WO2022198378A1 - β-LACTAMASE INHIBITOR COMPOSITION WITH STABLE QUALITY, USE THEREOF AND METHOD THEREFOR - Google Patents

Abstract

The embodiments of the present invention relate to the technical field of medicine, in particular to a β-lactamase inhibitor composition with a stable quality, the use thereof and a method therefor. The pharmaceutical composition of the embodiments of the present invention has improved hygroscopicity and better stability, so that the stability of materials in a preparation process can be ensured, and the pharmaceutical composition is particularly suitable for further preparing compound antibiotics. Moreover, experiments show that the β-lactamase inhibitor composition of the embodiments of the present invention can better improve the sensitivity of antibiotics to drug-resistant bacteria, and the prepared compound antibiotics have a stronger antimicrobial activity to drug-resistant bacteria.

Description

A kind of β-lactamase inhibitor composition with stable quality and its use and method technical field

Embodiments of the present invention relate to the technical field of medicine, and in particular, to a β-lactamase inhibitor composition with stable quality and use and method thereof.

Background technique

In the 1940s it was discovered that bacteria can develop resistance to antibiotics by producing beta-lactamases. By inhibiting β-lactamase, the resistance of bacteria can be reduced and the activity of antibiotics can be increased. To date, β-lactamase is still the main cause of bacterial resistance. Through successive researches, a variety of β-lactamase inhibitors have been discovered, from the initial olive acid and clavulanic acid, to sulbactam and tazobactam, to avibactam and borax that have emerged in recent years. Bataan et al.

The antibacterial activity of β-lactamase inhibitors is basically weak, and even if they have antibacterial activity, their antibacterial spectrum is very narrow. People mainly combine β-lactamase inhibitors with antibiotics in combination or compound preparations. For example, compound preparations such as ampicillin sulbactam, piperacillin tazobactam, cefoperazone sulbactam, ceftazidime avibactam, meropenem and borbactam. In these compound preparations, a larger proportion of antibiotics is usually used to provide antibacterial activity, and a smaller proportion of β-lactamase inhibitor is used to provide β-lactamase inhibitory activity. The principle of β-lactamase inhibitor inhibition of β-lactamase is called "suicide inactivation", that is, after the β-lactamase inhibitor binds to β-lactamase, while the enzyme is inactivated, β-lactamase inhibits The chemical structure of the agent itself is also destroyed.

One of the reasons β-lactamase inhibitors protect antibiotics from attack by β-lactamases is that their affinity for the enzyme is usually higher than that of antibiotics, but this often results in a less stable chemical structure. For example, clavulanic acid is particularly sensitive to damp heat; sulbactam and tazobactam have improved stability through structural modification on the basis of clavulanic acid, but still have strong hygroscopicity. The increase in the moisture content of the material will lead to accelerated degradation reactions, which may lead to unqualified product quality. In addition, when these β-lactamase inhibitors and antibiotics are made into compound preparations, it also brings risks to the stability of the compound preparations. Therefore, it is necessary to study methods for improving the stability of β-lactamase inhibitors.

SUMMARY OF THE INVENTION

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

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

The second object of the present invention is to provide the use of the above-mentioned pharmaceutical composition.

A third object of the present invention is to provide a method of preventing or treating bacterial infection.

The technical solution of the present invention is shown below.

The embodiment of the first aspect of the present invention provides a pharmaceutical composition comprising ceftazidime and a beta-lactamase inhibitor, wherein the weight ratio of the ceftazidime and the beta-lactamase inhibitor is less than or equal to 1:15. Preferably, the weight ratio of ceftazidime and β-lactamase inhibitor is 1:15～1:2000; for example, the weight ratio is 1:15, 1:20, 1:50, 1:80, 1:100, 1 :500, 1:1000, 1:1500 or 1:2000. Preferably, the weight ratio of the ceftazidime to the β-lactamase inhibitor is 1:15-1:1000; for example, the weight ratio is 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, 1:1000.

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

According to some embodiments of the present invention, in the pharmaceutical composition, the ceftazidime and the beta-lactamase inhibitor are present together (eg, as a mixture).

According to some embodiments of the present invention, the pharmaceutical composition further comprises a beta-lactam antibiotic, which is not ceftazidime.

According to some embodiments of the present invention, the β-lactam antibiotics include penicillin antibiotics, penem antibiotics, carbapenem antibiotics, cephalosporin antibiotics, cephamycin antibiotics, oxycephem antibiotics and at least one of the monocyclic beta-lactam antibiotics.

According to some embodiments of the present invention, the β-lactam antibiotics are selected from the group consisting of amoxicillin, ampicillin, apoxicillin, aducillin, azlocillin, bamcillin, carbenicillin, indacillin, chloromethan Acillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, maytancillin, methicillin, mezlocillin, nafcillin, oxacillin, penacillin, fenecillin, Mecillin, penicillin, penicillin G, penicillin V, phenoxymethyl penicillin, piperacillin, pimacillin, propicillin, sulfenicillin, phthalicillin, temoxicillin, ticarcillin, pimecillin, benzyl Benzathine penicillin, benzathine penicillin G, benzathine penicillin V, benzathine penicillin, cefotaxime, cefoxitin, cefacetonitrile, cefmenoxime, cefoxime, cefodizime, cefpirome, cefpiramide, cefazolam , cefpodoxime axetil, cefdrol, cefcapine, cefepime, ceftaroline, cefoperazone, cefadroxil, cefepime, cefotaxime, ceftazidime, cefditoren, ceftriaxone, cefra Zong, cefotaxime, cefazolin, cefpirin, ceftizole, cefamandol, cefamandole, cefotiam, cefuroxime, cefuroxime axetil, ceftizoxime, cefsulodin, cefmetazole , cefminox, cephalexin, cefradine, cefaclor, cefprozil, cefuroxime axetil, cefixime, cefbutene, cefdinir, cefoxidone, ceftriaxine, cefoxidine, cefotetan, Chlorocarbon cephalosporin, cefretet, fluoxefaclor, laoxacephate, cefpodoxime, ceftobiprole medocaril, ceftaroline fosamil, cefiderocol, cefolozine ( ceftolozane), cefothiamidine, cefditoren pivoxil, meropenem, ertapenem, doripenem, biapenem, panipenem, tipipenem, thiopenem, imipenem, ammonia At least one of Trinum, Carrumonam, Faropenem, and Tipipenem pivoxil.

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

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.

According to some embodiments of the present invention, in the pharmaceutical composition, the β-lactam antibiotic may be present as a separate component, or may be present together with other components (eg, as a mixture). When present as separate components, they can be administered concurrently with the other components or separately. "At the same time" means at about the same time, and "separately" means at different times.

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

According to some embodiments of the present invention, the pharmaceutically acceptable excipients can be selected from any pharmaceutically acceptable excipients known in the art according to actual needs. In some examples, the pharmaceutically acceptable excipients are selected from fillers, binders, bases, disintegrants, lubricants, solvents, solubilizers, flavoring agents, colorants, taste-masking agents, pH adjusting agents , isotonic agents, suspending agents, thickening agents, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, propellants, absorption enhancers, absorption delaying agents and coating materials at least one.

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

According to some embodiments of the present invention, the pharmaceutical composition is in solid form. For example powder etc.

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

According to some embodiments of the present invention, the pharmaceutical composition may be administered by any suitable method for delivering the composition or a component thereof or the active ingredient to the site of need. The method of administration can vary depending on a number of factors, for example, the nature of the components or active ingredients of the pharmaceutical composition, the site of possible or actual infection, the microorganisms (eg bacteria) involved, the severity of the infection, the age of the subject, and physical condition, etc. Some non-limiting examples of methods of administering the compositions to a subject in accordance with embodiments of the present invention include gastrointestinal, intravenous, subcutaneous, intramuscular, sublingual, dermal, otic Topical administration, ocular administration, oral inhalation administration, nasal inhalation administration.

The embodiment of the second aspect of the present invention also provides the use of the pharmaceutical composition according to any embodiment of the first aspect of the present invention in preparing a medicament for preventing or treating bacterial infection.

According to some embodiments of the present invention, the bacteria are beta-lactamase-producing bacteria.

According to some embodiments of the invention, some non-limiting examples of the bacteria include Streptococcus, Neisseria, Haemophilus influenzae, Salmonella, Moraxella catarrhalis, Acinetobacter, Escherichia coli), Pseudomonas aeruginosa, Staphylococcusaureus, Enterococcus, anaerobes, Enterobacter, Bacteroides, anaerobes, Proteus vulgaris, Proteus mirabilis Bacillus, Klebsiella (Klebsiella), Citrobacter (Citrobacter) and so on.

According to some embodiments of the present invention, the bacterial infection comprises a bacterial infectious disease.

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

A third aspect embodiment of the present invention provides a method of preventing or treating a bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of the first aspects of the present invention.

According to some embodiments of the present invention, the bacteria are beta-lactamase-producing bacteria.

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

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

According to some embodiments of the present invention, the pharmaceutical composition may be administered by any suitable method for delivering the composition or its components or the active ingredient to the site of need. The method of administration can vary depending on a number of factors, for example, the nature of the components or active ingredients of the pharmaceutical composition, the site of possible or actual infection, the microorganisms (eg bacteria) involved, the severity of the infection, the age of the subject, and physical condition, etc. Some non-limiting examples of methods of administering the pharmaceutical composition to a subject according to embodiments of the present invention include gastrointestinal, intravenous, subcutaneous, intramuscular, sublingual, dermal, Auricular, ocular, oral inhalation, nasal inhalation.

The specific dosage of the pharmaceutical composition described in the embodiment of the present invention may need to be adjusted accordingly due to various factors, these factors include but are not limited to: the severity of the subject's condition, the subject's age, gender, weight, Routes of administration and dosage forms, etc.

definition

As used herein, the term "ceftazime" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts, polymorphs, solvates, hydrates of any chemical purity, but not esters of the compound . In some embodiments, ceftazidime in embodiments of the invention may be ceftazidime ((6R,7R)-7-[[[(2Z)-2-(2-amino-1,3-thiazole- 4-yl)-2-methoxyiminoacetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 -Carboxylic acid, CAS number: 65052-63-3), ceftazidime sodium ((6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxy) Sodium imino)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, CAS number: 65243-25 -6).

As used herein, the term "sulbactam" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts, polymorphs, solvates, hydrates of any chemical purity. In some embodiments, sulbactam in embodiments of the invention can be sulbactam ((2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-aza Bicyclo[3.2.0]heptane-2-carboxylic acid-4,4-dioxide), sulbactam sodium ((2S,5R)-3,3-dimethyl-7-oxo-4-thio Hetero-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide) and the like.

As used herein, the term "tazobactam" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts, polymorphs, solvates, hydrates of any chemical purity. In some embodiments, tazobactam in embodiments of the invention can 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), tazobactam sodium ((2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-aza Bicyclo[3.2.0]heptane-2-carboxylate sodium 4,4-dioxide).

As used herein, the term "ceftazidime" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, active metabolites, prodrugs of any chemical purity. In some embodiments, the ceftazidime in embodiments of the present invention may be ceftazidime pentahydrate ((6R,7R)-7-[[(2-amino-4-thiazolyl)-[(1-carboxy-1-methyl ethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-methylpyridinium inner salt pentahydrate).

As used herein, the term "cefoperazone" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts of any chemical purity, polymorphs, solvates, hydrates, active metabolites, prodrugs. In some embodiments, the cefoperazone may be cefoperazone ((6R,7R)-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl in embodiments of the present invention ]-7-[(R)-2-(4-Ethyl-2,3-dioxo-1-piperazinecarbonylamino)-2-p-hydroxyphenyl-acetamido]-8-oxo- 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid), cefoperazone sodium ((6R,7R)-3-[[(1-methyl-1H-tetrazole-5 -yl)thio]methyl]-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarbonylamino)-2-p-hydroxyphenyl-acetamido ]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, sodium salt).

As used herein, the term "cefotaxime" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts of any chemical purity, polymorphs, solvates, hydrates, active metabolites, prodrugs. In some embodiments, the cefotaxime in embodiments of the present invention may be cefotaxime sodium ((6R,7R)-3-[(acetoxy)methyl]-7-[2-(2-aminothiazole) -4-yl)-2-(methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, sodium salt).

As used herein, the term "ceftriaxone" includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts of any chemical purity, polymorphs, solvates, hydrates, active metabolites, prodrugs. In some embodiments, ceftriaxone in embodiments of the present invention may be ceftriaxone sodium ((6R,7R)-7-[[(2Z)-(2-aminothiazol-4-yl)(methoxy Imino)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 threesesquihydrate).

As used herein, "free acid" refers to the compound itself, which is the relative concept of a salt of a compound.

"Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable and relatively non-toxic inorganic/organic acid or base addition salt of a compound. "Polymorph" refers to a substance formed by microscopically different ordered arrangements of multiple compound molecules without changing the molecular structure of a single compound. "Solvate" refers to a substance formed by non-covalent bonding of compound molecules with a solvent. When the solvent is water, it can also be called "hydrate".

The term "preventing" as used herein refers to preventing or reducing the development of a given disease after use in the presence of factors that may trigger the given disease.

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

As used herein, the term "therapeutically effective amount" refers to an amount sufficient to cure, alleviate or partially inhibit the clinical manifestations of a given disease. An amount suitable for accomplishing this purpose is defined as a "therapeutically effective amount". The effective amount for each purpose depends on the severity of the disease or injury as well as factors such as the subject's weight and general state of health.

As used herein, the term "composition" refers to a mixture of one or more components or an association between more than one component. The components can be physically mixed together or physically separated from each other. For a "combination" of more than one active ingredient, the active ingredients may be present in the same pharmaceutical agent at the same time, or separately in multiple different pharmaceutical agents.

As used herein, the term "pharmaceutically acceptable" generally refers to use in the pharmaceutical arts and is not harmful to the product or to the subject.

As used herein, the term "excipient" may be any conventional excipient in the pharmaceutical field. The choice of specific excipients depends on the form of the pharmaceutical formulation or/and the mode of administration.

As used herein, the term "infection" includes the presence of bacteria in or on a subject that would benefit the subject if their growth was inhibited. Thus, the term "infection" refers to the undesired normal flora in addition to the presence of bacteria. The term "infection" includes infections caused by bacteria.

As used herein, the term "skin and soft tissue infection", also known as skin and skin structure infection, is an inflammatory disease caused by the invasion of the epidermis, dermis and subcutaneous tissue by pyogenic pathogens.

As used herein, the term "urogenital infection" is an infectious disease caused by the invasion of the urogenital system by pathogenic bacteria for various reasons.

As used herein, the term "intra-abdominal infection" refers to a series of intra-abdominal infectious diseases, mainly including infection of a single organ in the abdominal cavity (such as acute cholecystitis, acute appendicitis, etc.), peritonitis, and intra-abdominal abscess, and can also be involved according to the scope of infection And the severity is divided into simple intra-abdominal infection and complex intra-abdominal infection.

As used herein, the term "respiratory infection" is a disease in which pathogenic microorganisms invade and multiply in the respiratory system.

As used herein, the term "bacteremia" is the entry of bacteria from an inflammatory lesion into the bloodstream through blood vessels or lymphatics, where the bacteria can be found in the blood, but the patient has no symptoms of systemic toxicity.

As used herein, the term "meningitis" is a serious infectious disease of the central nervous system, which can be caused by many bacteria, among which meningococcus causes the most, followed by influenza bacillus, pneumococcus, Escherichia coli and other gram Positive bacilli, staphylococcus, listeria, anaerobic bacteria, etc.

As used herein, the term "surgical site infection" includes both surgical incision infections and infections of surgical organs and surrounding tissues.

As used herein, the term "antibiotic" refers to any substance, compound or combination of substances or combination of compounds capable of: (i) inhibiting, reducing or preventing the growth of bacteria; (ii) inhibiting or reducing the ability of bacteria to produce an infection in a subject or (iii) inhibiting or reducing the ability of bacteria to multiply or remain infectious in the environment. The term "antibiotic" also refers to compounds capable of reducing bacterial infectivity or virulence.

As used herein, the term "beta-lactam antibiotic" refers to a compound that has antibiotic properties and contains a beta-lactam core in its molecular structure.

As used herein, the term "beta lactamase" refers to any enzyme or protein or any other that breaks down a beta lactam ring. The term "beta-lactamase" includes enzymes produced by bacteria and having the ability to partially or fully hydrolyze the beta-lactam rings in beta-lactam antibiotics.

As used herein, the term "beta-lactamase inhibitor" refers to a compound capable of partially or completely inhibiting the activity of one or more beta-lactamases.

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

As used herein, the terms "a," "an," and "the" and similar terms should be construed to encompass both the singular and the plural unless otherwise indicated herein or otherwise clearly contradicted by context.

Beneficial effects of the present invention:

In some cases, the combination or combination of β-lactamase inhibitors and β-lactam antibiotics is more common, and most of them discuss the changes in the bacteriostatic effect after the combination of the two, usually using a larger proportion of antibiotics In order to provide antibacterial activity, a small proportion of β-lactamase inhibitor is assisted to provide anti-enzyme activity, so as to play a synergistic role; and the improvement of drug stability is mainly based on the crystal form of the raw drug, the type of excipients, the Start with the pH value of the composition, packaging container, etc. However, the inventors surprisingly found in research that a specific beta-lactam antibiotic, ceftazidime, can reduce the hygroscopicity of beta-lactamase inhibitors when used in a small proportion, and further found that even after long-term storage , the content of β-lactamase inhibitor changes very little, and the content of ring-opening impurities is extremely low, which greatly improves the stability of the product. On this basis, the use of this stable β-lactamase inhibitor in combination with β-lactam antibiotics can better restore sensitivity to bacteria and better improve the bacteriostatic effect of β-lactam antibiotics .

Detailed ways

Reference will now be made to exemplary embodiments, which will be described herein using specific language. It should be understood, however, that these embodiments are not intended to limit the scope of the present invention. Substitutes and further improvements to the features of the invention described herein, as well as any other applications of the principles of the invention described herein, are deemed to be within the scope of the invention to any person skilled in the art or related fields that may conceive of it based on this specification. . All patents, patent applications, and references cited in this specification are incorporated by reference in their entirety. The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial sources.

Unless otherwise specified, the ratios in the compositions of the present invention are calculated based on the free acid of the components.

Unless otherwise specified, the drugs used in the embodiments of the present invention are all APIs.

Example 1 Hygroscopicity test of different compositions of β-lactamase inhibitors

This test tests the hygroscopicity of different compositions of beta-lactamase inhibitors.

In an environment with a temperature of 25°C±1°C and a relative humidity of 30%±2%, take 100 g of sulbactam and tazobactam (calculated as free acid), respectively, and add cephalosporins: ceftriaxone, cefoperazone Ketone, cefotaxime, ceftazidime, ceftazidime pivoxil, 2 g (calculated as free acid); pulverize, pass through a 200-mesh sieve, mix well, and take 10 g for later use. Separately take 10 g of sulbactam and tazobactam (calculated as free acid), grind, pass through a 200-mesh sieve, and set aside. Each sample was subjected to the hygroscopicity test at the same time.

The test method for hygroscopicity refers to the 2020 edition of the Chinese Pharmacopoeia: take a dry stoppered glass weighing bottle (outer diameter 50mm, height 15mm), and place it in an artificial climate box (set temperature is 25°C ± 1°C, relative humidity) one day before the test. within 80%±2%), accurately weigh the weight (denoted as m1). Take an appropriate amount of the test product, spread it flat in the above weighing bottle, the thickness of the test product is about 1mm, and accurately weigh it (recorded as m2). The weighing bottle was opened and placed with the bottle cap under the above constant temperature and humidity conditions for 24 hours. Close the lid of the weighing bottle, and accurately weigh the weight (denoted as m3). The weight gain rate was calculated according to the formula, the weight gain rate=(m3-m2)/(m2-m1)×100%.

Table 1 Weight gain rates of different compositions of β-lactamase inhibitors under the same humidity

sample

Weight gain rate

Sulbactam	1.52%
Sulbactam + ceftriaxone	1.38%
Sulbactam + cefoperazone	1.47%
Sulbactam + Cefotaxime	1.68%
Sulbactam + ceftazidime	0.81%
Sulbactam + ceftazidime	1.55%
Tazobactam	2.49%
Tazobactam + Ceftriaxone	2.32%
Tazobactam + Cefoperazone	2.42%
Tazobactam + Cefotaxime	2.58%
Tazobactam + Cefetamet	1.16%
Tazobactam + ceftazidime	2.23%

The larger the weight gain rate, the stronger the hygroscopicity of the sample. β-lactamase inhibitor compounds such as sulbactam and tazobactam have strong hygroscopicity, and cephalosporins usually have certain hygroscopicity, but a small amount of cephalosporins usually does not cause much hygroscopicity to the composition. influences. However, the test showed that when the β-lactamase inhibitor was combined with ceftazidime, the weight gain rate of the composition was significantly lower than that of other combinations or the β-lactamase inhibitor alone, indicating that ceftazim can significantly reduce the β-lactamase inhibitor. Hygroscopicity of lactamase inhibitors.

Example 2 The effect of different contents of ceftazidime on hygroscopicity of β-lactamase inhibitor

The effect of ceftazidime dosage on hygroscopicity of β-lactamase inhibitor was further studied.

Referring to the method of Example 1, compositions containing sulbactam and ceftazidime in different proportions, and compositions containing tazobactam and ceftamid in different proportions were prepared respectively. Moisture test was carried out in the same way. The results are shown in Table 2. It can be seen from Table 2 that not all ratios of ceftazidime can reduce the hygroscopicity of β-lactamase inhibitors. , Cefetamet has a better effect of reducing hygroscopicity.

Table 2 The weight gain rate of the composition of β-lactamase inhibitor and different dosage of ceftazidime under the same humidity

Example 3 Stability test of β-lactamase inhibitor composition

To further understand the effect of changes in hygroscopicity on the stability of β-lactamase inhibitors, accelerated stability tests were performed.

Under industrial conditions, the preparation of antibiotic preparations often requires multiple mixing, and operations such as mixing and sub-packaging may deteriorate the stability of materials (especially hygroscopic materials). Therefore, by increasing the mixing time and times to simulate industrial antibiotic preparations preparation.

Simulate the preparation conditions of antibiotic preparations: respectively take the various β-lactamase inhibitor compositions prepared in Example 2, mix them with a single-cone ribbon mixer for 30 minutes, respectively pack them under aseptic conditions, and use them as samples to be tested. sample. Another β-lactamase inhibitor (sulbactam or tazobactam) without ceftazidime was taken as the sample to be tested.

Each sample to be tested was placed for 6 months in an environment with a temperature of 40 °C ± 2 °C and a humidity of 75% ± 5%, and high performance liquid chromatography (HPLC) was used to detect β-lactamase in each sample in October and June respectively. The content of inhibitors and the content of main impurities were used to investigate the changes in the quality of the samples to be tested.

The HPLC detection conditions are as follows (refer to the US Pharmacopoeia):

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

Tazobactam: Column: 4.6mm×25cm; 5μm packing L1, mobile phase: dissolve 1.32g of diammonium hydrogen phosphate in 750mL of water, adjust the pH to 2.5 with 5% v/v phosphoric acid, and then dilute to 1000mL with water , 30 mL of acetonitrile was added, and mixed; the detection wavelength was 210 nm.

Table 3 Mobile phase of sulbactam HPLC detection

time (minutes)	mobile phase A	Acetonitrile
0	98	2
7.5	50	50
8.5	50	50
9.0	98	2
12.5	98	2

Note: Mobile phase A in Table 3 is 5.4g/L potassium dihydrogen phosphate adjusted to pH 4.0 with dilute phosphoric acid.

The contents of sulbactam and main impurities in each sample in 0 and 6 months are shown in Table 4. The results show that after 6 months, the active ingredient content of the combination of ceftazidime and sulbactam is above 99.1%, and The content of ring impurities was 0.04-0.11%, and the change was not significant compared with that in 0 months; the active ingredient content of sulbactam alone dropped to 97.2% after 6 months, and the content of ring-opening impurities was 0.34%, which was similar to that of sulbactam. Compared with 0 months, there is a big change; it can be seen that the addition of ceftazidime significantly inhibits the degradation of active ingredients, reduces the content of ring-opening impurities, and improves the stability of the composition.

Table 4 The quality change of sulbactam composition in accelerated stability test

Note: The ring-opening impurity of sulbactam in Table 4 is (2S)-2-amino-3-methyl-3-sulfinylbutyric acid.

The content of tazobactam and the content of main impurities in each sample in 0 months and 6 months are shown in Table 5. The results show that after 6 months, the active ingredient content of the combination of ceftazidime and tazobactam is more than 99.1% , the content of ring-opening impurities was 0.13-0.22%, and the change was not significant compared with 0 months; while the active ingredient content of tazobactam alone dropped to 98.1% after 6 months, and the content of ring-opening impurities was 0.82 %, compared with 0 months, the content of active ingredients decreased significantly, and the content of ring-opening impurities increased significantly; it can be seen that the addition of ceftazidime significantly inhibited the degradation of active ingredients, reduced the content of ring-opening impurities, and improved the composition. stability of the material.

Table 5 The quality change of tazobactam composition accelerated stability test

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)butanoic acid .

In conclusion, the stability test results show that the combination of β-lactamase inhibitor and ceftazidime has higher active ingredient content and lower impurity content, and has better stability than β-lactamase inhibitor alone. sex. In particular, for a single β-lactamase inhibitor, although the change in the content of the active ingredient was within the limits of the quality standard, the ring-opening impurities increased significantly, indicating that the quality of the drug is still unstable. In addition, because the β-lactamase inhibitor mainly relies on the lactam ring to exert its inhibitory effect, its ring-opening impurities will not have the ability to inhibit the enzyme at all, and may reverse the binding between the β-lactamase inhibitor and the enzyme. An increase in impurities may adversely affect drug efficacy.

Example 4 β-lactamase inhibitor composition is used to prepare compound antibiotics

The β-lactamase inhibitor composition with stable quality in Example 3 is particularly suitable for preparing compound antibiotics. For example, it is combined with the third-generation cephalosporins ceftazidime, cefoperazone, cefotaxime, ceftriaxone, etc. to form various compound preparations. One of the compositions in Example 3 is exemplified below, and other compositions can be compared.

Take commercially available ceftriaxone, pass through a 200-mesh sieve after pulverizing, take 2000 g and put it into a single-cone spiral-ribbon mixer, and take another sulbactam+ceftazidime (100:1) composition prepared according to the method in Example 2 1010g, put into the same single-cone spiral-ribbon mixer, fully mixed, and packaged under aseptic conditions to obtain compound antibiotic injection—ceftriaxone-sulbactam (2:1). According to the same method, ceftriaxone-tazobactam (3:1), ceftriaxone-tazobactam (6:1), cefotaxime-tazobactam (6:1), cefotaxime (6:1) were prepared Bactam (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), cefoperazone-sulbactam ( 1:1) and other compound preparations.

In order to compare the differences between these compound antibiotics and common compound antibiotics, common compound antibiotics were also prepared. Using commercially available cephalosporins and commercially available beta-lactamase inhibitors as raw materials, the raw materials do not contain ceftazidime; prepared by the same method as above: ceftriaxone sulbactam contrast agent (2:1), ceftriaxone Tazobactam Contrast Media (3:1), Cefotaxime Tazobactam Contrast Media (6:1), Cefotaxime Sulbactam Contrast Media (2:1), Cefotaxime Tazobactam Contrast Media (3:1) :1), cefoperazone-tazobactam contrast agent (8:1), cefoperazone-sulbactam contrast agent (1:1), etc.

Among them, cefotaxime sulbactam (2:1), cefotaxime tazobactam (6:1), cefotaxime sulbactam contrast agent (2:1) and cefotaxime tazobactam were selected for comparison (6:1), as well as commercially available cefotaxime injection, to test the bacteriostatic activity of these antibiotics. Test method: 37 strains of clinically isolated β-lactamase-producing Escherichia coli were tested for drug sensitivity according to the CLSI micro-broth dilution method, and the MIC value of each drug was determined. The drug dilution concentration range was 0.03-256 μg/mL, and the MIC was the lowest drug concentration that inhibited the visible growth of bacteria after 24 hours of incubation at 37°C. The results are shown in Table 6.

Table 6 Antibacterial activity of antibiotics against β-lactamase-producing Escherichia coli

The test results showed that the β-lactamase-producing bacteria were resistant to individual antibiotics. Combination of β-lactamase inhibitors and antibiotics can make bacteria resensitized to antibiotics. However, the compound antibiotic prepared from the β-lactamase inhibitor composition (including ceftazidime) according to the embodiment of the present invention has stronger antibacterial activity compared with ordinary compound antibiotics, and shows that the MIC ₅₀ and the MIC range are both smaller than those of ordinary compound antibiotics. .

Although this invention has been disclosed with reference to specific embodiments, it will be apparent that other embodiments and variations of this invention can be devised by others skilled in the art without departing from the true spirit and scope of this invention, the appended claims The claims are intended to be construed to include all such embodiments and equivalent variations.

Claims (19)

1. A pharmaceutical composition is characterized in that it comprises ceftazidime and a beta-lactamase inhibitor, wherein the weight ratio of ceftazidime and beta-lactamase inhibitor is less than or equal to 1:15.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of ceftazidime and beta-lactamase inhibitor is 1:15-1:2000.
3. The pharmaceutical composition according to claim 1, wherein the weight ratio of ceftazidime and beta-lactamase inhibitor is 1:15-1:1000.
4. The pharmaceutical composition according to claim 1, wherein the β-lactamase inhibitor is selected from clavulanic acid, sulbactam, tazobactam, or any combination thereof.
5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a β-lactam antibiotic, and the β-lactam antibiotic is not ceftazidime.
6. The pharmaceutical composition according to claim 5, wherein the β-lactam antibiotics include penicillin antibiotics, penem antibiotics, carbapenem antibiotics, cephalosporins antibiotics, cephalosporins At least one of antibiotics, oxycephem antibiotics and monocyclic beta-lactam antibiotics.
7. The pharmaceutical composition according to claim 6, wherein the β-lactam antibiotic is selected from the group consisting of amoxicillin, ampicillin, aspicillin, azithromycin, azlocillin, baminocillin, carbenicillin , Carindacillin, Clomethicillin, Cloxacillin, Dicloxacillin, Epicillin, Flucloxacillin, Hetacillin, Metancillin, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Peel Nacillin, phenacillin, mecillin, penicillin, penicillin G, penicillin V, phenoxymethyl penicillin, piperacillin, pimacillin, propicillin, sulfenbenicillin, phthalicillin, temoxicillin, tica Acillin, pimecillin, benzathine penicillin, benzathine penicillin G, benzathine penicillin V, benzyl penicillin, cefotaxime, cefoxitin, cefacetonitrile, cefmenoxime, cefnicil, cefidiazine, cefpirome, Cefpiramide, cefazolam, cefpodoxime axetil, cefdoxime, cefcapine, cefepime, ceftaroline, cefoperazone, cefadroxil, cefepime, cefotaxime, ceftazidime, cefditoren , ceftriaxone, cefrazone, cefotaxime, cefazolin, cefpirin, ceftizole, cefamandole, cefamandox, cefotiam, cefuroxime, cefuroxime axetil, ceftizoxime, Cefsulodin, cefmetazole, cefminox, cephalexin, cefradine, cefaclor, cefprozil, cefuroxime axetil, cefixime, cefbutene, cefdinir, cefoxidone, ceftriaxine, cefotaxime Sadin, cefotetan, chlorocarbon cephalosporin, cefretet, fluoroox cephalosporin, laoxetan, cefpodoxime, cefbiloxacide, ceftaroline axetil, cefdil, ceftlozam, cefathiamidine, Cefditoren pivoxil, meropenem, ertapenem, doripenem, biapenem, panipenem, tipipenem, thiopenem, imipenem, aztreonam, carrumonem , at least one of faropenem and tipipenem pivoxil.
8. The pharmaceutical composition according to claim 7, wherein the β-lactam antibiotic is selected from at least one of ceftazidime, cefoperazone, cefotaxime and ceftriaxone.
9. The pharmaceutical composition according to claim 5, wherein the weight ratio of the β-lactamase inhibitor to the β-lactam antibiotic is 1:1-1:10.
10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant selected from the group consisting of fillers, adhesives , base, disintegrating agent, lubricant, solvent, solubilizer, flavoring agent, coloring agent, taste masking agent, pH adjusting agent, isotonicity agent, suspending agent, thickening agent, preservative, stabilizer, antioxidant At least one of an agent, a wetting agent, a surfactant, a suspending agent, a propellant, an absorption enhancer, an absorption delaying agent, and a coating material.
11. The pharmaceutical composition according to any one of claims 1 to 9, wherein the dosage form of the pharmaceutical composition is an oral dosage form, an injection dosage form, an inhalation dosage form or a transdermal dosage form.
12. Use of the pharmaceutical composition of any one of claims 1 to 11 in the preparation of a medicament for preventing or treating bacterial infection.
13. The use according to claim 12, wherein the bacteria are β-lactamase-producing bacteria.
14. The use according to claim 12 or 13, wherein the bacterial infection comprises: skin and soft tissue infection, bone and/or joint infection, genitourinary infection, intra-abdominal infection, respiratory infection, bacteremia, At least one of meningitis and surgical site infection.
15. A method of preventing or treating a bacterial infection, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 11.
16. The method according to claim 15, wherein the bacteria are β-lactamase-producing bacteria.
17. The method according to claim 15 or 16, wherein the bacteria include Streptococcus, Neisseria, Haemophilus influenzae, Salmonella, Moraxella catarrhalis, Acinetobacter, Escherichia coli, Pseudomonas aeruginosa At least one of Pseudomonas, Staphylococcus aureus, Enterococcus, Anaerobic Coccus, Enterobacter, Bacteroides, Anaerobic, Proteus vulgaris, Proteus mirabilis, Klebsiella, and Citrobacter .
18. The method according to claim 15, wherein the bacterial infection comprises skin and soft tissue infection, bone and/or joint infection, genitourinary infection, intra-abdominal infection, respiratory infection, bacteremia, meningitis and at least one of surgical site infections.
19. The method of claim 15, wherein the method of administering the pharmaceutical composition to a subject in need thereof comprises gastrointestinal administration, intravenous administration, subcutaneous administration, intramuscular administration, sublingual administration Medicine, skin administration, ear administration, ocular administration, oral inhalation administration, nasal inhalation administration.