WO2019126910A1 - 含有哌拉西林的组合物、其药物制剂及其应用 - Google Patents

含有哌拉西林的组合物、其药物制剂及其应用 Download PDF

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WO2019126910A1
WO2019126910A1 PCT/CN2017/118177 CN2017118177W WO2019126910A1 WO 2019126910 A1 WO2019126910 A1 WO 2019126910A1 CN 2017118177 W CN2017118177 W CN 2017118177W WO 2019126910 A1 WO2019126910 A1 WO 2019126910A1
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composition
piperacillin
sulbactam
ampicillin
pharmaceutical preparation
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PCT/CN2017/118177
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English (en)
French (fr)
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孙天宇
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湘北威尔曼制药股份有限公司
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Priority to US16/771,429 priority Critical patent/US11534438B2/en
Priority to PCT/CN2017/118177 priority patent/WO2019126910A1/zh
Priority to EP17936693.5A priority patent/EP3733176B1/en
Priority to CN201780097174.6A priority patent/CN111511368B/zh
Publication of WO2019126910A1 publication Critical patent/WO2019126910A1/zh

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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

  • the present invention relates to a composition containing piperacillin and uses thereof.
  • Acinetobacter baumannii is an important pathogen that causes infections in the respiratory, blood, abdominal, central nervous, urinary and skin soft tissues.
  • CHINET China's bacterial resistance monitoring
  • Acinetobacter baumannii is the most common pathogen in respiratory specimens, suggesting that this strain has a very important influence in respiratory diseases.
  • pulmonary infection caused by Acinetobacter baumannii has become an important cause of death.
  • the proportion of Acinetobacter baumannii was as high as 10.8%, second only to Escherichia coli and Klebsiella pneumoniae.
  • Peron-like carbapenem antibiotics have always had a good effect on Acinetobacter baumannii infection. However, with widespread use, multi-drug resistance and extensive drug resistance have emerged, and many Acinetobacter baumannii have been lacking sensitivity to the Peinan class.
  • Other clinical treatment options include polymyxin, cefoperazone and sulbactam. However, the strong nephrotoxicity of polymyxin limits its application, and the resistance of cefoperazone sulbactam to Acinetobacter baumannii is also becoming more and more prominent.
  • the resistance rate of Acinetobacter baumannii to cefoperazone sulbactam is 30%, and the 2016 report shows that this proportion has increased to 43%. Therefore, there is an urgent clinical need for a safer and more effective drug for the treatment of drug-resistant Acinetobacter baumannii infection.
  • the object of the present invention is to solve the problem of drug resistance of Acinetobacter baumannii, in particular, the resistance of Acinetobacter baumannii to cefoperazone sulbactam.
  • Bacterial resistance is a complex problem.
  • the mechanisms of drug resistance include bacterial production of drug inactivation enzymes, bacterial alteration of drug targets, changes in bacterial cell membrane permeability, and overexpression of bacterial intracellular and external efflux pumps.
  • Piperacillin is a commonly used penicillin antibacterial in clinical practice. However, it has been reported that the resistance rate of Acinetobacter baumannii to piperacillin has also reached more than 70%. Surprisingly, however, the inventors have obtained a composition containing piperacillin and other components which have a very good antibacterial action against Acinetobacter baumannii, thereby achieving the object of the present invention.
  • the invention provides a composition containing piperacillin, the composition further comprising ampicillin and sulbactam, wherein the weight ratio of piperacillin, ampicillin and sulbactam is 200-400: 0.02-6 :100.
  • the weight ratio of piperacillin, ampicillin and sulbactam in the composition of the present invention may be 200-400:0.02-3:100, further preferably 200:0.02-3:100, 300:0.02 -3:100, or 400:0.02-3:100.
  • Another preferred embodiment may be a weight ratio of piperacillin, ampicillin and sulbactam in the composition of the invention of from 200 to 400:0.04 to 6:100, further preferably from 200:0.04 to 6:100, 300: 0.04-6:100, or 400:0.04-6:100.
  • the composition of the invention consists of piperacillin, ampicillin and sulbactam.
  • the invention also provides a pharmaceutical formulation comprising a composition of the invention.
  • the pharmaceutical preparation may be an injection.
  • the injection may be in the form of a dry powder or a solution prepared by dissolving in a solvent.
  • the dry powder form may be a sterile powder needle or a lyophilized powder needle.
  • the solvent may be a conventional solvent suitable for clinical use, such as an aqueous solution of glucose or an aqueous solution of sodium chloride.
  • composition or pharmaceutical preparation of the present invention can be produced by a conventional method in the art.
  • the invention also provides a method of treating a bacterial infection, the method comprising the use of a composition or pharmaceutical formulation of the invention.
  • the invention also provides the use of a composition or pharmaceutical formulation of the invention in the manufacture of a medicament for the treatment of bacterial infections.
  • the bacterium is a drug-resistant Acinetobacter baumannii.
  • said resistance refers to resistance to cefoperazone sulbactam.
  • piperacillin ampicillin
  • sulbactam sulbactam
  • piperacillin ampicillin
  • sulbactam may refer to their free acids.
  • Different forms such as salts, polymorphs, hydrates or solvates.
  • piperacillin ((2S,5R,6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1-) Piperazine formylamino)-2-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid), piperacillin sodium ((2S, 5R,6R)-3,3-Dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido ]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-formic acid salt), ampicillin ((2S,5R,6R)-3,3-dimethyl -6-[(R)-2-amino-2-phenylacetamido]-7-oxo-4-thia-1-azabicy
  • the pharmaceutical preparation in the present invention is prepared according to a certain dosage form requirement and can be directly supplied to a medicine for use by a subject.
  • the composition of the present invention may contain a certain amount of moisture or impurities.
  • the pharmaceutical preparation of the present invention may contain a certain amount of excipients.
  • a certain amount of sulbactam and ampicillin are used in the piperacillin composition of the present invention to improve the drug resistance of Acinetobacter baumannii.
  • the prior art preparation containing sulbactam is also used for the treatment of Acinetobacter baumannii infection, it is generally considered to be the effect of sulbactam itself.
  • the present invention found that a small amount of ampicillin in the composition exerted an unusual synergistic effect on the drug-resistant Acinetobacter baumannii.
  • the mechanism may be that the ampicillin molecule increases the permeability of the cell membrane by first attacking the drug-resistant bacteria, increasing the probability and concentration of other drugs in the cell.
  • composition and preparation of the invention can be used for clinical treatment of infectious diseases caused by drug-resistant Acinetobacter baumannii, especially when Acinetobacter baumannii is resistant to drugs such as cefoperazone and sulbactam.
  • the therapeutic effect has significant technical effects and clinical advantages.
  • Examples 3-6 The operation of Examples 3-6 was similar to that of Example 1, and the amounts of piperacillin and sulbactam were the same as in Example 1, except that the amounts of ampicillin in each of the examples were gradually increased, being 1 g, 3 g, 10 g, and 15g.
  • Comparative Example 1-2 The operation of Comparative Example 1-2 was similar to that of Example 1, and the amounts of piperacillin and sulbactam were the same as in Example 1, except that the amounts of ampicillin in Comparative Examples 1-2 were 60 g and 200 g, respectively.
  • Comparative Example 3 The operation of Comparative Example 3 was similar to that of Example 1, and the amounts of piperacillin and sulbactam were the same as in Example 1, except that ampicillin was not used.
  • Examples 7-8 The operation of Examples 7-8 was similar to that of Example 1, except that the piperacillin was used in an amount of 1500 g in both examples, the amount of sulbactam was 500 g, and the amount of ampicillin was 5 g and 15 g, respectively.
  • Examples 10-14 The operation of Examples 10-14 was similar to that of Example 9, and the amounts of piperacillin and sulbactam were the same as in Example 9. The difference was that the amount of ampicillin in each of the examples was gradually increased, being 0.2 g, 0.7 g, 3 g, 5 g, and 15 g, respectively.
  • Comparative Examples 4-5 The operation of Comparative Examples 4-5 was similar to that of Example 9, and the amounts of piperacillin and sulbactam were the same as in Example 9. The difference was that the amounts of ampicillin in Comparative Examples 4-5 were 80 g and 300 g, respectively.
  • Test samples were the respective compositions of Examples 1-14 and Comparative Examples 1-5, meropenem, sulbactam, cefoperazone sulbactam.
  • the test animals were ICR mice.
  • the test strains were ATCC19606 (Standardella acinetobacter standard strain), CBP-R (Carbapenem-resistant Acinetobacter baumannii strain), CPZ/SR (resistant to cefoperazone and sulbactam Baumannii strain)
  • ATCC19606 Standardella acinetobacter standard strain
  • CBP-R Carbapenem-resistant Acinetobacter baumannii strain
  • CPZ/SR resistant to cefoperazone and sulbactam Baumannii strain
  • the standard bacteria are from ATCC, and the other bacteria are from clinical isolation.
  • test sample dose range Dilute the test strain with 5% high-activity dry yeast to 10 -1 , 10 -2 , 10 -3 , 10 -4 different concentrations of diluted bacterial solution , and inject the test animals intraperitoneally 0.5ml / mouse. The number of mouse deaths was recorded after infection, and the minimum bacterial count that caused 100% death in mice was recorded as 1 MLD. The mice infected with 1MLD bacteria were prepared with 5% high-activity dry yeast. Immediately and 6 hours later, pre-tests were carried out with three different concentrations of test samples at high, medium and low concentrations to record the survival of the mice after infection. The results are based on the designed dose of the animal protection test. Appropriate doses were 70% or more of the infected animals in the highest concentration group, and more than 70% of the infected animals in the lowest concentration group died.
  • mice that were fasted to avoid water and 25-30 g before the experiment were randomly divided into several groups: (1) ATCC 19606, (2) CBP-R, and (3) CPZ/.
  • the concentration of 5 test samples in each group was 10 animals in each group, and 10 animals were set as blank control group.
  • Each mouse was intraperitoneally injected with 0.5 ml of 1 MLD of bacterial liquid, resulting in an infection model.
  • 0.2 ml/mouse of different concentrations of the test sample was injected subcutaneously at 0 h and 6 h after infection, and the blank control group was given an equal volume of sterile water for injection. The observation was continued for 7 days, and the deaths of the animals in each group were recorded.
  • Calculating 50% effective dose of each test sample (ED 50) by Bliss method. The smaller the ED 50 , the better the bacteriostatic effect of the test sample in vivo, and the better the protective effect on the test animals.
  • Table 1 lists the main results of this trial.
  • Table 1 ED 50 for different compositions of animals infected with Acinetobacter baumannii
  • each test sample was effective against bacteria. Relatively speaking, the unilateral efficacy of meropenem or sulbactam is more advantageous.
  • the present invention provides a composition comprising piperacillin.
  • the composition of the present invention contains piperacillin, and also contains a certain proportion of ampicillin and sulbactam, wherein the weight ratio of piperacillin, ampicillin and sulbactam is 200-400:0.02-6: 100.
  • the invention also provides pharmaceutical formulations comprising the compositions and uses thereof.
  • the composition and the pharmaceutical preparation of the invention can significantly inhibit the drug-resistant Acinetobacter baumannii, in particular, the carbapenem antibiotic or the DCbaphenone-resistant Acinetobacter baumannii infection can To a good therapeutic effect, it has significant clinical advantages, and has good economic value and application prospects.

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Abstract

本发明提供了一种含有哌拉西林的组合物，该组合物中含有哌拉西林，还含有一定比例的氨苄西林和舒巴坦。本发明还提供了其药物制剂和应用。本发明的组合物和药物制剂可抑制耐药性鲍曼不动杆菌，特别是对碳青霉烯类抗生素或对头孢哌酮舒巴坦耐药的鲍曼不动杆菌感染能起到治疗作用。

Description

含有哌拉西林的组合物、其药物制剂及其应用 技术领域
本发明涉及一种含有哌拉西林的组合物及其应用。
背景技术
鲍曼不动杆菌是一种重要的致病菌，可引起呼吸、血液、腹腔、中枢神经、泌尿和皮肤软组织等系统的感染。据中国细菌耐药性监测(CHINET)2016年报告显示，鲍曼不动杆菌是呼吸道标本中占比最高的病原菌，提示该菌在呼吸道疾病中具有非常重要的影响。特别对于长期住院的危重病人，鲍曼不动杆菌引起的肺部感染已成为重要的致死原因。另外，在所有临床分离菌中，鲍曼不动杆菌的占比也高达10.8％，仅次于大肠杆菌和肺炎克雷伯菌。
一直以来，培南类碳青霉烯抗生素对鲍曼不动杆菌感染具有较好的作用。但随着广泛使用，出现了多重耐药和广泛耐药，很多鲍曼不动杆菌已经对培南类缺乏敏感性。临床上其他的药物治疗选择还有多粘菌素、头孢哌酮舒巴坦等。但多粘菌素较强的肾毒性限制了其应用，而头孢哌酮舒巴坦对鲍曼不动杆菌的耐药性问题也日益凸显。
据2010年CHINET报告显示，鲍曼不动杆菌对头孢哌酮舒巴坦的耐药率为30％，而2016年报告显示这一比例已经增长到43％。因此，对于更加安全有效的治疗耐药性鲍曼不动杆菌感染的药物，存在迫切的临床需求。
发明内容
本发明的目的是解决鲍曼不动杆菌的耐药性问题，特别是鲍曼不动杆菌对头孢哌酮舒巴坦耐药的问题。
细菌的耐药是一个复杂的问题，耐药的机制包括细菌产生药物灭活酶、细菌改变药物作用靶点、细菌细胞膜通透性的改变、细菌胞内外排泵的过度表达等。哌拉西林是临床常用的青霉素类抗菌药。但是据报道，鲍 曼不动杆菌对哌拉西林的耐药率也已经达到70％以上。然而意外地是，发明人通过研究得到一种含有哌拉西林和其他组分的组合物，该组合物对鲍曼不动杆菌具有非常好的抗菌作用，从而实现了本发明的目的。
本发明提供了一种含有哌拉西林的组合物，所述组合物中还含有氨苄西林和舒巴坦，其中哌拉西林、氨苄西林和舒巴坦的重量比为200-400:0.02-6:100。
优选地，本发明中组合物中，哌拉西林、氨苄西林和舒巴坦的重量比可以是200-400:0.02-3:100，进一步优选可以是200:0.02-3:100、300:0.02-3:100、或400:0.02-3:100。另一种优选方案为本发明组合物中哌拉西林、氨苄西林和舒巴坦的重量比可以是200-400:0.04-6:100，进一步优选可以是200:0.04-6:100、300:0.04-6:100、或400:0.04-6:100。
优选地，本发明的组合物由哌拉西林、氨苄西林和舒巴坦组成。
本发明还提供了一种药物制剂，该药物制剂中含有本发明的组合物。
优选地，所述的药物制剂可以是注射剂。进一步优选地，所述注射剂可以是干粉形式，也可以是用溶剂溶解后所配制成的溶液形式。所述的干粉形式可以是无菌粉针或冻干粉针。所述的溶剂可以是适宜临床使用的常规溶剂，例如葡萄糖水溶液或氯化钠水溶液等。
本发明的组合物或药物制剂可以通过本领域常规方法进行制备得到。
本发明还提供了一种细菌感染疾病的治疗方法，所述方法包括使用本发明所述的组合物或药物制剂。或者是，本发明还提供了一种本发明所述组合物或药物制剂在制备治疗细菌感染疾病方面的应用。
优选地，所述的细菌为耐药性鲍曼不动杆菌。
进一步优选地，所述的耐药是指对头孢哌酮舒巴坦耐药。
需要说明的是，本发明中的“哌拉西林”、“氨苄西林”或“舒巴坦”等名称是一种统称，即哌拉西林、氨苄西林或舒巴坦可以是指它们的游离酸、盐、多晶型物、水合物或溶剂化物等不同的形式。例如常见的有哌拉西林酸((2S,5R,6R)-3,3-二甲基-6-[(R)-2-(4-乙基-2,3-二氧代-1-哌嗪甲酰氨 基)-2-苯乙酰氨基]-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酸)、哌拉西林钠((2S,5R,6R)-3,3-二甲基-6-[(R)-2-(4-乙基-2,3-二氧代-1-哌嗪甲酰氨基)-2-苯乙酰氨基]-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酸钠盐)、氨苄西林酸((2S,5R,6R)-3,3-二甲基-6-[(R)-2-氨基-2-苯乙酰氨基]-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酸)、氨苄西林钠((2S,5R,6R)-3,3-二甲基-6-[(R)-2-氨基-2-苯乙酰氨基]-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酸钠盐)、舒巴坦酸((2S,5R)-3,3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-羧酸-4,4-二氧化物)、舒巴坦钠((2S,5R)-3,3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-羧酸钠-4,4-二氧化物)等。本发明中的药物制剂是指按照一定的剂型要求所制成的，可以直接提供给使用对象使用的药品。本发明中的组合物中可以含有一定含量的水分或杂质。本发明的药物制剂中可以含有一定含量的辅料。
本发明的哌拉西林组合物中使用一定量的舒巴坦和氨苄西林以改善鲍曼不动杆菌的耐药性。虽然现有技术中含有舒巴坦的制剂也用于鲍曼不动杆菌感染的治疗，但一般认为是舒巴坦本身所起的作用。而本发明首次发现组合物中少量的氨苄西林对于抗耐药性的鲍曼不动杆菌起到了不同寻常的增效作用。其机制可能是，氨苄西林分子通过首先进攻耐药菌，使细胞膜通透性增加，增加了其他药物在细胞内的机率和浓度。
本发明的组合物和制剂可用于临床上治疗耐药性鲍曼不动杆菌引起的感染性疾病，特别是当鲍曼不动杆菌对头孢哌酮舒巴坦等药物耐药后仍然能起到治疗效果，具有显著的技术效果和临床优势。
具体实施方式
下面用实施例对本发明进行进一步阐述，但并不用于限制本发明的技术方案和技术效果。
实施例1 哌拉西林组合物的制备
取哌拉西林钠(以哌拉西林酸计1000g)、氨苄西林钠(以氨苄西林酸计0.1g)和舒巴坦钠(以舒巴坦酸计500g)，用单锥螺带式混合机将三 种物料充分混合均匀，得到一种组合物。取一部分组合物在无菌条件进行分装，得到干粉形式的注射剂(无菌粉针)。另取一部分组合物用100倍量(ml/g)的0.9％氯化钠水溶液溶解，分装，得溶液形式的注射液。
实施例2 哌拉西林组合物的制备
取哌拉西林酸1000g、氨苄西林酸0.3g和舒巴坦酸500g，用含有343g碳酸氢钠的水溶液溶解后，冻干，分装，得到一种含组合物的干粉形式注射剂(冻干粉针)。
实施例3-6 哌拉西林组合物的制备
实施例3-6的操作与实施例1相似，哌拉西林和舒巴坦的量与实施例1相同，不同的是各实施例中氨苄西林的用量逐渐增多，分别为1g、3g、10g和15g。
对比例1-2
对比例1-2的操作与实施例1相似，哌拉西林和舒巴坦的量与实施例1相同，不同的是对比例1-2中氨苄西林的用量分别为60g和200g。
对比例3
对比例3的操作与实施例1相似，哌拉西林和舒巴坦的用量与实施例1相同，不同的是未使用氨苄西林。
实施例7-8 哌拉西林组合物的制备
实施例7-8的操作与实施例1相似，不同的是两个实施例中哌拉西林的用量均为1500g，舒巴坦的用量均为500g，而氨苄西林的用量分别为5g和15g。
实施例9 哌拉西林组合物的制备
取哌拉西林钠(以哌拉西林酸计1000g)、氨苄西林酸0.1g和舒巴坦钠(以舒巴坦酸计250g)，用多向运动混合机充分混合均匀，得到一种组合物。取一部分组合物，在无菌条件进行分装，得到干粉形式的注射剂。
实施例10-14 哌拉西林组合物的制备
实施例10-14的操作与实施例9相似，哌拉西林和舒巴坦的量与实施 例9相同。不同的是各实施例中氨苄西林的用量逐渐增多，分别为0.2g、0.7g、3g、5g和15g。
对比例4-5
对比例4-5的操作与实施例9相似，哌拉西林和舒巴坦的量与实施例9相同。不同的是对比例4-5中氨苄西林的用量分别为80g和300g。
实验例1 不同组合物对鲍曼不动杆菌引起试验动物感染的保护作用研究
试验材料：试验样品为实施例1-14和对比例1-5中的各组合物、美罗培南、舒巴坦、头孢哌酮舒巴坦。试验动物为ICR小鼠。试验菌株为ATCC19606(鲍曼不动杆菌标准菌株)、CBP-R(耐碳青霉烯类鲍曼不动杆菌菌株)、CPZ/S-R(耐头孢哌酮舒巴坦鲍曼不动杆菌菌株)，其中标准菌来自ATCC，其他菌来自临床分离。
摸索试验样品剂量范围：将试验菌株用5％高活性干酵母稀释为10 -1、10 -2、10 -3、10 -4不同浓度的稀释菌液，分别对试验动物进行腹腔注射0.5ml/鼠。感染后记录小鼠死亡数，致小鼠100％死亡的最低菌量记录为1MLD。用5％高活性干酵母配制1MLD菌量感染小鼠，即刻和6小时后，用高、中、低三个不同浓度的试验样品剂量进行预试验，记录感染后小鼠的存活数，以此结果为依据来设计动物保护试验的给药剂量。合适的给药剂量为最高浓度组70％以上的感染动物存活，最低浓度组70％以上的感染动物死亡。
动物保护试验：取实验前18h禁食不禁水、体重25-30g的小鼠，雌雄各半，随机分成几组：(1)ATCC 19606组，(2)CBP-R组，(3)CPZ/S-R组，每组5个试验样品浓度，每组10只动物，并设10只动物作空白对照组。每鼠均腹腔注射1MLD量的菌液0.5ml，造成感染模型，于感染后0h和6h分别皮下注射不同浓度的试验样品液0.2ml/鼠，空白对照组给予等体积的灭菌注射用水。连续观察7天，记录各组动物的死亡情况。用Bliss法计算出各试验样品的50％有效剂量(ED 50)。ED 50越小表明试验样品体内抑菌效果越好，对试验动物的保护作用越好。
试验结果：以S、A、B、C、D代表不同的ED 50级别。S：ED 50≤20mg/kg；A：20mg/kg＜ED 50≤50mg/kg；B：50mg/kg＜ED 50≤100mg/kg；C：100mg/kg＜ED 50≤200mg/kg；D：ED 50＞200mg/kg。表1列出了这项试验的主要结果。
表1：不同组合物对鲍曼不动杆菌感染动物的ED 50情况
Figure PCTCN2017118177-appb-000001
上述试验中，对于未产生耐药性的鲍曼不动杆菌标准菌株，各试验样品均能有效抑菌。相对而言，美罗培南或舒巴坦的单方药效更有优势。
对于耐药性的鲍曼不动杆菌，美罗培南或舒巴坦单方的药效明显下降，头孢哌酮舒巴坦复方未能提供更好的效果，而本发明的哌拉西林组合物具有明显更好的抑菌作用，显示出强大的协同作用。氨苄西林的量影响这种作用，当少量氨苄西林存在时，组合物对耐药菌的作用较好。
上文用一般性说明、具体实施方式及试验，对本发明作了详尽的描述。在本发明的基础上，本领域技术人员可以对之作合理的修改或改进。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明的内容。
工业实用性
本发明提供一种含有哌拉西林的组合物。本发明所述组合物中含有哌拉西林，还含有一定比例的氨苄西林和舒巴坦，其中，所述哌拉西林、氨苄西林和舒巴坦的重量比为200-400:0.02-6:100。本发明还提供了包含所述组合物的药物制剂及其应用。本发明所述的组合物和药物制剂可显著抑制耐药性鲍曼不动杆菌，特别是对碳青霉烯类抗生素或对头孢哌酮舒巴坦耐药的鲍曼不动杆菌感染能起到很好的治疗作用，具有显著的临床优势，具有较好的经济价值和应用前景。

Claims (10)

  1. 一种含有哌拉西林的组合物，所述组合物中还含有氨苄西林和舒巴坦，其中哌拉西林、氨苄西林和舒巴坦的重量比为200-400:0.02-6:100。
  2. 根据权利要求1所述的组合物，其中哌拉西林、氨苄西林和舒巴坦的重量比为200-400:0.02-3:100，或200-400:0.04-6:100。
  3. 根据权利要求1所述的组合物，该组合物由哌拉西林、氨苄西林和舒巴坦组成。
  4. 一种药物制剂，含有权利要求1-3中任一所述的组合物。
  5. 根据权利要求4所述的药物制剂，所述药物制剂为注射剂。
  6. 根据权利要求5所述的药物制剂，所述注射剂为干粉形式的注射剂或者溶液形式的注射剂。
  7. 根据权利要求6所述的药物制剂，所述干粉形式的注射剂为无菌粉针或冻干粉针。
  8. 一种细菌感染疾病的治疗方法，所述方法包括使用权利要求1-3所述的组合物或权利要求4-7所述的药物制剂。
  9. 根据权利要求8所述的治疗方法，所述的细菌为耐药性鲍曼不动杆菌。
  10. 根据权利要求9所述的治疗方法，所述的耐药为对头孢哌酮舒巴坦耐药。
PCT/CN2017/118177 2017-12-25 2017-12-25 含有哌拉西林的组合物、其药物制剂及其应用 WO2019126910A1 (zh)

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