAS No.: 65243-25-6).

[0038] As used herein, the term "sulbactam" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salt of any chemical purity, polymorph, solvate, and hydrate. In some specific embodiments, sulbactam in the embodiments of the present invention may be sulbactamic acid ((2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid-4,4-dioxide), sulbactam sodium ((2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium-4,4-dioxide), etc.

[0039] As used herein, the term "tazobactam" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salt of any chemical purity, polymorph, solvate, and hydrate. In some specific embodiments, tazobactam in the embodiments of the present invention may be tazobactam acid ((2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide) or tazobactam sodium ((2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium 4,4-dioxide).

[0040] As used herein, the term "ceftazidime" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salt of any chemical purity, polymorph, solvate, hydrate, active metabolite, and prodrug. In some specific embodiments, ceftazidime in the embodiments of the present invention may be ceftazidime pentahydrate ((6R,7R)-7-[[(2-amino-4-thiazolyl)-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-methylpyridinium inner salt pentahydrate).

[0041] As used herein, the term “cefotaxime” includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salt of any chemical purity, polymorph, solvate, hydrate, active metabolite, and prodrug. In some specific embodiments, cefoperazone in the embodiments of the present invention can be cefoperazone ((6R,7R)-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazincarbamate)-2-p-hydroxyphenyl-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid) or cefoperazone sodium ((6R,7R)-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazincarbamate)-2-p-hydroxyphenyl-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid sodium salt).

[0042] As used herein, the term "cefotaxime" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salt of any chemical purity, polymorph, solvate, hydrate, active metabolite, and prodrug. In some specific embodiments, cefotaxime in the embodiments of the present invention may be cefotaxime sodium ((6R,7R)-3-[(acetoxy)methyl]-7-[2-(2-aminothiazolyl-4-yl)-2-(methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate sodium salt).

[0043] As used herein, the term "cefatrione" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salt of any chemical purity, polymorph, solvate, hydrate, active metabolite, and prodrug. In some specific embodiments, ceftrione in the embodiments of the present invention may be ceftrione sodium ((6R,7R)-7-[[(2Z)-(2-aminothiazolyl-4-yl)(methoxyimino)acetyl]amino]-3-[[(2-methyl-6-hydroxy-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-hydroxy acid disodium salt trihexahydrate).

[0044] As used in this article, "free acid" refers to the compound itself, which is a relative concept to the salt of the compound.

[0045] "Pharmaceutical salts" refer to pharmaceutically acceptable and relatively non-toxic inorganic / organic acid or base addition salts of compounds. "Polymorphs" refer to substances formed by multiple compound molecules arranged in different ordered ways at the microscopic level without altering the structure of individual compounds. "Solvates" refer to substances formed by the non-covalent bonding of compound molecules with a solvent; when the solvent is water, it can also be called "hydrates."

[0046] The term "prevention" as used in this article refers to the use of a method to prevent or reduce the occurrence of a given disease in the presence of factors that may cause the disease.

[0047] As used herein, the term "treatment" includes delaying or reducing symptoms caused by a given disease. The term treatment specifically includes controlling the progression of the disease and related symptoms.

[0048] As used herein, the term "therapeutic effective dose" refers to a dose sufficient to cure, alleviate, or partially suppress the clinical manifestations of a given disease. A dose suitable for achieving this purpose is defined as "therapeutic effective dose." The effective dose for each purpose depends on factors such as the severity of the disease or lesion, as well as the subject's weight and general health status.

[0049] As used herein, the term "composition" refers to a mixture of one or more components or a combination of more than one component. The components may be physically mixed together or physically separated. For a "combination" of more than one active component, these active components may be present simultaneously in the same pharmaceutical preparation or may be present separately in several different pharmaceutical preparations.

[0050] As used in this article, the term "pharmaceutically acceptable" generally means that it is safe for use in the pharmaceutical industry and is harmless to the product or the patient.

[0051] As used herein, the term "excipient" can refer to any conventional excipient in the pharmaceutical field. The specific excipient chosen depends on the form of the pharmaceutical formulation and / or the route of administration.

[0052] As used herein, the term "infection" includes the presence of bacteria within or on an object, the growth of which would be beneficial to the object if inhibited. Thus, the term "infection" refers not only to the presence of bacteria but also to undesirable normal flora. The term "infection" includes infections caused by bacteria.

[0053] As used in this article, the term "skin and soft tissue infection," also known as infection of the skin and skin structures, is an inflammatory disease caused by pyogenic pathogens invading the epidermis, dermis, and subcutaneous tissue.

[0054] As used in this article, the term "genitourinary infection" refers to an infectious disease caused by pathogens invading the genitourinary system due to various causes.

[0055] As used in this article, the term "intra-abdominal infection" refers to a range of infectious diseases of the abdominal cavity, mainly including infections of a single abdominal organ (such as acute cholecystitis, acute appendicitis, etc.), peritonitis, and abdominal abscesses. It can also be classified into simple intra-abdominal infections and complicated intra-abdominal infections according to the scope and severity of the infection.

[0056] As used in this article, the term "respiratory infection" is a disease caused by pathogenic microorganisms invading and multiplying in the respiratory system.

[0057] As used in this article, the term "bacteremia" refers to the entry of bacteria from an inflammatory lesion into the bloodstream via blood vessels or lymphatic vessels, resulting in detectable bacteria in the blood, but without systemic poisoning symptoms in the patient.

[0058] As used in this article, the term "meningitis" is a serious infectious disease of the central nervous system. Many bacteria can cause this disease, with meningococcus being the most common cause, followed by Haemophilus influenzae, Streptococcus pneumoniae, Escherichia coli and other Gram-positive bacilli, Staphylococcus aureus, Listeria monocytogenes, and anaerobic bacteria.

[0059] As used in this article, the term "surgical site infection" includes surgical incision infection and infection of the surgical organ and surrounding tissues.

[0060] As used herein, the term "antibiotic" means any substance, compound, or combination of substances or compounds that is capable of: (i) inhibiting, reducing, or preventing the growth of bacteria; (ii) inhibiting or reducing the ability of bacteria to cause infection in an object; or (iii) inhibiting or reducing the ability of bacteria to multiply or remain infectious in the environment. The term "antibiotic" also refers to compounds that can reduce the infectivity or toxicity of bacteria.

[0061] As used herein, the term "β-lactam antibiotics" refers to compounds that have antibiotic properties and contain a β-lactam nucleus in their molecular structure.

[0062] As used herein, the term "β-lactamase" refers to any enzyme or protein or other enzyme that breaks down the β-lactam ring. The term "β-lactamase" includes enzymes produced by bacteria that have the ability to partially or completely hydrolyze the β-lactam ring in β-lactam antibiotics.

[0063] As used herein, the term "β-lactamase inhibitor" refers to a compound that can partially or completely inhibit the activity of one or more β-lactamases.

[0064] As used herein, the term "object" refers to vertebrates or invertebrates, including mammals. The term "object" includes humans, animals, birds, fish, or amphibians. Typical, non-limiting examples of "objects" include humans, cats, dogs, horses, sheep, cattle, pigs, lambs, rats, mice, and guinea pigs.

[0065] As used herein, the terms “an,” “a,” and “the,” and similar terms should be understood to cover both the singular and the plural, unless otherwise stated in the invention or the context clearly contradicts them.

[0066] The beneficial effects of this invention are:

[0067] In some cases, the combination or co-use of β-lactamase inhibitors and β-lactam antibiotics is quite common. Most studies focus on the changes in antibacterial efficacy after combined use. Typically, a larger proportion of the antibiotic is used to provide antibacterial activity, while a smaller proportion of the β-lactamase inhibitor is used to provide enzyme-inhibiting activity, thus achieving a synergistic effect. Improvements to drug stability often focus on the crystal form of the active pharmaceutical ingredient, the type of excipients, the pH value of the composition, and the packaging container. However, the inventors of this invention surprisingly discovered that using a specific β-lactam antibiotic, cefotaxime, at a smaller proportion can reduce the hygroscopicity of the β-lactamase inhibitor. Furthermore, they found that even after long-term storage, the content of the β-lactamase inhibitor changed very little, and the content of open-ring impurities was extremely low, significantly improving product stability. Based on this, using this stable β-lactamase inhibitor in combination with β-lactam antibiotics can better restore bacterial sensitivity and further enhance the antibacterial efficacy of the β-lactam antibiotics. Detailed Implementation

[0068] Exemplary embodiments will now be described herein using specific language. However, it should be understood that these embodiments are not intended to limit the scope of the invention. Any substitutions and further modifications to the features of the invention described herein, as well as any other applications of the principles of the invention described herein, that can be conceived by those skilled in the art and related fields based on this specification, are considered to be within the scope of the invention. All patents, patent applications, and references cited in this specification are incorporated herein by reference in their entirety. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available.

[0069] Unless otherwise specified, the proportions in the compositions of the embodiments of the present invention are calculated based on the free acidity of the components.

[0070] Unless otherwise specified, all drugs used in the embodiments of this invention are active pharmaceutical ingredients (APIs).

[0071] Example 1: Hygroscopicity test of different compositions of β-lactamase inhibitors

[0072] This experiment tested the hygroscopicity of different compositions of β-lactamase inhibitors.

[0073] In an environment with a temperature of 25℃±1℃ and a relative humidity of 30%±2%, 100g of sulbactam and tazobactam (based on free acid) were taken respectively, and 2g of cephalosporin compounds (cefotaxime, cefoperazone, cefotaxime, cefotaxime, and cefotaxime ester) were added respectively; the mixtures were pulverized, passed through a 200-mesh sieve, and mixed evenly, with 10g taken for later use. Separately, 10g of sulbactam and tazobactam (based on free acid) were taken, ground, and passed through a 200-mesh sieve, with later use. Hygroscopicity tests were performed on all samples simultaneously.

[0074] The hygroscopicity test method is based on the 2020 edition of the Chinese Pharmacopoeia: Take a dry, stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and place it in an artificial climate chamber (temperature set at 25℃±1℃, relative humidity at 80%±2%) one day before the test, and accurately weigh it (recorded as m1). Take an appropriate amount of the test sample and spread it evenly in the weighing bottle, with a sample thickness of about 1 mm, and accurately weigh it (recorded as m2). Leave the weighing bottle open and place it under the above constant temperature and humidity conditions for 24 hours, along with the cap. Close the cap of the weighing bottle and accurately weigh it (recorded as m3). Calculate the weight gain rate according to the formula: Weight gain rate = (m3-m2) / (m2-m1)×100%. The hygroscopicity test results for each group are shown in Table 1.

[0075] Table 1. Weight gain of different β-lactamase inhibitor compositions at the same humidity.

[0076]

[0077]

[0078] A higher weight gain rate indicates a stronger hygroscopicity of the sample. β-lactamase inhibitors such as sulbactam and tazobactam have strong hygroscopicity, and cephalosporins generally also have some hygroscopicity, but small amounts of cephalosporins usually do not significantly affect the hygroscopicity of the composition. However, experiments have shown that when a β-lactamase inhibitor is combined with cefotaxime, the weight gain rate of the composition is significantly lower than other combinations or β-lactamase inhibitors alone, indicating that cefotaxime can significantly reduce the hygroscopicity of β-lactamase inhibitors.

[0079] Example 2: Effect of different concentrations of cefotaxime on the hygroscopicity of β-lactamase inhibitors

[0080] The effect of cefotaxime dosage on the hygroscopicity of β-lactamase inhibitors was further investigated.

[0081] Following the method described in Example 1, compositions containing different ratios of sulbactam and cefotaxime, as well as compositions containing different ratios of tazobactam and cefotaxime, were prepared. Hygroscopicity tests were performed using the same method. The results are shown in Table 2. Table 2 shows that cefotaxime can reduce the hygroscopicity of β-lactamase inhibitors in not all ratios. Within the range of cefotaxime to β-lactamase inhibitor ratios of 1:15 to 2000, cefotaxime has a better effect in reducing hygroscopicity.

[0082] Table 2. Weight gain of combinations of β-lactamase inhibitors and different dosages of cefotaxime at the same humidity.

[0083]

[0084]

[0085] Example 3: Stability test of the β-lactamase inhibitor composition

[0086] To further understand the effect of hygroscopic changes on the stability of β-lactamase inhibitors, accelerated stability tests were conducted.

[0087] Under industrial conditions, the preparation of antibiotic preparations often requires multiple mixing processes. However, mixing and dispensing operations may degrade the stability of materials (especially hygroscopic materials). Therefore, the preparation of antibiotic preparations in an industrial setting is simulated by increasing the mixing time and number of mixing cycles.

[0088] Simulated antibiotic preparation conditions: Various β-lactamase inhibitor compositions prepared in Example 2 were mixed for 30 minutes using a single-cone ribbon mixer, and then aseptically dispensed as test samples. Separately, β-lactamase inhibitors (sulbactam or tazobactam) without cefotaxime were prepared using the same method and used as test samples.

[0089] Each sample was placed at a temperature of 40℃±2℃ and a humidity of 75%±5% for 6 months. The content of β-lactamase inhibitor and the content of major impurities in each sample at 0 months and 6 months were detected by high performance liquid chromatography (HPLC) to investigate the changes in the quality of the samples.

[0090] The HPLC detection conditions are as follows (referencing the United States Pharmacopeia):

[0091] Sulbactam: 4 mm × 15 cm column; 3 μm packing L1; mobile phase as shown in Table 3; detection wavelength 215 nm.

[0092] Tazobactam: Column: 4.6 mm × 25 cm; 5 μm packing L1; Mobile phase: 1.32 g diammonium hydrogen phosphate was dissolved in 750 mL of water, the pH was adjusted to 2.5 with 5% v / v phosphoric acid, then diluted to 1000 mL with water, 30 mL of acetonitrile was added and mixed; Detection wavelength: 210 nm.

[0093] Table 3. Mobile phase for sulbactam HPLC detection

[0094] 0 98 2 7.5 50 50 8.5 50 50 9.0 98 2 12.5 98 2

[0095] Note: In Table 3, mobile phase A is 5.4 g / L potassium dihydrogen phosphate adjusted to pH 4.0 with dilute phosphoric acid.

[0096] Table 4 shows the contents of sulbactam and major impurities in each sample at 0 months and 6 months. The results show that after 6 months, the content of active ingredient in the combination of cefotaxime and sulbactam was above 99.1%, and the content of open-ring impurities was 0.04-0.11%, with little change compared to 0 months. However, the content of active ingredient in sulbactam alone decreased to 97.2% after 6 months, and the content of open-ring impurities was 0.34%, showing a significant change compared to 0 months. It can be seen that the addition of cefotaxime significantly inhibited the degradation of active ingredient, reduced the content of open-ring impurities, and improved the stability of the composition.

[0097] Table 4. Mass changes in sulbactam compositions during accelerated stability testing

[0098]

[0099] Note: The ring-opening impurity of sulbactam in Table 4 is (2S)-2-amino-3-methyl-3-sulfinylated butyric acid.

[0100] Table 5 shows the contents of tazobactam and major impurities in each sample at 0 and 6 months. The results show that after 6 months, the active ingredient content of the cefotaxime and tazobactam combination was above 99.1%, and the open-ring impurity content was 0.13-0.22%, with little change compared to 0 months. However, the active ingredient content of tazobactam alone decreased to 98.1% after 6 months, and the open-ring impurity content was 0.82%. Compared to 0 months, the active ingredient content decreased significantly, and the open-ring impurity content increased significantly. It can be seen that the addition of cefotaxime significantly inhibited the degradation of the active ingredient, reduced the content of open-ring impurities, and improved the stability of the composition.

[0101] Table 5. Mass changes of tazobactam compositions in accelerated stability tests.

[0102]

[0103]

[0104] Note: The ring-opening impurity of tazobactam in Table 5 is (2S,3S)-2-amino-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid.

[0105] In summary, the stability test results indicate that, compared to β-lactamase inhibitors alone, the combination of β-lactamase inhibitor and cefotaxime has a higher content of active ingredient and a lower content of impurities, demonstrating better stability. In particular, for β-lactamase inhibitors alone, although the variation in the content of the active ingredient was within the limits of the quality standards, the increase in open-ring impurities was significant, indicating that the drug quality is still unstable. Furthermore, since β-lactamase inhibitors mainly exert their inhibitory effect through the lactam ring, their open-ring impurities will have no inhibitory ability whatsoever and may even conversely restrict the binding between the β-lactamase inhibitor and the enzyme; therefore, the increase of this impurity may have an adverse effect on the efficacy.

[0106] Example 4: β-lactamase inhibitor composition used in the preparation of compound antibiotics

[0107] The stable β-lactamase inhibitor composition in Example 3 is particularly suitable for preparing combination antibiotics. For example, it can be combined with third-generation cephalosporins such as ceftazidime, cefoperazone, cefotaxime, and ceftriaxone to form various combination formulations. One composition from Example 3 is given below as an example; other compositions can be described by analogy.

[0108] Take commercially available ceftriaxone, pulverize it and pass it through a 200-mesh sieve. Take 2000g and put it into a single-cone ribbon mixer. Take another 1010g of the sulbactam + cefotaxime (100:1) composition prepared according to the method of Example 2 and put it into the same single-cone ribbon mixer. Mix it thoroughly and uniformly. Dispense it under aseptic conditions to obtain the compound antibiotic injection - ceftriaxone-sulbactam (2:1). Following the same method, compound preparations of ceftriaxone tazobactam (3:1), ceftriaxone tazobactam (6:1), cefotaxime tazobactam (6:1), cefotaxime sulbactam (2:1), ceftazidime tazobactam (3:1), ceftazidime tazobactam (5:1), cefoperazone tazobactam (8:1), cefoperazone tazobactam (4:1), cefoperazone tazobactam (6:1), cefoperazone sulbactam (3:1), cefoperazone sulbactam (2:1), and cefoperazone sulbactam (1:1) were prepared.

[0109] To compare the differences between these combination antibiotics and ordinary combination antibiotics, ordinary combination antibiotics were also prepared. Using commercially available cephalosporin compounds and commercially available β-lactamase inhibitors as raw materials, without cefotaxime, the following contrast agents were prepared using the same method described above: ceftriaxone-tazobactam contrast agent (2:1), ceftriaxone-tazobactam contrast agent (3:1), cefotaxime-tazobactam contrast agent (6:1), cefotaxime-tazobactam contrast agent (2:1), ceftazidime-tazobactam contrast agent (3:1), cefoperazone-tazobactam contrast agent (8:1), and cefoperazone-tazobactam contrast agent (1:1).

[0110] The antibacterial activity of cefotaxime-sulbactam (2:1), cefotaxime-tazobactam (6:1), cefotaxime-sulbactam contrast agent (2:1), and cefotaxime-tazobactam contrast agent (6:1), as well as commercially available cefotaxime injection, was tested. Test method: Antimicrobial susceptibility testing was performed on 37 clinically isolated β-lactamase-producing *Escherichia coli* strains using the CLSI microbroth dilution method, and the MIC value of each drug was determined. The drug dilution concentration ranged from 0.03 to 256 μg / mL, and the MIC was the lowest drug concentration that inhibited visible bacterial growth after 24 hours of incubation at 37°C. The results are shown in Table 6.

[0111] Table 6. Antibiotic activity against β-lactamase-producing Escherichia coli

[0112]

[0113] Experimental results show that β-lactamase-producing bacteria are resistant to single antibiotics. Combination antibiotics consisting of β-lactamase inhibitors and antibiotics can restore bacterial sensitivity to antibiotics. Furthermore, the combination antibiotic prepared from the β-lactamase inhibitor composition (containing cefotaxime) of this invention exhibits stronger antibacterial activity compared to conventional combination antibiotics, as shown by the MIC... 50 Both the MIC range and the MIC range are smaller than those of ordinary compound antibiotics.

[0114] Although the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the invention can be devised by those skilled in the art without departing from the true spirit and scope of the invention, and the appended claims are intended to be construed as including all such embodiments and equivalent variations.

Claims

1. A pharmaceutical composition containing cefotaxime, further containing sulbactam and cefotaxime, wherein the weight ratio of cefotaxime to sulbactam is 1:15 to 1:2000, and the weight ratio of sulbactam to cefotaxime is 1:1 to 1:

10.

2. A pharmaceutical composition containing cefotaxime, further containing tazobactam and cefotaxime, wherein the weight ratio of cefotaxime to tazobactam is 1:15 to 1:2000, and the weight ratio of tazobactam to cefotaxime is 1:1 to 1:

10.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The dosage form of the pharmaceutical composition is an injectable dosage form.

4. The use of the pharmaceutical composition of claim 3 in the preparation of a medicament for the prevention or treatment of Escherichia coli infection.

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