WO2022042546A1 - Composition pharmaceutique antibactérienne combinée et son utilisation - Google Patents

Composition pharmaceutique antibactérienne combinée et son utilisation Download PDF

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Publication number
WO2022042546A1
WO2022042546A1 PCT/CN2021/114298 CN2021114298W WO2022042546A1 WO 2022042546 A1 WO2022042546 A1 WO 2022042546A1 CN 2021114298 W CN2021114298 W CN 2021114298W WO 2022042546 A1 WO2022042546 A1 WO 2022042546A1
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Prior art keywords
berberine
combination
antibiotic
composition
berberine hydrochloride
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PCT/CN2021/114298
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English (en)
Chinese (zh)
Inventor
王苹
黄鹤
李晓波
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天津现代创新中药科技有限公司
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Publication of WO2022042546A1 publication Critical patent/WO2022042546A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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

Definitions

  • the invention relates to the field of pharmaceutical compositions, in particular to a combined antibacterial pharmaceutical composition comprising berberine and antibiotics and application thereof.
  • Acinetobacter baumannii is a class of Gram-negative bacilli, non-motile, catalase-positive, oxidase-negative and strictly aerobic bacteria, which are considered to be one of the important pathogens causing nosocomial infections.
  • Acinetobacter baumannii can cause a variety of acquired diseases, including pneumonia, skin and soft tissue infections, wound infections, urinary tract infections, etc. Among them, the infection with the highest mortality rate is pneumonia that requires ventilator-assisted treatment. Disease or patients who have undergone major surgical procedures are more common, accounting for about 40%-70%.
  • Antibiotic resistance of Acinetobacter baumannii has increased significantly over the past decade, and a report from the Bacterial Resistance Surveillance System of the China Bacterial Resistance Surveillance Network shows that between 2005 and 2014, carbapenems The drug-resistant A. baumannii species increased from 31% to 66.7%.
  • combination therapy has emerged as an option to improve treatment outcomes and possibly prevent the emergence of new Potential options for drug resistance.
  • the clinical combination treatment plan mainly focuses on the combination of antibiotics and antibiotics. Based on the drug resistance spectrum of the infected bacteria, an appropriate combination of drugs can be selected.
  • Berberine also known as berberine, is a pale yellow isoquinoline alkaloid that is widely present in the roots, rhizomes and bark of Berberis plants.
  • Berberine hydrochloride the most common form of berberine, is considered a drug with various medical potentials, including antibacterial, antiviral, antidiarrheal, antipyretic, and anti-inflammatory effects.
  • traditional Chinese medicines containing berberine, such as Coptis chinensis are used as traditional antibacterial drugs for the treatment of gastroenteritis, abdominal pain and diarrhea. They have been used for more than 2000 years, and a large number of clinical research data have accumulated, indicating that berberine is a Safe clinical antibacterial agent.
  • Acinetobacter baumannii With the increasing drug resistance of Acinetobacter baumannii, it has become resistant to traditional therapeutic antibiotics such as carbapenems, and it is difficult to use it alone. Some newer antibiotics, such as tigecycline or colistin, have relatively low resistance rates, but are expensive to treat and have certain side effects. At present, combination drugs are often used clinically to combat infections caused by multidrug-resistant Acinetobacter baumannii, but sometimes some strains have a relatively broad drug resistance spectrum, and the available antibiotic combinations are limited.
  • the present invention provides a combined antibacterial drug composition, which comprises a combination of berberine and an antibiotic;
  • the antibiotic is selected from one or two of sulbactam, tigecycline, amikacin, ciprofloxacin, meropenem and tetracycline.
  • the berberine may be in the form of its pharmaceutically acceptable salt, such as berberine hydrochloride or berberine sulfate.
  • the weight ratio of the berberine to the antibiotic may be (1-4096): 1, such as (1-1024): 1, such as (2-512: 1), exemplarily 4: 1, 8:1, 16:1, 32:1, 64:1, 128:1, 256:1, 512:1, or 4096:1.
  • the combined antibacterial pharmaceutical composition comprises one of the following combinations:
  • the weight ratio of the two can be (2-512): 1, such as (4-256): 1, (8-128): 1, exemplarily 2:1, 4:1, 8:1, 16:1, 32:1, 64:1 or 128:1;
  • the weight ratio of the two can be (1-4096): 1, for example (1-256): 1, (2-128): 1, (4- 64):1, exemplarily 8:1, 16:1, 32:1, 64:1 or 4096:1;
  • the weight ratio of the two can be (1-1024):1, such as (2-512:1), exemplarily 4:1, 8:1 , 16:1, 32:1, 64:1, 128:1, 256:1 or 512:1;
  • the combination of berberine hydrochloride and meropenem, the weight ratio of the two can be (2-512): 1, such as (4-256): 1, (8-128): 1, exemplarily 8 :1, 16:1, 32:1, 64:1 or 128:1;
  • the weight ratio of the two can be (1-256):1, such as (2-128:1), exemplarily 4:1, 8:1 , 16:1, 32:1, 64:1, 128:1 or 256:1;
  • the weight ratio of the two can be (1-256): 1, such as (2-128: 1), exemplarily 4: 1, 8: 1, 16: 1, 32:1, 64:1, 128:1 or 256:1.
  • the combined antibacterial pharmaceutical composition comprises one of the combinations of (1)-(4) above.
  • the weight percentage of the berberine in the composition may be 5.0%-90.0%, for example, 10.0%-85.0%, 15.0%-80.0%, 20%-75.0%, 25% %-70%; the weight percentage of the antibiotic in the composition can be 0.01%-50.0%, such as 0.05%-45.0%, 0.1%-40.0%, 0.2%-35%, 0.3%-30% .
  • the combined antibacterial pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or solvent.
  • the combined antibacterial pharmaceutical composition can be prepared into oral preparations or injections by conventional methods, such as tablets, granules, capsules, sustained-release preparations, injections, powders or infusions, and the like.
  • the pharmaceutically acceptable carriers or excipients include but are not limited to fillers, disintegrants, binders, wetting agents, lubricants, flavoring agents, pH adjusters, isotonicity adjusters, antioxidants, Metal ion chelating agents, etc.
  • fillers useful in the present invention include, but are not limited to, microcrystalline cellulose, lactose, mannitol, starch or dextrin, or a combination of two or more thereof.
  • disintegrants examples include, but are not limited to, sodium carboxymethyl starch, croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl starch, crospovidone, low-substituted hydroxypropyl based cellulose or cornstarch, or a combination of two or more thereof.
  • binders useful in the present invention include, but are not limited to, hypromellose, povidone, methylcellulose, or sodium carboxymethylcellulose, or a combination of two or more thereof.
  • wetting agents useful in the present invention include, but are not limited to, water or aqueous ethanol.
  • lubricants useful in the present invention include, but are not limited to, magnesium stearate, talc, or micronized silica gel, or a combination of two or more thereof.
  • flavoring agents examples include, but are not limited to, sucrose, stevioside, or aspartame, or a combination of two or more thereof.
  • pH adjusting agents useful in the present invention include, but are not limited to, sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, citric acid, citrate, acetic acid, acetate, glycine or lysine. amino acid, or a combination of two or more thereof; according to an embodiment of the present invention, the pH adjusting agent adjusts the pH value between 5.5 and 8.5, preferably between 6.5 and 7.5.
  • isotonicity modifiers useful in the present invention include, but are not limited to, sodium chloride, dextrose, glycerol, sorbitol, maltose, mannitol, or propylene glycol, or a combination of two or more thereof.
  • antioxidants useful in the present invention include, but are not limited to, sodium sulfite, sodium bisulfite, or sodium metabisulfite, or a combination of two or more thereof.
  • metal chelating agents useful in the present invention include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or ethylenediaminetetraacetic acid sodium salt (EDTA-Na), especially ethylenediaminetetraacetic acid disodium salt.
  • EDTA ethylenediaminetetraacetic acid
  • EDTA-Na ethylenediaminetetraacetic acid sodium salt
  • a pharmaceutically acceptable solvent useful in the present invention is water for injection.
  • the present invention also provides the application of the combined antibacterial drug composition for preparing antibacterial drugs.
  • the antibacterial drug is used against infections caused by Acinetobacter baumannii, especially multidrug-resistant Acinetobacter baumannii.
  • Berberine hydrochloride a monomer component of traditional Chinese medicine selected by the present invention, is cheap and easy to obtain, and has accumulated more than 2,000 years of clinical experience, and basically has no toxic and side effects.
  • the working concentration is between 16-512 mg/L.
  • the working concentration is determined according to the MIC of berberine hydrochloride.
  • strain MDRAb-1 MIC of berberine hydrochloride is 256 mg/L
  • the working concentration is between 16-128 mg/L, and the effect is significant when the concentration is 128 mg/L
  • strain MDRAb-2 MIC of berberine hydrochloride is 256 mg/L
  • 1024mg/L the working concentration is between 128-512mg/L, and the effect is significant when the concentration is 256 and 512mg/L.
  • the combination of berberine and antibiotics has a significant effect against multidrug-resistant Acinetobacter baumannii, and the bacteriostatic index is less than 1, showing superposition or synergy; the MIC value of antibiotics is reduced by at least 2 times; it can also make multidrug-resistant Acinetobacter baumannii is resensitized to antibiotics. Therefore, the combined antibacterial drug composition of the present invention has a significant inhibitory effect on drug-resistant bacteria, especially multidrug-resistant Acinetobacter baumannii.
  • MDRAb-1 and MDRAb-2 Two multi-drug resistant Acinetobacter baumannii strains (MDRAb-1 and MDRAb-2) were selected in the experiment, which are resistant to traditional quinolones, cephalosporins, aminoglycosides, carbapenems, penicillin resistance to antibiotics such as tetracyclines and tetracyclines.
  • All antibacterial drugs were prepared using sterile salt-free distilled water.
  • the concentration of berberine hydrochloride, sulbactam and meropenem preparation mother solution is 2048mg/L
  • the concentration of tigecycline mother solution is 2560mg/L
  • the concentration of amikacin and tetracycline mother solution is 4096mg/L
  • the concentration of ciprofloxacin mother solution is 64mg/L.
  • the MIC of antimicrobials was determined using the microbroth dilution method in accordance with the experimental guidelines of the American Society for Clinical Laboratory Standardization CLSI document M100, and all tests were performed in cation-adjusted Mueller Hinton broth (CAMHB).
  • CAMHB cation-adjusted Mueller Hinton broth
  • the MIC is defined as the lowest concentration of antimicrobial agent that inhibits bacterial growth by more than 90%, while this reference is roughly equivalent to no visible bacterial growth. Three wells were replicated for each concentration and at least three independent assays were performed. Escherichia coli ATCC 25922 was used as the quality control strain.
  • Inhibition rate (1-(OD 600nm drug treatment group- OD 600nm negative control group )/(OD 600nm positive control group- OD 600nm negative control group )) ⁇ 100%
  • a checkerboard design was used to determine the synergistic effect of antibiotics and berberine hydrochloride against multidrug-resistant Acinetobacter baumannii.
  • the experimental procedure was as follows: A series of two-fold dilutions of the antibacterial agent were prepared based on previously determined MIC values.
  • FIC values were defined as follows: synergistic effect, FIC ⁇ 0.5; additive effect, 0.5 ⁇ FIC ⁇ 1; irrelevant effect, 1 ⁇ FIC ⁇ 2; antagonism, FIC>2.
  • concentrations of berberine hydrochloride and antibiotics are 16, 32, 64, 128mg/L (MDRAb-1) and 64, 128, 256, 512mg/L (MDRAb-2)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique antibactérienne combinée comprenant de la berbérine et un antibiotique. L'antibiotique est un ou deux choisis parmi le sulbactam, la tigécycline, l'amikacine, la ciprofloxacine, le méropénème et la tétracycline. La combinaison de médicaments de la berbérine et de l'antibiotique a un effet inhibiteur significatif sur Acinetobacter baumannii pharmaco-résistante. L'indice antibactérien est inférieur à 1, qui représente un effet additif ou synergique. La combinaison de médicaments peut réduire efficacement la valeur de concentration minimale inhibitrice (CMI) de l'antibiotique, et peut également resensibiliser l'Acinetobacter baumannii pharmaco-résistante à l'antibiotique.
PCT/CN2021/114298 2020-08-24 2021-08-24 Composition pharmaceutique antibactérienne combinée et son utilisation WO2022042546A1 (fr)

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CN202010868371.7A CN111939156B (zh) 2020-08-24 2020-08-24 一种联合抗菌药物组合物及其应用
CN202010868371.7 2020-08-24

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CN111939156B (zh) * 2020-08-24 2022-04-12 天津现代创新中药科技有限公司 一种联合抗菌药物组合物及其应用
CN114042100B (zh) * 2021-10-28 2023-05-02 湖南农业大学 含中药提取物的抗菌组合物及其应用

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