WO2018010403A1 - 药用纳米材料组合物dg-5用于抗耐药菌的用途 - Google Patents

药用纳米材料组合物dg-5用于抗耐药菌的用途 Download PDF

Info

Publication number
WO2018010403A1
WO2018010403A1 PCT/CN2017/000429 CN2017000429W WO2018010403A1 WO 2018010403 A1 WO2018010403 A1 WO 2018010403A1 CN 2017000429 W CN2017000429 W CN 2017000429W WO 2018010403 A1 WO2018010403 A1 WO 2018010403A1
Authority
WO
WIPO (PCT)
Prior art keywords
resistant bacteria
bacteria
silver
medicinal
drug
Prior art date
Application number
PCT/CN2017/000429
Other languages
English (en)
French (fr)
Inventor
刘进军
李强柏
司徒健超
Original Assignee
长沙迪谷纳米生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 长沙迪谷纳米生物科技有限公司 filed Critical 长沙迪谷纳米生物科技有限公司
Priority to US16/350,779 priority Critical patent/US20190247429A1/en
Publication of WO2018010403A1 publication Critical patent/WO2018010403A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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 invention belongs to the technical field of medicine and relates to the preparation of a medicinal nano silver composition DG-5 and its use in anti-drug resistant drugs, including Methicillin-Resistant Staphylococcus Aureus (MRSA). And vancomycin-resistant enterococci (VRE), especially for superbugs such as Enterobacter cloacae, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, etc. Inhibitory effect.
  • MRSA Methicillin-Resistant Staphylococcus Aureus
  • VRE vancomycin-resistant enterococci
  • Silver ions and silver-containing compounds can kill or inhibit bacteria, viruses, algae and fungi.
  • Silver has the effect of fighting disease, so it is also known as pro-biometal.
  • Silver is harmless to normal human cells.
  • the antibacterial properties of silver were widely used in the pharmaceutical industry as early as the 16th century.
  • Silver curable antibacterial was also recorded in the "Compendium of Materia Medica" written by Li Shizhen, a famous Chinese medicine practitioner in the Ming Dynasty. If the wound is covered with silver to prevent ulceration, the skin wound is wrapped with gauze and wrapped with silver cloth. The baby is born with silver nitrate solution to prevent mucosal infection.
  • metal silver has broad-spectrum antibacterial, long-acting antibacterial, strong sterilization, strong permeability and no drug resistance, it does not find any irritating reaction to the skin, and can promote wound healing, cell growth and damaged cells.
  • the repair, without any toxic reaction characteristics, silver-containing medical devices have become a hot topic in recent years.
  • New nano silver antibacterial fibers, nano silver dressings, nano silver gels, nano silver antibacterial catheters, and nano silver condoms have been continuously developed. Since 2004, 29 kinds of medical products containing nano-silver have obtained the registration approval of the provincial food and drug administration and entered clinical application. In February 2016, the State Food and Drug Administration approved the first seven products to enter clinical applications.
  • nano silver powders on the market are mostly prepared by chemical methods, and various particle sizes and shapes are mixed, and the purity, performance and distribution accuracy and stability are difficult to determine, and the collection, storage and transportation of nano powders are difficult. Research needs to be strengthened, and the safety of biological and pharmaceutical applications is even more difficult to guarantee.
  • the nano silver products available on the market are limited by the existing nano silver preparation technology, and most of them are made of elemental metal silver or other silver-containing compounds by using physical or chemical methods to form nano-scale metal silver powder. The usual physical methods (such as ball milling) in the preparation process are difficult to reach the nanometer scale.
  • the electrolysis method has low output and high cost, and is not suitable for industrial application.
  • the medicinal nanosilver composition DG-5 can be used for medical applications against resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), especially for the culvert Superbugs such as Enterobacter, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii have strong inhibitory effects.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococcus
  • the present invention provides pharmaceutical applications of the medicinal nanomaterial compositions for use against drug resistant bacteria, including in the preparation of corresponding pharmaceuticals.
  • the present invention provides the use of a medicinal nanomaterial composition DG-5 for the preparation of a medicament, wherein the medicament is for use against a drug resistant bacteria, the composition consisting of the following components: spherical nanosilver powder 1-2 g /L, glucose 1- 2g / L, the rest is water; the spherical nano silver powder particle size is 0.1 ⁇ 5nm (purchased from Hunan Optics Valley Nano Technology Co., Ltd.), the purity of silver in spherical nano silver powder ⁇ 99.99%.
  • the resistant bacteria include Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterococcus faecalis, Streptococcus pneumoniae or Staphylococcus aureus.
  • the resistant bacteria may also include super-resistant bacteria such as Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa or Acinetobacter baumannii.
  • the medicinal nanomaterial composition may be used alone or in combination with other agents.
  • the invention also provides an antimicrobial drug comprising the medicinal nanomaterial composition and one or more pharmaceutically acceptable carriers.
  • the carrier is, for example, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, an adsorption carrier, a lubricant, or a combination thereof.
  • the antibacterial agent is in the form of, for example, an injection, a tablet, a pill, a capsule, a suspension or an emulsion, as needed.
  • Nanomaterials exhibit many special physical and chemical properties due to their unique surface effects, small size effects, quantum size effects and macroscopic quantum tunneling effects, especially in the fields of mechanics, thermals, magnetism, optoelectronics, electronics, etc.
  • the bulk material presents a huge difference.
  • the inventors believe that the development of nanotechnology provides a new direction in anti-infection research, and many nanomaterials exhibit potential antibacterial activity. After processing metallic silver into nano-silver, its specific surface area is extremely large, showing obvious surface effect, small size effect and macroscopic tunneling effect.
  • the combined effect of these effects greatly enhances the antibacterial ability of silver, especially ultra-fine particle size nano-silver (particle size less than 5nm), so that the effective concentration of nano-silver antibacterial can reach nanomolar level, much lower than the micromolar level of silver ions. .
  • the nano-silver of the present invention utilizes leading edge nanotechnology to nano-silver and achieve a nano-scale (0.1-100 nm) metallic silver particle size.
  • a very small amount of nano-silver can produce powerful bactericidal effects, such as killing in a few minutes More than 650 bacteria.
  • the invention relates to a medicinal nano silver composition DG-5.
  • the nano silver powder (0.1-5 nm) of Hunan Optics Nanotechnology Co., Ltd. is selected as medicinally acceptable glucose and pure water as its stabilizer and diluent.
  • the composition is reduced as much as possible, and on the other hand, the medicinal safety of the composition is ensured from the material.
  • Figure 1 is a test panel map. Among them, lines A and B: ciprofloxacin (CIP), the highest test concentration of 64 ⁇ g / ml, 2 times the dilution. Lines C and D: DG-5, the highest test concentration is 30 ⁇ g/ml, diluted by 2 times.
  • SC Sterile control
  • Compound solvent, 1.1xCAMHB or CAMHBII no compound.
  • Example 1 Medicinal nanomaterial composition DG-5 consisting of the following concentrations of components: spherical nanosilver powder 1-2 g/L, glucose 1-2 g/L, and the balance being water; spherical nanosilver powder particle size
  • the purity of silver in the spherical nano silver powder is ⁇ 99.99%, which is 0.1 to 5 nm (purchased from Hunan Optics Valley Nanotechnology Co., Ltd.).
  • Example 2 Determination of activity of medicinal nanomaterial composition DG-5 against 5 resistant strains (Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterococcus faecalis, Streptococcus pneumoniae, Staphylococcus aureus).
  • the minimum inhibitory concentration was used as an indicator of antimicrobial activity.
  • the minimum inhibitory concentration refers to the minimum inhibitor concentration (MIC) that inhibits the apparent growth of a certain microorganism.
  • the minimum inhibitory concentration is determined by reference to the micro-culture dilution method of the Clinical and Laboratory Standards Institute Guidelines (CLSI).
  • CLSI Clinical and Laboratory Standards Institute Guidelines
  • This study examined the minimum inhibitory concentration of one test sample DG-5 and one control antibiotic ciprofloxacin against five strains of bacteria.
  • Test sample DG-5 was double-diluted in a 96-well plate from the highest detection concentration of 30 ⁇ g/ml. The test plate is placed in a normal incubator at 35 ⁇ 2 ° C for 16-20 After an hour, the bacterial growth in the wells was observed and recorded.
  • the minimum inhibitory concentration of the referenced ciprofloxacin was consistent with the historical data.
  • the minimum inhibitory concentration of the test sample DG-5 against 5 strains of bacteria was determined to be between 1.875-15
  • TSA Trypticase soy agar
  • TSA II TSA + 5% sheep blood
  • CAMHB ion-corrected Mueller Hinton broth
  • CAMHB II ion-corrected Mueller Hinton broth
  • sheep blood Quad Five 630-500
  • horse blood Quad Five 205-500.
  • Test sample DG-5 300 ⁇ g/ml was supplied by Changsha Digu Nano. Ciprofloxacin (Sigma 17850). One-time shake flask, 250ml (Corning 430183). Disposable plate, 100mm (VWR 25384-302). 96-well microtiter plate (Greiner 650162).
  • Bacterial resuscitation 5 strains of bacteria used for the minimum inhibitory concentration test were stored frozen in a -80 ° C low temperature refrigerator and revived 2 days earlier. Scrap a small amount of frozen bacteria in a sterile inoculating loop and streak the appropriate solid medium plates and incubate in a suitable gas culture environment for 35-24 hours at 35 ⁇ 2 °C (Streptococcus pneumoniae: TSA II, 5 %CO 2 Enterococcus faecalis: TSA II, normal atmospheric environment, the remaining 3 strains of bacteria: TSA, general atmospheric environment). 5-10 morphologically similar colonies were picked from the above culture dishes using a sterile inoculating loop and re-streaked onto a suitable solid medium plate. It is then placed in a suitable gas culture environment for 35-24 hours at 35 ⁇ 2 °C.
  • Test plate preparation test plate map (see Figure 1): row A and row B: ciprofloxacin (CIP), the highest test concentration of 64 ⁇ g / ml, 2 times the dilution. Lines C and D: DG-5, the highest test concentration is 30 ⁇ g/ml, diluted by 2 times.
  • Sterile control (SC) Compound solvent, 1.1xCAMHB or CAMHBII, no compound.
  • Colony count The inoculated bacteria were diluted from 10 -1 to 10 -7 with liquid medium (eg, 100 ⁇ l of bacterial inoculum + 900 ⁇ l of 1.1 x CAMHB). 100 ⁇ l of the above bacterial dilution was evenly spread on TSA plates at 2 dilutions per dilution. After the medium was absorbed by TSA for 10 minutes, the inverted plate was incubated at 35 ⁇ 2 ° C for 24 hours in an incubator. Bacterial inocula typically contain 1-2x10 8 colonies per ml, it is generally down conversion assay plate per well 2.5-5x10 4 colonies.
  • liquid medium eg, 100 ⁇ l of bacterial inoculum + 900 ⁇ l of 1.1 x CAMHB.
  • Minimum inhibitory concentration record and colony count Open the compound management system and check that the bar code and compound arrangement of each test plate are correct. Place the test plate on the plate reading device and adjust the mirror to record the bacterial growth in each well. At the same time, each test board was photographed with QCount software. The minimum inhibitory concentration of each compound was recorded by reference to the guidelines of the Clinical and Laboratory Standards Institute. The number of colonies of the bacterial inoculum at different dilutions on the TSA plates was counted and the bacterial inoculum was calculated.
  • test sample DG-5 was double-diluted in a 96-well plate from the highest detection concentration of 30 ⁇ g/ml.
  • Bacterial inoculum in the assay plates were resuscitated from different solid medium plates and diluted in CAMHB or CAMHB II, while growth controls and sterile controls were placed in the assay plates.
  • the test plates were observed and recorded for 16-20 hours at 35 ⁇ 2 ° C in a common incubator and the minimum inhibitory concentration of each compound against different bacteria was recorded.
  • Tables 1 and 2 record the minimum inhibitory concentration values for 2 independent replicates, respectively.
  • the minimum inhibitory concentration of the control compound ciprofloxacin was consistent with that reported in the literature.
  • the bacterial inoculum size of the test plates was counted and recorded in Table 3.
  • Example 3 Determination of activity of medicinal nanomaterial composition DG-5 against 5 strains of super-resistant bacteria.
  • the medicinal nanomaterial composition DG-5 was resistant to 5 strains of super-resistant bacteria (Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Bowman not The activity of the bacterium was measured.
  • the minimum inhibitory concentration of the referenced ciprofloxacin was consistent with the historical data.
  • the minimum inhibitory concentration of the test sample DG-5 against 5 strains of bacteria was between 1.875-3.75 ⁇ g/ml, which was much better than the positive.
  • the antibacterial activity of the control drug ciprofloxacin was between 1.875-3.75 ⁇ g/ml, which was much better than the positive. The antibacterial activity of the control drug ciprofloxacin.
  • TSA Trypticase soy agar
  • Test sample DG-5 300 ⁇ g/ml was supplied by Changsha Digu Nano. Ciprofloxacin (Sigma 17850). One-time shake flask, 250ml (Corning 430183). Disposable plate, 100mm (VWR 25384-302). 96-well microtiter plate (Greiner 650162).
  • Bacterial resuscitation 5 strains of bacteria used for the minimum inhibitory concentration test were stored frozen in a -80 ° C low temperature refrigerator and revived 2 days earlier. A small amount of frozen bacteria was scraped off with a sterile inoculating loop and streaked on a suitable solid medium plate, and placed in a common incubator at 35 ⁇ 2 ° C for 20-24 hours. 5-10 morphologically similar colonies were picked from the above culture dishes using a sterile inoculating loop and re-streaked onto a suitable solid medium plate. Then, it was placed in a normal incubator for 35-24 hours at 35 ⁇ 2 °C.
  • Inoculation of bacteria The liquid medium was taken out from the refrigerator at 4 ° C and allowed to stand at room temperature for heating. Five to 10 bacterial single colonies were picked from the above-mentioned solid culture dish and resuspended in 500 ⁇ l of 1.1 x CAMHB, and the OD 600 was adjusted to 0.1 to 0.13 with a spectrophotometer. The bacteria were diluted 400 times with 1.1 x CAMHB. The prepared bacterial inoculum was inoculated into a 96-well assay plate within 15 minutes. The number of bacteria inoculated was obtained by counting the colonies of the plates.
  • Test plate preparation test plate map (see Figure 1), line A and line B: ciprofloxacin (CIP), the highest test concentration of 64 ⁇ g / ml, 2 times the ratio of dilution. Lines C and D: DG-5, the highest test concentration is 30 ⁇ g/ml, diluted by 2 times.
  • Compound dilution Transfer 120 ⁇ l of the compound to the starting well of the dilution plate (A1, B1, C1 and D1) and transfer 60 ⁇ l of dimethyl sulfoxide (DMSO for dilute ciprofloxacin) or DG-5 solvent. To other holes. Each compound was serially diluted 2 times from column 1 to column 11 (ie, 60 ⁇ l of compound was pipetted from column 1 to column 2 and mixed, and 60 ⁇ l of compound was taken from column 2 to column 3 and mixed. Evenly, add 60 ⁇ l of compound from column 3 to column 4 and mix, and so on to the 11th column).
  • DMSO dimethyl sulfoxide
  • Colony count The inoculated bacteria were diluted from 10 -1 to 10 -7 with liquid medium (eg, 100 ⁇ l of bacterial inoculum + 900 ⁇ l of 1.1 x CAMHB). 100 ⁇ l of the above bacterial dilution was evenly spread on TSA plates at 2 dilutions per dilution. After the medium was absorbed by TSA for 10 minutes, the inverted plate was incubated at 35 ⁇ 2 ° C for 24 hours in an incubator.
  • liquid medium eg, 100 ⁇ l of bacterial inoculum + 900 ⁇ l of 1.1 x CAMHB.
  • Minimum inhibitory concentration record and colony count After opening the compound management system to confirm the barcode and compound arrangement of each test plate, place the test plate on the plate reading device, adjust the mirror to record the bacterial growth in each well. . At the same time, each test board was photographed with QCount software. The minimum inhibitory concentration of each compound was recorded by reference to the guidelines of the Clinical and Laboratory Standards Institute. The number of colonies of the bacterial inoculum at different dilutions on the TSA plates was counted and the bacterial inoculum was calculated.
  • test sample DG-5 was double-diluted in a 96-well plate from the highest detection concentration of 30 ⁇ g/ml.
  • the bacterial inoculum in the assay plate was resuscitated from TSA and diluted in CAMHB, while growth controls and sterile controls were placed in the assay plates.
  • Test plate in ordinary culture The minimum inhibitory concentration of each compound against different bacteria was observed and recorded after raising the cells at 35 ⁇ 2 ° C for 16-20 hours.
  • Tables 1 and 2 record the minimum inhibitory concentration values for 2 independent replicates, respectively. The results showed that the intra-group repeats and the inter-group replicates were consistent, and the minimum inhibitory concentration values of the control compound ciprofloxacin were consistent with historical data. The bacterial inoculation amount of the test plate was recorded and reported in Table 3.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种药用纳米材料组合物DG-5的制备及其在抗耐药菌药物中的用途。本发明的纳米材料组合物DG-5对数种超级耐药菌（Superbugs）具有抑制作用，可用于制备抗菌药物。该药物可通过外用，口服，皮下、静脉或肌肉注射等给药途径使用。

Description

药用纳米材料组合物DG-5用于抗耐药菌的用途 技术领域
本发明属于医药技术领域，涉及药用纳米银组合物DG-5的制备及其在抗耐药菌药物中的用途，包括对耐甲氧西林金黄色葡萄球菌(Methicillin-Resistant Staphylococcus Aureus，MRSA)和耐万古霉素肠球菌(VRE)，尤其是对阴沟肠杆菌，铜绿假单胞菌，大肠埃希菌，肺炎克雷伯菌，鲍曼不动杆菌等超级细菌(Superbugs)具有很强的抑制效果。
背景技术
近年来，抗生素耐药菌株的不断增加严重威胁着公众的健康。早在上世纪40年代，青霉素作为第一种有效的抗生素，曾经成功解决了临床上金黄色葡萄球菌感染这一难题。随后研发成功的各种抗生素如大环内酯类，氨基甙类抗生素等又使肺炎、肺结核等致命疾病的死亡率大为降低。然而，人类战胜细菌的时代远没有到来。事实上，许多抗生素在应用多年后出现了不同程度的药效减低，天然青霉素在控制金葡菌感染方面早已失去药用价值。在被称为抗生素″黄金时代″的上世纪五六十年代，全世界每年死于感染性疾病的人数约为700万，而这一数字到了1999年上升到2000多万。在号称世界上科技最发达国家的美国，1982至1992年间死于传染性疾病的人数上升了40％，而死于败血症的人数上升了89％。造成病死率升高的主要原因是耐药菌带来的用药困难。
长久以来，细菌的耐药性并未引起足够的重视，仍有医生们相信现有药物足以对付耐药菌。如对天然青霉素耐药的金葡菌，可以用氨苄青霉素，头孢菌素等，甚至于对头孢菌素耐药的耐甲氧西林金葡菌(MRSA)，还可以用万古霉素。但是在1992年，美国首次发现了万古霉素产生耐药性的MRSA，美国疾病控制和预防中心2016年5月证实：发现首例携带MCR-1基因的细菌，称之为“无敌细菌病例”，对现阶段全部抗生素都具有耐药性，包括对人体肾脏有损害，于上世纪七八十代停止用于人体被视为最后一道防线的粘菌素。为人类滥用抗生素敲响了警钟。
在我国，由于滥用抗生素的情况十分普遍，抗生素应用率远远高于各国平均水平，同时，医生滥开氨苄西林等广谱抗菌类药物，导致人体内菌群失调并诱发二次感染的情况更是屡见不鲜。近年中国和英国研究人员在英国《柳叶刀·传染病》杂志上曾经报告，在中国家禽和人类身上发现携带MCR-1基因的细菌，而未引起足够重视。时至今日，我国的耐药菌问题已变得十分突出，耐药菌引起的医院内感染人数，已占到住院感染患者总人数的30％左右。解决细菌耐药性问题已经是迫在眉睫。在加强对临床医生的在职教育，严格杜绝滥用抗生素和建立细菌耐药性的动态监测等监管措施之外，加快新型抗生素的研制步伐已是刻不容缓。
近年来，随着耐药菌的抗药能力越来越强，甚至出现所谓超级耐药菌(Superbugs)，全球各大药物公司又开始在新型抗生素的研发方面加强投入。研究开发结构新颖的，毒性较低的，具有我国自主知识产权的新型抗耐药菌药物有着十分重要的现实意义。近年来我国也有少量发明专利涉及抗耐药菌领域：CN101584694A，CN101195627A，CN101428026A，CN100586433C，CN100441580C，CN1308047A，CN101074235A，CN100519533C，CN101786979A，CN102464603B。其中CN102464603B报道吲哚满二酮类衍生物及其在制备抗耐药菌药物中的用途，特别是对耐甲氧西林金黄色葡萄球菌等耐药细菌有很强的抑制效果。
另一方面，金属银的广谱杀菌作用早已为人们所知。银离子和含银化合物可以杀死或者抑制细菌、病毒、藻类和真菌。银有对抗疾病的效果，所以又被称为亲生物金属。银对人体正常细胞无害。银的抗菌性能早在16世纪就被广泛地应用于医药界，我国明代著名医药家李时珍所著《本草纲目》中也记载银可抗菌。如用银片覆盖伤口预防溃烂，用银丝织成纱布包裹皮肤创伤，婴儿出生时滴上硝酸银溶液可防止黏膜感染。20世纪30年代，抗生素的发现一度使人们忽视了对银抗菌性能的利用。然而，随着抗生素等化学药物的滥用，越来越多的微生物通过变异产生了耐药性，使得一些由耐药性细菌引起的疾病无法医治。近年来，金属银作为生物安全性高、稳定性好的金属材料引起广泛关注，也使具备高效、广谱及不易产生耐药性等优点的银系杀菌剂再次引起人们的重视。
由于金属银具有广谱抗菌、长效抗菌、强效杀菌、渗透性强且无任何的耐药性，对皮肤也未发现任何刺激反应，并能够促进伤口的愈合、细胞的生长及受损细胞的修复，无任何毒性反应的特性，含银的医疗器械成为近年来研究的热点。新型的纳米银抗菌纤维、纳米银敷料、纳米银凝胶、纳米银抗菌导管，纳米银避孕套不断地被开发出来。2004年以来，已有29种含纳米银的医疗产品取得了省级食品药品监督管理局的注册批件，进入临床应用。2016年2月，国家食品药品管理局首次批准了7种产品进入临床应用。
然而，目前市场上的纳米银粉末多以化学方法制备，各种粒径、形状混存，其纯度、性能和分布的精确性、稳定性均难确定，纳米粉末的收集、存放、运输等技术研究尚待加强，生物、药物应用的安全性更难保障。市场上已有的纳米银产品，受现有纳米银制备技术的限制，绝大部分是将单质金属银或其他含银化合物利用物理或化学的方法，制成纳米级别的金属银粉末。在制备过程中通常的物理方法(如球磨法)难以达到纳米级。电解法产量低，成本高，又不宜于工业化应用。而化学方法的制备一直为获取高纯度的纳米粉末产品所困惑，特别在产业化过程中，其各种“酸根”的分离、杂质的清除极难实现，另外，还存在还原剂的影响。从而限制了纳米银材料在各个领域尤其是生物、医药领域的应用。目前尚未见到有关纳米银抗超级耐药菌的报道。
发明内容
本发明的目的在于提供一种新的药用纳米材料组合物DG-5及其在抗耐药菌药物中的用途。所述药用纳米银组合物DG-5能够用于抗耐药菌的医疗应用，包括对耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素肠球菌(VRE)，尤其是对阴沟肠杆菌，铜绿假单胞菌，大肠埃希菌，肺炎克雷伯菌，鲍曼不动杆菌等超级细菌(Superbugs)有很强的抑制效果。
本发明提供了所述药用纳米材料组合物用于抗耐药菌的医药应用，包括在相应药物制备中的用途。
本发明提供了一种药用纳米材料组合物DG-5在药物制备中的用途，其中所述药物用于抗耐药菌，所述组合物由下述成分组成：球形纳米银粉末1-2g/L，葡萄糖1- 2g/L，其余为水；所述球形纳米银粉末粒径为0.1～5nm(购自湖南光谷纳米科技有限公司)，球形纳米银粉末中银的纯度≥99.99％。
所述耐药菌包括肺炎克雷伯杆菌、乙酸钙不动杆菌、粪肠球菌、肺炎链球菌或金黄色葡萄球菌。
所述耐药菌还可包括超级耐药菌，例如阴沟肠杆菌、肺炎克雷伯菌、大肠埃希菌、铜绿假单胞菌或鲍曼不动杆菌。
根据不同的实施方式，所述药用纳米材料组合物可以是单独使用或与其它药剂联合使用。
本发明还提供了一种抗菌药物，含有所述药用纳米材料组合物以及一种或多种药学上可接受的载体。
根据不同的实施方式，所述载体为例如稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂或它们的组合。
根据需要，所述抗菌药物的剂型为例如注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂。
利用纳米技术的优势，本发明人对纳米材料进行了深入的研究。纳米材料因其独特的表面效应、小尺寸效应、量子尺寸效应和宏观量子隧道效应，表现出很多特殊的物理和化学性质，特别是在力学、热学、磁学、光电、电子等方面与同质的块体材料呈现出巨大的差异。本发明人认为纳米技术的发展对抗感染研究提供了新的方向，许多纳米材料表现出了潜在的抗菌活性。将金属银加工成纳米银后，其比表面积极大，显示明显的表面效应、小尺寸效应和宏观隧道效应。这些效应的综合作用大大地增强了银的抗菌能力，特别是超细粒径纳米银(粒径小于5nm)使得纳米银抗菌的有效浓度可以达到纳摩尔水平，远低于银离子的微摩尔水平。
本发明的纳米银就是利用前沿纳米技术将银纳米化，将粒径做到纳米级(0.1～100nm)金属银。极少量的纳米银就可产生强大的杀菌作用，比如可在数分钟内杀死 650多种细菌。关于纳米银及其制备方法可参考本发明人于2015年2月10日提交的中国发明专利申请CN201510066287.2，其内容在此通过参考引用全部纳入本文。
本发明涉及药用纳米银组合物DG-5选用湖南光谷纳米科技有限公司的纳米银粉末(0.1～5nm)选择了医药上可接受的葡萄糖、纯水作为其稳定剂和稀释剂，一方面尽可能减少组合物品种，另一方面从材质上确保其组合物的药用安全性。
附图说明
图1为试验板图谱。其中，A行和B行：环丙沙星(CIP)，最高测试浓度64μg/ml，2倍倍比稀释。C行和D行：DG-5，最高测试浓度30μg/ml，2倍倍比稀释。生长对照(Growth control，GC)：化合物溶剂，含有细菌接种物的1.1xCAMHB或CAMHBII，无化合物。无菌对照(Sterile control，SC)：化合物溶剂，1.1xCAMHB或CAMHBII，无化合物。
具体实施方式
本发明的技术方案可以通过下述实施例来进一步描述，但这些实施例仅作为说明，而不是对本申请的保护范围进行限制。
实施例1：药用纳米材料组合物DG-5，由如下浓度的成分组成：球形纳米银粉末1-2g/L，葡萄糖1-2g/L，其余为水；所述球形纳米银粉末粒径为0.1～5nm(购自湖南光谷纳米科技有限公司)，球形纳米银粉末中银的纯度≥99.99％。
实施例2：药用纳米材料组合物DG-5抗5株耐药菌(肺炎克雷伯杆菌，乙酸钙不动杆菌，粪肠球菌，肺炎链球菌，金黄色葡萄球菌)的活性测定。
本研究采用最小抑菌浓度作为抗菌活性指标。最小抑菌浓度指可抑制某种微生物出现明显生长的最低化合物浓度(Minimum inhibitory concentration，MIC)。最小抑菌浓度参照临床和实验室标准研究所指南(Clinical and Laboratory Standards Institute Guidelines，CLSI)的微量培养基稀释法加以测定。本研究检测了一个测试样品DG-5和一个对照抗生素环丙沙星对5株细菌的最小抑菌浓度。测试样品DG-5在96孔板中从最高检测浓度30μg/ml进行两倍倍比稀释。试验板放入普通培养箱35±2℃培养16-20 小时后，观察孔中细菌生长情况并加以记录。一同被检测的参照物环丙沙星的最小抑菌浓度与历史数据一致，最终判定测试样品DG-5对5株细菌的最小抑菌浓度在1.875-15μg/ml之间。
1.材料
细菌菌株
Figure PCTCN2017000429-appb-000001
培养基：胰酶大豆琼脂(Trypticase soy agar，TSA)(BD BBL 211043)TSA+5％绵羊血(TSA II)；离子校正的马-欣二氏肉汤(Cation-adjusted Mueller Hinton broth，CAMHB)(BD BBL212322)；CAMHB+3％马血(CAMHB II)；绵羊血(Quad Five 630-500)；马血(Quad Five 205-500)。
试剂和耗材：测试样品DG-5(300μg/ml)由长沙迪谷纳米提供。环丙沙星(Sigma 17850)。一次性摇瓶，250ml(Corning 430183)。一次性平皿，100mm(VWR 25384-302)。96孔微量滴定板(Greiner 650162)。
2.方法
细菌复苏：用于最小抑菌浓度测试的5株细菌冻存于-80℃低温冰箱，提前2天复苏。用无菌接种环刮取少许冻存的细菌在合适的固体培养基平皿上划线接种，放入合适的气体培养环境中35±2℃培养20-24小时(肺炎链球菌：TSA II，5％CO2粪肠球菌：TSA II，普通大气环境，其余3株细菌：TSA，普通大气环境)。用无菌接种环从上述培养皿中挑取5-10个形态相似的菌落，再次划线接种于合适的固体培养基平皿上。随后放入合适的气体培养环境中35±2℃培养20-24小时。
接种细菌准备：将液体培养基从4℃冰箱取出放置室温加热。从上述固体培养皿中挑取5-10个细菌单菌落重悬于500μl的1.1 x CAMHB中，用分光光度计调节OD600至0.1～0.13。用相应的液体培养基(CAMHB或CAMHBII)将革兰氏阳性细菌(G+)稀释280倍，革兰氏阴性细菌(G-)稀释400倍(比如35.6μl的G+细菌培养物稀释于10ml的CAMHB中或25μl G-细菌培养物稀释于10ml的CAMHB中)。
●肺炎链球菌：CAMHBII
●其余4株细菌：CAMHB
试验板准备：试验板图谱(见图1)：A行和B行：环丙沙星(CIP)，最高测试浓度64μg/ml，2倍倍比稀释。C行和D行：DG-5，最高测试浓度30μg/ml，2倍倍比稀释。生长对照(Growth control，GC)：化合物溶剂，含有细菌接种物的1.1xCAMHB或CAMHBII，无化合物。无菌对照(Sterile control，SC)：化合物溶剂，1.1xCAMHB或CAMHBII，无化合物。
化合物稀释：转移120μl的化合物到稀释板的起始孔中，再转60μl的二甲亚砜(DMSO，用于稀释环丙沙星)或DG-5的溶剂至其他孔中。依次从第1列到第11列对每个化合物进行2倍倍比稀释(即从第1列吸取60μl化合物至第2列并混匀，再从第2列吸取60μl化合物到第3列并混匀，再从第3列吸取60μl化合物到第4列并混匀，以此类推稀释至第11列)。从稀释板中转移2μl的环丙沙星和10μl的DG-5到5块试验板每块板的相应孔中，同时加入2μl的100％DMSO或10μl的DG-5溶剂到无化合物孔中(GC和SC孔)。加入98μl的细菌接种物至试验板的A1-A12和B1-B11孔中，同时加入90μl的细菌接种物至试验板的C1-C12和D1-D11孔中。加入98μl的培养基至试验板的B12孔中，同时加入90μl的培养基至试验板的D12孔中。体系加完后用无菌盖盖住5块试验板，放入离心机1000rpm离心30秒，再放入普通培养箱35±2℃培养16-20小时。
菌落计数：将接种细菌用液体培养基从10-1稀释至10-7(比如100μl的细菌接种物+900μl的1.1x CAMHB)。将100μl上述细菌稀释液均匀涂布于TSA平皿中，每个稀释度2个重复。待培养基被TSA吸收10分钟后，反转平皿在培养箱中35±2℃培养24小时。 细菌接种物通常每毫升含有1-2x108个菌落，所以换算下来通常试验板每孔含有2.5-5x104个菌落。
最小抑菌浓度记录及菌落数统计：打开化合物管理系统检查每块试验板的条形码和化合物排布是否正确。将试验板置于读板设备上，调节反射镜观察记录每个孔中细菌生长情况。同时用QCount软件对每块试验板拍照。参照临床和实验室标准研究所指南记录每个化合物的最小抑菌浓度。统计不同稀释度细菌接种物在TSA平皿的菌落数并计算细菌接种量。
3.结果
本研究参照临床和实验室标准研究所指南的微量培养基稀释法检测了一个测试样品DG-5和一个对照抗生素环丙沙星对5株细菌的最小抑菌浓度。测试样品DG-5在96孔板中从最高检测浓度30μg/ml进行两倍倍比稀释。试验板中的细菌接种物从不同的固体培养基平皿复苏并稀释于CAMHB或CAMHB II中，同时在试验板中设置了生长对照和无菌对照。试验板在普通培养箱35±2℃培养16-20小时后观察并记录每个化合物对不同细菌的最小抑菌浓度。表1和表2分别记录了2次独立重复试验的最小抑菌浓度值。对照化合物环丙沙星的最小抑菌浓度值与文献中报道的一致。试验板细菌接种量统计并记录于表3。
表1.第1次试验的最小抑菌浓度值
Figure PCTCN2017000429-appb-000002
表2.第2次试验的最小抑菌浓度值
Figure PCTCN2017000429-appb-000003
表3.五株细菌接种菌落数(第1次试验和第2次试验)
Figure PCTCN2017000429-appb-000004
实施例3：药用纳米材料组合物DG-5抗5株超级耐药菌的活性测定。
采用实施例2同样的方法，对药用纳米材料组合物DG-5抗5株超级耐药菌(阴沟肠杆菌，肺炎克雷伯菌，大肠埃希菌，铜绿假单胞菌，鲍曼不动杆菌)的活性进行了测定。一同被检测的参照物环丙沙星的最小抑菌浓度与历史数据一致，最终判定测试样品DG-5对5株细菌的最小抑菌浓度在1.875-3.75μg/ml之间，远优于阳性对照药物环丙沙星的抗菌活性。
1.材料
细菌菌株
细菌种属 革兰氏染色分类 编号
阴沟肠杆菌 G- EC9866
肺炎克雷伯菌 G- KP30006
大肠埃希菌 G- EC30026
铜绿假单胞菌 G- PA9347
鲍曼不动杆菌 G- AB2810565
培养基：胰酶大豆琼脂(Trypticase soy agar，TSA)(BD BBL 211043)
离子校正的马-欣二氏肉汤(Cation-djusted Mueller Hinton broth，CAMHB)(BD BBL212322)
试剂和耗材：测试样品DG-5(300μg/ml)由长沙迪谷纳米提供。环丙沙星(Sigma 17850)。一次性摇瓶，250ml(Corning 430183)。一次性平皿，100mm(VWR 25384-302)。96孔微量滴定板(Greiner 650162)。
2.方法
细菌复苏：用于最小抑菌浓度测试的5株细菌冻存于-80℃低温冰箱，提前2天复苏。用无菌接种环刮取少许冻存的细菌在合适的固体培养基平皿上划线接种，放入普通培养箱中35±2℃培养20-24小时。用无菌接种环从上述培养皿中挑取5-10个形态相似的菌落，再次划线接种于合适的固体培养基平皿上。随后放入普通培养箱中35±2℃培养20-24小时。
接种细菌准备：将液体培养基从4℃冰箱取出放置室温加热。从上述固体培养皿中挑取5-10个细菌单菌落重悬于500μl的1.1 x CAMHB中，用分光光度计调节OD600至0.1～0.13。再用1.1 x CAMHB将细菌稀释400倍。准备好的细菌接种物在15分钟内接种于96孔试验板中。接种的细菌数量通过平皿菌落计数获得。
试验板准备：试验板图谱(见图1)，A行和B行：环丙沙星(CIP)，最高测试浓度64μg/ml，2倍倍比稀释。C行和D行：DG-5，最高测试浓度30μg/ml，2倍倍比稀释。 生长对照(Growth control，GC)：含有细菌接种物的1.1xCAMHB或DG-5溶剂，无化合物。无菌对照(Sterile control，SC)：1.1xCAMHB或DG-5溶剂，无化合物。
化合物稀释：转移120μl的化合物到稀释板的起始孔中(A1、B1、C1和D1)，再转60μl的二甲亚砜(DMSO，用于稀释环丙沙星)或DG-5的溶剂至其他孔中。依次从第1列到第11列对每个化合物进行2倍倍比稀释(即从第1列吸取60μl化合物至第2列并混匀，再从第2列吸取60μl化合物到第3列并混匀，再从第3列吸取60μl化合物到第4列并混匀，以此类推稀释至第11列)。从稀释板中转移2μl的环丙沙星和10μl的DG-5到5块试验板每块板的相应孔中，同时加入2μl的100％DMSO或10μl的DG-5溶剂到无化合物孔中(GC和SC孔)。加入98μl的细菌接种物至试验板的A1-A12和B1-B11孔中，同时加入90μl的细菌接种物至试验板的C1-C12和D1-D11孔中。加入98μl的培养基至试验板的B12孔中，同时加入90μl的培养基至试验板的D12孔中。体系加完后用无菌盖盖住5块试验板，放入离心机1000rpm离心30秒，再放入普通培养箱35±2℃培养16-20小时。
菌落计数：将接种细菌用液体培养基从10-1稀释至10-7(比如100μl的细菌接种物+900μl的1.1x CAMHB)。将100μl上述细菌稀释液均匀涂布于TSA平皿中，每个稀释度2个重复。待培养基被TSA吸收10分钟后，反转平皿在培养箱中35±2℃培养24小时。
最小抑菌浓度记录及菌落数统计：打开化合物管理系统确认每块试验板的条形码和化合物排布正确后，将试验板置于读板设备上，调节反射镜观察记录每个孔中细菌生长情况。同时用QCount软件对每块试验板拍照。参照临床和实验室标准研究所指南记录每个化合物的最小抑菌浓度。统计不同稀释度细菌接种物在TSA平皿的菌落数并计算细菌接种量。
3.结果
本研究参照临床和实验室标准研究所指南的微量培养基稀释法检测了一个测试样品DG-5和一个对照抗生素环丙沙星对5株细菌的最小抑菌浓度。测试样品DG-5在96孔板中从最高检测浓度30μg/ml进行两倍倍比稀释。试验板中的细菌接种物从TSA复苏并稀释于CAMHB中，同时在试验板中设置了生长对照和无菌对照。试验板在普通培 养箱35±2℃培养16-20小时后观察并记录每个化合物对不同细菌的最小抑菌浓度。表1和表2分别记录了2次独立重复试验的最小抑菌浓度值。结果表明，组内重复和组间重复数据一致，对照化合物环丙沙星的最小抑菌浓度值与历史数据一致。试验板细菌接种量统计后记录于表3。
表1.第1次试验的最小抑菌浓度值
Figure PCTCN2017000429-appb-000005
表2.第2次试验的最小抑菌浓度值
Figure PCTCN2017000429-appb-000006
表3.五株细菌接种菌落数(第1次试验和第2次试验)
Figure PCTCN2017000429-appb-000007

Claims (8)

  1. 一种药用纳米材料组合物DG-5在药物制备中的用途，其中所述药物用于抗耐药菌，所述组合物由下述成分组成：球形纳米银粉末1-2g/L，葡萄糖1-2g/L，其余为水；所述球形纳米银粉末粒径为≤0.1～5nm，其中银的纯度≥99.99％。
  2. 根据权利要求1所述的用途，其中所述耐药菌为肺炎克雷伯杆菌、乙酸钙不动杆菌、粪肠球菌、肺炎链球菌或金黄色葡萄球菌。
  3. 根据权利要求1所述的用途，其中所述耐药菌为超级耐药菌。
  4. 根据权利要求3所述的用途，其中所述超级耐药菌为阴沟肠杆菌、肺炎克雷伯菌、大肠埃希菌、铜绿假单胞菌或鲍曼不动杆菌。
  5. 根据权利要求1所述的用途，其中所述组合物为单独使用或与其它药剂联合使用。
  6. 一种抗菌药物，所述药物含有权利要求1所述的药用纳米材料组合物DG-5以及一种或多种药学上可接受的载体。
  7. 根据权利要求6所述的抗菌药物，其中所述载体为稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂或它们的组合。
  8. 根据权利要求6所述的抗菌药物，其中所述抗菌药物的剂型为注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂。
PCT/CN2017/000429 2016-07-13 2017-07-11 药用纳米材料组合物dg-5用于抗耐药菌的用途 WO2018010403A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/350,779 US20190247429A1 (en) 2016-07-13 2017-07-11 Use of nano-material composition DG-5 for the treatment of drug-resistant bacteria

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610548369.5 2016-07-13
CN201610548369.5A CN106176810A (zh) 2016-07-13 2016-07-13 药用纳米材料组合物dg‑5用于抗耐药菌的用途

Publications (1)

Publication Number Publication Date
WO2018010403A1 true WO2018010403A1 (zh) 2018-01-18

Family

ID=57477143

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/000429 WO2018010403A1 (zh) 2016-07-13 2017-07-11 药用纳米材料组合物dg-5用于抗耐药菌的用途

Country Status (3)

Country Link
US (1) US20190247429A1 (zh)
CN (1) CN106176810A (zh)
WO (1) WO2018010403A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106176810A (zh) * 2016-07-13 2016-12-07 长沙迪谷纳米生物科技有限公司 药用纳米材料组合物dg‑5用于抗耐药菌的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104721227A (zh) * 2015-02-10 2015-06-24 长沙迪谷纳米生物科技有限公司 一种药用纳米银浆料及其制备方法
CN106176810A (zh) * 2016-07-13 2016-12-07 长沙迪谷纳米生物科技有限公司 药用纳米材料组合物dg‑5用于抗耐药菌的用途

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1299578C (zh) * 2004-02-13 2007-02-14 黄德欢 用金属银制备纳米抗菌银粉的方法
KR100693293B1 (ko) * 2005-02-15 2007-03-12 한국타미나 주식회사 금속의 나노입자를 이용한 항곰팡이성 및 냄새제거 기능을 갖는 무방부제의 세정용 물티슈 및 그 물티슈의 제조방법
CN100360214C (zh) * 2005-08-05 2008-01-09 上海沪正纳米科技有限公司 纳米银基甲醛消除液及其制备方法
CN101941075A (zh) * 2009-07-03 2011-01-12 北京印刷学院 一种含纳米银的抗菌剂的合成方法
CN101999412B (zh) * 2010-11-19 2014-05-28 深圳兰度生物材料有限公司 一种纳米银溶液及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104721227A (zh) * 2015-02-10 2015-06-24 长沙迪谷纳米生物科技有限公司 一种药用纳米银浆料及其制备方法
CN106176810A (zh) * 2016-07-13 2016-12-07 长沙迪谷纳米生物科技有限公司 药用纳米材料组合物dg‑5用于抗耐药菌的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JAAFAR FAEZ KADHIM ET AL.: "Characterization of Biosynthesized Silver Nanoparticles and Their Effect on Multi Drug Resistant Bacteria and Acute Lymphoblastic Leukemia Cells", WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, vol. 5, no. 2, 28 February 2016 (2016-02-28), pages 677 - 693, XP055459115, ISSN: 2278-4357 *

Also Published As

Publication number Publication date
CN106176810A (zh) 2016-12-07
US20190247429A1 (en) 2019-08-15

Similar Documents

Publication Publication Date Title
Mulcahy et al. Pseudomonas aeruginosa biofilms in disease
Dosler et al. Inhibition and destruction of Pseudomonas aeruginosa biofilms by antibiotics and antimicrobial peptides
Mazur et al. Synergistic ROS-associated antimicrobial activity of silver nanoparticles and gentamicin against staphylococcus epidermidis
CN110520114B (zh) 包含银和抗生素的纳米体系及其用于治疗细菌感染的用途
Wang et al. A functionalized surface modification with vanadium nanoparticles of various valences against implant-associated bloodstream infection
Singh et al. Antibiofilm and membrane-damaging potential of cuprous oxide nanoparticles against Staphylococcus aureus with reduced susceptibility to vancomycin
CN110123801B (zh) 一种多臂aie分子在制备抗菌药物中的用途和抗菌药物
Chen et al. Antimicrobial coating: Tracheal tube application
LV13745B (en) Silver/water, silver gels and silver based compositions, and methods for making and using the same
Huang et al. Metal nanoparticles and nanoparticle composites are effective against Haemophilus influenzae, Streptococcus pneumoniae, and multidrug-resistant bacteria
Mohammed et al. ZnO, TiO2 and Ag nanoparticles impact against some species of pathogenic bacteria and yeast
Hubka et al. In vitro susceptibility of canine and feline Escherichia coli to fosfomycin
WO2018010403A1 (zh) 药用纳米材料组合物dg-5用于抗耐药菌的用途
Zhang et al. Long-term antibacterial activity of guanidinium carbon dots without detectable resistance for the effective treatment of pneumonia caused by Gram-negative bacteria
Disaanayake et al. Efficacy of some colloidal silver preparations and silver salts against Proteus bacteria, one possible cause of rheumatoid arthritis
Raheem et al. ANTIBACTERIAL ACTIVITY OF SILVER NANOPARTICLES EXTRACTED FROM PROTEUS MIRABILIS AN D HEALING THE WOUND IN RABBIT.
Bianchini Fulindi et al. Zinc-based nanoparticles reduce bacterial biofilm formation
Thamer et al. Synergistic effect of Zinc Oxide nanoparticles and Vancomycin on Methicillin resistant Staphylococcus aureus
EP2950804B1 (en) Antibiotic preparation and use thereof
Alnasrawi et al. Antibacterial activity of some nanoparticles against some pathogenic bacteria that isolated from urinary tract infections patient
Wang et al. Novel functionalized selenium nanowires as antibiotic adjuvants in multiple ways to overcome drug resistance of multidrug-resistant bacteria
CN114272246A (zh) 尿嘧啶在制备抗感染药物中的应用
Maria Holban Magnetite nanoshuttles for fighting Staphylococcus aureus infections: a recent review
Faustova et al. The effect of local anesthetics against planktonic forms and film formation of S. aureus strains and its dependence on antiseptics activity
CN116350613B (zh) Bms-303141用于制备抗革兰氏阳性细菌感染药物中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17826742

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17826742

Country of ref document: EP

Kind code of ref document: A1