WO2017020861A1 - 头花蓼组合物抗幽门螺旋杆菌的用途 - Google Patents

头花蓼组合物抗幽门螺旋杆菌的用途 Download PDF

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WO2017020861A1
WO2017020861A1 PCT/CN2016/093626 CN2016093626W WO2017020861A1 WO 2017020861 A1 WO2017020861 A1 WO 2017020861A1 CN 2016093626 W CN2016093626 W CN 2016093626W WO 2017020861 A1 WO2017020861 A1 WO 2017020861A1
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pharmaceutical composition
weight
parts
composition according
preparation
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PCT/CN2016/093626
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English (en)
French (fr)
Inventor
王子厚
周益成
张姝
丁莉梅
胡伏莲
罗昭逊
莫非
张丽艳
张淑华
金鑫
李正亮
周宏艳
何云
马领弟
郑伟霞
朱晓龙
赵书琴
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浙江众康药业有限公司
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Priority claimed from PCT/CN2015/086156 external-priority patent/WO2017020279A1/zh
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Publication of WO2017020861A1 publication Critical patent/WO2017020861A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/718—Coptis (goldthread)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/78—Saururaceae (Lizard's-tail family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8969—Polygonatum (Solomon's seal)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 field of traditional Chinese medicine, and particularly relates to a pharmaceutical composition comprising a flower bud and a berberine, and the use thereof for preparing an antibacterial, in particular, a medicament against Helicobacter pylori.
  • the head flower bud is the dry whole grass or aboveground part of the Polygonum capitatum Buch.-Ham.ex D.Don. It is a commonly used medicine in the folk areas of China, especially in the Miao area.
  • the head flower is sweet, spicy and cool; it has the functions of clearing away heat and dampness, detoxification and relieving pain, and blood stasis, diuretic and drenching.
  • pharmacological studies have shown that the head flower bud has a wide range of pharmacological activities, including analgesic, cooling, diuretic, anti-inflammatory, antibacterial and the like.
  • H.pylori H.p or HP in this context
  • HP infection is an important cause of a variety of chronic stomach diseases such as peptic ulcer, gastritis, and gastric cancer.
  • PPI proton pump inhibitor
  • expectorant the eradication rate is 90%.
  • these drug eradication programs have problems of toxic side effects, easy secondary resistance, double infection, and patient dependence.
  • H.pylori is a damp-heat and detoxification, which belongs to the category of "evil gas". It is difficult for a single Chinese medicine to cope with the complex and changeable condition of the disease. The role of the symptoms.
  • the invention is based on the single-flavored medicine of the head flower, and the other Chinese medicine is used to form the head flower bud composition, which improves the anti-Hp activity and has a good antibacterial effect on the gram-resistant bacteria, especially the methicillin-resistant epidermis.
  • Staphylococcus methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus.
  • the addition of heat-clearing and detoxifying, tonic, diuresis, qi, blood circulation, dehumidification, phlegm, blood circulation, warming, dispelling cold, digestion can reduce the adverse reactions of single-flavor drugs.
  • the composition has heat and dampness, spleen and qi.
  • It is an object of the present invention to provide a pharmaceutical composition comprising a flower bud, a berberine, and a composition for the preparation of Antibacterial, especially the application of drugs that inhibit H. pylori.
  • a first aspect of the present invention provides a pharmaceutical composition, characterized in that the composition comprises a head flower bud and a berberine.
  • Preferred compositions include 20-60 parts by weight of the head flower and 2-6 parts by weight of the berberine.
  • the composition consists of a flower bud, a berberine and a tonic drug.
  • Preferred compositions include 20-60 parts by weight of the head flower, 2-6 parts by weight of the coptis, and 2-20 parts by weight of the tonic.
  • the present invention also provides a process for the preparation of the above pharmaceutical composition extract.
  • the present invention also discloses formulations containing a pharmaceutical composition which is formulated with a pharmaceutically acceptable excipient into a pharmaceutically acceptable oral formulation.
  • the oral preparation is selected from various available regular release preparations and sustained release preparations.
  • the sustained-release preparation is selected from the group consisting of a skeleton type, a membrane-controlled type, an osmotic pump type, and a gastric retention type sustained-release preparation.
  • the gastric retention type sustained release preparation is preferably a gastric floating agent.
  • the invention also discloses the use of any one of the pharmaceutical compositions of the invention in the preparation of an antibacterial drug.
  • the pathogen is selected from the group consisting of Gram-positive methicillin-resistant Staphylococcus aureus S. aureus (Methicllin-resistant, MRSA), methicillin-sensitive Staphylococcus aureus S. aureus (Methicin-suseptable), methoxy Stalinococcus epidermidis (MRSE), methicillin-sensitive Staphylococcus epidermidis (MSSE), also selected from Gram-negative Escherichia coli, Eco + , large intestine H. (non-ESBLS) Escherichia Coli, Eco - , Klebsiella Klebsiella (ESBLs) K. penumonia, KPN + , Klebsiella pneumoniae (non-ESBLs) K. penumonia, Pseudomonas aeruginosa (PAE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-sensitive Staphylococcus au
  • the invention also discloses the use of any one of the pharmaceutical compositions of the invention in the preparation of a medicament for preventing/treating Helicobacter pylori.
  • the present invention provides a novel pharmaceutical composition
  • a novel pharmaceutical composition comprising a head flower bud and a berberine.
  • Preferred compositions include 20-60 parts by weight of the head flower and 2-6 parts by weight of the berberine.
  • compositions include cep, berberine, and tonic.
  • compositions include 20-60 parts by weight of the head flower, 2-6 parts by weight of the coptis, and 2-20 parts by weight of the tonic.
  • the tonic drugs according to the present invention include, but are not limited to, licorice, Codonopsis, Atractylodes, Radix Paeoniae Alba, jujube, ginseng, tea, astragalus, and huangjing.
  • the preferred tonic is selected from the group consisting of licorice, scutellaria, atractylodes, white peony, and huangjing.
  • the preferred parts by weight of the tonic medicinal materials in the pharmaceutical composition of the present invention are as follows:
  • compositions are selected from any of the following groups:
  • composition according to the first aspect of the present invention characterized in that the composition is obtained by extracting the head flower buds and other medicinal materials with an inorganic or organic solvent alone or in a mixed solvent.
  • composition according to the first aspect of the present invention characterized in that the composition is obtained by extracting and mixing the head flower buds and other medicinal materials with two or more mixed solvents of water and ethanol, acetone, and ethyl acetate.
  • a pharmaceutical composition according to the first aspect of the present invention characterized in that the composition is obtained by extracting 5-30 times of water from the head flower and other herbs.
  • composition according to the first aspect of the present invention characterized in that the composition is obtained by extracting 5-30 times of a 30-100% organic solution of the head flower buds and other medicinal materials.
  • the pharmaceutical composition according to the first aspect of the present invention characterized in that the composition is extracted from 5-30 times of 30-99% of lower alcohol (C1-C5), acetone, acetic acid solution by head flower buds and other medicinal materials. And get.
  • lower alcohol C1-C5
  • acetone acetic acid solution by head flower buds and other medicinal materials. And get.
  • composition obtained by extracting 5-30 times of a 30-99% aqueous solution of ethanol as an extraction solvent.
  • the aqueous ethanol solution is preferably a 70% ethanol solution, and the solution is selected to be 6-8 times.
  • composition according to the first aspect of the present invention characterized in that the composition is obtained by extracting and mixing 5-15 times of a mixed solution of an alcohol and an ester of 5-95% of an anthraquinone and other medicinal materials.
  • composition according to the first aspect of the present invention characterized in that the composition is obtained by extracting and extracting 5-15 times of a mixed solution of 5-95% ethanol and ethyl acetate as an extraction solvent. .
  • composition according to the first aspect of the present invention characterized in that the composition is obtained by extracting 5 to 20 times of ethyl acetate, petroleum ether and diethyl ether from the head flower and other herbs.
  • composition prepared according to the method comprising the steps of: 5 to 30 times (e.g., 5 to 15 times, for example, 6 to 12) of the medicinal material constituting the composition.
  • water water
  • ethanol ethanol aqueous solution decoction and / or reflux extraction 1 to 5 times (for example, 2 to 3 times)
  • each 0.5 to 5 hours for example, 0.5 to 3 hours, for example, 1 to 3 hours
  • the filtrate was concentrated and dried.
  • composition prepared according to the method comprising the steps of: taking a medicinal material constituting the composition, adding 5 to 30 times (for example, 5 to 15 times, for example, 6 to 12 times) water is decoctioned at 50-100 ° C for 1 to 5 times (for example, 2 to 3 times), 0.5 to 5 hours each time (for example, 0.5 to 3 hours, for example, 1 to 3 hours), filtered and combined
  • the extract is concentrated to a thick paste having a relative density of 1.1 to 1.5 (for example, 1.2 to 1.4), and dried under reduced pressure.
  • composition prepared according to the method comprising the steps of: taking a medicinal material constituting the composition, adding 5 to 30 times (for example, 5 to 15 times, for example, 6 to 12 times) 30-99% ethanol aqueous solution is refluxed for 1 to 5 times (for example, 2 to 3 times) for 0.5 to 5 hours each time (for example, 0.5 to 3 hours, for example, 1 to 3 hours), and the extracts are filtered and combined. It is concentrated to a thick paste having a relative density of 1.1 to 1.5 (for example, 1.2 to 1.4) at 60 to 90 ° C (for example, 65 to 75 ° C), and dried under reduced pressure.
  • the above pharmaceutical composition further comprises one or more other drugs selected from the group consisting of: an antimicrobial agent, a proton pump inhibitor, a gastric mucosal protective agent, an antacid, and an H 2 receptor antagonist.
  • Preferred antimicrobial agents include, but are not limited to, penicillins such as amoxicillin, macrolides such as clarithromycin, and nitrazoles such as metronidazole.
  • Preferred proton pump inhibitors include, but are not limited to, omeprazole, lansoprazole, pantoprazole
  • Preferred gastric mucosal protective agents include, but are not limited to, sucralfate, smecta
  • Preferred antacids such as aluminum hydroxide magnesium
  • H 2 receptor antagonists such as cimetidine, ranitidine, famotidine.
  • the invention also discloses a method for preparing a pharmaceutical composition extract, characterized in that the step of the method is selected from any one or more of the following:
  • (1-7) is obtained by extracting and obtaining 5 to 15 times of a mixed solvent of 5 to 95% of an alcohol and an ester;
  • the invention includes all of the pharmaceutical composition extracts prepared by the above methods.
  • a second aspect of the invention provides a pharmaceutical formulation composition.
  • compositions of the present invention further comprise one or more non-toxic physiologically acceptable carriers.
  • the acceptable carriers include any excipients known in the art and excipients that function as controlled release. Commonly used excipients include diluents, binders, wetting agents, disintegrants, lubricants, glidants, porogens, plasticizers, fillers, solubilizers, and emulsifiers.
  • the diluent may be, but not limited to, starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.;
  • the humectant may be but not Limited to water, ethanol, isopropanol, etc.
  • the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin pulp, sodium carboxymethyl cellulose, methyl fiber , hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrants can be, but are not limited to, dry starch, microcrystalline cellulose, low substitution Hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl star
  • the excipient that acts to slow release is selected from one or more of a hydrophilic gel material, a waxy material, and an insoluble material.
  • the hydrophilic gel material may be selected from the group consisting of hydroxypropylmethylcellulose, carbopol, sodium carboxymethylcellulose and alginate
  • the waxy lipid material may be selected from the group consisting of cetyl alcohol and ten.
  • the insoluble material may be selected from the group consisting of ethyl cellulose, acrylic resin, polyoxyethylene and polyethylene.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the invention also relates to formulations comprising a pharmaceutical composition and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition Any dosage form suitable for human or animal use can be prepared by combining the composition with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the formulation can be prepared according to methods well known in the art.
  • the composition of the present invention is usually contained in a pharmaceutical preparation in an amount of 6 to 12 g.
  • the pharmaceutical preparation of the present invention is preferably an oral preparation for the purpose of administration and enhancing the therapeutic effect.
  • the oral preparation prepared by the pharmaceutical composition of the present invention comprises a granule, a tablet, a pill, a capsule, an oral liquid preparation and the like, and a sustained release preparation comprising a skeleton type and a film.
  • Controlled, osmotic pump type, gastric retention type sustained release controlled release preparation, microcapsule, nanoparticle, liposome and other drug new carrier sustained release sustained release preparation, gastric retention type The controlled release formulation is preferably a gastric floating agent.
  • the preparation process of the preparation is as follows:
  • the raw material was 31% of the composition, 31% of the IV acrylic resin, 31% of stearyl alcohol, 7% of MCC101, and an appropriate amount of magnesium stearate was added, and the film was directly compressed by a dry method to obtain a floating tablet of the first calyx composition.
  • a third aspect of the invention provides the use of a pharmaceutical composition for the preparation of an antibacterial agent; and the use of Coptidis in the preparation of an antibacterial agent.
  • the use according to the third aspect of the present invention is characterized in that the pathogen is selected from the group consisting of Gram-positive methicillin-resistant Staphylococcus aureus S. aureus (Methicllin-resistant, MRSA), methicillin-sensitive golden yellow Staphylococcus epidermidis (MRSE), methicillin-sensitive Staphylococcus epidermidis (MSSE), also selected from Gram-negative bacteria large intestine ESBLS Escherichia Coli, Eco + , Escherichia coli (non-ESBLS) Escherichia Coli, Eco - , Klebsiella Klebsiella (ESBLs) K. penumonia, KPN + , Klebsiella pneumonia (non-ESBLs) K. penumonia , Pseudomonas aeruginosa (PAE), Helicobacter pylori.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE me
  • extraction may be impregnation at normal temperature, or extraction at elevated temperatures (e.g., boiling and/or reflux), or a combination of these modes of operation. It may further comprise further processing the extract, such as further purification, such as solvent removal, precipitation removal impurities, solvent extraction, resin adsorption separation, and the like.
  • extract will include extracts of any purity that can be used to achieve any of the objectives of the invention, and the extraction purity of the extract can vary over a wide range.
  • the invention has the beneficial effects that the composition improves the single anti-Helicobacter pylori activity of the head flower bud, and the minimum antibacterial requirement of the water extract composition A for Hp ATCC700392 is 9.84 mg/ml, and the crude drug content of berberine is 0.98mg/ml, lower than the requirement of unilateral calyx unilateral (36.68mg/ml) and berberine unilateral (1.37mg/ml), enhancing the antibacterial synergistic effect between the head flower bud and the berberine; alcohol extracting composition A, composition B.
  • the minimum antibacterial requirement of the composition C to Hp ATCC700392 is 3.63, 19.48, 17.16 (mg/ml), which is lower than the requirement of the first flower (40.44 mg/ml);
  • the minimum antibacterial requirement of the composition A, the composition B and the composition C for Hp SS1 was 3.63, 2.44, 2.15 (mg/ml), respectively, which was lower than that of the head flower (5.06 mg/ml).
  • the required content; the minimum antibacterial requirement of the alcohol extracting composition B for the metronidazole-resistant strain is 4.87 mg/ml, which is lower than that required for the single flower (10.11 mg/ml).
  • the composition has good antibacterial activity.
  • the minimum antibacterial crude drug content of the water extracting composition A against Gram-positive bacteria was ⁇ 0.082 mg/ml, and the crude drug content of Rhizoma Coptidis and the head flower buds were 0.204 and 0.621 mg/ml, respectively; the lowest against Gram-negative bacteria
  • the crude drug content of the bacteria was ⁇ 0.0824 mg/ml, and the crude drug content of the berberine unilateral and the head flower buds were 0.204 and 5.175 mg/ml, respectively.
  • Figure 1 shows the results of clinical drug-resistant strain verification.
  • Figure 2 shows the results of in vitro inhibition of the composition against H. pylori.
  • Example 2 Referring to the same method as in Example 1, except that 750 g of medicinal herbs, 75 g of fried berberine, 250 g of Codonopsis pilosula, 250 g of medlar, and 150 g of dried tangerine peel were weighed, and the extract powder of the present example was obtained, 154 g.
  • Example 2 The same procedure as in Example 1 was carried out, except that 900 g of the medicinal material calyx was weighed and extracted, and 89 g of the extract powder of this example was obtained.
  • Example 2 The same procedure as in Example 1 was carried out, except that 660 g of the medicinal material of Rhizoma Coptidis was weighed, and 133 g of the extract powder of this example was obtained.
  • the method was the same as in the same manner as in Example 5 except that 300 g of medicinal materials, 30 g of fried berberine, 100 g of Codonopsis pilosula, 100 g of medlar, and 60 g of dried tangerine peel were weighed, and the extract powder of this example was obtained, 95 g.
  • Example 5 Refer to the same method as in Example 5, except that the medicinal material head flower bud 300g, fried berberine 30g, Codonopsis pilosula 100g, 100 g of glutinous rice and 100 g of schisandra were extracted to obtain 102 g of the extract powder of this example.
  • Example 5 The same procedure as in Example 5 was carried out, except that 1000 g of the medicinal material calyx was weighed and extracted, and the extract powder of this example was obtained, 109 g.
  • Example 5 The same procedure as in Example 5 was carried out except that 520 g of the Rhizoma Coptidis medicinal material was weighed, and the extract powder of this example was obtained, 95 g.
  • Example 2 Referring to the same method as in Example 1, the difference was that 80 kg of head flower buds, 8 kg of fried berberine, and 16 kg of raw licorice were weighed and extracted to obtain 8.1 kg of the extract powder of this example.
  • Example 2 Referring to the same method as in Example 1, the difference was that 54 kg of the flower head flower, 5.6 kg of fried berberine, 17.6 kg of Codonopsis pilosula, 17.6 kg of medlar, and 10.4 kg of dried tangerine peel were weighed, and the extract powder of this example was obtained, 17.0 kg.
  • Example 2 Referring to the same method as in Example 1, the difference was that 48 kg of the flower head flower, 4.8 kg of fried berberine, 16 kg of Codonopsis pilosula, 16 kg of medlar, and 16 kg of Schisandra were weighed, and the extract powder of this example was obtained, 20.0 kg.
  • Example 14 Preparation of fried yellow water extract extract powder
  • Example 2 Referring to the same method as in Example 1, the difference was that 76 kg of the medicinal material was weighed and extracted, and the extract powder of this example was obtained, 3.1 kg.
  • Example 2 The same procedure as in Example 1 was carried out except that 500 g of the head flower buds, 50 g of fried berberine, and 100 g of raw licorice were weighed and extracted to obtain the extract powder of the present example, 64.2 g.
  • Example 2 The same procedure as in Example 1 was carried out except that 300 g of the medicinal material head flower, 30 g of fried berberine, 100 g of Codonopsis pilosula, 100 g of medlar, and 60 g of dried tangerine peel were weighed, and the extract powder of this example was obtained, 78 g.
  • Example 2 The same procedure as in Example 1 was carried out, except that 300 g of the medicinal flower head flower, 30 g of fried berberine, 100 g of Codonopsis pilosula, 100 g of medlar, and 100 g of Schisandra were weighed, and the extract powder of this example was obtained, 85.4 g.
  • Example 2 The same procedure as in Example 1 was carried out, except that 600 g of the medicinal plant head flower was weighed and extracted, and the extract powder of this example was obtained, 50.2 g.
  • Example 2 The same procedure as in Example 1 was carried out except that 300 g of the medicinal material head flower, 30 g of fried berberine, 100 g of Codonopsis pilosula, and 100 g of medlar were weighed, and the extract powder of this example was obtained, 78.8 g.
  • Example 5 The same procedure as in Example 5 was carried out except that 300 g of the medicinal material calyx, 30 g of fried berberine, 100 g of Codonopsis pilosula, and 100 g of medlar were weighed, and the extract powder of this example was obtained, 79 g.
  • Example 2 The same procedure as in Example 1 was carried out except that 300 g of the medicinal material head flower, 30 g of fried berberine, 100 g of medlar, and 60 g of dried tangerine peel were weighed, and the extract powder of this example was obtained, 64 g.
  • Example 5 The same procedure as in Example 5 was carried out except that 300 g of the medicinal material head flower, 30 g of fried berberine, 100 g of medlar, and 60 g of dried tangerine peel were weighed, and the extract powder of this example was obtained, 66 g.
  • Example 2 Referring to the same method as in Example 1, the difference was that 300 g of the medicinal material calyx, 30 g of fried berberine, 100 g of Codonopsis pilosula, and 100 g of Schisandra were weighed, and the extract powder of the present example was obtained, 80 g.
  • Example 5 Referring to the same method as in Example 5, the difference was that 300 g of the medicinal material head flower, 30 g of fried berberine, 100 g of Codonopsis pilosula, and 100 g of schisandra were weighed, and the extract powder of this example was obtained, 84 g.
  • Example 2 The same procedure as in Example 1 was carried out except that 300 g of the medicinal material head flower, 30 g of fried berberine, 100 g of medlar, and 100 g of schisandra were weighed, and the extract powder of this example was obtained, 86 g.
  • Example 5 The same procedure as in Example 5 was carried out except that 300 g of the medicinal material head flower, 30 g of fried berberine, 100 g of medlar, and 100 g of schisandra were weighed, and the extract powder of this example was obtained, 88 g.
  • Test Example 1 Composition (Example 1) Detection of antibacterial activity against H. pylori standard strains and clinical strains.
  • the strain used was H. pylori ATCC700392 and the Helicobacter pylori SS1 international standard sequencing strain, which was purchased from ATCC (American Type Culture Collection).
  • Drug-resistant strains collected in clinical digestive medicine, verified by drug sensitivity test. Three strains (named) and their characteristics were clinically isolated:
  • HP R-1 type it is resistant to metronidazole
  • HP R-2 type it is resistant to amoxicillin
  • HPR-3 It is resistant to clarithromycin.
  • composition obtained in a part of the embodiment of the present invention the single flower extract of the head flower obtained in Examples 4 and 9.
  • Helicobacter pylori ATCC700392 and Helicobacter pylori SS1 strains and clinical H.pylori-resistant amoxicillin, H.pylori-resistant clarithromycin, and H.pylori-resistant metronidazole were removed from the -80 °C refrigerator and placed at 37 °C. Dissolved in a water bath, uniformly coated on the Columbia blood plate containing the mixed antibiotics, and placed in a 37 ° C three-gas incubator (85% N 2 , 10% CO 2 , 5% O 2 ). Cultivate for 48 hours. The culture characteristics, Gram stain, urease identification, catalase identification and oxidase identification of the two standard strains and three clinical strains were carried out.
  • Clinical drug-resistant strain verification test The clinical strain of Helicobacter pylori cultured for 72 hours was prepared with brain heart infusion broth, and the concentration was adjusted to 1 ⁇ 9 ⁇ 108 CFU/mL, respectively, and the bacteria were stained with sterile cotton swab. The suspension was uniformly applied to a drug culture dish and a blank culture dish at a concentration of 256 ⁇ g/mL of metronidazole, 256 ⁇ g/mL of clarithromycin and 256 ⁇ g/mL of amoxicillin, and two tablets were applied to each drug concentration, and placed in a microplate. Incubate at 37 ° C for 72 h in an aerobic environment. Under the condition that H.pylori grew well on a blank culture dish, the growth was observed, and Gram stain and biochemical identification tests were performed on the grown bacteria.
  • Bacterial solution coating Draw a concentration of 108 CFU/mL bacterial solution with a disposable cotton swab and apply evenly on the surface of the agar. Two plates were coated for each concentration of each sample. At the same time, a negative control (ie no bacteria added), a growth control (ie no experimental sample), and a solvent control were provided for each two plates.
  • Biochemical test positive for urease test, positive for oxidase test, positive for catalase test; observed under microscope oil mirror, typical seagull-like, S-shaped, Gram-negative.
  • H. pylori-resistant amoxicillin H. pylori-resistant clarithromycin
  • H. pylori-resistant metronidazole Three clinically resistant strains of H. pylori-resistant amoxicillin, H. pylori-resistant clarithromycin, and H. pylori-resistant metronidazole were collected and the drug resistance was verified. At the drug concentration of metronidazole 256 ⁇ g / mL, clarithromycin 256 ⁇ g / mL, amoxicillin 256 ⁇ g / mL were good growth, no difference with the blank group.
  • the MIC of the first flower bud composition to Hp ATCC700392 and SS1 was 0.5 mg/ml.
  • Test Example 2 Detection of antibacterial activity of the head bud composition against the Helicobacter pylori standard strain and the clinical isolate.
  • the first flower bud composition obtained in Examples 2-3, 5-8, and 9 was used as a reagent to test the resistance to ATCC700392, Helicobacter pylori SS1 international standard sequencing strain, and Helicobacter pylori. Antibacterial activity of metronidazole strain, Helicobacter pylori-resistant amoxicillin strain, and Helicobacter pylori-resistant clarithromycin strain.
  • the minimum inhibitory concentration (MIC) of HPATCC700392 was 4 mg/ml in the case of the single-side preparation of the head flower, and the experiment was repeated three times. In this experiment, all the compositions were tested against five species of H. pylori. The MIC value is between 0.5 and 64 mg/ml. The antibacterial effect of Coptidis Rhizoma is good, and its MIC value is between ⁇ 0.0625-0.25mg/ml. The experimental results are shown in Table 2.
  • Test Example 3 Experiment on the antibacterial activity of the composition against Gramella
  • Methicillin-resistant Staphylococcus aureus S. aureus (Methicl-resistant, MRSA) 6 strains, methicillin-sensitive Staphylococcus aureus S. aureus (Methicin-suseptable, MSSA) 6 strains, methicillin-resistant epidermal grape 5 strains of staphylococcus epidermidis (MRSE), 5 strains of methicillin-sensitive Staphylococcus epidermidis (MSSE), Escherichia coli (ESBLS), Eco + 6 strains, Escherichia coli (non-ESBLS) Escherichia Coli, Eco-6 strain, Klebsiella pneumoniae (ESBLs) K.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MSSA methicillin-sensitive Staphylococcus aureus S. aureus
  • MSSA methicillin-resistant epidermal grape 5 strains of staphylococcus epidermidis
  • MSSE methicillin-
  • Cefepime (standard) is derived from the standard of China Food and Drug Control Institute; the head of the flower bed is supplied by Guiyang Medical College with the batch number of 14196 and the crude drug content of 10.35g/g.
  • the minimum inhibitory concentration of the in vitro antibacterial sample was determined by the agar double dilution method with the head flower unilateral, fried berberine unilateral and cefepime as the reference medicinal materials.
  • the bacteria were inoculated with a multi-point inoculation instrument (MIT-P, SUKUMA), the inoculum amount was about 104 CFU/ml, 27 strains of bacteria were inoculated per dish, 54 strains were inoculated in 2 dishes, and the lid was covered.
  • the cells were cultured in a 35-37 ° C incubator for 18-20 hours, and the results were observed.
  • the minimum concentration of the drug in which no bacterial growth was observed in the plate was judged as the minimum inhibitory concentration (MIC).
  • the bacteria were inoculated with a multi-point inoculation instrument (MIT-P, SUKUMA), the inoculum volume was about 10 4 CFU/ml, 27 strains of bacteria were inoculated per dish, 54 strains were inoculated in 2 dishes, and the lid was covered.
  • the cells were cultured in a 35-37 ° C incubator for 18-20 hours, and the results were observed.
  • the experimental results show that the first flower bud composition has a good inhibitory effect on Gram-negative bacteria and Gram-positive bacteria.
  • the experimental results are shown in Table 3.

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Abstract

一种药物组合物及其用途。具体涉及包括头花蓼和黄连的药物组合物，及其在制备抗菌，特别是针对幽门螺旋杆菌的药物中应用。

Description

头花蓼组合物抗幽门螺旋杆菌的用途 技术领域
本发明属于中药领域，具体涉及一种药物组合物，包含头花蓼和黄连，及其在制备抗菌，特别是针对幽门螺旋杆菌的药物的应用。
背景技术
头花蓼为蓼科植物头花蓼(Polygonum capitatum Buch.-Ham.ex D.Don)的干燥全草或地上部分，是我国民间特别是苗族居住地区的常用药。头花蓼味甘、辛，性凉；具有清热利湿，解毒止痛，和血散瘀，利尿通淋等功效。近几年来药理研究表明，头花蓼具有广泛的药理活性，有镇痛、降温、利尿、抗炎、抗菌等作用。幽门螺旋杆菌(Helicobacter pylori，在本文中可简称为H.pylori、Hp或HP)是普遍存在于人胃黏膜中的一种微需氧的革兰氏阴性菌。HP感染是引起多种慢性胃病如消化性溃疡、胃炎、胃癌的重要病因。目前国际上推荐的一线治疗方案主要以质子泵抑制剂(PPI)或铋剂为基础，合并两种抗生素组成的三联疗法，根除率达90％。但目前这些药物根除方案存在毒副作用大、易继发耐药、产生二重感染、患者依存性的问题。
中医药是根除幽门螺杆菌的一种新选择，随着中草药市场的不断发掘，越来越多的中药显示对Hp有较好的抑菌效果，研究以单味中药为主。CN 102824417A(中国专利申请号201210352856.6，公开日2012年12月19日)公开了头花蓼或其提取物用于治疗HP的新方法，据信该药或其提取物对HP的体外抑菌效果明显。
然而中医学认为人体是一个有机的整体，各个脏器循环运转相互影响，H.pylori为湿热郁毒，属“邪气”范畴，单味中药难以应付病情的复杂多变及发展，只能起到治标的作用。
本发明在头花蓼单味药的基础上，加以其他中药组成头花蓼组合物，提高了抗Hp的活性，对革兰氏菌具有较好的抗菌效果，特别是对耐甲氧西林表皮葡萄球菌、甲氧西林敏感金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌。且加入清热解毒、补益、利水渗湿、行气、活血化瘀、去湿化痰、活血化瘀、温阳散寒、消食的药材，能够减少单味药的不良反应。组合物具有清热利湿，健脾益气。用于脾胃气虚，湿热中阻所致的胃脘胀痛、嗳气吞酸、恶心呕吐、食欲不振等作用，是对H.pylori敏感的中药组方，在根除H.pylori的同时，能够调节胃肠平衡，防治脾胃受损、肝脾不和，有效治疗普通胃炎及由幽门螺旋杆菌引起的慢性胃炎等症。本发明中的药物组合物在制备预防/治疗由幽门螺旋杆菌引起的慢性胃炎的药物中的应用尚未见报道。
发明内容
发明概述
本发明的目的在于提供一种药物组合物，包括头花蓼、黄连，还提供组合物用于制备有 效抗菌，特别是抑制幽门螺旋杆菌的药物的应用。
为此，本发明第一方面提供了一种药物组合物，其特征在于，所述的组合物包括头花蓼、黄连。优选的组合物包括头花蓼20-60重量份、黄连2-6重量份。
在本发明的具体实施方案中，所述的组合物由头花蓼、黄连和补益药物组成。优选的组合物包括头花蓼20-60重量份、黄连2-6重量份、补益药物2-20重量份。
本发明还提供了上述药物组合物提取物的制备方法。
本发明还公开含有药物组合物的制剂，所述的组合物与药学上接受的辅料制成药剂学上接受的口服制剂。
所述的口服制剂选自各种可用的常释制剂和缓控释制剂。
所述的缓控释制剂选自骨架型、膜控型、渗透泵型、胃内滞留型缓控释制剂。
所述的胃内滞留型缓控释制剂优选为胃漂浮剂。
本发明还公开了本发明任意一组药物组合物在制备抗菌的药物中的应用。
所述的病菌选自革兰氏阳性菌甲氧西林耐药金黄色葡萄球菌S.aureus(Methicllin-resistant，MRSA)、甲氧西林敏感金黄色葡萄球菌S.aureus(Methicin-suseptable)、甲氧西林耐药表皮葡萄球菌(staphylococcus epidermidis，MRSE)、甲氧西林敏感表皮葡萄球菌(staphylococcus epidermidis，MSSE)，还选自革兰氏阴性菌大肠埃希菌(ESBLS)Escherichia Coli，Eco+，大肠埃希菌(非ESBLS)Escherichia Coli，Eco-，肺炎克雷伯(ESBLs)K.penumonia，KPN+，肺炎克雷伯(非ESBLs)K.penumonia，铜绿假单胞菌(Pseudomonas aeruginosa，PAE)。
本发明还公开了本发明任意一组药物组合物在制备预防/治疗幽门螺旋杆菌的药物中的应用。
发明详述
本发明提供了一种新的药物组合物，所述的组合物包括头花蓼、黄连。优选的组合物包括头花蓼20-60重量份、黄连2-6重量份。
优选的组合物包括头花蓼、黄连、补益药物。
更优选的组合物包括头花蓼20-60重量份、黄连2-6重量份、补益药物2-20重量份。
本发明所述的补益药物包括但不限定于甘草、党参、白术、白芍、大枣、人参、茶叶、黄芪、黄精。
优选的补益类选自甘草、黄芪、白术、白芍、黄精。
本发明药物组合物中补益类药材的优选的重量份比例如下：
Figure PCTCN2016093626-appb-000001
进一步优选的组合物选自如下任意一组：
(1)头花蓼10-90重量份、黄连1-10重量份、甘草2-20重量份；
(2)头花蓼20-60重量份、黄连2-6重量份、黄精9-15重量份；
(3)头花蓼20-60重量份、黄连2-6重量份、党参9-18重量份；
(4)头花蓼20-60重量份、黄连2-6重量份、党参9-18重量份、甘草4-9重量份。
其中
(1)优选为头花蓼10-90重量份、黄连1-10重量份、甘草2-20重量份；
(2)更优选头花蓼20-60重量份、黄连2-6重量份、甘草4-9重量份；
(3)最优选头花蓼30重量份、黄连3重量份、甘草6重量份；
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经无机、有机溶剂单独或混合溶剂提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经水与乙醇、丙酮、乙酸乙酯的两种、多种混合溶剂提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经5-30倍的水提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经5-30倍的30-100％的有机溶液提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经5-30倍的30-99％的低级醇(C1-C5)、丙酮、乙酸溶液提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经5-30倍的30-99％的乙醇水溶液为提取溶剂提取并获得。在一个实施例中，所述的乙醇水溶液优选为70％乙醇溶液，选取溶液倍数为6-8倍。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经5-15倍的5-95％的醇与酯混合溶液为提取溶剂提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经5-15倍的5-95％的乙醇与乙酸乙酯混合溶液为提取溶剂提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是头花蓼和其他药材经5-20倍的乙酸乙酯、石油醚、***提取并获得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是按照包括如下步骤的方法制备：由组成组合物的药材用5～30倍(例如5～15倍，例如6～12倍)的水、乙醇、乙醇水溶液煎煮和/或回流提取1～5次(例如2～3次)，每次0.5～5小时(例如0.5～3小时，例如1～3小时)，过滤并浓缩滤液，干燥。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是按照包括如下步骤的方法制备：取组成组合物的药材，加5～30倍(例如5～15倍，例如6～12倍)的水，在50～100℃左右煎煮提取1～5次(例如2～3次)，每次0.5～5小时(例如0.5～3小时，例如1～3小时)，过滤并合并提取液，经浓缩至相对密度为1.1～1.5(例如1.2～1.4)的稠膏，减压干燥，即得。
根据本发明第一方面的药物组合物，其特征在于，所述组合物是按照包括如下步骤的方法制备：取组成组合物的药材，加5～30倍(例如5～15倍，例如6～12倍)的30～99％的乙醇水溶液回流提取1～5次(例如2～3次)，每次0.5～5小时(例如0.5～3小时，例如1～3小时)，过滤并合并提取液，60～90℃(例如65～75℃)浓缩至相对密度为1.1～1.5(例如1.2～1.4)的稠膏，减压干燥，即得。
上述药物组合物，其中还包含一种或多种其他的药物，该药物选自：抗微生物药、质子泵抑制剂、胃黏膜保护剂、制酸剂、H2受体拮抗剂。
优选的抗微生物药包括但不限定于青霉素类例如阿莫西林，大环内酯类例如克拉霉素，硝咪唑类例如甲硝唑
优选的质子泵抑制剂包括但不限定于奥美拉唑、兰索拉唑、泮托拉唑
优选的胃黏膜保护剂包括但不限定于硫糖铝、思密达
优选的制酸剂，如氢氧化铝镁合剂
优选的H2受体拮抗剂，如西咪替丁、雷尼替丁、法莫替丁。
本发明还公开药物组合物提取物的制备方法，其特征在于，所述的方法的步骤选自以下任意一项或多项：
(1-1)经无机、有机溶剂单独或混合溶剂提取并获得；
(1-2)经水与乙醇、丙酮、乙酸乙酯的二种、多种混合溶剂提取并获得；
(1-3)经5～30倍水做溶剂提取并获得；
(1-4)经5-30倍的30-99％的低级醇(C1-C5)、丙酮、乙酸溶液提取并获得；
(1-5)经5～30倍的30～99％的乙醇水溶液为提取溶剂并经提取并获得；
(1-6)经6～8倍的70％乙醇水溶液为溶剂提取并获得；
(1-7)经5～15倍的5～95％醇与酯的不同混合溶剂提取并获得；
(1-8)经5～20倍的乙酸乙酯、石油醚、***作为提取溶剂并经提取并获得；
(2)按照包括如下步骤的方法制备：由组成组合物的药材用水、乙醇、乙醇水溶液煎煮和/或回流提取，过滤并浓缩滤液，干燥；
(3)按照包括如下步骤的方法制备：称取组成组合物的药材，加5～30倍的水煎煮，50～100℃提取1～5次，每次0.5～5小时，过滤并合并提取液，经浓缩至相对密度为1.1～1.5的稠膏，减压干燥，即得；
(4)按照包括如下步骤的方法制备：称取组成组合物的药材，加6～8倍的水煎煮，85～100℃提取2次，每次1～1.5小时，过滤并合并提取液，经浓缩至相对密度为1.2～1.3的稠膏，减 压干燥，即得；
(5)按照包括如下步骤的方法制备：称取组成头花蓼组合物的药材，加5～30倍的乙醇、30～99％乙醇水溶液回流提取1～5次，每次0.5～5小时，过滤并合并提取液，经浓缩至相对密度为1.1～1.5的稠膏，减压干燥，即得；
(6)按照包括如下步骤的方法制备：称取组成头花蓼组合物的药材，加6～8倍的70％乙醇水溶液回流提取2次，每次1～1.5小时，过滤并合并提取液，经浓缩至相对密度为1.2～1.3的稠膏，减压干燥，即得。
本发明包括所有上述方法制备的药物组合物提取物。
本发明第二方面提供了一种药物制剂组合物。
为了使用的方便本发明中的组合物还包含一种或多种无毒生理学可接受的载体。所述的可接受的载体包括本领域公知的任何辅料及起控释作用的辅料。常用的辅料包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂、致孔剂、增塑剂、填充剂、增溶剂和乳化剂。稀释剂可以是但不限于淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是但不限于水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、***胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是但不限于干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是但不限于滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇；增溶剂和乳化剂可以是但不限于乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。起缓控释作用的辅料可以选自亲水性凝胶材料、蜡脂类材料和不溶性材料的一种或多种。所述的亲水性凝胶材料可以选自羟丙基甲基纤维素、卡波普、羧甲基纤维素钠和海藻酸盐，所述的蜡脂类材料可以选自十六醇、十八醇、蜂蜡、山嵛酸甘油酯、硬脂酸和巴西棕榈蜡，所述的不溶性材料可以选自乙基纤维素、丙烯酸树脂、聚氧乙烯和聚乙烯。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为此本发明还涉及包含药物组合物和药学上可接受的载体制成的制剂。可通过将组合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。该制剂可根据本领域公知的方法制备。本发明中的组合物在其药物制剂中的含量通常为6-12g。
为达到用药目的，增强治疗效果，本发明的药物制剂优选为口服制剂。
本发明中的药物组合物制备的口服制剂包括颗粒剂、片剂、丸剂、胶囊剂、口服液制剂等有关的常释制剂与缓控释制剂，所述的缓控释制剂包括骨架型、膜控型、渗透泵型、胃内滞留型缓释缓控释制剂，微囊、纳米粒、脂质体等药物新载体缓释缓控释制剂，胃内滞留型 缓控释制剂优选为胃漂浮剂。
以胃漂浮剂为例，该制剂的制备工艺如下：
原料为31％的组合物，31％IV丙烯酸树脂，31％十八醇，7％MCC101，加入适量硬脂酸镁，干法直接压片得到头花蓼组合物胃内漂浮片。
本发明第三方面提供了药物组合物在制备抗菌药物的应用；以及黄连在制备抗菌药物中的应用。
根据本发明第三方面的应用，其特征在于，所述的病菌选自革兰氏阳性菌甲氧西林耐药金黄色葡萄球菌S.aureus(Methicllin-resistant，MRSA)、甲氧西林敏感金黄色葡萄球菌S.aureus(Methicin-suseptable)、甲氧西林耐药表皮葡萄球菌(staphylococcus epidermidis，MRSE)、甲氧西林敏感表皮葡萄球菌(staphylococcus epidermidis，MSSE)，还选自革兰氏阴性菌大肠埃希菌(ESBLS)Escherichia Coli，Eco+，大肠埃希菌(非ESBLS)Escherichia Coli，Eco-，肺炎克雷伯(ESBLs)K.penumonia，KPN+，肺炎克雷伯(非ESBLs)K.penumonia，铜绿假单胞菌(Pseudomonas aeruginosa，PAE)、幽门螺旋杆菌。
在本发明中，术语“提取”可以是常温下的浸渍，或者在升高的温度下的提取(例如煎煮和/或回流)，或者这些操作方式的结合。还可以进一步包括对提取物进行进一步处理，例如进一步纯化，例如除溶剂、沉淀除杂质、溶剂萃取、树脂吸附分离等。
如本文所述的，术语“提取物”将包括可用于实现本发明任何目的的任何纯度的提取物，提取物的提取纯度可以在较大的范围内变化。
有益技术效果
本发明的有益效果在于：组合物提高了头花蓼单方抗幽门螺旋杆菌活性，水提组合物A对Hp ATCC700392的最低抑菌所需头花蓼生药含量为9.84mg/ml，黄连生药含量为0.98mg/ml，低于头花蓼单方(36.68mg/ml)和黄连单方(1.37mg/ml)所需含量，增强头花蓼与黄连间的抗菌协同作用；醇提组合物A、组合物B、组合物C对Hp ATCC700392的最低抑菌所需头花蓼生药含量分别为3.63、19.48、17.16(mg/ml)，低于头花蓼单方(40.44mg/ml)所需含量；醇提组合物A、组合物B、组合物C对Hp SS1的最低抑菌所需头花蓼生药含量分别为3.63、2.44、2.15(mg/ml)，低于头花蓼单方(5.06mg/ml)所需含量；醇提组合物B对耐甲硝唑菌株的最低抑菌所需头花蓼生药含量4.87mg/ml，低于头花蓼单方(10.11mg/ml)所需含量。
组合物具有良好的抗菌活性。水提组合物A对革兰氏阳性菌最低抑菌生药含量为＜0.082mg/ml，黄连单方与头花蓼所需生药含量分别为0.204、0.621mg/ml；对革兰氏阴性菌最低抑菌生药含量为＜0.0824mg/ml，黄连单方与头花蓼所需生药含量分别为0.204、5.175mg/ml。
附图说明
图1显示了临床耐药株验证结果。
图2显示了组合物对幽门螺旋杆菌体外抑制的结果。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例
实施例1：制备组合物A醇提浸膏粉()
称取头花蓼1350g、炒黄连135g、甘草270g，洗净，加入8倍量的70％乙醇进行水浴回流1.5小时，滤过；滤渣加入6倍量70％的乙醇，水浴回流提取1小时，滤过。合并两次滤液，浓缩得浸膏，减压干燥，得到本实施例浸膏粉，186g。
实施例2：制备组合物B醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼750g、炒黄连75g、党参250g、茯苓250g、陈皮150g进行提取，得本实施例浸膏粉，154g。
实施例3：制备组合物C醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼600g、炒黄连60g、党参200g、茯苓200g、五味子200g进行提取，得本实施例浸膏粉，140g。
实施例4：制备头花蓼单方醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼900g进行提取，得本实施例浸膏粉，89g。
实施例5：制备炒黄连醇提浸膏粉
参考实施例1相同方法，不同之处在于称取炒黄连药材660g，得本实施例浸膏粉，133g。
实施例6：制备组合物A水煎浸膏粉
称取头花蓼600g、炒黄连60g、生甘草120g，洗净，加入8倍量水煎煮1.5小时，滤过；滤渣加入6倍量水煎煮1.5小时，滤过，合并两次滤液，滤液浓缩为浸膏，减压干燥，得到本实施例浸膏粉，122g。
实施例7：制备组合物B水煎浸膏粉
方法参考实施例5相同方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、茯苓100g、陈皮60g进行提取，得本实施例浸膏粉，95g。
实施例8：制备组合物C水煎浸膏粉
参考实施例5相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、 茯苓100g、五味子100g进行提取，得本实施例浸膏粉，102g。
实施例9：制备头花蓼单方水煎浸膏粉
参考实施例5相同的方法，不同之处在于称取药材头花蓼1000g进行提取，得本实施例浸膏粉，109g。
实施例10：制备炒黄连水煎浸膏粉
参考实施例5相同的方法，不同之处在于称取炒黄连药材520g，得本实施例浸膏粉，95g。
实施例11：制备组合物A水提浸膏粉
参考实施例1相同的方法，不同之处在于称取头花蓼80kg、炒黄连8kg、生甘草16kg，进行提取，得到本实施例浸膏粉，8.1kg。
实施例12：制备组合物B水提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼54kg、炒黄连5.6kg、党参17.6kg、茯苓17.6kg、陈皮10.4kg进行提取，得本实施例浸膏粉，17.0kg。
实施例13：制备组合物C水提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼48kg、炒黄连4.8kg、党参16kg、茯苓16kg、五味子16kg进行提取，得本实施例浸膏粉，20.0kg。
实施例14：制备炒黄连水提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材炒黄连76kg进行提取，得本实施例浸膏粉，3.1kg。
实施例15：制备组合物A醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取称取头花蓼500g、炒黄连50g、生甘草100g，进行提取，得到本实施例浸膏粉，64.2g。
实施例16：制备组合物B醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、茯苓100g、陈皮60g进行提取，得本实施例浸膏粉，78g。
实施例17：制备组合物C醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、茯苓100g、五味子100g进行提取，得本实施例浸膏粉，85.4g。
实施例18：制备头花蓼醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼600g进行提取，得本实施例浸膏粉，50.2g。
实施例19：制备组合物D醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、茯苓100g进行提取，得本实施例浸膏粉，78.8g。
实施例20：制备组合物D水煎浸膏粉
参考实施例5相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、茯苓100g进行提取，得本实施例浸膏粉，79g。
实施例21：制备组合物E醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、茯苓100g、陈皮60g进行提取，得本实施例浸膏粉，64g。
实施例22：制备组合物E水煎浸膏粉
参考实施例5相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、茯苓100g、陈皮60g进行提取，得本实施例浸膏粉，66g。
实施例23：制备组合物F醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、五味子100g进行提取，得本实施例浸膏粉，80g。
实施例24：制备组合物F水煎浸膏粉
参考实施例5相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、党参100g、五味子100g进行提取，得本实施例浸膏粉，84g。
实施例25：制备组合物G醇提浸膏粉
参考实施例1相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、茯苓100g、五味子100g进行提取，得本实施例浸膏粉，86g。
实施例26：制备组合物G水煎浸膏粉
参考实施例5相同的方法，不同之处在于称取药材头花蓼300g、炒黄连30g、茯苓100g、五味子100g进行提取，得本实施例浸膏粉，88g。
药理实验
试验例1：组合物(实施例1)对幽门螺旋杆菌标准株及临床菌株抗菌活性检测。
1)实验菌株：
临床菌株：所用菌株为幽门螺旋杆菌ATCC700392、幽门螺旋杆菌SS1国际标准测序株，购自ATCC(美国菌种保藏中心)。
耐药菌株：收集于临床消化内科，经药敏实验验证。临床分离到三种菌株(命名)及其特性分别为：
HP R-1型：其对甲硝唑耐药，
HP R-2型：其对阿莫西林耐药，
HPR-3型：其对克拉霉素耐药。
2)试验使用的主要试剂
哥伦比亚血琼脂粉、脑心浸液琼脂干粉购自英国Oxoid公司，盐酸万古霉素、两性霉素、多粘菌素B、磺胺(TMP)、阿莫西林、克拉霉素、甲硝唑购自美国Sigma公司，触酶、氧化酶、尿素酶购自生物梅里埃公司，无菌脱纤维羊血购自南京便诊生物科技有限公司，无水乙醇(分析纯)购自重庆重庆川东化工有限公司化学试剂厂，二甲基亚砜(DMSO)分析纯购自北京萦莱宝科技有限公司。
3)试验样品
本发明一部分实施例所得组合物；实施例4、9所得头花蓼单方浸膏。
4)主要试剂和材料的制备：
4.1)含药平皿的配制：
根据体外药敏实验要求，实验时每个菌株的每个药物浓度需设置2个平行实验，实验需重复3次。每次于三角烧瓶中称取1.95g哥伦比亚血琼脂粉溶解于39.5mL去离子水中，高压灭菌后，待培养基冷却至50～55℃时加入5mL脱纤维无菌羊血(10％)、0.5mL混合抗生素(1％)，再加入对应稀释度的药液5mL，混匀后倒入2个无菌平皿(d＝90mm)中，凝固后4℃保存。头花蓼单方及组合物溶液的稀释度及对应平板的含药浓度见表1。
4.2)含溶媒血平板的配制(溶剂对照)：方法同含样品血平板的配制，即加入相应体积相应浓度的二甲亚砜替代样品母液，以双蒸水作为溶剂则不需配制。
5)实验方法
5.1)幽门螺旋杆菌标准株及临床耐药株的复苏培养及菌株的鉴定
从-80℃冰箱中取出幽门螺旋杆菌ATCC700392和幽门螺旋杆菌SS1菌株及临床H.pylori耐阿莫西林株、H.pylori耐克拉霉素株、H.pylori耐甲硝唑株，置于37℃水浴箱中溶解，用接种环醮取菌液均匀涂布于含混合抗生素的哥伦比亚血平板上，置于37℃三气培养箱(85％N2，10％CO2，5％O2)中培养48h。对这两株标准菌株及三株临床株进行培养特性、革兰染色、尿素酶鉴定、过氧化氢酶鉴定、氧化酶鉴定。
5.2)菌液配制：将血平板上的菌落或菌苔刮至预冷含15mL脑心浸液肉汤管中，离心洗涤一次后，重悬于4℃脑心浸液肉汤中，将此菌液作10倍、100倍、1000倍稀释后，在紫外分光光度计上测菌液的OD600值，结果位于0.1～1.0之间的OD值与菌液浓度有较好的线性关系，菌液含量的计算公式如下：菌量/mL＝2.2×108×OD600值×稀释倍数，将菌液稀释得到108CFU/mL。在15min内完成菌液配制和接种，接种过程中菌液需保持在4℃。
5.3)临床耐药株验证试验：将培养72h的幽门螺杆菌临床菌株用脑心浸液肉汤制备菌悬液，调配其浓度在1～9×108CFU/mL，分别用无菌棉签沾取菌悬液均匀涂布于浓度为甲硝唑256μg/mL，克拉霉素256μg/mL，阿莫西林256μg/mL的药物培养皿及空白培养皿上，每个药物浓度涂抹两个平皿，置于微需氧环境中37℃培养72h。以空白培养皿上H.pylori生长良好的情况下，以观察其生长情况，并对所生长细菌做革兰氏染色和生化鉴定试验。
5.4)头花蓼组合物的体外抗菌活性实验
5.4.1)菌液涂布：用一次性棉棒蘸取浓度为108CFU/mL菌液，在琼脂表面均匀涂布。按每种样品每个浓度均涂布2块平板。同时设阴性对照(即不加菌)、生长对照(即不加实验样品)、溶剂对照各两块平板。
5.4.2)培养：置于37℃三气培养箱中培养48h后观察结果。每个样品的每种菌株体外抗菌活性实验重复三次。
5.4.3)在阴性对照(即不加菌)无生长、生长对照(即不加药)生长良好、溶剂对照(即仅加溶剂)未见生长抑制现象的条件下，以完全无菌生长的样品最高稀释度为该菌株对相应样品的最低抑菌浓度(MIC)。
6)实验结果：
6.1)幽门螺杆菌的鉴定
两株幽门螺杆菌ATCC700392和SS1及临床分离株在普通哥伦比亚血平板上置于微需氧条件下培养48h，菌落呈针尖状无色透明，光滑湿润，边缘整齐，凸起，呈小水滴样，菌苔灰 白色，发油光。
生化试验：尿素酶试验阳性，氧化酶试验阳性，过氧化氢酶试验阳性；在显微镜油镜下观察，典型的海鸥状，S状，革兰染色阴性。
6.2)耐药株的验证
将临床已收集分离的H.pylori耐阿莫西林株、H.pylori耐克拉霉素株、H.pylori耐甲硝唑株共3种临床耐药株进行复苏，并对耐药情况核实。在药物浓度为甲硝唑256μg/mL，克拉霉素256μg/mL，阿莫西林256μg/mL是均生长状态良好，与空白组无区别。
6.3)头花蓼组合物的体外抗菌试验结果见表2。
头花蓼组合物对Hp ATCC700392和SS1的MIC为0.5mg/ml。
在本实验的平行试验中，同样验证了阿莫西林、甲硝唑、克拉霉素三者对上表中5种幽门螺旋杆菌的敏感性，结果显示三种药物对ATCC700392和SS1均敏感，而HP R-1对克拉霉素耐药，对另外两种药物敏感；HP R-2对阿莫西林耐药，对另外两种药物敏感；HP R-3对甲硝唑耐药，对另外两种药物敏感。头花蓼单方对Hp ATCC700392和SS1的MIC为4mg/ml，验证之前的实验结果。
试验例2：头花蓼组合物对幽门螺旋杆菌标准株及临床分离菌株抗菌活性检测。
基本上参考试验例1的方法，分别以实施例2-3、5-8、9所得头花蓼组合物为试药，测试其对ATCC700392、幽门螺旋杆菌SS1国际标准测序株、幽门螺旋杆菌耐甲硝唑株、幽门螺旋杆菌耐阿莫西林株、幽门螺旋杆菌耐克拉霉素株的抗菌活性。在阴性对照(即不加菌)无生长、生长对照(即不加药)生长良好、溶剂对照(即仅加溶剂)未见生长抑制现象，甲硝唑、阿莫西林、克拉霉素对照均对HP ATCC700392有抑制作用，头花蓼单方制剂对照对HPATCC700392的最低抑菌浓度(MIC)为4mg/ml的情况下，实验做重复三次，本实验中所有组合物样品对五种幽门螺旋杆菌的MIC值在0.5～64mg/ml之间。黄连抑菌效果较好，其MIC值在＜0.0625-0.25mg/ml之间。实验结果见表2。
表1实验样品溶液的稀释浓度
Figure PCTCN2016093626-appb-000002
表2本发明实施例的组合物对幽门螺旋杆菌体外抑菌结果(MIC)
Figure PCTCN2016093626-appb-000003
Figure PCTCN2016093626-appb-000004
试验例3：组合物对革兰氏菌抗菌活性检测实验
1)试验菌株
1.1)受试菌株
甲氧西林耐药金黄色葡萄球菌S.aureus(Methicllin-resistant，MRSA)6株、甲氧西林敏感金黄色葡萄球菌S.aureus(Methicin-suseptable，MSSA)6株、甲氧西林耐药表皮葡萄球菌(staphylococcus epidermidis，MRSE)5株、甲氧西林敏感表皮葡萄球菌(staphylococcus epidermidis，MSSE)5株、大肠埃希菌(ESBLS)Escherichia Coli，Eco+6株、大肠埃希菌(非ESBLS)Escherichia Coli，Eco-6株、肺炎克雷伯(ESBLs)K.penumonia，KPN+6株、肺炎克雷伯(非ESBLs)K.penumonia，KPN-6株、铜绿假单胞菌(Pseudomonas aeruginosa，PAE)5株、铜绿假单胞菌(Pseudomonas aeruginosa，PAE)5株。以上菌株均为2013年6月至2014年10月在四川地区、北京地区、上海等收集的临床分离致病菌。在收集单位经VITEK-60自动微生物鉴定仪鉴定。
1.2)质控菌株
金黄色葡萄球菌CMCC26003；大肠埃希菌ATCC25922；铜绿假单胞菌ATCC27853。购自中华人民共和国***临床检测中心。
2)实验试剂与材料
头孢吡肟(标准品)源自中国食品药品检定研究院标准品；头花蓼水提单方由贵阳医学院提供，批号为14196，生药含量10.35g/g。
3)实验方法
以头花蓼单方、炒黄连单方、头孢吡肟为对照药材，用琼脂二倍稀释法进行样品体外抗菌的最低抑菌浓度。
3.1)头孢吡肟对照品
称取药品9.5mg，加入4.1ml的生理盐水，混匀，各吸取1ml于两个培养皿中，再加入15ml的培养基，使其终浓度为145ug/ml，再吸取2ml于西林瓶中，再在该西林瓶中加入2ml的生理盐水，混匀，各吸取1ml加入两个平皿中，再加入15ml的培养基，使其终浓度为72.4ug/ml，依照此法倍比稀释，使平皿内所含药物终浓度依次为128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03、0.015、0.008ug/ml。待冷却后用多点接种仪(MIT-P，SUKUMA)接种细菌，接种菌量约为104CFU/ml，每皿接种27株菌，2个皿接种54株菌，盖上皿盖。置于35-37℃培养箱内培养18-20h，观察记录结果。以平皿内未见细菌生长的药物最低浓度，判断为最低抑菌浓度(Minimal Inhibitory Concentration，MIC)。
3.2)头花蓼单方、黄连浸膏及试验样品配制方法
取灭菌烧杯，加入已称量好的中药样品7.68g，再定量加入约50℃的已融化的M-H琼脂培养基60ml，混匀后分别吸取15ml于两个平皿中，使其浓度为128mg/ml，再在剩余的30ml培养基中加入30ml培养基，混匀，分别再从中吸取15ml于2个培养皿中，使其浓度为64mg/ml，依照此法倍比稀释，使每皿内所含药物终浓度依次为128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03、0.015、0.008mg/ml。待冷却后用多点接种仪(MIT-P，SUKUMA)接种细菌，接种菌量约为104CFU/ml，每皿接种27株菌，2个皿接种54株菌，盖上皿盖。置于35-37℃培养箱内培养18-20h，观察记录结果。
4)实验结果
实验结果表明，头花蓼组合物对革兰氏阴性菌及革兰氏阳性菌有较好的抑制效果。实验结果见表3。
表3本发明实施例对革兰氏菌的抑菌MIC结果表
Figure PCTCN2016093626-appb-000005

Claims (20)

  1. 一种药物组合物，其特征在于，所述的组合物包括头花蓼、黄连。
  2. 一种药物组合物，其特征在于，所述的组合物包括头花蓼20-60重量份、黄连2-6重量份。
  3. 根据权利要求1-2中任一项的组合物，其特征在于，所述的组合物包括头花蓼、黄连和补益药物。
  4. 根据权利要求3的药物组合物，其特征在于，所述的组合物包括头花蓼20-60重量份、黄连2-6重量份、补益药物2-20重量份。
  5. 根据权利要求3的药物组合物，其特征在于，所述的补益药物选自甘草、党参、白术、白芍、大枣、人参、茶叶、黄芪、黄精。
  6. 根据权利要求5的药物组合物，其特征在于，所述的组合物选自如下任意一组：
    (1)头花蓼10-90重量份、黄连1-10重量份、甘草2-20重量份；
    (2)头花蓼20-60重量份、黄连2-6重量份、黄精9-15重量份；
    (3)头花蓼20-60重量份、黄连2-6重量份、党参9-18重量份；
    (4)头花蓼20-60重量份、黄连2-6重量份、党参9-18重量份、甘草4-9重量份。
  7. 根据权利要求6的药物组合物，其特征在于，所述的组合物选自：
    头花蓼20-60重量份、黄连2-6重量份、甘草4-9重量份。
  8. 根据权利要求9的药物组合物，其特征在于，所述的组合物选自：
    头花蓼30重量份、黄连3重量份、甘草6重量份。
  9. 根据权利要求1-8中任一项的药物组合物，其中还包含一种或多种其他的药物，该药物选自：抗微生物药、质子泵抑制剂、胃黏膜保护剂、制酸剂、H2受体拮抗剂。
  10. 根据权利要求9的组合物，其特征在于，
    所述的抗微生物药选自青霉素类例如阿莫西林，大环内酯类例如克拉霉素，硝咪唑类例如甲硝唑
    所述的质子泵抑制剂选自奥美拉唑、兰索拉唑、泮托拉唑
    所述的胃黏膜保护剂选自硫糖铝、思密达
    所述的制酸剂，如氢氧化铝镁合剂
    所述的H2受体拮抗剂，如西咪替丁、雷尼替丁、法莫替丁。
  11. 一种药物组合物提取物的制备方法，其特征在于，所述的方法的选自以下任意一项或多项：
    (1-1)权利要求1-8中任意一项的药物组合物经无机、有机溶剂单独或混合溶剂提取并获得；
    (1-2)权利要求1-8中任意一项的药物组合物经水与乙醇、丙酮、乙酸乙酯的二种、多种混合溶剂提取并获得；
    (1-3)权利要求1-8中任意一项的药物组合物经5～30倍水做溶剂提取并获得；
    (1-4)权利要求1-8中任意一项的药物组合物经5-30倍的30-99％的低级醇(C1-C5)、丙酮、乙酸溶液提取并获得；
    (1-5)权利要求1-8中任意一项的药物组合物经5～30倍的30～99％的乙醇水溶液为提取溶剂并经提取并获得；
    (1-6)权利要求1-8中任意一项的药物组合物经6～8倍的70％乙醇水溶液为溶剂提取并获得；
    (1-7)权利要求1-8中任意一项的药物组合物经5～15倍的5～95％醇与酯的不同混合溶剂提取并获得；
    (1-8)权利要求1-8中任意一项的药物组合物经5～20倍的乙酸乙酯、石油醚、***作为提取溶剂并经提取并获得；
    (2)按照包括如下步骤的方法制备：权利要求1-8中任意一项的药物组合物，用水、乙醇、乙醇水溶液煎煮和/或回流提取，过滤并浓缩滤液，干燥；
    (3)按照包括如下步骤的方法制备：权利要求1-8中任意一项的药物组合物，加5～30倍的水煎煮，50～100℃提取1～5次，每次0.5～5小时，过滤并合并提取液，经浓缩至相对密度为1.1～1.5的稠膏，减压干燥，即得；
    (4)按照包括如下步骤的方法制备：权利要求1-8中任意一项的药物组合物，加6～8倍的水煎煮，85～100℃提取2次，每次1～1.5小时，过滤并合并提取液，经浓缩至相对密度为1.2～1.3的稠膏，减压干燥，即得；
    (5)按照包括如下步骤的方法制备：权利要求1-8中任意一项的药物组合物，加5～30倍的乙醇、30～99％乙醇水溶液回流提取1～5次，每次0.5～5小时，过滤并合并提取液，经浓缩至相对密度为1.1～1.5的稠膏，减压干燥，即得；
    (6)按照包括如下步骤的方法制备：权利要求1-8中任意一项的药物组合物，加6～8倍的70％乙醇水溶液回流提取2次，每次1～1.5小时，过滤并合并提取液，经浓缩至相对密度为1.2～1.3的稠膏，减压干燥，即得。
  12. 权利要求11的制备方法制备的药物组合物提取物。
  13. 一种药物制剂组合物，其特征在于，含有作为活性成分的权利要求1-10中任意一项的药物组合物和\或权利要求12的药物组合物提取物与药学上接受的辅料。
  14. 根据权利要求13的药物制剂组合物，其特征在于，所述的药物制剂组合物是口服制剂。
  15. 根据权利要求14的药物组合物，其特征在于，所述的口服制剂选自各种可用的常释制剂和缓控释制剂。
  16. 根据权利要求15的药物组合物，其特征在于，所述的缓控释制剂选自骨架型、膜控型、渗透泵型、胃内滞留型缓控释制剂。
  17. 根据权利要求16的药物组合物，其特征在于，所述的胃内滞留型缓控释制剂选自为胃漂浮剂。
  18. 权利要求1-10中任意一项的药物组合物和\或权利要求12的药物组合物提取物在制备抗菌的药物中的应用。
  19. 根据权利要求17或18中任一项的应用，其特征在于，所述的病菌选自革兰氏阳性菌甲氧西林耐药金黄色葡萄球菌S.aureus(Methicllin-resistant，MRSA)、甲氧西林敏感金黄色葡萄球菌S.aureus(Methicin-suseptable)、甲氧西林耐药表皮葡萄球菌(staphylococcus epidermidis，MRSE)、甲氧西林敏感表皮葡萄球菌(staphylococcus epidermidis，MSSE)，还选自革兰氏阴性菌大肠埃希菌(ESBLS)Escherichia Coli，Eco+，大肠埃希菌(非ESBLS)Escherichia Coli，Eco-，肺炎克雷伯(ESBLs)K.penumonia，KPN+，肺炎克雷伯(非ESBLs)K.penumonia，铜绿假单胞菌(Pseudomonas aeruginosa，PAE)。
  20. 权利要求1-10中任意一项的药物组合物和\或权利要求12的药物组合物提取物在制备预防/治疗幽门螺旋杆菌的药物中的应用。
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CN108524616A (zh) * 2018-06-21 2018-09-14 南京海昌中药集团有限公司 一种白芍配方颗粒剂及其制备方法
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