WO2022198378A1 - Composition inhibitrice de bêta-lactamases présentant une qualité stable, utilisation et méthode associées - Google Patents

Composition inhibitrice de bêta-lactamases présentant une qualité stable, utilisation et méthode associées Download PDF

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Publication number
WO2022198378A1
WO2022198378A1 PCT/CN2021/082063 CN2021082063W WO2022198378A1 WO 2022198378 A1 WO2022198378 A1 WO 2022198378A1 CN 2021082063 W CN2021082063 W CN 2021082063W WO 2022198378 A1 WO2022198378 A1 WO 2022198378A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
infection
antibiotics
ceftazidime
lactamase inhibitor
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PCT/CN2021/082063
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English (en)
Chinese (zh)
Inventor
孙天宇
高太平
蒋娟艳
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广州新创忆药物临床研究有限公司
广州新创意生物医药有限公司
湘北威尔曼制药股份有限公司
广州威尔曼新药研发有限公司
南京康福顺药业有限公司
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Application filed by 广州新创忆药物临床研究有限公司, 广州新创意生物医药有限公司, 湘北威尔曼制药股份有限公司, 广州威尔曼新药研发有限公司, 南京康福顺药业有限公司 filed Critical 广州新创忆药物临床研究有限公司
Priority to CN202180001071.1A priority Critical patent/CN113194943B/zh
Priority to PCT/CN2021/082063 priority patent/WO2022198378A1/fr
Priority to CN202211296199.8A priority patent/CN115581700A/zh
Publication of WO2022198378A1 publication Critical patent/WO2022198378A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Embodiments of the present invention relate to the technical field of medicine, and in particular, to a ⁇ -lactamase inhibitor composition with stable quality and use and method thereof.
  • the antibacterial activity of ⁇ -lactamase inhibitors is basically weak, and even if they have antibacterial activity, their antibacterial spectrum is very narrow. People mainly combine ⁇ -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 ⁇ -lactamase inhibitor is used to provide ⁇ -lactamase inhibitory activity.
  • ⁇ -lactamase inhibitor inhibition of ⁇ -lactamase is called "suicide inactivation", that is, after the ⁇ -lactamase inhibitor binds to ⁇ -lactamase, while the enzyme is inactivated, ⁇ -lactamase inhibits The chemical structure of the agent itself is also destroyed.
  • ⁇ -lactamase inhibitors protect antibiotics from attack by ⁇ -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.
  • 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.
  • these ⁇ -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 ⁇ -lactamase inhibitors.
  • 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.
  • 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 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.
  • the weight ratio of ceftazidime and ⁇ -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.
  • the weight ratio of the ceftazidime to the ⁇ -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.
  • the beta-lactamase inhibitor is selected from clavulanic acid, sulbactam or tazobactam, or any combination thereof.
  • the beta-lactamase inhibitor is sulbactam and/or tazobactam.
  • the ceftazidime and the beta-lactamase inhibitor are present together (eg, as a mixture).
  • the pharmaceutical composition further comprises a beta-lactam antibiotic, which is not ceftazidime.
  • the ⁇ -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.
  • the ⁇ -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, ce
  • the ⁇ -lactam antibiotic is selected from at least one of ceftazidime, cefoperazone, cefotaxime and ceftriaxone.
  • the weight ratio of the ⁇ -lactamase inhibitor to the ⁇ -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.
  • the ⁇ -lactam antibiotic in the pharmaceutical composition, 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.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients can be selected from any pharmaceutically acceptable excipients known in the art according to actual needs.
  • 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.
  • the pharmaceutical composition is a pharmaceutical preparation or an intermediate of a pharmaceutical preparation.
  • the pharmaceutical composition is in solid form.
  • solid form For example powder etc.
  • 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.
  • 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.
  • 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.
  • the bacteria are beta-lactamase-producing bacteria.
  • 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.
  • the bacterial infection comprises a bacterial infectious disease.
  • 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.
  • SSTI skin and soft tissue infection
  • IAI intraperitoneal infection Infection
  • respiratory system infection respiratory system infection
  • bacteremia bacteremia
  • meningitis surgical site infection
  • 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.
  • the bacteria are beta-lactamase-producing bacteria.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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
  • sulbactam includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts, polymorphs, solvates, hydrates of any chemical purity.
  • 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.
  • tazobactam includes not only the compound molecule itself, but also its free acid, pharmaceutically acceptable salts, polymorphs, solvates, hydrates of any chemical purity.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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-ethy
  • 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.
  • 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).
  • 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.
  • 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).
  • 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”.
  • preventing refers to preventing or reducing the development of a given disease after use in the presence of factors that may trigger the given disease.
  • treating includes delaying or reducing symptoms caused by a given disease.
  • treatment specifically includes controlling the progression of the disease and associated symptoms.
  • terapéuticaally 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.
  • 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.
  • the active ingredients may be present in the same pharmaceutical agent at the same time, or separately in multiple different pharmaceutical agents.
  • the term “pharmaceutically acceptable” generally refers to use in the pharmaceutical arts and is not harmful to the product or to the subject.
  • 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.
  • infection includes the presence of bacteria in or on a subject that would benefit the subject if their growth was inhibited.
  • the term “infection” refers to the undesired normal flora in addition to the presence of bacteria.
  • infection includes infections caused by bacteria.
  • 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.
  • urogenital infection is an infectious disease caused by the invasion of the urogenital system by pathogenic bacteria for various reasons.
  • 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.
  • respiratory infection is a disease in which pathogenic microorganisms invade and multiply in the respiratory system.
  • bacteria 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.
  • 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.
  • surgical site infection includes both surgical incision infections and infections of surgical organs and surrounding tissues.
  • 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.
  • antibiotic also refers to compounds capable of reducing bacterial infectivity or virulence.
  • beta-lactam antibiotic refers to a compound that has antibiotic properties and contains a beta-lactam core in its molecular structure.
  • beta lactamase refers to any enzyme or protein or any other that breaks down a beta lactam ring.
  • beta-lactamase includes enzymes produced by bacteria and having the ability to partially or fully hydrolyze the beta-lactam rings in beta-lactam antibiotics.
  • beta-lactamase inhibitor refers to a compound capable of partially or completely inhibiting the activity of one or more beta-lactamases.
  • 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.
  • the combination or combination of ⁇ -lactamase inhibitors and ⁇ -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
  • a small proportion of ⁇ -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.
  • the use of this stable ⁇ -lactamase inhibitor in combination with ⁇ -lactam antibiotics can better restore sensitivity to bacteria and better improve the bacteriostatic effect of ⁇ -lactam antibiotics .
  • the ratios in the compositions of the present invention are calculated based on the free acid of the components.
  • the drugs used in the embodiments of the present invention are all APIs.
  • Example 2 The effect of different contents of ceftazidime on hygroscopicity of ⁇ -lactamase inhibitor
  • ceftazidime dosage was further studied.
  • 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 ⁇ -lactamase inhibitors. , Cefetamet has a better effect of reducing hygroscopicity.
  • Table 2 The weight gain rate of the composition of ⁇ -lactamase inhibitor and different dosage of ceftazidime under the same humidity
  • 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.
  • 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 ⁇ -lactamase in each sample in October and June respectively.
  • HPLC high performance liquid chromatography
  • 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.
  • HPLC detection conditions are as follows (refer to the US Pharmacopoeia):
  • Sulbactam chromatographic column 4mm ⁇ 15cm; 3 ⁇ m packing L1; mobile phase as shown in Table 3; detection wavelength 215nm.
  • Tazobactam Column: 4.6mm ⁇ 25cm; 5 ⁇ m 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.
  • Mobile phase A in Table 3 is 5.4g/L potassium dihydrogen phosphate adjusted to pH 4.0 with dilute phosphoric acid.
  • 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.
  • 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 .
  • the stability test results show that the combination of ⁇ -lactamase inhibitor and ceftazidime has higher active ingredient content and lower impurity content, and has better stability than ⁇ -lactamase inhibitor alone. sex.
  • the ring-opening impurities increased significantly, indicating that the quality of the drug is still unstable.
  • the ⁇ -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 ⁇ -lactamase inhibitor and the enzyme. An increase in impurities may adversely affect drug efficacy.
  • Example 4 ⁇ -lactamase inhibitor composition is used to prepare compound antibiotics
  • the ⁇ -lactamase inhibitor composition with stable quality in Example 3 is particularly suitable for preparing compound antibiotics.
  • it is combined with the third-generation cephalosporins ceftazidime, cefoperazone, cefotaxime, ceftriaxone, etc. to form various compound preparations.
  • 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.
  • ceftriaxone 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).
  • 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.
  • 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.
  • 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 ⁇ -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 ⁇ g/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.
  • the test results showed that the ⁇ -lactamase-producing bacteria were resistant to individual antibiotics.
  • Combination of ⁇ -lactamase inhibitors and antibiotics can make bacteria resensitized to antibiotics.
  • the compound antibiotic prepared from the ⁇ -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. .

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Abstract

Les modes de réalisation de la présente invention concernent le domaine technique de la médecine, en particulier une composition inhibitrice de bêta-lactamases présentant une qualité stable, une utilisation et une méthode associées. La composition pharmaceutique des modes de réalisation de la présente invention présente une hygroscopicité améliorée et une meilleure stabilité, de façon que la stabilité des substances dans une méthode de préparation puisse être assurée et la composition pharmaceutique est particulièrement appropriée pour la préparation ultérieure d'antibiotiques composés. De plus, des expériences montrent que la composition inhibitrice de bêta-lactamases des modes de réalisation de la présente invention peut davantage améliorer la sensibilité des antibiotiques à des bactéries résistantes aux médicaments, et les antibiotiques composés préparés présentent une activité antimicrobienne plus forte vis-à-vis des bactéries résistantes aux médicaments.
PCT/CN2021/082063 2021-03-22 2021-03-22 Composition inhibitrice de bêta-lactamases présentant une qualité stable, utilisation et méthode associées WO2022198378A1 (fr)

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PCT/CN2021/082063 WO2022198378A1 (fr) 2021-03-22 2021-03-22 Composition inhibitrice de bêta-lactamases présentant une qualité stable, utilisation et méthode associées
CN202211296199.8A CN115581700A (zh) 2021-03-22 2021-03-22 质量稳定抑菌活性高的含头孢噻肟舒巴坦或头孢噻肟他唑巴坦的药物组合物

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WO2022198378A1 (fr) * 2021-03-22 2022-09-29 广州新创忆药物临床研究有限公司 Composition inhibitrice de bêta-lactamases présentant une qualité stable, utilisation et méthode associées
CN114025767A (zh) * 2021-09-18 2022-02-08 湘北威尔曼制药股份有限公司 一种含有头孢哌酮钠和他唑巴坦钠的药物组合物及其应用
CN116808047A (zh) * 2022-03-22 2023-09-29 南京优科生物医药股份有限公司 一种头孢噻肟或其盐和他唑巴坦或其盐的应用

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