WO2020244572A1 - 植物选择性抑菌组合物及其用途 - Google Patents

植物选择性抑菌组合物及其用途 Download PDF

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WO2020244572A1
WO2020244572A1 PCT/CN2020/094321 CN2020094321W WO2020244572A1 WO 2020244572 A1 WO2020244572 A1 WO 2020244572A1 CN 2020094321 W CN2020094321 W CN 2020094321W WO 2020244572 A1 WO2020244572 A1 WO 2020244572A1
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composition
skin
antibacterial
phellodendron
coptis
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PCT/CN2020/094321
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English (en)
French (fr)
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徐丽华
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苏州思源天然产物研发有限公司
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Publication of WO2020244572A1 publication Critical patent/WO2020244572A1/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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/238—Saposhnikovia
    • 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)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • 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
    • 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)
    • A61K36/75—Rutaceae (Rue 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/756—Phellodendron, e.g. corktree
    • 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
    • A61P31/02—Local antiseptics
    • 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
    • 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
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • 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 relates to the field of antibacterial disinfectants, in particular to a plant bacteriostatic agent that selectively resists bacterial infections.
  • antibacterial agents include synthetic antibiotics, bactericides, preservatives, natural antibacterial agents, and Chinese medicine. Although people continue to pursue the broad-spectrum and powerful effects of antibacterial agents, not all bacteria need to be inhibited. From the perspective of human health, there are a large number of probiotics and pathogenic bacteria, especially the skin, mucous membranes, and intestinal tract, which are beneficial to the human body. Only when the pathogenic bacteria multiply, the proportion of probiotics and pathogenic bacteria is unbalanced, and the body's micro-ecological protection barrier is damaged, which can cause diseases, such as HPV (human papillomavirus) infection, enteritis, chronic diarrhea, etc.
  • HPV human papillomavirus
  • Microorganisms that can settle on the skin for a long time and grow and reproduce are the normal flora that truly constitute human skin. It is now known that the most abundant anaerobic Propionibacterium on the skin can decompose triacylglycerol in sebum into free fatty acids. This fatty acid has an inhibitory effect on the conditional pathogens on the skin surface, such as Staphylococcus aureus, Streptococcus, Candida albicans and Dermatomyces. The second largest number on the skin is Staphylococcus epidermidis. This bacterium can secrete autolysozyme. The resident bacteria on the skin are not sensitive to this enzyme, but it can dissolve some pathogenic passing bacteria.
  • probiotics are Propionibacterium and Staphylococcus surface
  • pathogenic bacteria are Staphylococcus aureus, Streptococcus, Candida albicans, etc. (Skin and intestinal microecology and probiotics_Zhao Qiming, Chinese Aesthetic Medicine, September 2018, Vol. 27, No. 9)
  • the total amount of normal vaginal mucosa microecology can reach 109/mL, of which Lactobacillus accounts for about 70%-95%. It maintains the acidic environment of the vagina through colonization resistance, biological antagonism, and decomposition of vaginal epithelial cell glycogen to produce lactic acid. It is divided into H2O2 and bacteriocins. , Bacteriocins and biosurfactants and stimulate the body’s immune defenses to inhibit other bacteria and
  • the growth of pathogenic bacteria maintains the "self-purification" effect of the vagina.
  • the main probiotics in the oral cavity are Lactobacillus, Bifidobacterium and Enterococcus Among them, there are relatively few studies on the application of bifidobacteria as obligate anaerobes in the oral cavity. Lactobacilli are mostly facultative anaerobes, suitable for survival and colonization in the oral cavity, and are also the most studied probiotic species.
  • the probiotics are mainly Lactobacillus, and the pathogenic bacteria are Staphylococcus aureus, Streptococcus, Escherichia coli, Candida albicans, etc.
  • antibacterial agents used in food, feed, medical and other fields mainly include antibiotics and chemical preservatives.
  • Antibacterial ingredients of antibiotics such as chloramphenicol
  • chemical preservatives such as quaternary ammonium salts, ethanol, triclosan, etc.
  • they are difficult to be decomposed by the human body. When accumulated to a certain amount, they may have potential toxic and side effects, so there are hidden safety hazards, and they may also be used in use. Sensory discomfort and irritation.
  • bacteriostatic agents are broad-spectrum bacteriostatic agents and have no specific antibacterial specificity.
  • the biological inhibitors used in recent years, such as various mycins, are based on protein, and their preparation costs and process requirements are higher than traditional chemically synthesized antibacterial reagents. Therefore, the prior art requires a bacteriostatic agent that can differentially treat the probiotics of the skin and mucous membranes, but has a strong effect on pathogenic bacteria, simple preparation process, and safe environment.
  • an object of the present invention is to provide a plant bacteriostatic product with simple raw material components and easy preparation.
  • a plant bacteriostatic composition which contains active ingredients, the active ingredients are from Coptis chinensis: Phellodendron chinense: Red peony root: White fresh peel: Parsnip in weight ratio of 1:0.5 ⁇ 2:0.5 ⁇ 2:0.5 ⁇ 3:0.5 ⁇ 2, and a pharmaceutically acceptable carrier.
  • Coptis: Phellodendron: Red Peony: White Fresh Peel: Parsnip is 1:1:1:1.3:1.
  • Rhizoma Coptidis Phellodendron amurense, Red Peony Root, and White Fresh Peel are the supernatants extracted through the following steps:
  • the windproof is an extract obtained by water distillation.
  • the active ingredient extracts are mixed, and a concentration of 0.2-0.5 crude drug g/ml for external use is prepared according to the ratio of the medicinal materials, and the optimal concentration is 0.3 g crude drug/ml.
  • composition of the present invention can be formulated with various pharmaceutically acceptable carriers, and formulated into various forms according to its specific application.
  • the pharmaceutically acceptable carrier is selected from excipients, disintegrants, binders, lubricants, diluents, buffers, osmotic pressure regulators, preservatives, humectants , Emulsifier, dispersant, stabilizer, cosolvent.
  • the composition is selected from lotions, tablets, ointments, creams, suppositories, films, liniments, aerosols, foams, eye drops, and ear drops.
  • the concentration of the active ingredient in the composition is 0.2-0.5 g/ml, and the weight is the total weight of Coptis Rhizoma: Phellodendron chinense: Phellodendron chinense: Paeonia lactiflora: Paeonia lactiflora: Parsnid.
  • the optimal concentration of the active ingredient in the composition is 0.3g/ml.
  • the active ingredient content standard of the composition is: paeoniflorin is greater than or equal to 200mg/100ml; berberine is greater than or equal to 30mg/100ml; berberine is greater than or equal to 300mg/100ml; volatile oil is greater than or equal to 0.02ml/100ml .
  • the bacteriostatic agent is an external bacteriostatic agent.
  • the bacteriostatic agent is preferably a lotion.
  • the inventors selected Coptis chinensis, Phellodendron amurense, Radix Paeoniae Rubra, Radix Rhizoma Phellodendron chinense, Radix Paeoniae Rubra, Radix Paeoniae Rubra, and white fresh peel from numerous Chinese herbal medicines for clearing away heat and detoxification as the medicine composition of the lotion. Clearing heat and detoxification, red peony roots for clearing heat and cooling blood are ministerial medicine, white fresh skin is used as supplementary medicine for dispelling wind, detoxification and relieving itching, and anti-wind, dispelling wind and relieving surface is used as medicine.
  • Coptis the dried rhizome of Coptis Chinesis Franch, Coptis Chinesis Franch, Coptudeltoidea C. FChenget Hisao or Coptistecta Wall.
  • the above three types are commonly called “Weilian”, “Yalian” and “Yunlian” respectively.
  • the three kinds of Coptis all contain a variety of alkaloids, mainly berberine BR, with a content as high as 3.6%.
  • eoptisine eoptisine
  • jatrorrhizine jatrorrhizine
  • methyl berberine wornnine
  • Coptis Used for damp heat and fullness, vomiting, diarrhea, jaundice, high fever and dizziness, hyperthermia, upset and insomnia, red eyes and sore eyes, toothache, diminished thirst and carbuncle sores; external treatment of eczema, eczema, ear canal Pus.
  • Coptis is an ancient antibacterial drug. It has been used clinically for a long time in reducing fever and pain, and resisting intestinal bacterial infections. In recent years, it has been found that Coptidis has anti-arrhythmia, lowering blood lipids, lowering blood sugar, and anti-platelet aggregation.
  • Cork the name of Chinese medicine. It is the dry bark of Phellodendron chinense Schneid. Xi is called "Chuan Huang Bai”. After peeling the bark, remove the rough bark and dry it in the sun. There is heat-clearing in Chinese medicine. Dampness, purging fire, detoxification. It has the effect of treating heat dysentery, diarrhea, diminishing thirst, jaundice, dysfunction, dreams, drenching turbidity, hemorrhoids, blood in the stool, leucorrhea, bone steaming and fatigue, red eyes, swelling and pain, tongue sores, sore swelling and poison.
  • Red peony the name of Chinese medicine. It is the dry root of Paeonia lactiflora Pall. or Paeonia veitchii Lynch of the Ranunculaceae family. Excavate in spring and autumn, remove rhizomes, fibrous roots and silt, and dry. Bitter, slightly cold. Return to the liver channel. It has the effects of clearing heat and cooling blood, promoting blood circulation and removing blood stasis.
  • Fangfeng the name of Chinese medicine. Also known as Tongyun, Huiyun, Huicao, Hundred Branches, Hundred Species. It is the dry root of Saposhnikovia divaricata (Turcz.) Schischk.), a perennial herb. It likes cool climate, is cold and drought tolerant, and is mainly produced in Hebei, Heilongjiang, Sichuan, Inner Mongolia and other places. The roots of the windbreak can be used. The taste is pungent and sweet, and the nature is mild. It has the effects of dispelling wind and relieving skin, eliminating dampness, relieving pain, and relieving spasm.
  • Baixianpi has high medicinal value, and has the effect of clearing away heat and dampness, expelling wind and detoxification. Oral use is mainly used for clearing away heat and dampness, purging fire and detoxification, dispelling wind and relieving itching, jaundice, red urine, damp-heat arthralgia; externally used for eczema, scabies, itchy skin, skin ulcers, and dripping yellow water. Baixianpi has a long history of medicinal use, which was first published in "Shen Nong's Materia Medica".
  • distilled fresh skin contains distillate, distilled lactone, sitosterol, choline, and sphaerosterone. It has different degrees of inhibition to a variety of pathogenic fungi.
  • White fresh peel also has antipyretic effect.
  • the inventors formulated for the first time an antibacterial composition containing only Coptis chinensis, Phellodendron chinense, red peony root, fenfeng, and white fresh peel as active ingredients.
  • the antibacterial composition has simple formula, convenient material selection and low production cost.
  • Coptis, Phellodendron chinense, red peony root, and white fresh peel can be purified by simple ethanol percolation and concentration to obtain the supernatant. For wind-proof, only water distillation is required to extract the volatile oil. In the purification process, no complicated and expensive organic solvents or complicated and expensive laboratory methods other than ethanol are used, so that the production cost is greatly saved.
  • the antibacterial composition has selective antibacterial, anti-inflammatory and antipruritic effects within the following proportioning range.
  • the active ingredient of the antibacterial composition of the present invention can also be made into an antibacterial preparation together with a carrier commonly used in pharmacology.
  • the carriers commonly used in pharmacology are selected from excipients, disintegrants, binders, lubricants, diluents, buffers, osmotic pressure regulators, preservatives, humectants, emulsifiers, dispersants, stabilizers, auxiliary agents Solvent.
  • the preparation can be formulated into a variety of dosage forms, such as lotions, tablets, ointments, creams, suppositories, films, liniments, aerosols, foams and the like. These products can be used in a variety of different occasions.
  • the preparation when used as a lotion, it can be mixed with moist wipes, such as wipes, scouring pads, swabs, paper towels, etc., to wipe surfaces that need antibacterial disinfection, or directly apply to the skin; Added to various personal care products, such as facial tissues, bathroom fabrics (such as towels, bath balls, etc.), or made into feminine care products, or various shampoos, bath lotions, soaps, kitchen detergents, laundry And other household cleaning products.
  • the product can also be widely used for bacteriostasis and disinfection in public places, such as restaurants, stations, public telephones and other areas where the public is frequented and contacted.
  • the additives commonly used in formulating lotions are water; various surfactants, such as polysorbate 20 (such as Tween 20 TM ; ICI Americas), polysorbate 80 (such as Tween 80 TM ; ICI Americas), poloxamer, etc.
  • polysorbate 20 such as Tween 20 TM ; ICI Americas
  • polysorbate 80 such as Tween 80 TM ; ICI Americas
  • poloxamer etc.
  • Nonionic surfactants cationic surfactants such as tetrabutylammonium bromide and benzethoxyammonium chloride or its pure components; tin octoate (tin (II) 2-ethylhexanoic acid) and tetradecyl sulfonic acid Anionic surfactants such as sodium; and amphoteric or zwitterionic surfactants such as dodecyl dimethyl (3-sulfopropyl) ammonium hydroxide and internal salt (such as sodium dodecyl sulfonate, dodecyl Anionic or cationic surfactants such as sodium sulfate; wetting agents (such as glycerin), stabilizers, dyes, penetration enhancers and antioxidants, etc.
  • conventional additives such as fragrances can also be added. These additives are all in the field Known to the skilled person.
  • the antibacterial composition described herein preferably contains an aqueous component.
  • aqueous component refers to any substance consisting essentially of water, mainly water, water-soluble alcohol (such as ethanol, propanol, or isopropanol), or a mixture thereof, or a majority of the substance.
  • the aqueous component may optionally contain one or more water-soluble softeners, including but not limited to low molecular weight aliphatic glycols, such as propylene glycol and butylene glycol; polyols, such as glycerol and sorbitol; and polyoxyethylene polymers , Such as polyethylene glycol 200.
  • water-soluble softeners including but not limited to low molecular weight aliphatic glycols, such as propylene glycol and butylene glycol; polyols, such as glycerol and sorbitol; and polyoxyethylene polymers , Such as polyethylene glycol 200.
  • water-soluble softeners including but not limited to low molecular weight aliphatic glycols, such as propylene glycol and butylene glycol; polyols, such as glycerol and sorbitol; and polyoxyethylene polymers , Such as polyethylene glycol 200.
  • the specific type and amount of the water-soluble softening agent used
  • the aqueous component is preferably deionized, distilled or purified water.
  • Preferred compositions contain about 3% to 98.899%, preferably about 5% to 98%, more preferably about 10% to 97.5%, and most preferably about 38% to 95.99% of the aqueous component.
  • ingredients that enhance the mildness to the skin may be added.
  • These ingredients include cationic and nonionic polymers, co-surfactants, wetting agents and mixtures thereof.
  • Another group of mildness enhancers are lipid skin moisturizers.
  • lipophilic skin moisturizers When used in the antibacterial composition herein, lipophilic skin moisturizers are used, and they are used at a level of about 0.1%-30%, preferably about 0.2%-10%, and most preferably about 0.5%-5% by weight of the composition.
  • composition of the present invention may also include an effective amount of degreasing and/or anti-sticking agent to reduce the greasy feeling or stickiness associated with lipophilic skin moisturizers.
  • degreaser as used herein means a preparation that prevents, reduces and/or eliminates the greasy or heavy skin feel normally associated with lipophilic substances.
  • anti-sticking agent as used herein means a formulation that prevents, reduces and/or eliminates the sticky or tacky skin feel normally associated with ingredients such as humectants.
  • a lipophilic skin moisturizer when used as the flexibility enhancer in the composition herein, it may also contain about 0.1%-10%, preferably about 0.1%-8%, more preferably about 0.1%-5% by weight of the antibacterial composition. stabilizer.
  • composition of the present invention when used as a cleaning composition, it may further include a thickener, a stabilizer, and the like.
  • composition of the present invention may also contain various other optional ingredients.
  • CTFA International Cosmetic Ingredient Dictionary, 6th edition, 1995, incorporated herein for reference describes a wide variety of unrestricted cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for the composition of the present invention.
  • Non-limiting examples of component functional groups are described on page 537 of this reference book.
  • Examples of these functional groups include: abrasives, anti-acne agents, anti-caking agents, antioxidants, adhesives, biological additives, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, Denaturants, drug astringents, emulsifiers, topical anesthetics, film forming agents, perfume components, wetting agents, opacifiers, plasticizers, preservatives, volatile agents, reducing agents, skin bleaching agents, skin conditioning agents (softening Agents, wetting agents, miscellaneous and occlusive agents), skin protectants, solvents, coloring agents, hydrotropes, stabilizers, suspending agents (non-surfactants), sunscreens, UV absorbers and viscosity
  • augmenting agents aqueous phase and non-aqueous phase
  • other functional groups known to those skilled in the art for use herein include solubilizers, sequestering agents, keratolytic agents, and the like.
  • the antibacterial composition of the present invention can be used to disinfect and cleanse the skin.
  • skin disinfection and cleansing methods involve external use of the composition of the present invention in a safe and effective amount to the skin.
  • the present invention can be used when the cleaning method that requires soap and water cannot be realized or is inconvenient.
  • the amount of the applied composition, the frequency of application, and the period of use can be determined according to the required level of disinfection and cleansing, for example, the degree of microbial contamination and/or skin contamination.
  • the composition is applied to the skin once a day, more preferably at least three times a day.
  • Typical amounts of antimicrobial agent used is preferably from about 0.1mg / cm 2 -20mg / cm 2 , more preferably from about 0.5mg / cm 2 -10mg / cm 2 , most preferably from about 1-5mg / cm 2 skin to be cleaned.
  • the antibacterial composition of the present invention is used for cleaning and disinfecting human and/or animal skin.
  • non-skin surfaces such as household surfaces, such as countertops, cookware surfaces, food preparation surfaces (cutting boards, plates, pots and pans, etc.); major household facilities, such as refrigerators, freezers, washing machines, automatic dryers , Stoves, microwave ovens, dishwashers, cabinets, walls, floors, bathroom surfaces, shower curtains, trash cans and/or recycling bins, etc. apply an effective amount of the antibacterial composition of the present invention.
  • the present invention may also include related articles, which include an administration container containing the antibacterial composition.
  • the container contains instructions for using the antibacterial composition of the present invention.
  • the drug delivery container can be made of any conventional materials used to make containers, including but not limited to: polyethylene, polypropylene, polyacetaldehyde, polycarbonate; polyethylene terephthalate, polyvinyl chloride , Polystyrene, polyethylene, vinyl acetate and rubber elastomer mixture. Other materials may include stainless steel and glass.
  • the preferred container is made of a transparent material, such as polyethylene terephthalate.
  • the administration container is a vacuum press applicator.
  • the vacuum pressing applicator is any manually activated device for pressing to produce a quantitative as known droplet.
  • the preferred vacuum press container is made of a translucent material, such as polyethylene terephthalate.
  • the product of the present invention can also be preferably prepared as a swab for personal cleansing, reducing germs on the skin, and providing residual effects on bacteria.
  • safe and effective amount means a certain amount of a compound or composition, the amount of which is sufficient to significantly cause a positive effect, antiviral/antimicrobial benefits, including the independent benefits disclosed herein, but low enough to avoid serious The side effect is to provide a reasonable profit: risk ratio within the reasonable judgment of the technician.
  • the present invention may contain the necessary and optional ingredients and components described herein. It consists of, or consists essentially of, the necessary and optional ingredients and components described herein.
  • antibacterial composition generally refers to a composition used to inactivate, destroy or kill bacteria.
  • the term also refers to a composition for treating diseases caused by or related to these bacteria, such as minor wound infections and moderate microbial skin infections (such as dandruff, genital itching, athlete's foot, etc.).
  • the inventor also provided a quality standard for detecting antibacterial compositions, using berberine ⁇ 3.0 mg/ml; berberine ⁇ 0.3 mg/ml; paeoniflorin ⁇ 2.0 mg/ml and volatile oil ⁇ 0.0002 ml/ml.
  • the production quality of the antibacterial composition can be well controlled.
  • This standard is a relatively complete standard among the current lotions, which is higher and detailed than the existing domestic and international standards for lotions containing Chinese herbal medicines, and the actual feasibility of this standard has been verified by many pilot tests.
  • the above extraction liquid is fed at a weight ratio of 0.3g crude drug/ml, mixed, added with conventional auxiliary materials of lotion, adjusted pH 5-6, filtered, and filled, and it is ready.
  • Formulation 2 Coptis 9kg, Phellodendron chinense 6kg, Paeoniae Rubra 12kg, White fresh peel 15kg, 90% ethanol percolation for 15 hours to extract, after vacuum concentration, 0.8g crude drug/ml water sedimentation, stand for 3-6 days to take the supernatant for use.
  • the above extraction liquid is fed at a weight ratio of 0.4g crude drug/ml, mixed, added with conventional auxiliary materials of lotion, adjusted pH 5-6, filtered, and filled to obtain.
  • the above extract is fed at a weight ratio of 0.2g crude drug/ml, mixed, added with conventional auxiliary materials for lotion, adjusted pH 5-6, filtered, and filled to obtain.
  • the HPLC method is used for the determination, and there are a variety of methods reported in the literature, which are optional.
  • the mobile phase is methanol-water-phosphoric acid (28:72:0.1)
  • the flow rate is 1.0ml/min
  • the detection wavelength is 230nm
  • the column temperature is 25°C.
  • the HPLC method is used for the determination, and there are a variety of methods reported in the literature, which are optional.
  • the mobile phase is selected as acetonitrile-water-triethylamine-phosphoric acid (25:75:0.5:0.33), the flow rate is 1.0ml/min, the detection wavelength is 345nm, and the column temperature is 25°C.
  • the HPLC method is used for the determination, and there are a variety of methods reported in the literature, which are optional. This article chooses the same method as berberine.
  • the mobile phase is acetonitrile-water-triethylamine-phosphoric acid (25:75:0.5:0.33), the flow rate is 1.0ml/min, the detection wavelength is 345nm, and the column temperature is 25°C.
  • Penicillin sodium for injection 800,000 U/branch, Shandong Lukang Pharmaceutical Co., Ltd.
  • Nystatin tablets 500,000 units/tablet, Zhejiang Zhenyuan Pharmaceutical Co., Ltd.
  • Nutrient broth culture medium Microbial Reagent Factory of Jiangsu Center for Disease Control and Prevention.
  • Standard Staphylococcus aureus ATCC25923
  • Standard Escherichia coli 441490
  • Standard B Streptococcus pyogenes 32210
  • Staphylococcus epidermidis Lactobacillus, Propionibacterium, purchased from Beina Biotechnology Co., Ltd.
  • the drug solution tube is turbid, it means that the bacteria grow, and the test drug has no antibacterial effect; if the drug solution tube is clear, it means that the bacterial growth is inhibited, and the drug solution with the largest dilution that can inhibit the growth of bacteria is the smallest of the drug Inhibitory concentration (MIC).
  • MIC drug Inhibitory concentration
  • the drug solution tube is turbid, it means that the bacteria grow, and the test drug has no antibacterial effect; if the drug solution tube is clear, it means that the bacterial growth is inhibited, and the drug solution with the largest dilution that can inhibit the growth of bacteria is the smallest of the drug Inhibitory concentration (MIC).
  • MIC drug Inhibitory concentration
  • the experimental results show that the spray lotion and compound Sophora flavescens lotion of formula 1 are effective against Staphylococcus aureus, Escherichia coli, Streptococcus pyogenes, Staphylococcus epidermidis, Lactobacillus, Propionibacterium, and Candida albicans.
  • the bacteria have strong bacteriostasis, and the MIC is 0.00625 ⁇ 0.2ml/ml, that is, 1.875 ⁇ 60mg crude drug/ml.
  • the lotion of the present invention and the positive drug compound kushen lotion, penicillin, and nystatin tablets are effective against Staphylococcus aureus, Lactobacillus, Propionibacterium, Escherichia coli, Streptococcus b Antibacterial effect of different strains such as Coccus and Candida albicans.
  • the research results show that the lotion of the present invention and the compound Sophora flavescens lotion have different inhibitory effects on the tested strains, including cocci, bacilli and fungi, and all show broad-spectrum antibacterial effects.
  • the MIC of the lotion of the present invention against the pathogenic bacteria Staphylococcus aureus, Escherichia coli, Streptococcus beta and Candida albicans are 0.00625, 0.01, 0.0025, 0.01ml/ml, respectively, and Staphylococcus epidermidis, Lactobacillus, Propionic acid
  • the MIC of Bacillus is 0.025, 0.025, and 0.05ml/ml, some of which are better than the Chinese medicine control compound Sophora flavescens lotion. Therefore, the lotion of the present invention has selective bacteriostasis in vitro, and its inhibitory effect on pathogenic bacteria is obviously stronger than that of probiotics. The inhibitory effect is better than that of the Chinese medicine control compound Sophora flavescens lotion. It has broad antibacterial spectrum and strong selective bacteriostasis. Obvious advantages, broad prospects for development and application.
  • the antibacterial lotion was tested for skin allergy.
  • the auxiliary control group was given the preparation blank, the test product groups were given a mask, and the positive control group was given 2-mercaptobenzothiazole.
  • Each group had 10 animals, half male and half male. Shave off the skin and hair on both sides of the back of the guinea pig 24 hours before administration.
  • the depilatory area is about 3cm ⁇ 3cm. During the sensitization period, evenly apply the test or control substance to the left depilatory area, fix it in a suitable way and apply for 6 hours.

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Abstract

一种植物选择性抑菌组合物及其制备选择性抑菌剂的用途，含有活性成分，所述活性成分由按重量计1：0.5～2：0.5～2：0.5～3：0.5～2的黄连：黄柏：赤芍：白鲜皮：防风组成，以及药物学上可接受的载体。

Description

植物选择性抑菌组合物及其用途 技术领域
本发明涉及抗菌消毒剂领域，具体是选择性抵抗细菌感染的植物抑菌剂。
背景技术
细菌的异常生长会引起疾病，需要使用抗抑菌剂。常用的抗抑菌剂有合成的抗生素、杀菌剂、防腐剂以及天然抑菌剂、中药等。尽管人们不断追求抗菌剂的广谱强效，然而并非所有细菌都需要抑制，从对于人体健康角度来说，细菌有益生菌和致病菌，尤其是皮肤、粘膜、肠道内存在大量对人体有益的细菌，只有在致病菌大量繁殖的时候，益生菌和致病菌比例失衡，机体微生态保护屏障受损，才会导致疾病，如HPV(人乳头瘤病毒)感染、肠炎、慢性腹泻等，甚至引起生理变化导致癌症，如HPV(人乳头瘤病毒)感染导致宫颈癌。因此，临床需要可以抑制致病菌生长而对益生菌影响小的选择性抗抑菌剂。(皮肤菌群与医院感染_府伟灵，国外医学临床生物化学与检验学分册，1989-05-01)。
中药等天然成分，对细菌的杀灭作用虽然大多没有化药广泛和强效，但很多成分对致病菌具有选择性抑制作用，这个特点是化药缺乏的，因此中药、天然药更加适合作为皮肤、粘膜、肠道内的抗抑菌剂。目前作为选择性抑菌剂的临床中药外用配方报道较少，而在中药替代动物饲用抗生素达到选择性抑菌作用的应用上却有见报道(选择性抑菌复方中草药提取物的研制_郝红伟，中国食品科学技术学会第十届年会暨第七届中美食品业高层论坛论文摘要集)。中医药有大量的外用配方治疗皮肤粘膜疾病，长期医疗实践说明药效可靠、安全性好、副作用少，我们可以进行研究筛选优化重组，以得到抑菌选择性好的外用制剂配方,更好保护皮肤和粘膜微生态平衡，促进自然健康。
能够长期定居于皮肤上并进行生长繁殖的微生物，才是真正构成了人类皮肤的正常菌群。现在已知道皮肤上数量最多的还是厌氧的丙酸杆菌，它能将皮脂中三酰甘油分解成游离脂肪酸。这种脂肪酸对于皮肤表面的条件致病菌，如金黄色葡萄球菌、链球菌、白念珠菌和皮肤廯菌等有抑制作用。皮肤上数量占第二位的是表皮葡萄球菌，这种细菌能分泌自溶酶，皮肤常住菌对此酶不敏感，但能溶解一些条件致 病性的过路菌。因此，对于皮肤来说益生菌是丙酸杆菌和表面葡萄球菌等，致病菌是金黄色葡萄球菌、链球菌、白念珠菌等。(皮肤和肠道微生态与益生菌_赵启明，中国美容医学2018年9月第27卷第9期)
正常阴道粘膜微生态总量可达109/mL，其中乳杆菌约占70％～95％，通过定植抗力、生物拮抗、分解阴道上皮细胞糖原产生乳酸来维持阴道酸性环境，分H2O2、细菌素、类细菌素和生物表面活性剂及刺激机体的免疫防御作用来抑制其他菌和
致病菌的生长，维持阴道“自净”作用。(女性一生不同阶段阴道微生态菌群特征研究进展_马薇，中国实用妇科与产科杂志2016年8月第32卷第8期)口腔中的益生菌主要有乳酸杆菌、双歧杆菌和肠球菌，其中双歧杆菌为专性厌氧菌在口腔中的应用研究相对较少。乳酸杆菌多为兼性厌氧菌，适合在口腔中存活定植，也是被研究得最多的益生菌种类。(益生菌与口腔健康的研究进展_李林，口腔护理用品工业，第二十七卷第五册，2017年10月)。因此，对于粘膜来说益生菌主要是乳杆菌，致病菌是金黄色葡萄球菌、链球菌、大肠杆菌、白念珠菌等。
目前，在食品、饲料、医疗等领域中使用的抑菌试剂主要有抗生素和化学防腐剂两类。抗生素类的抑菌成分例如氯霉素等众所周知由于其过度使用，已经出现了越来越多耐药性的菌株，因此广谱抗生素的滥用已经成为了现在的一个难题。且抗生素残留后不易被快速降解。而对于化学防腐剂等，如季铵盐、乙醇、三氯生等，则难以被人体分解，积累到一定量后可能具有潜在的毒副作用，因此存在安全性隐患，而且在使用上也可能有感官上的不适和刺激感。这些抑菌试剂而且都是广谱抑菌剂，并没有针对性的抑菌特异性。近年来使用的生物抑制剂例如各种菌素等基础是蛋白质，其制备成本和工艺要求都高于传统的化学合成抑菌试剂。因此，现有技术需要一种能够差异处理对皮肤粘膜益生菌作用弱，而对致病菌作用强，且制备工艺简单，对环境安全的抑菌剂。
发明内容
因此，本发明的一个目的是提供一种原料成分简单，而且易于配制的植物抑菌产品。在本发明的一个方面，提供了一种植物抑菌组合物，其含有活性成分，所述活性成分由按重量计黄连：黄柏：赤芍：白鲜皮：防风以重量比为1：0.5～2：0.5～2：0.5～3：0.5～2组成，以及药物学上可接受的载体。优选黄连：黄柏：赤芍：白鲜皮：防风为1：1：1：1.3：1。
在该方面的一个优选例中，
黄连、黄柏、赤芍、白鲜皮是通过以下步骤提取的上清液：
a)乙醇提取；b)浓缩并沉淀去除杂质。
在该方面的另一个优选例中，防风是通过水蒸馏提取的提取液。
在本发明的一个优选例中，将活性成分提取液混合，并按药材比例制备浓度为含药材量0.2～0.5生药g/ml的外用抑菌组合物，最佳浓度0.3g生药/ml。
本发明的组合物可以和各种药物学上可接受的载体配制，并根据其具体用途配制成各种形式。
在该方面的另一个优选例中，药物学上可接受的载体选自赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、渗透压调节剂、防腐剂、保湿剂、乳化剂、分散剂、稳定剂、助溶剂。
在该方面的还有一个优选例中，组合物选自洗剂，片剂、软膏剂、霜剂、栓剂、膜剂、搽剂、气雾剂、泡沫剂、滴眼剂、滴耳剂。
在该方面的还有一个优选例中，组合物中活性成分的浓度为0.2-0.5g/ml，其中所述重量是黄连：黄柏：赤芍：白鲜皮：防风的总重量。组合物中活性成分的最佳浓度为0.3g/ml。
在该方面的另一个优选例中，组合物活性成分含量标准为：芍药苷大于等于200mg/100ml；黄连碱大于等于30mg/100ml；小檗碱大于等于300mg/100ml；挥发油大于等于0.02ml/100ml。
在本发明的另一个方面，提供了上述组合物在制备抑菌剂中的用途。优选抑菌剂是外用抑菌剂。在另一个优选例中，该抑菌剂优选是洗剂。
具体实施方式
发明人从众多清热解毒中草药中，根据中医药理论和临床传统应用，筛选出黄连、黄柏、赤芍、防风、白鲜皮作为该洗剂的药物组成，其中黄柏清热燥湿为君药，黄连清热解毒、赤芍清热凉血为臣药，白鲜皮祛风解毒止痒为佐，防风祛风解表为使药。
黄连，毛莨科植物黄连(CoptisChinesisFranch)、三角叶黄连(coptudeltoideaC。FChengetHisao)或云连(CoptistectaWall)的干燥根茎。以上3种分别习称“味连”、“雅连”、“云连”。三种黄连均含有多种生物碱，主要是小蘖碱(berberineBR)，含量高达3.6％以上。其次为黄连碱(eoptisine)、药根碱(jatrorrhizine)、甲基黄连碱(worenine)等。黄连主要功能为清热燥湿、泻火解毒。用于湿热痞满、呕吐、泻痢、黄疸、高热神昏、心火亢盛、心烦不寐、目赤 吞酸、牙痛、消渴及痈肿疗疮；外治湿疹、湿疮、耳道流脓。黄连是一味古老抗菌药，临床上长期以来用于降热镇痛、抗肠道细菌感染，近年来发现黄连还有抗心律失常、降血脂、降血糖、抗血小板聚集等药理作用。
黄柏，中药名。为芸香科植物黄皮树Phellodendron chinense Schneid.的干燥树皮。习称“川黄柏”。剥取树皮后，除去粗皮，晒干。中医上有清热。燥湿，泻火，解毒。治热痢，泄泻，消渴，黄疸，痿躄，梦遗，淋浊，痔疮，便血，亦白带下，骨蒸劳热，目赤肿痛，口舌生疮，疮疡肿毒的作用。
赤芍，中药名。为为毛茛科植物芍药Paeonia lactiflora Pall.或川赤芍Paeonia veitchii Lynch的干燥根。春、秋二季采挖，除去根茎、须根及泥沙，晒干。苦，微寒。归肝经。有清热凉血，活血祛瘀的功效。
防风，中药名。别名铜芸、回云、回草、百枝、百种。为伞形科植物防风(Saposhnikovia divaricata(Turcz.)Schischk.)的干燥根，多年生草本植物，其喜凉爽气候，耐寒，耐干旱，主产于河北、黑龙江、四川、内蒙古等地。防风的根可生用。味辛、甘，性微温。有祛风解表，胜湿止痛，止痉的功效。
白鲜皮为芸香科多年生草本植物白鲜皮(CORTEX DICTAMNI)的根皮。味苦，性寒。白鲜皮药用价值较高，功效清热燥湿，祛风解毒。内服主要用于清热燥湿，泻火解毒，祛风止痒，黄疸尿赤，湿热痹痛；外用于湿疹，疥癣，皮肤瘙痒，肌肤溃烂，黄水淋漓等症。白鲜皮药用历史悠久，始载于《神农本草经》。现代医学研究及临床应用证明，白鲜皮含有白鲜碱，白鲜内脂、谷甾醇、胆碱、梣皮酮等。对多种致病真菌均有不同程度的抑制作用。白鲜皮还有解热作用。
发明人首次配制了仅含有黄连、黄柏、赤芍、防风、白鲜皮作为活性成分的抗菌组合物。这种抗菌组合物配方简单，取材方便且生产成本低。黄连、黄柏、赤芍、白鲜皮可通过简单的乙醇渗漉浓缩取上清的方法进行纯化，防风则仅需水蒸馏提取挥发油。在纯化过程中并不采用除乙醇外的任何复杂昂贵的有机溶剂或复杂昂贵的实验室方法，从而使得生产成本大大节约。
发明人出乎意料地发现，在以下配比范围内抗菌组合物均有选择性抑菌和抗炎止痒效果，黄连：黄柏：赤芍：白鲜皮：防风以重量比为1：0.5～2：0.5～2：0.5～3：0.5～2，该洗剂最佳组方是最佳配比是黄连：黄柏：赤芍：白鲜皮：防风为1：1：1：1.3：1。
本发明的抗菌组合物的活性成分也可以与药物学上常用的载体一起制成抗菌制剂。药物学上常用的载体选自赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、渗透压调节剂、防腐剂、保湿剂、乳化剂、分散剂、稳定剂、助溶剂。视使用 的场合不同，该制剂可配制成多种剂型，例如洗剂，片剂、软膏剂、霜剂、栓剂、膜剂、搽剂、气雾剂、泡沫剂等。这些产品可用于各种不同的场合。例如，该制剂作为洗剂时，可以与湿润的擦拭物，例如抹布，百洁布，拭子，纸巾等混合，从而用于拭抹需要抑菌消毒的表面，或者直接用于皮肤；还可以加到各种个人护理产品中，例如擦面纸、浴室织物(例如毛巾、浴球等)，或制成女性用护理产品，或各种香波、浴液、肥皂、厨房用洗涤剂、衣物洗涤剂等各种家用清洁产品。该产品也可广泛的用于公共场所的抑菌消毒，例如用于餐厅、车站、公用电话等公众往来和接触频繁的区域。
配制洗剂中常规使用的添加剂是水；各种表面活性剂，如聚山梨酯20(如Tween 20 TM；ICI Americas)，聚山梨酯80(如Tween 80 TM；ICI Americas)和泊落沙姆等非离子表面活性剂；溴化四丁铵和氯化苯甲乙氧铵或其纯组分等阳离子表面活性剂；辛酸锡(锡(II)2-乙基己酸)和十四烷基磺酸钠等阴离子表面活性剂；和氢氧化十二烷基二甲基(3-磺丙基)铵，内盐等两性或两性离子表面活性剂(例如十二烷基磺酸钠、十二烷基硫酸钠等阴离子或阳离子表面活性剂；润湿剂(如甘油)、稳定剂、染料、渗透增强剂和抗氧化剂等。视用途不同，还可加入芳香剂等常规添加剂、这些添加剂都是本领域技术人员已知的。
本文所述的抗菌组合物优选含有水性组分。为了本发明的目的，术语“水性组分”指任何基本上由水、主要由水、水溶性醇(例如乙醇、丙醇或异丙醇)或其混合物组成或其占大部分的物质。
水性组分可任选含有一种或多种水溶性软化剂，包括但不限于低分子量脂族二醇，例如丙二醇和丁二醇；多醇，例如甘油和山梨醇；和聚氧乙烯聚合物，例如聚乙二醇200。使用的水溶性软化剂的具体类型和量将随所需的组合物美观特征而变化，且不难由本领域技术人员确定。
水性组分优选是去离子、蒸馏或纯化的水。优选的组合物含有约3％-98.899％，优选约5％-98％，更优选约10％-97.5％，最优选约38％-95.99％的水性组份。
为了实现本发明所需的温和度，可加入增强对皮肤温和度的任选成分。这些成分包括阳离子和非离子聚合物、助表面活性剂、湿润剂及其混合物。另一组温和度增强剂是脂类皮肤湿润剂，当亲脂性皮肤湿润剂被涂到使用者皮肤上时，它对抗菌组合物使用者提供了湿润的益处。当用于本文的抗菌组合物时，使用亲脂性皮肤湿润剂，它们以占约0.1％-30％，优选约0.2％-10％，最优选约0.5％-5％组合物重量的水平使用。
对于本发明的组合物还可包括有效量的脱脂和/或防粘剂，来减少与亲脂性皮 肤湿润剂有关的油腻感或粘性。本文所用的术语“脱脂剂”意味着一种防止、减少和/或消除通常与亲脂性物质有关的油腻或厚重的皮肤触感的制剂。本文所用的术语“防粘剂”意味着一种防止、减少和/或消除通常与湿润剂等成分有关的粘稠或发粘的皮肤触感的制剂。
当用亲脂性皮肤湿润剂作为本文组合物中的柔性增强剂时，还可含有约0.1％-10％，优选约0.1％-8％，更优选约0.1％-5％抗菌组合物重量水平的稳定剂。
本发明的组合物作为清洁组合物使用时，还可包含增稠剂、稳定剂等。
本发明的组合物还可含有各种各样的其他可任选成分。CTFA国际化妆品成分字典，第6版，1995，在此引入以供参考，描述了各种各样常用于皮肤护理工业的不受限制的化妆品和药物成分，它们适用于本发明的组合物。成分功能组的非限制性例子在该参考书的第537页有描述。这些功能组的例子包括：研磨剂、抗痤疮剂、抗结块剂、抗氧化剂、粘合剂、生物添加剂、膨胀剂、螯合剂、化学添加剂、着色剂、化妆品收敛剂、化妆品生物杀伤剂、变性剂、药物收敛剂、乳化剂、外用麻醉剂、膜形成剂、香料组分、湿润剂、乳浊剂、增塑剂、防腐剂、挥发剂、还原剂、皮肤漂白剂、皮肤调理剂(软化剂、湿润剂、溶剂油(miscellaneous)和闭塞剂)、皮肤保护剂，溶剂、发色剂，水溶助长剂，稳定剂，悬浮剂(非表面活性剂)，防晒剂、紫外光吸收剂和粘度增加剂(水相和非水相)、其它对于本领域技术人员已知的用于本文的功能组的例子包括增溶剂、多价螯合剂和角质层分解药等。
本发明的抗菌组合物可用于消毒和清洁皮肤。通常，皮肤消毒和清洁方法涉及对皮肤外用安全有效量的本发明的组合物。当不能实现需要肥皂和水的清洁方法，或不方便时，可使用本发明。涂用的组合物量、涂用频率和使用时间段可根据所需的消毒和清洁水平，例如，微生物污染和/或皮肤污染的程度而定。优选每天对皮肤涂用一次该组合物，更优选至少每天三次。所用的抗菌剂的典型量优选是约0.1mg/cm 2-20mg/cm 2，更优选约0.5mg/cm 2-10mg/cm 2，最优选约1-5mg/cm 2要清洁的皮肤。优选本发明的抗菌组合物用于清洁和消毒人和/或动物的皮肤。
本发明还包含在非皮肤表面，例如家用表面，如工作台面、炊具表面、食物制备表面(砧板、盘、罐和平底锅等)；主要家用设施，例如冰箱、冷柜、洗衣机、自动烘干机、炉、微波炉、洗碗碟机、橱柜、墙壁、地板、浴室表面、浴帘；垃圾筒和/或回收箱等涂用有效量的本发明的抗菌组合物的方法。
本发明还可包含涉及制品，它包括含有本抗菌组合物的给药容器。优选容器含有使用本发明的抗菌组合物的说明书。所述给药容器可用任何用于制造容器的常规 材料制造，这些材料包括但不限于：聚乙烯、聚丙烯、聚乙醛、聚碳酸酯；聚对苯二甲酸乙二醇酯、聚氯乙烯、聚苯乙烯、聚乙烯、乙酸乙烯酯和橡胶弹性体的混合物。其它材料可包括不锈钢和玻璃。优选的容器是用透明材料制成的，例如聚乙烯对苯二甲酸乙二醇酯。
还优选一种制品，其中给药容器是真空按压给药器。所述真空按压给药器是任何手工激活装置，用于按压产生定量的如已知的液滴。优选的真空按压容器是用半透明材料制成的，例如聚对苯二甲酸乙二醇酯。
本发明的制品还可优选制备成用于个人清洁，减少皮肤上的病菌的拭片，提供对细菌的残留作用。
本文所用的术语“安全和有效量”意味着一定量的化合物或组合物，其量足够显著引起积极作用，抗病毒/抗微生物益处，包括本文公开的独立益处，但足够低，以避免严重的副作用，即提供在技术人员合理判断范围内的合理的收益：风险比。
本文所用的所有百分数和比例，除非另外说明，是以重量计，所有测量是在25℃进行的，除非另外指定。本发明可包含本文描述的必需和可任选的成分和组分。由，或基本上由本文所描述的必需的和可任选的成份和组分组成。
本文所用的词语“抗菌组合物”一般指用于灭活、破坏或杀死细菌的组合物。该词语还指用于治疗由这些细菌导致或有关的疾病，例如轻微伤口感染和中度微生物皮肤感染(如头皮屑、阴部瘙痒(crotch itch)、脚癣等)的组合物。
发明人还提供了一种检测抗菌组合物的质量标准，采用小檗碱≥3.0mg/ml；黄连碱≥0.3mg/ml；芍药苷≥2.0mg/ml，挥发油≥0.0002ml/ml的标准，可良好的控制抗菌组合物的生产质量。该标准是目前洗剂中相对完善的标准，较现有国内外含中草药的洗剂质量标准均高且详细，且经过多次中试证实了该标准的实际可行性。
下面的实施例是为了说明本发明，不是为了限制。
实施例1植物抑菌组合物的制备：
材料来源：
黄连、黄柏、赤芍、白鲜皮、防风(亳州利健药业有限公司，符合药典标准)
乙醇(苏州利华酒业有限公司，食品级)
2.采用了以下配方：
配方1、黄连9kg、黄柏9kg、赤芍9kg、白鲜皮12kg，70％乙醇渗漉24小时提取，减压浓缩后0.6g生药/ml水沉，静置3-6天取上清备用。
防风9kg，水蒸馏10小时，得挥发油蒸馏液备用。
以上提取液按0.3g生药/ml重量比投料，混合，加入洗剂常规辅料，调pH5-6，过滤，灌装，即得。
配方2、黄连9kg、黄柏6kg、赤芍12kg、白鲜皮15kg，90％乙醇渗漉15小时提取，减压浓缩后0.8g生药/ml水沉，静置3-6天取上清备用。
防风12kg，水蒸馏12小时，得挥发油蒸馏液备用。
以上提取液按0.4g生药/ml重量比投料，混合，加入洗剂常规辅料，调pH5-6，过滤，灌装，即得。
配方3、黄连9kg、黄柏12kg、赤芍6kg、白鲜皮18kg，60％乙醇渗漉36小时提取，减压浓缩后0.4g生药/ml水沉，静置3-6天取上清备用。
防风6kg，水蒸馏8小时，得挥发油蒸馏液备用。
以上提取液按0.2g生药/ml重量比投料，混合，加入洗剂常规辅料，调pH5-6，过滤，灌装，即得。
3.配方提取物的中试结果：
按照上述配方投料50kg分别提取所获得的有效成分提取率可见下表：
Figure PCTCN2020094321-appb-000001
实施例2植物抑菌组合物的质量检测：
1.试验方法：
1.1 pH：将样品10％水溶液用酸度计测定。
1.2芍药苷含量测定：
用HPLC法进行测定，方法有多种文献报道，可任选。本文选择流动相为甲醇-水-磷酸(28:72:0.1)，流速为1.0ml/min，检测波长为230nm，柱温为25℃。
1.3黄连碱含量测定：
用HPLC法进行测定，方法有多种文献报道，可任选。本文选择流动相为乙腈-水-三乙胺-磷酸(25:75:0.5:0.33)，流速为1.0ml/min，检测波长为345nm，柱温为25℃。
1.4小檗碱含量测定：
用HPLC法进行测定，方法有多种文献报道，可任选。本文选择与黄连碱相同的方法。流动相为乙腈-水-三乙胺-磷酸(25:75:0.5:0.33)，流速为1.0ml/min，检测波长为345nm，柱温为25℃。
1.5挥发油
取本品500ml,置1000ml容量瓶中,按中国药典2005版一部附录ⅩD甲法测定，挥发油含量按100ml计应不得低于0.2ml。
1.6总固体
精密量取本品25ml，置105℃干燥至恒重并已称重的蒸发皿中,蒸干溶剂,在105℃干燥至恒重,总固体按100ml计应为3.0g-6.0g。
1.7总灰分
精密量取本品25ml，置105℃干燥至恒重并已称重的坩埚中,蒸干溶剂,或精密称取总固体检测项下残渣的50％，置于已恒重的坩埚中，先炭化(约300℃)2小时，再移入600±25℃马福炉中灼烧至恒重，总灰份按100ml计应不大于0.5g。
2.植物抑菌洗剂的产品标准如下表2所示：
表2植物抑菌洗剂的产品标准
Figure PCTCN2020094321-appb-000002
3.中试产品的检测结果：
试验中对于实施例1中制备的几批产品进行了检测，其检测结果如下表3所示。所有配方都是深黄色透明液体。
表3抑菌组合物的质量检测结果
Figure PCTCN2020094321-appb-000003
如上表所述，检测的所有批次的产品都符合质量标准。
实施例3植物抑菌洗剂的抑菌性能测定
1.1实验材料与仪器
1.1.1药品与试剂
(1)实施例1中配方1的抑菌组合物制剂，含量0.3g生药/ml，由苏州思源天然产物研发有限公司提供。
(2)制剂空白：含量0g生药/ml，由苏州思源天然产物研发有限公司提供。
(3)复方苦参洗剂：150ml/瓶，浙江中法制药有限公司。
(4)注射用青霉素钠：80万U/支，山东鲁抗医药股份有限公司。
(5)制霉素片：50万单位/片，浙江震元制药有限公司。
(6)氯化钠：上海久亿化学试剂有限公司。
(7)营养肉汤培养基：江苏省疾病预防控制中心微生物试剂厂。
(8)营养琼脂培养基：杭州天和微生物试剂有限公司。
(9)改良马丁培养基：北京三药科技开发公司。
(10)沙保罗氏琼脂培养基：杭州天和微生物试剂有限公司。
(11)小牛血清，杭州四季青生物工程材料有限公司。
(12)脱纤绵羊血：购自江宁县防疫站。
1.1.2仪器
(1)Sartorius电子天平：BS110S，北京赛多利斯天平有限公司生产。
(2)全自动高压灭菌锅：日本SANYO。
(3)超净工作台：苏州净化设备厂。
(4)生化培养箱：SHP-80型，上海森信实验仪器有限公司。
1.1.3菌株
(1)标准金黄色葡萄球菌(ATCC25923)、标准大肠杆菌(441490)、标准乙型化脓性链球菌(32210)、以上均由江苏省疾病控制预防中心微生物试剂厂提供。
(2)标准白色念珠菌(98100)，由江苏省药品检验所提供。
(3)表皮葡萄球菌、乳杆菌、丙酸杆菌，购自北纳生物技术有限公司。
1.2实验方法：
1.2.1细菌的增菌培养方法及过程
取金黄色葡萄球菌、大肠杆菌、表皮葡萄球菌、乳杆菌菌株、丙酸杆菌少许，分别接种于营养肉汤培养基中；取乙型化脓性链球菌少许，接种于含有20％小牛血清的肉汤培养基中，以上细菌均于37℃培养18h。取18h培养的各菌株营养肉汤培养物，用营养肉汤作10 3倍稀释后用于实验。取白色念珠菌菌株少许，接种于改良马丁培养基中，35℃培养24h。取24h培养的白色念珠菌培养物，用改良马丁培养基10 3倍稀释后用于实验。
1.2.2二倍稀释法(试管法)
取灭菌试管11支，第1管加入营养肉汤液体培养基1.6ml，其余每管1ml，分别取受试药稀释液0.4ml加入第一管中，混匀后取1ml至第2管，依次稀释，第10管吸出1ml弃去，第11管不加药液作为对照。每管加入稀释菌液0.1ml，37℃培养24h，取出后观察细菌生长情况。如药液管混浊，即表示细菌生长，供试药物无抑菌作用；如药液管清亮则表示细菌生长受到抑制，其能抑制细菌生长的最大稀释度的药液，即为该药物的最小抑菌浓度(MIC)。
取灭菌试管11支，第1管加入改良马丁液体培养基1.6ml，其余每管1ml，分别取受试药稀释液0.4ml加入第一管中，混匀后取1ml至第2管，依次稀释，第10管吸出1ml弃去，第11管不加药液作为对照。每管加入稀释菌液0.1ml，35℃培养24h，取出观察细菌生长情况。如药液管混浊，即表示细菌生长，供试药物无抑菌作用；如药液管清亮则表示细菌生长受到抑制，其能抑制细菌生长的最大稀释度的药液，即为该药物的最小抑菌浓度(MIC)。
1.3实验结果：
表1受试药体外抗菌活性(n＝2)
Figure PCTCN2020094321-appb-000004
Figure PCTCN2020094321-appb-000005
注：+无抑菌作用
综上所述，实验结果表明：配方1的喷雾洗剂、复方苦参洗剂对金黄色葡萄球菌、大肠杆菌、乙型化脓性链球菌、表皮葡萄球菌、乳杆菌、丙酸杆菌、白色念珠菌均具有较强的抑菌作用，MIC在0.00625～0.2ml/ml，即1.875～60mg生药/ml。
1.4.结论
本实验通过体外抗菌实验测定本发明的洗剂及阳性药物复方苦参洗剂、青霉素、制霉素片对金黄色葡萄球菌、乳杆菌、丙酸杆菌、大肠杆菌、乙型链球菌、表皮葡萄球菌及白色念珠菌等不同菌株的抑菌作用。研究结果表明本发明的洗剂、复方苦参洗剂对所检测的菌株都有不同的抑制作用，包括球菌、杆菌和真菌，均显示出广谱抑菌效果。但本发明的洗剂对致病菌金黄色葡萄球菌、大肠杆菌、乙型链球菌及白色念珠菌的MIC分别为0.00625、0.01、0.0025、0.01ml/ml，表皮葡萄球菌、乳杆菌、丙酸杆菌其MIC0.025、0.025、0.05ml/ml，部分还优于中药对照复方苦参洗剂。因此，本发明的洗剂体外具有选择抑菌作用，对致病菌抑制作用明显强于益生菌，抑制作用均优于中药对照复方苦参洗剂，具有抗菌谱广、选择抑菌作用强的明显优势，开发应用前景广泛。
实施例4植物抑菌洗剂的安全性测试
为了提供试验安全用药的剂量范围，对该抑菌洗剂进行了皮肤过敏实验。
1.1皮肤刺激试验
选用8只家兔，雌雄各半，试验前24h对给药区进行脱毛处理，左右各一块，去毛范围3cm×3cm。破损皮肤组在用药部位用无菌注射器针头划“井”字，以渗出血为度。左侧脱毛处涂药0.5ml，右侧涂等量辅料对照。皮肤涂抹面膜，每天 一次连续14d给药，给药体积均为0.5g/只，每次涂抹前及后1h仔细观察涂药处有无红斑、水肿，并对其评分，末次涂抹后连续观察3d。试验结果发现，3个实施例的洗剂均无刺激性。
受试物对家兔多次性刺激试验
Figure PCTCN2020094321-appb-000006
1.2、皮肤过敏试验
选用60只豚鼠，豚鼠随机分成5组，设辅料对照组给予制剂空白、供试品3组给予面膜、阳性对照组给予2-巯基苯并噻唑，每组10只动物，雌雄各半。给药前24h剃去豚鼠背部两侧皮肤毛发，去毛区范围约3cm×3cm，致敏期间给药时将供试品或对照品均匀涂抹于左侧去毛部位，适宜方法固定，涂抹6h后用水去除供试品；激发阶段给药时将供试品或对照品均匀涂抹于右侧剃毛部位，适宜方法固定，涂抹6h后用水去除供试品。各组动物均致敏给药3次，每隔7天左右给药一次。激发阶段给药1次。给药方式为皮肤涂抹给药，给药剂量为0.2g/只动物。一般在致敏后1h和24h及激发后24h、48h观察皮肤红斑、水肿和其他异常反应，按相应标准对红斑和水肿进行评分，根据评分标准判定受试物、制剂空白的致敏作用。试验结果表明，3个配方的洗剂均未见过敏现象。
豚鼠皮肤过敏试验红斑积分值及过敏反应发生率
Figure PCTCN2020094321-appb-000007
Figure PCTCN2020094321-appb-000008
最后，应该理解的是，虽然本说明书的各方面通过参照特定实施例突出显示，但是本领域技术人员将容易地理解，这些公开的实施例仅仅阐述说明这里公开的主题的原理。因此，应当理解，所公开的主题并不局限于特定的方法，协议和/或本文描述的试剂等。这样，所公开的主题的各种修改或改变或替代结构可根据本文中的教示而不脱离本说明书的精神。最后，在此使用的术语仅仅是为了描述具体实施例的目的，而不是用来限制本发明的范围，其仅由权利要求书限定。因此，本发明并不限于具体所示和所述的内容。
本文描述了本发明的某些实施方式，包括本发明人已知的实施本发明所需的最佳模式。当然，阅读以上说明书后，所述实施方式的变型将是本领域普通技术人员所明白的。本发明人预期，普通技术人员将适当地利用这些变型，本发明人旨在使本发明在本文具体描述之外以其他方式进行实施。因此，根据申请原则，本发明包括所附权利要求书所涉及主题的所有改进和等同形式。而且，所有可能的变型中上述要素的任意组合包括在本发明范围内，除非另有说明或者清楚指出相反。
本文所述本发明可选的实施方式、要素或步骤的分组不应解释为限制性的。每个组成员都可被单独提到或要求保护，或与本文公开的其他组成员的任何组合。预计出于便利和/或专利性的原因，组中可以包括或者删除一个或多个成员。在发生任何这种包括或者删除时，认为说明书包括经修饰的组，因而满足所附权利要求书中使用的所有马库什组(Markush group)的书写描述。
除非另有说明，本说明书和权利要求书所用的表示特征、项目、数量、参数、性质、属性术语等等的所有数值应理解为在所有情况下均被术语“约”修饰。如本文所用，术语“约”表示限定的特征、项目、数量、参数、属性涵盖了所述特征、项目、数量、参数、特性或属性的值在之上或之下加上或减去10％。因此，除非有相反说明，以下说明书和所附权利要求中所述的数值参数是近似值。例如，质谱分析仪可以在测定给定分析物的质量时轻微变化，术语离子质量或离子的质/荷比的“约”是指+/-0.50原子质量单位。
并非试图限制等同原则应用于权利要求的范围，最起码的，每个数值至少应根 据所记录的有效数字的位数并考虑到运用了常用的取整规则进行解释。
使用术语"可"或"可能"参考一个实施方式或实施方式的一方面还携带有“不”或“不能”的替代含义。这样，如果本说明书公开的实施方式或实施方式的一方面可以是或者可被包含作为本发明的主题的一部分，则负面限制或排除条件也被明确地表示，也就是说一个实施方式或者实施方式的一个方面可以不是或不能被包含作为本发明的主题。以类似的方式，使用术语"任选地"参考一个实施方式或实施方式的一方面意味着这样的实施方案或实施方式的方面可以被包括作为本发明主题的部分或可不被包括作为本发明的主题。无论这种负面限制或是禁入条件应用将基于负面限制或排除条件叙述在所要求保护的主题。
虽然限定本发明宽泛范围的数值范围是近似值，但是具体实施例中列出的数值范围和值是尽可能准确记录的。然而，任何数值范围或值不可避免地包含由其各自的测量过程中存在的标准偏差所必然造成的某些误差。本文中对数值范围的引用仅仅是一种速记方法，单独表示落在该范围内的各个独立的值。除非另有说明，否则，各个独立的数值范围包括在说明书范围内，如同它们被单独引用。
描述本发明的内容时使用的术语“一个”、“一种”、“该”等类似表达(尤其在权利要求书的内容中)应解释为涵盖单数和复数，除非另有说明或者清楚指出相反。所有本文所述的方法可以任何合适的顺序进行，除非另有说明或上下文明确另有所指。本文涉及的任何和所有实施例，或者示例性的语言(例如，“例如”)的使用仅仅是为了更好地阐述本发明，而不是对本发明范围的限制。说明书中的所有语言都不应解释为指示对本发明实践所必需的非要求的元素。
本文所揭示的具体实施方式可以进一步被限制在权利要求书中使用“由…组成”或“基本由…组成”的用语。当在权利要求中使用时，无论是提交时的或是在每次修改添加，所述的过渡术语“由…组成”不包括没有在该权利要求中指定的任何元件，步骤或成分。过渡术语“基本由…组成”将权利要求的范围限制到指定的物质或步骤以及本质上不影响基本和新特征的那些。所述的本发明的实施方式固有地或明确地描述并且能够在本文中实现。
所有的专利，专利出版物和其它出版物引用和标识在本说明书中被单独和明确地以引用方式全文并入本文，用于描述和公开的目的，例如，这些出版物中描述的组合物和方法可以与本发明结合使用。提供本文讨论的出版物仅针对其在本申请提交日之前的公开。在这方面，不应被解释为承认本发明人无权凭借先前发明或任何其它原因占先于这些公开。因此，所有关于日期或表示为这些文档的内容的声明是基于申请人可获得的信息，不构成对这些文献的日期或内容的正确性的任 何认可。

Claims (10)

  1. 一种植物选择性抑菌组合物，其特征在于，所述组合物含有活性成分，所述活性成分由按重量计1：0.5～2：0.5～2：0.5～3：0.5～2的黄连：黄柏：赤芍：白鲜皮：防风组成，以及药物学上可接受的载体。
  2. 如权利要求1所述的组合物，其特征在于，所述黄连：黄柏：赤芍：白鲜皮：防风按重量计为1：1：1：1.3：1。
  3. 如权利要求1所述的组合物，其特征在于，所述黄连、黄柏、赤芍、白鲜皮是通过以下步骤提取的提取液：
    a)乙醇提取；b)浓缩并沉淀去除杂质；和c)取上清液。
  4. 如权利要求1所述的组合物，其特征在于，所述防风是通过水蒸馏提取的提取液。
  5. 如权利要求1所述的组合物，其特征在于，所述药物学上可接受的载体选自赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、渗透压调节剂、防腐剂、保湿剂、乳化剂、分散剂、稳定剂、助溶剂。
  6. 如权利要求1所述的组合物，其特征在于，所述组合物选自洗剂，片剂、软膏剂、霜剂、栓剂、膜剂、搽剂、气雾剂、泡沫剂、滴眼剂、滴耳剂。
  7. 如权利要求1所述的组合物，其特征在于，所述组合物中活性成分的浓度为0.2-0.5g/ml，其中所述重量是黄连：黄柏：赤芍：白鲜皮：防风的总重量。
  8. 如权利要求7所述的组合物，其特征在于，所述组合物活性成分含量标准为：总黄酮大于等于250mg/100ml；绿原酸大于等于15mg/100ml；氧化苦参碱大于等于200mg/100ml；挥发油大于等于0.02ml/100ml。
  9. 如权利要求1所述的组合物在制备选择性抑菌剂中的用途。
  10. 如权利要求9所述的用途，其特征在于，所述细菌选自金黄色葡萄球菌、大肠杆菌、乙型化脓性链球菌、表皮葡萄球菌、乳杆菌、丙酸杆菌、白色念珠菌。
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