CN101970560A - Disinfectant alcohol-soluble quaternary ammonium polymers - Google Patents

Disinfectant alcohol-soluble quaternary ammonium polymers Download PDF

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Publication number
CN101970560A
CN101970560A CN2009801075002A CN200980107500A CN101970560A CN 101970560 A CN101970560 A CN 101970560A CN 2009801075002 A CN2009801075002 A CN 2009801075002A CN 200980107500 A CN200980107500 A CN 200980107500A CN 101970560 A CN101970560 A CN 101970560A
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composition
microbial polymer
antimicrobial
polymer
glycol
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威廉·托基
格拉尔德·奥尔德曼
拉斯托姆·S·康加
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Quick Med Technologies Inc
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Quick Med Technologies Inc
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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    • C08G18/0804—Manufacture of polymers containing ionic or ionogenic groups
    • C08G18/0809—Manufacture of polymers containing ionic or ionogenic groups containing cationic or cationogenic groups
    • C08G18/0814—Manufacture of polymers containing ionic or ionogenic groups containing cationic or cationogenic groups containing ammonium groups or groups forming them
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    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
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    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
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    • 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
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    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
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    • C08G18/30—Low-molecular-weight compounds
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Abstract

An alcohol- or glycol-soluble, water-insoluble, disinfectant composition and a method of using the same for disinfecting and for providing a prolonged antimicrobial property to a variety of surfaces, including skin. The composition comprises (1) at least one glycol or a mixture of at least one glycol and an alcohol and (2) an antimicrobial polymer that is capable of imparting an antimicrobial property to a surface without the use of a metal or a metal-containing compound. The composition is applied to a surface and allowed to evaporate leaving a coating of antimicrobial polymer on the substrate. Alternatively, the composition is incorporated into or within the substrate.

Description

The quaternary ammonium polymer sterilizing agent of alcohol solubility
Technical field
The present invention relates to be used to apply antiseptic composition with bonding application.Sterilizing agent provides lasting antimicrobial acivity to reach the time phase of prolongation after they are applied to the surface.
Background technology
The health of humans and animals can be comprised bacterium, yeast, virus, fungi, mould and protozoon adverse influence by many microorganisms.Known humans and animals produces multiple disease with contacting of microorganism, it is uncomfortable not accommodate.
As everyone knows, using soap and water to clean crust (surface and the Surgical Operating Room instrument that for example are used for food preparation), food (for example fruit and plant) and skin (for example hand) can be from the many microorganism of these surface removals.By using the clear hand of soap to be to the removal major part of microorganism because the combining of the mechanical effect of the surfactivity of soap and cleaning process.Because it is effective cleaning in the microorganism that has existed of removing quite big quantity with soap, but if the effective words of microorganism that contact with the hand that has cleaned are subsequently also only had slight continuing or persistent effect, therefore usually recommend people will often wash one's hands to reduce the propagation of virus, bacterium and other microorganisms.Is important to the compliance of this recommendation for the personal health and the health of individuality, but is particularly important for the individuality of working in healthy and foodstuffs industry.
Be used for from the surface, comprise that the antimicrobial cleansing product of skin removed microorganism has the numerous species type to use.Be used for Personal hygiene and the personnel's of healthy and foodstuffs industry work the most frequently used type comprise comprise soap those and comprise pure those.
Traditional rinsing disinfectant products, for example washing composition and soap are normally effective for reducing the microbial numbers that exists on the surface when proper operation.For example, wash one's hands as health care personnel that (HCPHWT) is measured in test, as the Dial that comprises trichlorophenol by standard
Figure BPA00001216315000011
When liquid soap is used to wash one's hands, prove to make after one time 30 seconds wash one's hands that existing bacterial number reduces about 2.0-2.5 order of magnitude (99.0-99.7%) on the skin.In other words, after cleaning, the skin that is cleaned only pollutes the 0.3%-1.0% that does not clean skin institute polluted bacteria number that had before 30 seconds wash one's hands.Though when correctly using soap, can remove existing most of bacterium, but the persistence that is retained in lip-deep any antimicrobial acivity is minimum, therefore can be immediately after washing one's hands by beginning to take place the pollution once more of hand with contacting of other contaminated surfaces.In addition, because the cleaning process of these traditional rinsing disinfectant products of exploitation is used quite a large amount of water, so their use is limited to the position that can obtain quite big water gaging.
Another normally used sterilizing agent type is those products that comprise relative high levels of alcohol.Causing being present in the lip-deep quite most microorganism of handling based on the sterilizing agent of alcohol removes or inactivation immediately.Since alcohol easily under body temperature from skin evaporation, so based on alcohol, be generally the alcoholic acid sterilizing agent and have additional advantage as sterilizing agent.Purell Be to use the example of alcohol as the skin antiseptic of activeconstituents.Though correct use that sterilizing agent based on alcohol is general to be removed effectively or destroy the bacterium that was present on the skin before using, meeting is at once by beginning to take place the recontaminate of the skin of handling with contacting of other contaminated surfaces after processing.
Nearest studies show that, have and to be not suitable for providing the antimicrobial acivity of expected degree based on the sanitizer of alcohol less than approximate 60% pure content, and the effect that is higher than 95% pure content is also poor, because protein is not easy sex change [" Hand Hygiene Revisited:Another Look at Hand Sanitizers and Antibacterial Soap " SAFEFOOD NEWS-Spring 2004-the 8th volume under olighydria, the 3rd phase, Colorado State University Cooperative Extension].
Other water dissolvable activeconstituents has replaced alcohol or has been used for skin antiseptic with the alcohol combination.Birnbaum etc. (United States Patent (USP) 6,441,045) disclose the water dissolvable quaternary compound as skin antiseptic.Beerse etc. (United States Patent (USP) 6,217,887) disclose the antimicrobial composition that is used for skin, this means to stay rather than wash off, and it comprises antimicrobial acivity, anion surfactant and proton supply agent in comprising the solution that can reach 98.85% water.Petersen etc. (United States Patent (USP) 6,627,207) disclose the fast xerogel type sanitizing composition based on water with low pure content (＜30%).Osborne etc. (United States Patent (USP) 5,776,430 and 5,906,808) have described the topical anti-microbial cleanser compositions, comprise the alcohol of 0.65-0.85% chlorhexidine gluconate or pharmacologically acceptable salt and 50-60% sex change.Kross (United States Patent (USP) 5,597,561) discloses and has related to the adhesion sanitizing composition based on water that prophylaxis of microbial infects, and comprises protonic acid, metal chlorite and gelifying agent.Smyth etc. (United States Patent (USP) 5,916,568) disclose the fast dried hand hygiene sterilizing agent of being made up of alcohol, hydrogen peroxide and tenderizer and have prevented skin irritation with help.(United States Patent (USP) 6 such as Sawan, 180,584) antiseptic composition of being made up of polymeric film forming material in the carrier and metal biocide is disclosed, when it is applied to the surface, form the water-insoluble polymer thin film from the teeth outwards, the then non-leachability of biocide be bonded to film, compound with film, combine with film or be scattered in film.
Causton etc. (United States Patent (USP) 5,869,600) disclose the water-insoluble that comprises the par quaternary ammonium group, the purposes of pure soluble copolymers, as the film-forming polymer that uses as antiperspirant.
Adopted additive method will be attached to particular substrate based on the quaternary ammonium compound of reactive silane by siloxane bond.For example, AEGIS environmental product line comprises the product that utilizes dimethyl stearyl [3-(trimethoxy is silica-based) propyl group] ammonium chloride polymkeric substance, and uses usually and use based on the solution of alcohol.According to product description, AEM 5700 is 43% dimethyl stearyl [3-(trimethoxy the is silica-based) propyl group] ammonium chloride (3-(trimethoxysilyl) propyldimethyloctadecyl ammonium chloride) in the methyl alcohol, and it can be used for coating fabrics and other object surfaces.This method causes forming permanent covalent linkage between quaternary ammonium Antimicrobe compound and pending surface.Therefore it almost is impossible removing applied biocide, or even uses that to remove based on the solvent of alcohol also be impossible.In addition, active Trimethoxy silane based compound is virose and is not suitable for using on skin.
Sawan (United States Patent (USP) 6264936) has described such antimicrobial material, and it can be used for the antimicrobial coatings or the layer of meeting kill microorganisms when forming when contact on the substrate surface.Be characterized by the antimicrobial coatings of " non-leaching (non-leaching) " or layer and be the organic substrate that is cured on the substrate surface and with the combination of matrix bonded desinsection metallics.When microorganism contact coating or layer, the desinsection metallics is transferred to microorganism with the amount that is enough to kill microorganisms.Particularly, employed metallic antimicrobials is a silver.Though coating that this method is claimed to be provided " the non-leaching " only is that the fact that metallic antimicrobials " is transferred to " microorganism contradicts with the non-General Definition that leaches.In addition, well-known, though silver and silver salt have low-down solubleness, the mechanism of antimicrobial acivity depends on the limited strength of solution of silver ions.Really, Sawan afterwards (the 3rd row, the 9th row) above statement be defined as pronounce " quite low leachability ".In the preferred embodiment of the patent of Sawan, organic substance comprises the poly hexamethylene biguanide polymkeric substance, poly hexamethylene biguanide polymkeric substance and epoxide, and N for example, N-dimethylene diglycidylaniline is crosslinked to form crosslinked network or matrix.This cross-linking step is essential for the dissolving that prevents matrix.The material that Sawan describes needs general curing schedule in 80 ℃ to 120 ℃ scopes usually, and this is unaccommodated for many substrates, particularly human skin.In addition, known preferred organic substrate polymkeric substance (poly hexamethylene biguanide) when high density to people's cell toxic (seeing United States Patent (USP) 6,369,289 B1).Silver also causes some bad effects as the use of biocide.A shortcoming of this method is that some bacterium can produce resistance (the Silver S. to silver, " Bacterial silver resistance:molecular biology and uses and misuses of silver compounds. " FEMS Microbiology Reviews, 2003; 27:341-353).Another shortcoming of this method is that silver-colored diffusion can enter wound and may make skin dyeing potentially.Another shortcoming of silver is raw-material cost height.Similar methods is described in United States Patent (USP) 6,180, in 584,6,126,931,6,030632,5,869,073,5,849,311 and 5,817,325.
Therefore the means and the method that need be used for the improvement of disinfecting surface, it not only is used to the Personal hygiene improved, but also is used for reducing the potential pollution source of healthy and foodstuffs industry.When using the perishability sterilizing agent of current use, personnel in personnel in health industries (for example doctor, nurse and patient) and the foodstuffs industry (for example food processor, food preparator, cook and steward) must every day for several times and sometimes 20 times or more times ground to their dermal application sterilizing agent, for example soap.Therefore, need such sterilizing agent for Personal hygiene in healthy and the foodstuffs industry and health, this sterilizing agent is disinfecting surface and continue to have active in to resist subsequently and the surperficial microorganism that contacts of handled on this surface effectively.
Aspect all of health industries, feel to needs effective, persistent surface disinfectant.One aspect of the present invention is, the present invention will be used to perform the operation, injection, venous cutdown and the conduit skin degerming before inserting.Whenever skin is penetrated, staves or breach occurs, then microorganism can constitute a threat to patient's health and safety.For example, this type of pathogenic agent can be a kind of danger in surgical procedure.If incision site is not sterilized fully before operation, the microorganism that then is present on the skin enters incision and causes infection in surgical procedure or after the operation.In order to prevent that this type of from infecting, crucial is with the sterilizing agent that has high antimicrobial acivity and wide action spectrum incision site to be sterilized before operation.Because sustainable many hours of surgical procedure also is important to the initial sterilization of incision site time phase lasting and that provide lasting antimicrobial acivity to reach prolongation.In the U.S., food and drug administration requires skin sterilizing agent before operation can reduce the dry skin zone, for example at least 2.5 magnitudes of flora quantity on the belly or reach for reliable quantitative low excessively level (less than about 25cfu/cm 2).On moist skin, inguinal region for example, sterilizing agent must reduce initial bacterial population and reach minimum 3.2log (1.5 * 10 3Cfu/mL) and can keep this level and reach at least 4 hours.
Aspect all of foodstuffs industry, comprise food collect (cow teat sterilization), food-processing (for example butchery site), food product pack (canned fish factory) and food distribute (for example restaurant and food supply retail shop) also feel needs effective, lasting with persistent surface disinfectant.One embodiment of the invention are, when the people have food when handling responsibility composition will be useful, and when because same individuality has that food is handled and money processing responsibility and when being difficult to keep suitable health compound will be useful especially (for example deli shop cashier and steward).
The ability that many organisms produce the Antimicrobe compound resistance is serious problems.Common from organism in news media, the report that infects of X-1497 resistance streptococcus aureus (Staph.aureus) wildness (MRSA) for example.Known for many microbiotic and based on the system of metal (for example silver) this type of resistance has taken place.On the other hand, quaternary ammonium compound does not promote the generation of resistance organism.
Summary of the invention
Industrial application
The invention provides antiseptic composition, comprise suitable sterilization and comprise that to kinds of surface skin provides glycol or pure solubility, the water-insoluble anti-microbial polymer of the antimicrobial property of prolongation.
The invention provides antiseptic composition, be included in basically in the solvent of forming by glycol or anti-microbial polymer in the solvent of forming by the mixture that comprises two pure and mild alcohol basically alternatively, wherein anti-microbial polymer easily is dissolved in alcohol, glycol or the mixture, but water fast, and wherein solvent serves as the carrier that is used for to the described anti-microbial polymer of surface applications, and described thus surface obtains one deck anti-microbial polymer.
Advantage of the present invention is that anti-microbial polymer is given described surface with durable antimicrobial activity.
One embodiment of the invention are, so select anti-microbial polymer so that its antimicrobial acivity takes place because tagging mechanism, and this need or not discharge in the contacting with fluid with level leaching, the wash-out that will cause fluid disinfection.In addition, preferably, anti-microbial polymer can be obviously from the applied surperficial leaching of antimicrobial composition, wash-out or release.
In special embodiment of the present invention, the solvent that comprises alcohol is formed by being selected from following at least a glycol basically: the mixture of glycerine, ethylene glycol, propylene glycol, butyleneglycol, pentanediol, their isomers and derivative and above-mentioned any glycol.Preferably, the glycol content of disinfectant solution is between 60 weight % and 95 weight %.
In special embodiment of the present invention, the solvent that comprises alcohol is made up of the mixture of at least a pure and mild a kind of glycol basically, wherein alcohol is selected from ethanol, methyl alcohol and Virahol, and wherein glycol is selected from the mixture of glycerine, ethylene glycol, propylene glycol, butyleneglycol, pentanediol, their isomers and derivative and above-mentioned any glycol.Preferably, the alcohol of disinfectant solution-diol mixture content is between 60 weight % and 95 weight %.
In special embodiment of the present invention, anti-microbial polymer can be basically by containing the molecular composition that allyl group or vinyl monomer are partly derived or produced from least a.In some embodiments of the present invention, anti-microbial polymer is basically by comprising at least a molecular composition that contains the monomer segment of quaternary ammonium.
Embodiment of the present invention are, quaternary ammonium partly is covalently bond to anti-microbial polymer, perhaps be attached to the molecular structure of anti-microbial polymer by covalent chemical bond, and be the part of polymer molecular structure, and described quaternary ammonium part or be arranged in main polymer chain perhaps is arranged in polymer pendant groups.Therefore, quaternary ammonium part alternatively can be polymer architecture unitary part, can be incorporated in the polymer architecture or can be attached to polymer architecture." main chain " and " side group " is to be generally used for describing the term of polymer molecular structure and is that those skilled in the art are familiar with.
The antimicrobial polymerizable molecular of some of Shi Yonging is by progressively polymerization is synthetic in the present invention, for example be formed on the polyether polyols with reduced unsaturation that comprises at least one quaternary ammonium group in the monomer segment by difunctional alcohol and di-isocyanate reaction, described monomer segment is attached to the molecular structure of polymkeric substance by the covalent chemical bonding.Preferably, quaternary ammonium group quantity can be at least one mole (6.02x10 in the polyether polyols with reduced unsaturation 23) every 650g polyether polyols with reduced unsaturation.More preferably, quaternary ammonium group quantity will be at least one mole (6.02x10 in the polyether polyols with reduced unsaturation 23) every 350g polyether polyols with reduced unsaturation.
Antimicrobial polymerizable molecular can have 5 to 25,000, preferred 50 to 10,000 and more preferably 100 to 5,000 average degree of polymerization.
In one embodiment of the invention, antiseptic composition is applied to the surface, and this surface can be animal skin, human skin, no life porous surface or not have the non-porous surface of life.
For example, antiseptic composition can be applied to skin before medical procedures.Term " medical procedures " includes but not limited to that operation, injection, venous cutdown and conduit insert, and comprises other processes that break skin.And antiseptic composition can be applied to animal skin before animal doctor's process.Other processes that term " animal doctor's process " includes but not limited to perform the operation, animal skin or animal skin are inserted and break in injection, conduit.
In another embodiment of the present invention, antiseptic composition can be applied to the health care worker hand so that microorganism between the infected patient or the propagation between the infection site the patient drop to minimum.
In another embodiment of the present invention, antiseptic composition can be incorporated in the cosmetic formulations, to reduce or to prevent microorganism growth in the makeup.
Advantage of the present invention is that many anti-microbial polymer coating embodiments do not make skin dyeing significantly, and is colourless.
Another embodiment of the present invention provides antiseptic composition, and it comprises makes overlay visible dyestuff.In some embodiments, dyestuff is bonded to anti-microbial polymer, prevents that thus dye migration from going out overlay.
The advantage of the many embodiments of the present invention is that after solvent dissipation, overlay is normally tasteless.
Many embodiments of antiseptic composition have between approximate 5 and approximate 9, the pH between preferred 6.5 and 8.0.
A plurality of embodiments of antiseptic composition can be applied to skin to be selected from liquid, gel, foam and aerocolloidal form.
Randomly, antiseptic composition additionally comprises at least a additive that is selected from medicine, biocide, sanitas, thickening material, moistening agent, tenderizer, VITAMIN, interim dyestuff, permanent dyestuff and UV absorption agent.When examples of such additives was biocide, it can be the alcohol that also serves as the solvent with lasting active anti-microbial polymer.Biocide or sanitas additive can also be quaternary ammonium salt, biguanides or phenolic compound.In special embodiment, biocide that is added or sanitas are quaternary ammonium salts, for example benzalkonium chloride, benzethonium chloride, didecyldimethylammonchloride chloride or its mixture.In another embodiment, biocide that is added or sanitas are biguanides, for example chlorhexidine or poly hexamethylene biguanide.In another embodiment, biocide that is added or sanitas are phenolic compound, for example phenol or trichlorophenol.In some embodiments, tenderizer is the pure and mild surfactivity alcohol derivate of ethoxylation ethanoyl, squalane, Fatty Alcohol(C12-C14 and C12-C18), glycerine and siloxanes such as Simethicone, cyclomethicone or Simethicone or its mixture of glycerine, ethylene glycol, propylene glycol, butyleneglycol, pentanediol, dipropylene glycol, polypropylene glycol, polyoxyethylene glycol, mineral oil, Fatty Alcohol(C12-C14 and C12-C18), Wickenol 111, lanolin, lanolin derivative such as lanolin.In another embodiment, medicine is microbiotic, antiphlogiston, anodyne or narcotic.
In some embodiments, anti-microbial polymer can mix by other the different types of monomer of monomer and at least one with a kind and monomer copolymerizable be made, wherein at least a monomer has at least one quaternary ammonium part, has produced to be dissolved in the alcohol easily and the multipolymer of water fast.
In some embodiments, anti-microbial polymer can be made by polymerization single polymerization monomer, and wherein monomer has at least one quaternary ammonium part, has produced to be dissolved in the alcohol easily and the polymkeric substance of water fast.
In another optional embodiment of the present invention, such polymkeric substance is provided, it comprises dyestuff (for example fluorescein) and antimicrobial (for example quaternary ammonium) unit, these two kinds of unit all are covalently bond to polymer molecular structure, perhaps be attached to polymer molecular structure by covalent chemical bond, and be the part of polymer molecular structure therefore, and be arranged in or main polymer chain, perhaps in the polymer pendant groups.
Embodiment of the present invention provide polyether polyols with reduced unsaturation, this polyether polyols with reduced unsaturation easily is dissolved in substantially in the solvent of being made up of alcohol and/or glycol, but water fast, and this polyether polyols with reduced unsaturation comprises at least a quaternary ammonium part that is attached to polymer molecular structure by covalent chemical bond, and this polyether polyols with reduced unsaturation can provide durable antimicrobial activity when being applied to the surface.
Embodiment of the present invention are not have covalent chemical bond to form at anti-microbial polymer with between the substrate of its application anti-microbial polymer.In addition, anti-microbial polymer can be removed from the substrate of using anti-microbial polymer by the solvent that uses alcohol, glycol or have remarkable pure content.
One embodiment of the invention are metal or the metal-salts that are not used as biocide.
One embodiment of the invention are after anti-microbial polymer is applied to the surface, not need curing schedule to give anti-microbial polymer with insoluble.
Embodiment of the present invention are that the part less than approximate 50% total polymer weight of anti-microbial polymer is soluble in water or aqueous fluids.This embodiment has strengthened the lasting and rapid action characteristic of anti-microbial polymer.This active enhancing can use the lower molecular weight polymkeric substance to reach.
Embodiment of the present invention are that water-insoluble of the present invention and pure solubility or glycol solubility anti-microbial polymer can be used as polymeric device, comprise the parts of medical apparatus and household supplies.Anti-microbial polymer of the present invention can be used for producing film, fiber, gel, foam, tackiness agent, sealing agent or spackling, they can be incorporated in other article or be used to form other article, for example cosmetic formulations, suture line or wound dressing.
Another embodiment of the present invention is to artificial suture line, and for example medical suture line or multifilament polyester suture line provide permanent bioguard treatment.
Another embodiment of the present invention provides anti-microbial polymer, its be water-insoluble and or alcohol deliquescent or glycol is deliquescent, it can be incorporated into treats in antimicrobial wound dressing uses as non-leachability the Hdyrophilic polyurethane foam.
Embodiment of the present invention provide anti-microbial polymer, its be water-insoluble and or alcohol deliquescent or glycol is deliquescent, it can be incorporated in the curable overlay of the UV that can be applied to plastics film or plate.Coated film and plate further thermoforming or vacuum forming are the antimicrobial products with anticipated shape.
Embodiment of the present invention provide the method for sterilization substrate, comprise step: to comprise the water-insoluble anti-microbial polymer solution-treated substrate of quaternary ammonium part, wherein solvent and/or polymers soln can dissolve in whole or in part, absorb and enter or permeate substrate surface in other mode; Flood, inject, apply, adhere to, adhere to or infiltrate into substrate with dry substrate with the removal solvent and with anti-microbial polymer, wherein antimicrobial property is endowed substrate and is exposed to aqueous fluids and can not be removed.
Wherein the substrate of impregnated polymer can comprise and interpenetrates network (IPN).Substrate can be the polymkeric substance with final type of service such as film or fiber, and the polymkeric substance that uses in molding or forming operation after perhaps can being intended to for example is used to make the polymkeric substance of resin, ball, extrudate or powder.
Substrate can also be fabric, timber or paper.Substrate can partly be injected with polymers soln fully or only.Under the situation that part is injected, anti-microbial polymer will be deposited on substrate surface to a great extent or just be deposited under the substrate surface, and whole substrate inside is opposite with being deposited on.Substrate can be insoluble at the solvent that is used for preparing anti-microbial polymer solution; It is essential that yet solvent can penetrate into base material.For example, the special combination of some of polymkeric substance and solvent can cause solvent and polymers soln absorption to enter substrate, and does not cause the substrate dissolving.
Solvent can also all or part of dissolving substrate.For example, the polymers soln that can dissolve substrate fully can be applied to substrate reach be enough to allow substrate surface be aggregated thing solution influenced, but no longer than being enough to make substrate dissolved time phase.In this mode, the surface of substrate has become to be modified with anti-microbial polymer.
Embodiment of the present invention provide solution, and this solution comprises the water-insoluble anti-microbial polymer and at least a other polymkeric substance that contain the quaternary ammonium part that all is dissolved in the solvent.Anti-microbial polymer solution (in alcohol or in other solvent) can make up with the solution of different polymkeric substance, perhaps different polymkeric substance can be added to or be dissolved in the anti-microbial polymer solution to form compatible solution or mixture, and they can be further processed with preparation article or object; Typing or be shaped to film, pipe, plate, rod, fiber, overlay or powder; Perhaps be used to handle substrate.
Definition
As used herein, following term has following meanings:
" microorganism " or " microbe " refers to such as bacterium, virus, protozoon, yeast, fungi, mould or any organism of the spore that forms of these organisms or the combination of organism arbitrarily.
" antimicrobial " refers to the microbicidel of compound, composition, article or material or presses down microbiological property, this makes, and it can kill, destruction, deactivation or in and microorganism; Perhaps stop or reduction microbial growth, survival ability or breeding.
" sterilizing agent " is destruction, neutralization or the reagent that disturbs microorganism growth or survival in other mode.
" alcohol " meaning is meant to have molecular formula C nH 2n+2-x(OH) xVolatile liquid, wherein n is from 1 to 10 integer, and x is from 1 to 3 integer; And preferably wherein n is from 1 to 5, and x is 1 or 2; And more preferably wherein n is 2 or 3, and x is 1.Term " alcohol ", as used herein, the glycol (x=2,3) that comprises MHA (x=1) and have two or more hydroxyls.Preferred diol is avirulent.
" soluble " meaning is meant that material can be dissolved in a certain amount of particular fluid, for example glycol, alcohol or water.Soluble many polymkeric substance also are soluble in diol solvent in alcoholic solvent.
" easily dissolved " meaning is meant that the solute discussed is in fact 100% solvable, can be at specific solvent, for example particularly in the combination of glycol, alcohol or alcohol and glycol under room temperature formation comprise the solution of the solute that can reach 20wt%.
" undissolved " meaning is meant that material can significantly not be dissolved in excessive greatly (for example＞100 times) specific solvent such as the water.
" volatile " meaning is meant that solvent or liquid evaporate fully when room temperature.
" persistent " meaning is meant in water undissolved, can be by for example perspire, contacting or washing gently and removal easily with aqueous fluids with the accidental of aqueous fluids.
" giving " meaning is meant and basadly inculcates, authorizes, transmits, transmits or mix functional performance or character in other mode.For example, quaternary ammonium group can be given antimicrobial acivity with something.
" combination " meaning be meant basad in or substrate on inject, apply, adhere to, adhere to, flood, permeate, absorb, mix or otherwise physics mix some materials.
" non-hydrolyzable " key be can hydrolysis under the material that comprises this key is expected the standard conditions that this key exposed during normal the use chemical bond.For example, wound dressing of the present invention or sutural non-hydrolyzable key will not experience under the normal storage condition, can cause the hydrolysis type reaction of this type of bond rupture when for example being exposed to other aqueous mediums in Wound exudate, body fluid, microorganism, enzyme, sanitas, finish, ointment, ointment and the normal physiological pH scope.
" tagging " meaning is meant not and need or be released into the characteristic that contacting with fluid comes kill microorganisms with the level leaching, the wash-out that cause fluid disinfection.
" antimicrobial metal material " meaning is meant can give the metal of composition with the form of antimicrobial acivity, for example colloidal silver or metal-salt.The invention provides at the antimicrobial acivity that lacks in the presence of the antimicrobial metal material.
" substrate " sometimes with " surface " synonym, and the meaning be meant and need obtain any material of antimicrobial protection by using composition described herein.Substrate can be used as the stand-alone item of separating with composition and exists, and can comprise animal skin, human skin, no life porous surface or not have the non-porous surface of life.The surface can comprise polymkeric substance, resin, powder, fabric, timber, paper, skin, and can be the composition of ball, clothes, suture line, wound dressing and multiple other article.Alternatively, composition can form polymeric device or object with the substrate fusion, comprises for example film, fiber, plate, gel, foam, tackiness agent, sealing agent, spackling, plastotype, rod, pipe, medical apparatus, cosmetic formulations and household supplies.
Embodiment
An exemplary of the present invention is utilized anti-microbial polymer, and it has the polymerizable molecular of partly being made up of a kind of type monomers; Alternatively, polymerizable molecular can partly be made up of more than one type monomers.In exemplary of the present invention, the quaternary ammonium group of monomer segment is given polymerizable molecular with antimicrobial acivity.Desirably, this kind monomer segment that comprises quaternary ammonium group constitutes at least 2 weight % of polymerizable molecular, more preferably at least 10% of polymerizable molecular, and most preferably polymerizable molecular at least 25%.Preferably, the quaternary ammonium partial amt will be at least one mole (6.02 * 10 in the anti-microbial polymer 23) every 650g polymkeric substance.More preferably, the quaternary ammonium partial amt will be at least one mole (6.02 * 10 in the anti-microbial polymer 23) every 350g polymkeric substance.
Embodiment of the present invention are, quaternary ammonium partly is covalently bond to anti-microbial polymer, perhaps be attached to the molecular structure of anti-microbial polymer by covalent chemical bond, and be the part of polymer molecular structure, and described quaternary ammonium part or be arranged in main polymer chain, also be described as perhaps being arranged in the side group of polymkeric substance in the skeleton.Therefore, the quaternary ammonium part alternatively can be the unitary part of polymer architecture, can be incorporated in the polymer architecture, perhaps can be attached to polymer architecture." main chain " and " side group " is the term that is generally used for describing polymer molecular structure, and is that those skilled in the art are familiar with.Group in the main polymer chain also can be described as the group in the polymkeric substance " skeleton ".For the group of side group also can be described as " dangling " skeleton in polymer chain.
In a preferred embodiment of the invention, the quaternary ammonium of anti-microbial polymer partly is contained in main polymer chain or the skeleton, rather than overhangs polymer backbone.
In a preferred embodiment of the invention, the quaternary ammonium of anti-microbial polymer part is by non-hydrolyzable stable chemical structure be covalently linked to polymer molecular structure.The example of hydrolyzable key or structure comprises ester, acid amides and acid anhydride.The example of non-hydrolyzable key and structure comprises urethane, urea, ether (C-O-C), carbon-to-carbon (C-C) and carbon-nitrogen (C-N) key.
Anti-microbial polymer be formulated in water insoluble and in the aqueous solution of alcohol, glycol or its mixture of 75wt% at least dissolved easily.More preferably, with its be mixed with in water insoluble and in the solution of alcohol, glycol or its mixture of 50wt% at least dissolved easily, and most preferably it is mixed with in water insoluble and in the solution of alcohol, glycol or its mixture of 25wt% at least dissolved easily.Embodiment of the present invention are that the anti-microbial polymer that is dissolved in the solvent that comprises alcohol can be applied to the surface, comprises skin.
Polymkeric substance relative solubility in different solvents is important.The present invention relates in pure and mild glycol soluble but in water undissolved polymkeric substance.In the relative in a small amount known natural and synthetic polymer of number of different types only, proved this concrete combination of characteristic.Polymkeric substance can be divided into two groups usually: water-soluble with water-insoluble.Some insoluble polymers can be dissolved in the multiple organic solvent.Solubleness depends on the characteristic of particular polymers-solvent combination usually, produces the resolvability combination when the chemical structure of polymkeric substance and solvent is similar.Polarity of solvent may be most important Consideration.The polarity of some common solvent is up to the minimum order of polarity from polarity: water, ethanol, ether, toluene and hexane.Many water dissolvable polymkeric substance also are soluble in alcohol.In the middle of alcohol, the order that polarity reduces is methyl alcohol, ethanol and Virahol, and the polarity of methyl alcohol is near water.Therefore, the polymkeric substance of many water dissolvables solubilized more in methyl alcohol than in ethanol or Virahol.Ethanol, Virahol and non-toxicity glycol are to implement preferred solvent of the present invention.Virahol is not splendid solvent usually for most polymers.Very the person is undissolved in Virahol at the soluble polyethylene oxide of water camber, many other water dissolvable polymkeric substance, as poly-DADMAC, alginic acid ester, polyacrylic ester and even polyvinyl alcohol also be like this.Most natural and man-made polymers are undissolved in Virahol.Further need polymkeric substance water insoluble, this makes selects useful polymkeric substance to be used to implement the present invention even more crucial.
The solvent that comprises alcohol or comprise glycol can be used as dual purpose, and it is not only as carrier, but also as sterilizing agent at once.After comprising alcohol or comprising solvent evaporation, absorption or the dissipation of glycol, in skin or other substrates, stay the overlay of anti-microbial polymer.This overlay is persistent, and because it is not dissolved in water, so can be by for example perspire, contact or clean gently and removal easily with aqueous fluids with the accidental of aqueous fluids.
Embodiment of the present invention are that glycol includes but not limited to glycerine, ethylene glycol, propylene glycol, butyleneglycol or pentanediol as solvent and carrier.The various isomerss of glycerine, ethylene glycol, propylene glycol, butyleneglycol and pentanediol and derivative also are suitable solvent of the present invention.For example, pentanediol family comprises 1,4-pentanediol, 1,5-pentanediol, 2,4-pentanediol and other isomers.Other derivatives of glycol can be suitable solvent of the present invention.For example, the halo glycol can adopt in suitable embodiments of the present invention.
The volatility of glycol is usually unlike lower alcohol (for example ethanol); Yet glycol still can be as the solvents/carriers of anti-microbial polymer of the present invention.For example, when anti-microbial polymer was incorporated into the cosmetic formulations that is used for dermal application, propylene glycol can be used as solvents/carriers.Propylene glycol can absorb and enter skin, rather than evaporates, and has therefore stayed persistent anti-microbial polymer overlay.This method has been avoided the issuable undesirable action of use lower alcohol (for example skin irritation, xerosis cutis or combustibility).
Embodiment of the present invention are that the mixture that comprises pure and mild glycol is as solvent and carrier.Pure composition in the mixture can include, but are not limited to ethanol, methyl alcohol, Virahol and composition thereof.An exemplary of the present invention is, the pure composition of solvent mixture is a denatured alcohol, denatured alcohol SDA 3-C particularly, it is the commercial on-beverage level denatured alcohol that is defined as the ethanol (i.e. 95% ethanol/5% Virahol) with 5% Virahol denaturing agent by Alcohol and Tobacco Tax Devision of the Internal Revenue Service (IRS's wine and tobacco revenue department).The diol component of mixture can be the mixture of glycerine, ethylene glycol, propylene glycol, butyleneglycol, pentanediol or its isomers or derivative or above-mentioned any diol component for example.Preferably, the alcohol-glycol content of the combination of disinfectant solution mixture is between 60 weight % and 95 weight %.
Anti-microbial polymer can also be to be soluble in other organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran (THF), ethyl acetate, ethers, ester class, benzene, toluene, carbonates, hydro carbons or chlorinated hydrocarbons, and the anti-microbial polymer solution in any of these solvent can be used for preparing antimicrobial composition; Yet these solvents there is no need to provide sterilization at once as alcohol or glycol.
A feature of the present invention is that antimicrobial property for good and all locks in the polymer architecture.This can directly be incorporated into by the chemical functionality that will have antimicrobial property in the molecular structure of polymkeric substance and realize.This not only provides the weather resistance and the persistence of anti-microbial effect, but also prevent the antimicrobial composition of solubility, for example low-molecular-weight those antimicrobial compositions leach and enter substrate from antimicrobial overlay, and perhaps migration enters the zone of not wishing to have antimicrobial acivity.For example, when being applied to skin, composition will provide durable antimicrobial activity; Yet after based on the evaporation of the carrier solvent of alcohol, antimicrobial acivity will be not can not move out and infiltrates skin surface or enter in the cell from polymkeric substance, and it may have bad effect there.
The application's a advantage is; composition will be used for protection and (for example be in the contact biological warfare agent; military personnel and Postal Clerk) individuality, this or realize that by the skin of handling them perhaps realize on the devices by handling these individual contacts and the surface of material.
Embodiment of the present invention are that composition of the present invention can be used in (for example sterilization of cow teat, surgical procedure sterilization and the sterilization of animal doctor's process) on the animal skin.
Advantage of the present invention is that it utilizes quaternary ammonium compound as active antimicrobial agent, and quaternary ammonium compound does not promote to produce resistance organism, for example MRSA or VRE.The validity of example proof material of the present invention to this type of organism is provided below.
Antiseptic composition of the present invention can additionally comprise other inertia or activeconstituents.For example, can comprise that thickening material is to increase viscosity or the product of gel form is provided.Also can add additive, for example moistening agent, tenderizer, VITAMIN, UV absorption agent, medicine, biocide or other inertia and active agent.It is water-insoluble that examples of such additives needs not be, because they can play their purpose by temporary transient effect, perhaps additionally can be absorbed in the polymerization overlay and therefore stabilized and can easily not remove by aqueous fluids.In addition, permanent or interim dyestuff can be added in the composition, perhaps alternatively is applied to the polymerization overlay after polymkeric substance has been applied to the surface, so that serve as the visual indicator that the polymerization overlay exists.
Though composition of the present invention provides polymeric film or the overlay with non-leachability antimicrobial property, wish in composition, to mix extra biocide or sanitas in some cases so that extra effect to be provided.This extra reagent is not covalently bond to polymkeric substance, and is leachability therefore.This does not change the non-leachability of previously described anti-microbial polymer.When extra biocide is leached from composition fully, anti-microbial polymer will still provide the antimicrobial acivity of non-leachability.In addition, anti-microbial polymer matrix can be used for the slowing down leaching rate of additional agents, therefore prolong add the validity of reagent.The useful microbicidal additives or the example of anticorrosive additive comprise quaternary ammonium salt, biguanides and phenolic compound.In certain embodiments, biocide that is added or sanitas are quaternary ammonium salts, for example benzalkonium chloride, benzethonium chloride, didecyldimethylammonchloride chloride or its mixture.
In another embodiment, biocide that is added or sanitas are biguanides, for example chlorhexidine or poly hexamethylene biguanide.In another embodiment, biocide that is added or sanitas are phenolic compound, for example phenol or trichlorophenol.
Embodiment of the present invention are that composition can be mixed with liquid, gel, foam or aerosol spray, and can be applied to the surface, comprises people or other animal skins, to reach the anti-microbial effect of prolongation.
Synthetic and the application of following example proof glycol solubility, pure solubility, water-insoluble antimicrobial polymerizable molecular.Embodiment of the present invention are, these polymerizable moleculars can be by common two kinds of different monomers the free radical vinyl polymerization of mixture synthesize, be first monomer (A) and second monomer (B) in the middle of the mixture of described two kinds of different monomers, at least a monomer comprises quaternary ammonium group.The homopolymer of first monomer (A) and monomer A is water dissolvable normally, and second monomer (B) is normally water-insoluble.The common effectively solvent (for example alcohol or glycol) of monomer A and B can be used to prepare the homogeneous solution of suitable two kinds of monomer copolymerizables.The multipolymer of A+B is soluble in alcohol or glycol.Should be appreciated that this only is a possible exemplary process of compositions formulated, and those of skill in the art will recognize that existence can be used to prepare the multiple additive method of pure solubility, the antimicrobial polymerizable molecular of water-insoluble.Monomeric mixture also can be used to prepare suitable antimicrobial multipolymer more than three kinds or three kinds.
Embodiment of the present invention are that polymerizable molecular can for example form polyether polyols with reduced unsaturation by difunctional alcohol and di-isocyanate reaction by progressively polymerization is synthetic.Embodiment of the present invention are that the progressively polymkeric substance of other types also can use, and includes but not limited to polymeric amide (nylon), polyester and polyureas.Antimicrobial part is incorporated into the Antimicrobe compound realization that can have active functionality in the polymkeric substance by utilization.For example, Akzo Nobel provides a series of compounds of selling with trade(brand)name Ethoquad.An example is Ethoquad C/12-75DK, it is to have two the substituent methyl of active hydroxyethyl/C12 quaternary ammonium compounds, its can with vulcabond, Toluene-2,4-diisocyanate for example, 4-vulcabond (TDI) reaction is formed on the anti-microbial polyurethaneurea polymkeric substance that comprises the quaternary ammonium part in the main polymer chain structure.
In one embodiment of the invention, dye molecule can be incorporated into or be covalently bond to the anti-microbial polymer structure, thinks that composition provides the visual sign thing of non-leaching.For example, the fluorescein(e) dye molecule comprises two hydroxyls, and it can form the part of polyurethane structural with di-isocyanate reaction.When the mixture of fluorescein and Ethoquad C/12-75DK and TDI reaction, resulting polymkeric substance comprises dyestuff (fluorescein) and antimicrobial (quaternary ammonium) unit in the main polymer chain structure.
Antimicrobial part can also be incorporated in the polymkeric substance after forming polymkeric substance.This can pass through for example transesterify or other substitution reaction, as the reaction realization of Ethoquad and polyacrylic ester.
Institute's synthetic polymer molecule can have 5 to 25,000 (monomer segment/molecule), but more preferably 50 to 10,000 and 100 to 5000 mean polymerisation degree most preferably.The suitable vinyl monomer that is used to produce polymkeric substance includes but not limited to comprise allylic monomer, the monomer that comprises vinyl, styrene derivatives, allyl amine, ammonium salt, acrylate, methacrylic ester, acrylamide, Methacrylamide, dimethylaminoethyl methacrylate (tetravalence methyl chloride), dimethylaminoethyl methacrylate (tetravalence benzyl chloride), dimethylaminoethyl acrylate (tetravalence methyl chloride), dimethylaminoethyl acrylate (tetravalence benzyl chloride) and have structure C H 2=CR-(C=O)-X-(CH 2) n-N +R ' R " R " //Y -(wherein R is hydrogen or methyl, and n equals 2 or 3, and X is O, S or NH, R ', R " and R " ' be independently selected from H, C1 to C16 alkyl, aryl, arylamine, alkaryl and aralkyl, and Y -Be the negatively charged ion of quaternary nitrogen, diallyl dimethyl ammonium salt, vinyl pyridine and salt thereof and vinyl benzyl leptodactyline positive charge of contending with) other compounds.
The suitable radical initiator that is used to produce polymkeric substance includes but not limited to azo-compound such as AIBN and related compound and superoxide such as Benzoyl Peroxide, dicumyl peroxide, tert-butyl peroxide, Sodium Persulfate, hydrogen peroxide, sodium peroxide and usually as other superoxide and the hydroperoxide of radical polymerization initiator.Can also use light initiation polymerization, wherein use the suitable light trigger (for example benzophenone derivates) of initiated polymerization when being exposed to light.Can also use radio polymerization, wherein by being exposed to ionizing rays (for example gamma-rays) initiated polymerization.
Can adopt various test to measure the antimicrobial efficacy of anti-microbial polymer as herein described and composition." test of carrier persistence " or CPT are described in down.Have been found that composition of the present invention and material provide fabulous result when testing by CPT.The minimizing of bacterial population surpasses 6log (live organism reduces 99.9999%) usually.When using the test of CPT method, the material that the present invention describes can cause the bacterium of 3-log to reduce.Preferably, when using the test of CPT method, the material that the present invention describes can cause the bacterium of 4-log to reduce.More preferably, when using the test of CPT method, material of the present invention can cause the bacterium of 5-log to reduce.Still more preferably, when using the test of CPT method, material of the present invention can cause the bacterium of 6-log to reduce.Should be appreciated that CPT is compare test, wherein antimicrobial material is compared with the contrast material that biocide of no use is handled.The theoretical log minimizing of available maximum is limited by the growth of bacterial population on untreated control in concrete CPT test.Therefore, be lower than designation number even actual log reduces, 100% live organism elimination is possible but obtain in fact.
More of the present invention during use, hope be that the part (less than about 50 weight % of total polymer) of anti-microbial polymer is soluble in water or in the aqueous fluids.In this mode, can realize from the rapid action anti-microbial effect of the antimicrobial composition of solubility and combination interests from the lasting antimicrobial acivity of the prolongation that can not dissolve anti-microbial polymer.This can be by for example mixing hydrophilic unit so that water-soluble realization the to a certain degree to be provided to partial polymer in polymer architecture.For example, hydrophilic-CH 2-CH 2-O-CH 2-CH 2-unit can react in the anti-microbial polymer that is incorporated into based on urethane by two (2-hydroxyethyl) ethers and TDI.The increase of water dissolvable or the antimicrobial content of leachability can realize by the anti-microbial polymer that preparation has a molecular weight (less mean polymerisation degree) of reduction.The method that reduces polymericular weight or extent of polymerization is that those skilled in the art are familiar with.
Pure solubility of the present invention/the water-insoluble anti-microbial polymer is except as the overlay, can also be as the composition of poly-unit or object, and described poly-unit or object comprise for example medical treatment device and household supplies.This can realize by for example anti-microbial polymer or its solution and other polymkeric substance or its solution or polymerisable monomer or prepolymer or its solution being mixed.Anti-microbial polymer of the present invention can also be used to form film, fiber, gel, foam, tackiness agent, sealing agent and the spackling that can be used as the composition in medical treatment device, poly-unit or other objects.
One embodiment of the invention are to provide permanent bioguard treatment to staying the intravital artificial suture line of body, described artificial suture line is multifilament polyester suture line for example, as the Mersilene (uncoated) and the Ethibond Excel (poly-butylation thing coating) of Ethicon sale.These suture lines will help prevention significantly to threaten, gash postoperative infection (the Immer FF that for example after the heart operation process, causes complication, Durrer M, Muhlemann KS, Erni D, Gahl B, Carrel TP. " Deep sternal wound infection after cardiac surgery:modality of treatment and outcome ". Ann Thorac Surg.In September, 2005; 80 (3): 957-61).According to the document, the sickness rate of dark breastbone wound infection is between 1% and 3%.The staphylococcus (32.7%) that identifies mainly by streptococcus aureus (41.8%) and coagulase-negative by several bacterial spectrums that studies have shown that infects.Because with the cause that infects relevant morbid state, also wishing provides protection not to be subjected to the blood propagation infection by making suture line keep antimicrobial acivity.
Another embodiment of the present invention provides pure solubility/water-insoluble anti-microbial polymer, and it can be incorporated in the Hdyrophilic polyurethane foam for the treatment of as the wound dressing with non-leaching antimicrobial acivity.
Another embodiment of the present invention provides pure solubility/water-insoluble anti-microbial polymer, and it can be incorporated in the curable application system of UV and solidify overlay with non-leaching antimicrobial efficacy to give.The curable overlay of this UV can be applied to plastics film, this plastics film subsequently can thermoforming or vacuum forming be product with desired shape.
Another embodiment of the present invention provides pure solubility/water-insoluble anti-microbial polymer, and it can be used as tackiness agent, for example is used for fixing the composition of medical treatment device to the tackiness agent of skin, provides antimicrobial property to described tackiness agent thus.
Embodiment
Provide the following example to illustrate the present invention and to instruct those skilled in the art how to make and how to use this material.They can not be counted as and limit the scope of the invention.
The copolymerization of embodiment A 1:(2-(methacryloxypropyl) ethyl-trimethyl salmiac and butyl methacrylate
Prepare solution by dissolving 2.5g tetravalence vinyl monomer (75% aqueous solution of 2-(methacryloxypropyl) ethyl-trimethyl salmiac (Aldrich Chemical Co.)), 7.5g butyl methacrylate (Aldrich Chemical Co.) and 0.1g AIBN in 10g ethanol (2,2 '-azo two (2-methyl propionitrile)) (Aldrich Chemical Co.).Solution with argon gas bubbling 60 seconds to evict dissolved oxygen from, then at the argon gas lower seal in vial.Bottle was placed in 70 ℃ of baking ovens 24 hours.The solution that will comprise multipolymer then dilutes (1: 25) in ethanol.
Embodiment A 2: composition is to the application of skin
The solution that produces in the embodiment A 1 of approximate 1mL is placed on people volunteer's skin of dorsum of hand, scatter then and rub to drying with the finger of being with gloves.After the drying, stay inconspicuous film, its be not viscosity or be clamminess, in fact the volunteer is difficult to discover.Known dibromothymolsulfonphthalein (BTB) indicator dye is strongly in conjunction with quaternary ammonium compound.For the existence that makes the polymerization overlay as seen, the zone that will comprise the applied hand of solution of polymkeric substance is cleaned with the 0.5%BTB indicator dye aqueous solution of regulating pH to 10.Hand was cleaned 30 seconds under the mobile tap water of tepor, and gently rubbing hands refers to remove excessive BTB indicator dye solution.The skin area of handling with copolymer solution presents indigo plant/green, and skin does not on every side present this look, shows to have applied polymkeric substance.Only after scrubbing with the detergent solution brute force, overlay is reduced to the BTB indicator dye and measures the degree that no longer can indicate the existence of polymerization overlay.
Embodiment A 3:(vinyl benzyl) copolymerization of trimethyl ammonium chloride and butyl methacrylate (H-1).
Prepare solution by dissolving 2.5g tetravalence vinyl monomer (vinyl benzyl) trimethyl ammonium chloride (Aldrich Chemical Co.), 7.5g butyl methacrylate (Aldrich Chemical Co.) and 0.1gAIBN in 20g methyl alcohol (2,2 '-azo two (2-methyl propionitrile)) (Aldrich Chemical Co.).This solution with argon gas bubbling 60 seconds to evict dissolved oxygen from, then at the argon gas lower seal in vial.Bottle was placed in 70 ℃ of baking ovens 24 hours.The solution that will comprise multipolymer then dilutes (1: 2) in ethanol.Said composition is designated as among " H-1 " and the embodiment afterwards and is mentioned.
Embodiment A 4: to polypropylene set of applications compound
The solution that produces in embodiment A 3 is used for the internal surface of the several 15mL polypropylene centrifuge tubes of following coating: centrifuge tube is filled solution, the centrifuge tube that is full of is spent the night.Then, solution is poured out, and in being arranged to 50 ℃ low-temperature bake oven, alcohol is evaporated fully.In order to make as seen at the polymerization overlay of pipe on the inboard, the 0.5%BTB indicator dye aqueous solution of approximate 5mL is added in the pipe, shake then to cover the whole inside of pipe.Will manage flushing for several times with distilled water after, the internal surface of pipe is a mazarine still, shows that insoluble polymer is coated in the internal surface of pipe.
Embodiment A 5: the antimicrobial acivity of polymeric composition.
With streptococcus aureus overnight culture 10 -4Dilution 2mL aliquots containig (～1 * 10 8CFU/mL) be added to one as in embodiment A 4 in the handled polypropylene centrifuge tube in (sample) and the untreated polypropylene centrifuge tube (contrast).Be after 37 ℃ of incubated overnight, the slow rolling of pipe is contacted with the internal surface of pipe to guarantee a year bacterial cultures.Second day, will line on the microbial culture flat board from each serial dilution thing of managing the bacterial cultures of results.Obtain 2.5 * 10 from the culture of untreated control tube results 4CFU does not observe the clone and use from the flat board of the culture line of treatment samples QC results.Difference between the clone's number that calculates is transformed at least, and the bacterial population of 4.4log reduces.
Embodiment A 6: soluble but undissolved quaternary ammonium urethane (H3-C) in water synthetic in alcohol.
50g Ethoquad C/12-75DK (Akzo Nobel) places in the round-bottomed flask on the rotatory evaporator and is evaporated to drying.With residue (～37.5g) when stirring, heavily be dissolved in approximate 50 ℃ the 70mL tetrahydrofuran (THF) (THF).Add the 40g Toluene-2,4-diisocyanate, 4-vulcabond (TDI) mixes solution 1 hour, is dipped in simultaneously in-50 ℃ of water-baths.Increase at this time durations soltion viscosity, and when being cooled to room temperature, it is limpid that solution keeps.Solution is store overnight at room temperature, and observes viscosity some extra increases are arranged.Add 9g dipropylene glycol dipropylene glycol, and 50 ℃ of following mixing solutionss 4 hours.Then mixture is placed on the rotatory evaporator, to remove all volatile solvents (mainly being THF) by the vacuum stripped under～50 ℃.Then, mixture is dissolved in the 100mL Virahol, and repeating vacuum is stripped.Then mixture is dissolved in the 100mL Virahol once more, and repeating vacuum is stripped once more.Then mixture is dissolved in the 100mL Virahol again, is had～limpid, the thickness of 56wt% solid polymer content, pale yellow solution.Then, polymers soln is diluted to a plurality of concentration of from 1% to 10% solid, and these solution are used to apply multiple object, for example glass slide and polypropylene test tube.Overlay when drying after for limpid to opaque slightly, be not clamminess and adhere to substrate.In addition, can not remove overlay by in water or salts solution, cleaning.Think that the product polymkeric substance is included in and has the unitary linear polyester of quaternary ammonium in the main polymer chain structure.The product of this embodiment is numbered " H3-C ", and in the following embodiments as antimicrobial Liniment.
Embodiment A 7: comprise covalent bonding fluorescein part, soluble but undissolved quaternary ammonium urethane (H3-F) in water synthetic in alcohol
50mg fluorescein(e) dye (neutral molecule) is dissolved among the 3mL THF, and then with the 8g Toluene-2,4-diisocyanate, 4-vulcabond (TDI) mixes.Under-50 ℃, this solution was mixed 1 hour, store overnight at room temperature then, mix with 10g Ethoquad C/12-75DK (Akzo Nobel) then, the previous vacuum stripped of this Ethoquad C/12-75DK is removed isopropanol solvent and heavily is dissolved in the 14g tetrahydrofuran (THF) (THF) under approximate 50 ℃ when stirring.Then with this mixture in-50 ℃ of following mixed number hour, carry out vacuum stripped then.Mixture heavily is dissolved in the Virahol, then vacuum stripped.Dissolving/reextraction repeats once again, and product be dissolved in-the 50mL Virahol in.Find that solution has the solids content of 17.4wt%.Expect that the product of this reaction is the fluorescein-labeled linear polyester that comprises the quaternary ammonium part in the main polymer chain structure.In addition, the expection polymkeric substance comprises the fluorescein part in the main polymer chain structure.Fluorescein partly provides useful diagnostic tool to measure the existing of polymkeric substance, dispersion, persistence and migration.Described in previous embodiment, in multiple substrate, prepare overlay, and overlay equally has a similar characteristic with recited above those.The microslide of the glass of coating places the 50mL culture tube that comprises 15mL deionized water or 15mL phosphate-buffered salt, and places 37 ℃ wave and culture case a few hours.By visible light analysis (Spectronic 20) analytical solution under 495nm.Do not detect the leaching of fluorescein, show that dyestuff is incorporated in the polymer architecture fully.
Embodiment A 8: the preparation of antimicrobial coating composition
The above-mentioned tetravalence urethane (H3-C) and the glycerine of appropriate amount dilute in Virahol, obtain comprising the composition of 10wt%H3-C and 5wt% glycerine.It is limpid that solution keeps, and when preparation overlay on glass slide the film formation of polymkeric substance and adhesion characteristics not by disadvantageous effect.
Embodiment A 9: comprise the preparation of the antimicrobial coating composition (SS-1C) of skin soft agent
The above-mentioned tetravalence urethane (H3-C of embodiment A 6) and the glycerine of appropriate amount dilute in Virahol, and surplus is the final composition of Virahol (80wt%) to obtain comprising 10wt%H3-C, 5wt% propylene glycol and 5% dipropylene glycol.It is limpid that solution keeps, and do not have the film formation and the adhesion characteristics of impact polymer unfriendly when preparation overlay on glass slide or pigskin skin, and anti-microbial effect.Known propylene glycol and dipropylene glycol have the tenderizer characteristic and are widely used in the local skin product for example in lotion and the makeup.
Embodiment A 10: comprise the preparation of the antimicrobial coating composition of skin soft agent
The preparation of embodiment A 9 (SS-1C) dilutes than the ratio of three parts of Virahols than a Virahol and a SS-1C with a SS-1C with Virahol.
Embodiment A 11: comprise the preparation of the antimicrobial coating composition of skin soft agent and UV absorption agent
The preparation (SS-1C) of revising embodiment A 9 (SS-1C) does not absorb the UV line and prevents sunburn with protection skin to comprise UV and absorb or UV blocks and stops sun-prevention component.UV absorption or UV block barrier additive and are selected from: para-amino benzoic acid (PABA), PABA ester class, cinnamate derivative, benzophenone, salicylate class, Octocrilene, diphenylpropane-1,3-dione(DPPO), avobenzone, oxybenzone, zinc oxide and titanium dioxide.
Embodiment A 12: comprise the preparation of the antimicrobial coating composition of skin soft agent and vitamin-E
The preparation (SS-1C) of revising embodiment A 9 is to comprise 1% vitamin-E.Vitamin-E in fact is undissolved in water, but easily dissolving in alcohol.
Embodiment A 13: comprise the preparation of the antimicrobial coating composition (SS1C-BAC3) of microbicidal additives
Prepare antimicrobial coating composition (SS1C-BAC3) by the preparation (SS-1C) that mixes 1.1g benzalkonium chloride and 35.5g embodiment A 9.Benzalkonium chloride dissolves fully and solution is limpid colourless.Use the antimicrobial efficacy of ASTM testing method #E 1874-97 (" cleaning the standard method of test (Standard Test Method for Evaluation of Antibacterial Washes by Cup Scrub Technique) of technical evaluation antibacterium clean-out system by cup ") the test said composition of modification as described below.Variation comprises the pigskin skin that use obtains from the slaughterhouse, rather than living person volunteer's skin.Except the SS1C-BAC3 material, also prepare the placebo of forming by 5% propylene glycol in the Virahol and 5% dipropylene glycol.The result is as follows.
The cup scouring technology that is used for the modification of pigskin skin is summed up and the result
1. the preparation of pigskin skin sample and sterilization
1.1 use 9 sample-3 samples to be used to test product (SS1C-BAC3) in the method altogether, 3 samples are used to test placebo, and 3 samples are used for negative control.Followingly downcut sample: by the bottom of culture dish being retouched on skin and downcutting disk, so that sample has the suitable size of the culture dish bottom of fitting fully from a slice pigskin skin.Downcut each of 9 samples and place the bottom of culture dish under it from pieces of skin, stratum corneum in the above.
1.2,, be placed on the middle UV light of BSC (Biosafety cupboard) then dry about 10 minutes down in order to the thorough saturated towel wipe samples skin of 70% alcohol in case sample skin is placed in the culture dish.The lid of culture dish (facing up) is also placed in the sample next door under the UV light.
2. the application of test product and placebo
2.1 under UV light, after the drying, BSC is transformed into fluorescence, opens gas blower simultaneously, and on each skin, go out the square of 1x1 with the ink marks stroke.This is as the position of using.Open UV light several minutes once more, and lid faces up still, do not pollute when the mark skin guaranteeing.
2.2 BSC is changed back fluorescence again, open gas blower simultaneously, and lid is put back on the culture dish that comprises sample.
2.3 whenever next sample will cover from culture dish and take away, and each test product of 0.5mL is applied to first three sample (being applied in the specified square).Between using, each changes the aseptic straw head.
2.4 with placebo repeating step 2.2 3 times, and 3 remaining sample skins give over to negative control.
3. cup is cleaned the performance of technology
3.1 in case use after product and the placebo, each sample in 9 samples is covered with lid and stays in the BSC, and a sample is taken out and be used for test at every turn.
3.2 cup (about 1.5cm of diameter and high 1.5cm) is placed on the application site center of sample, gives firm pressure and seal to form cup/skin.With the cup flame drying then of at first in 95% alcohol, sterilizing.Go up when sealing with protection cup/skin when a people keeps constant compression force to cup, another person adds the 0.25mL inoculum in cup.In case after adding, make inoculum contact 5 minutes.
3.3 after 5 minutes, use in 95% alcohol sterilization and flame-dried glass stick skin wiping 30 seconds in the cup.After 30 seconds, with aseptic straw with fluid recovery to the 0.5mL neutralizing agent.
In case 3.4 after the recovery sample fluid, add the 0.25mL neutralizing agent to same test position and carry out recovery second time, and with the new glass stick wiping 30 seconds again that overdoes.Fluid recovery is extremely reclaimed in the identical solution with the wiping first time.
3.5 for remaining 8 sample repeating step 3.2-3.4.
4. data gathering
Carry out the standard series dilution by institute being reclaimed wiper fluid, use the spread plate technology to carry out bed board and the result is quantitative then.With dull and stereotyped overnight incubation, and all calculate log for negative control and placebo and reduce.
5. result
In the test of antimicrobial coating composition (SS1C-BAC3) to intestinal bacteria (E.coli), the performance of twice successive shows and can all kill, and this is corresponding to being the minimizing of average 4.5log in the bacterium alive of this example.
Placebo shows not influence of test organism.
Embodiment A 14: in alcohol soluble but in water undissolved and quaternary ammonium urethane (SS50H) synthetic of in molecular structure, mixing flexible hydrophobic units
Basically according to the method for embodiment A 6; Yet, using 1,6-hexylene glycol and Ethoquad wait mole (1: 1) mixture replacement Ethoquad.Find that resulting polymkeric substance is water-insoluble, and with Virahol unmixing at least in part; Yet it is solvable fully in ethanol.The solution (40.6wt% polymkeric substance) of this polymkeric substance in ethanol is dropped in the excessive greatly distilled water, simultaneously vigorous stirring.The sedimentary polymkeric substance of institute is by the filtration collection and at the vacuum oven inner drying.Resulting dry polymer has constituted and has surpassed 85% recovery to raw-material, although observe the considerable damage of institute's sedimentable matter in filtration, drying and removal process.This shows that polymkeric substance is obviously water insoluble.In addition, the redeposition of the type is handled (can leach) composition that expection can be removed any water dissolvable that may exist, if so expect complete non-leaching composition then the redeposition processing of the type is useful.
Embodiment A 15: soluble but undissolved and in molecular structure, mix flexible hydrophobic units and have the synthetic of low-molecular-weight quaternary ammonium urethane (SS25HL) in water in alcohol
Basically according to the method for embodiment A 14; Yet the Ethoquad that uses 3: 1 mol ratios is than 1, the 6-hexylene glycol.In addition, use the formation that has the short chain of hydroxyl end groups less than the TDI (～65%) of equimolar amount with promotion.Therefore expect that this material has lower molecular weight, and comprise relative higher proportion leach (water dissolvable) antimicrobial composition.Definite molecular weight the unknown of polymkeric substance; Yet this polymkeric substance that comparison shows that of viscosity has lower molecular weight between this polymers soln and above-mentioned those polymers solns.
Embodiment A 16: the comparison of the rapid action antimicrobial efficacy of multiple composition described herein
Use rapid action (5 minutes) antimicrobial efficacy of the composition that following procedural test describes in embodiment A 6, A14 and A15:
Preparation polymers soln (10% content in alcohol).Each solution of drawing 50mL joins in each hole of plastics 24 porocyte culture plates.Plate under hand-held hair dryer vortex with promote alcohol evaporation.Use standard method to prepare the working solution of bacterium.With 250mL bacterial solution (10 4Cfu/mL) be added in each coated hole.(37 ℃/100rpm) reach desired time (5 minutes, 15 minutes, 30 minutes or 60 minutes) at interval add the Letheen meat soup (neutralizing agent solution) of 250 μ L are then cultivated/shaken to 24 well culture plates.From the hole, take out solution, and place TSA to go up and the coating of use dressing plate coating technique 100 μ L, perhaps with spread plate behind the solution serial dilution.Flat board 37 ℃ of following overnight incubation, is calculated clone's number then and calculates antimicrobial efficacy.Carry out test at streptococcus aureus and serratia marcescens (Serratia marcescens).The relative antimicrobial efficacy of three kinds of polymkeric substance is through being defined as A15 (SS25HL)＞A14 (SS50H)＞A6 (H3C).Sample A15 shows and is only just all killing SA and SM after 5 minutes.Sample A14 shows and is only just all killing SA after 5 minutes.Sample A6 all kills SA after being presented at 30 minutes.
Embodiment A 17: with the preparation of the suture line material of antimicrobial composition coating
The polymkeric substance of the method preparation by embodiment A 6 is used to apply multifilament polyester suture line material Mersilene (uncoated) and Ethibond Excel (poly-butylation thing applies), and these two kinds of suture lines are by the Ethicon production and selling.Suture line (every～10cm long) cleaned 5 minutes in 70% Virahol, then in deionized water rinsing 3 times to remove surface contamination.Make suture line complete drying before anti-microbial polymer is used.Sample is placed the conical centrifuge tube of 50ml, and cover fully with the suitable treatment soln of 20ml (polymkeric substance of embodiment A 6 is dissolved in the Virahol with the concentration of 0.5,2.0 or 10 weight %).Pipe supersound process 3-5 minute is sunk into air on the high hydrophilic polyesters fiber with removal.From treatment soln, take out sample and make it dry down at 60-80 ℃.Coating process repeats twice to guarantee consistent cover degree (applying altogether 3 times).At clinical relevant bacterium, promptly streptococcus aureus SA (ATCC 6538), intestinal bacteria EC (ATCC 15597), Pseudomonas aeruginosa (Pseudomonas aeruginosa) PA (ATCC 15442) and X-1497 resistance streptococcus aureus MRSA (ATCC 33593) test suture line.Prepare bacterial suspension according to standard method.For all bacteriums, bacterial concentration is measured down in 580nm by spectrophotometer (Milton Roy Spectronic 20D spectrophotometer) in the suspension.To the measuring of streptococcus aureus～10 8Titre.Bacterial concentration in the use PBS adjustment storage solutions is to provide the standard inoculation thing (1 * 10 for experimental study 6Cfu/mL).Ultimate density also confirms by colony forming unit (cfu) method.That handle be cut into 4-5cm length, and storage is at room temperature up to use with suture line sample sterility contrast ground.Each aseptic suture line fragment places the hole that separates of aseptic big well culture plate, and contacts 4mL bacterial suspension 3 hours.Confirmed the stdn inoculation by serial plate count.Suture line freely floats in inoculated medium, uses vibrator to shake the time phase that reaches incubation step simultaneously under 120rpm.After the Contact test bacterial strain, the suture line fragment is cleaned (three times [3 *]) gently to remove non-adherent cell in PBS.Then, the suture line fragment is placed the PBS that comprises 0.25%Triton-X, vortex three times [3 *], and in same solution with 20kHz supersound process 2-5 minute.With the ultrasonic thing of suture line serial dilution in PBS, bed board then, and cultivated 24 hours down at 37 ℃.Attack for each inoculum, assess three suture line fragments.Microorganism is reclaimed and is expressed as log10cfu/cm suture line fragment.Obtain following result [log is reduced to the minimizing of comparing with former (uncoated) suture line material].
Table 1
Handle the average LR of organism
10% SA 5.99 (all killing)
2% SA 5.99 (all killing)
0.5％ SA 1.34
2％ EC 0.14
2％ PA 1.52
10％ MRSA 2.68
2％ MRSA 1.37
0.5％ MRSA 2.42
Embodiment A 18: solidify the plastics film that preparation is coated with antimicrobial composition by UV
The polymkeric substance of describing in the embodiment A 6 mixes with the curable coating composition of UV, and mixture is used to prepare the overlay on multiple plastic-substrates.Next use the test of " agar slurry method " (ASTM E 2180-01) to determine, when anti-microbial polymer content in the overlay is between 10 weight % of dry-coated coating and 30 weight %, overlay is to the various bacteria organism, comprise streptococcus aureus and intestinal bacteria, have tangible antimicrobial acivity.
Embodiment A 19: Hdyrophilic polyurethane foamy preparation with antimicrobial property
This embodiment proves that embodiment A 6 described pure resolvabilitys/water insoluble anti-microbial polymer mixing in preparation is used to prepare as the antimicrobial Hdyrophilic polyurethane foam of the non-leachability of wound dressing." water-based " solution is prepared as follows: dissolving 90mg EDTA four sodium in 12g water, the Pluronic F-88 surfactant soln (BASF) that adds 10g 0.25% then, 50% non-ionic dispersing agent (" NanoShield " ZN-3010 that adds 3g ZnO then, Alfa-Aesar) suspension, thorough mixing then.Approximate 1 minute of the 40% solution thorough mixing of polymkeric substance in Virahol described in the embodiment 6 of 25g Hypol-2000 (Dow) and 4g.In this mixture, add " water-based " solution then, and fully stir between approximate 20 seconds and 30 seconds,, and observe evidence foamy up to uniform mixing with steel knife.Then, mixture is poured on the silicone release paper, and on the surface of a piece of paper, covers second silicone release paper apace by the spacer of desired thickness (approximate 1/16 " to 1/4 ").Upper surface along second paper moves the straight flange spreader then, so that mixture is coated with into homogeneous thickness between two interleaving papers.Allow material at room temperature to solidify several minutes.Remove the top layer interleaving paper then.Resultingly still placed 110 ℃ of loft drier then 15 minutes attached to the foam on the interleaving paper of bottom.Then resulting yellow foam is taken off from interleaving paper and be used for using or test.
Observe solidified foam quick (＜5 seconds) absorption and place its lip-deep little water droplet.After immersing 5 minutes, foamy absorptive capacity (not dripping) is through being defined as its approximate 15.9 times of own wt in 1% salts solution.
According to ATCC method #100 test foam, find and the wound dressing of non-antimicrobial hydrophilic PU foam (Tielle, J﹠amp; The product of J) compares, obtain 5.99log for Candida albicans (Candida albicans) and reduce, obtain 7.81-log for streptococcus aureus and reduce, and obtain the 6.36-log minimizing for Pseudomonas aeruginosa.The non-leaching feature of foam antimicrobial acivity is by following test foam extract (24 hours, 37 ℃, 60cm 2The every 20mL PBS of foam) obtain proof: placing the extract droplet of 20 μ l, bed board has 10 6Marked region on the agar plate of cfu/mL streptococcus aureus.Be not observe growth inhibiting evidence at marked region after 37 ℃ of overnight incubation and the visual inspection subsequently.
Embodiment A 20: soluble but undissolved and have the synthetic of the quaternary ammonium urethane that mixes the flexible hydrophobic and/or hydrophilic unit in the molecular structure in water in alcohol
Except glycol ether (two (2-hydroxyethyl) ether) replace all or part of 1, outside the 6-hexylene glycol, according to the process described in the embodiment A 14.When the relative content of glycol ether is higher, polymerisate will be more hydrophilic.
Embodiment A 21: be used for lasting validity skin degerming, that have prolongation and comprise can leach antimicrobial (CHG) and stablizer/sanitas (EDTA) clarifying, based on the preparation of antimicrobial (SSG2) of gel
Following ingredients fully made up and mix: 10g 20%CHG (chlorhexidine gluconate to produce the expectation preparation of 100g, Aldrich) aqueous solution, (embodiment 6) solution of the 40%SS-1C in Virahol that is dissolved in 1.0g EDTA four sodium in the 4.0g water, 25g and 60g's is dissolved in 2%PEG[poly-(oxyethane) in 70/30 (volume %) isopropanol, (MW=600,000), Aldrich] solution.PEG is used for providing the heavy-gravity gel consistency to preparation.EDTA adds as stablizer and/or sanitas, and/or is used to increase antimicrobial validity.Use ASTM E 1874-97 " to be used for cleaning the standard method of test of technical evaluation antibacterium clean-out system ", the described composition of test on people volunteer by cup.Test organisms is a serratia marcescens, and obtains " all killing ", when with perishability contrast antiseptic composition (Purell hand hygiene sterilizing agent) when comparing, obtain on average the minimizing that the bacterium greater than 3.5log loads.When antimicrobial validity was being used preparation and tested in 4 hours during test in approximate 5 minutes and when being applied to skin after to skin, the result was similar.In addition, in addition clean with soap and water or alcohol handle skin after, detect tangible antimicrobial acivity once more.
Embodiment A 22: preparation with medical adhesives of antimicrobial property
The polymkeric substance of describing in the embodiment A 14 mixes with low Tg acrylate copolymer, obtains suitable composition as medical adhesives.Mixture is used to prepare the overlay on the plastic-substrates.Find that these overlays have useful adhesion characteristic.Next use the test of " agar slurry method " (ASTM E 2180-01) to determine, when the content of anti-microbial polymer in the overlay was between 10 weight % of dry-coated coating and 30 weight %, overlay had the antimicrobial acivity of tangible anti-various bacteria organism (comprising streptococcus aureus and intestinal bacteria).
Embodiment A 23: be used to be applied to the preparation of the antimicrobial barrier film of human skin, it has the flexible hydrophobic units that is incorporated in the molecular structure and it has lower molecular weight (solution " G11 ").
Basically according to the method for embodiment A 14; Yet, adopted 20g Ethoquad solution (75wt%) to 7.5g 1, the ratio of 6-hexylene glycol.In addition, use the formation that has the short chain of hydroxyl end groups less than the TDI (～65%) of equimolar amount with promotion.Therefore expect that this material has lower molecular weight, and comprise relative higher proportion leach (water dissolvable) antimicrobial composition.Definite molecular weight the unknown of polymkeric substance; Yet, this polymkeric substance that comparison shows that of the viscosity of this polymers soln and those solution recited above is had lower molecular weight.Resulting polymkeric substance is formulated into the solution with following ingredients: anti-microbial polymer (10 weight %), PEG 600K thickening material (1%), water (12%), Virahol (27%) and ethanol (50%).Said preparation is called as G-11 in the following discussion.
Cup wiping method is used for the antimicrobial validity according to serratia marcescens on the ASTM E 1874-97 anti-people volunteer's skin of test G-11 that " is used for cleaning by cup the standard method of test of technical evaluation antibacterium clean-out system ".Also carried out the other test of adopting rinse step.The result shows, even after with water rinse exsiccant film, G-11 also has high antibacterium validity, the results are shown in following table.
Figure BPA00001216315000261
*Show all and kill
*Rinse step is to use the 20 pumps (deionized water of every pump～1ml) from the standard spray bottle.
The following validity of estimating the G-11 preparation to the fungal organism Candida albicans:
Estimate G11 to the oidiomycetic validity of white by the Lawn coating
Estimate the G11 preparation to the oidiomycetic validity of white by the lawn coating technique.The culture of Candida albicans ATCC# MYA-905 and ATCC# 10231 was grown 48 hours yeast culture base meat soup from glycerol stock (glycerol stocks).Then culture is diluted to 10 -2Dilution serve as the work inoculum.Aseptic cotton carrier is saturated and evenly coat on the whole surface of yeast culture base agar in inoculum.Then the G11 suction of 3 30 μ L amounts is measured to agar, evenly spaced apart.Agar plate is moved in the incubator 48 hours, then evaluation result.
The result shows that G11 has stoped two growths of albicans strain in using the lawn dispensing area.
By glass slide carrier test evaluation Candida albicans
Two albicans strains, ATCC# MYA-905 and ATCC# 10231 grew 48 hours yeast culture base meat soup from glycerol stock.Then culture is diluted to 10 -2Dilution serve as the work inoculum.The G11 of 250 μ L is distributed on each glass slide carrier.After using, place the Biosafety cupboard to reach 10 minutes time of drying slide glass.The Candida albicans inoculum of 100 μ L being added on each slide glass, and distribute gently with asepsis ring, is 5 minutes duration of contact then.Use slide glass and three negative control slide glasss of three processing for each organism bacterial strain.
All slide glasss are recovered in the neutralization solution, and realize the counting of G11 the negative control slide glass by standard series dilution and plating.
The result shows that obtaining average 0.78log for bacterial strain MYA-905 reduces, and obtains average 1.71log minimizing for bacterial strain 10231.
Carry out antiviral efficiency analysis by independent experiment chamber (BCS Laboratories, Inc., Gainesville, Florida) to G11 skin health sterilizing agent sample.Use phage MS-2 to carry out analysis as the model that is used for the Human virus.In the research of many announcements, phage MS-2 has been widely used as the model at Human virus's deactivation, and this model is used for the potential ntiviral characteristic at water and health care industry evaluation physics and chemostefilant.Deactivation/survival of phage MS-2 is related well with many Human virus.Use the orifice plate model to carry out the antiviral validity test of G11.In brief, phage MS-2 (ATCC 15597B1; 30nmRNA virus is specific to intestinal bacteria C3000; ATCC 15597) as Human virus's alternative model.Before day of attack, comprise approximate 10 according to standard method (Snustad and Dean, 1971) mensuration 9The phage stock solution of plaque forming unit (pfu)/mL.The MS-2 stock solution is at phosphate buffered saline buffer (PBS; Fisher Scientific) is diluted to approximate 10 in 6Pfu/ml.This phage dilution is used to assess the phage-resistance validity of skin health sterilizing agent preparation.Experimental analysis is carried out in triplicate.(Corning Inc. carries out on NY) at 24 well culture plates in analysis.
Suction amount 100mL test soln in each orifice plate.In different time points, the MS-2 solution of 100 μ l is added in the hole that comprises G11.The time that selection is used to estimate is by determining the time of drying of G11 institute covering surfaces; Be dry 4 hours of t=0 (after adding G11 at once), dry 30 minutes of t=and t=.Depend on the time point after G11 adds, hole surface or contain sanitizer wet (t=0 minute), or the invisible dry film (t=30 minute and t=4 hour) that exists is gone up on the surface.When the hole is (time=0) when wetting, the solution physical property in the hole is mixed by repeating to inhale to put.
Phage and sanitizer are contacted with each other or 10 seconds or 5 minutes, to collect (less than 30 seconds) and the data of the antiviral validity of rapid action (5 minutes) at once.
After the duration of contact that is allowed, in each hole, add 2ml Difco neutralization buffer (Becton Dickinson, MD) with in and sanitizer and reclaim the MS-2 phage.Initial test shows, during this is enough to and the sterilizing agent that exists in the sanitizer.For t=30 minute and t=4 hour, allow the phage surface in contact or 10 seconds or 5 minutes that are added.For 5 minutes contact, flat board placed low speed orbital oscillation device (Hoefer, Red Rotor, San Francisco) last 5 minute.After specified duration of contact, in each orifice plate, add neutralization buffer.Contrast (at first) phage titre is following to be determined: add 100 μ l phage solutions in emptying aperture, add the 2ml neutralization buffer then.All situations adds down after the neutralization buffer in the above, inhales repeatedly and puts, and is transferred to then in the aseptic 15ml pipe.Before counting, the solution that will comprise phage dilutes in PBS.MS-2 phage number is by using host e. coli C3000 and fusing pancreatin soy agar (TSA in each sample; Becton Dickinson, agar plaque measurement counting MD) is plaque forming unit (pfu).Make flat board 37 ℃ of following overnight incubation, count then, and determine that percentage ratio compared with the control reduces.Each analyzes duplicate coating.The result of repeated experiments is suitable and validity is reproduced at each time point.The results are shown in the following table, and represent the mean number that from three parts of analyses, obtains.
Table 2: under the short contacting time (10 seconds) and extend contact time (5 minutes) of different time points after initial the application,
G11 skin health sterilizing agent is to the validity of MS-2 deactivation
Experiment and experiment condition Average MS2 pfu/ml * Deactivation validity to MS-2
0 minute time of drying; 10 duration of contact in second 5.8×10 2 99.84% deactivation
0 minute time of drying; 5 minute contact time 2.4×10 2 99.93% deactivation
30 minutes time of drying; 10 duration of contact in second 1.3×10 6 Can ignore (not observing deactivation)
30 minutes time of drying; 5 minute contact time 7.8×10 2 99.78% deactivation
4 hours time of drying; 10 duration of contact in second 1.7×10 5 Can ignore (not observing deactivation)
4 hours time of drying; 5 minute contact time 1.1×10 2 99.72% deactivation
The initial loading (untreated control) of reclaiming 3.5×10 5pfu/ml * N/A
*The plaque forming unit of pfu/ml=MS-2 from the neutralization buffer that reclaim in each hole.
Embodiment A 24: as the preparation of the antimicrobial propylene glycol solution of water-insoluble of solvent
Polymkeric substance described in the embodiment A 14, heavily is dissolved in the propylene glycol to remove alcoholic solvent subsequently in 50 ℃ of following vacuum-dryings, obtains 40% polymers soln in propylene glycol.Through to observe this solution be clarifying and be stable during in room temperature storage.
Embodiment A 25: be used to the preparation of physics that is applied to human skin and has improvement and the antimicrobial barrier film of improving looks characteristic
Although effectively, the composition of embodiment A 23 gives in being applied to the process of skin or after using people volunteer's feel it is " viscosity ", " gluing ", " coarse " or " stringy " for antimicrobial purpose.Through determine that physics that these are not expected and/or aesthetic effect are mainly by using thickening material (1%PEG 600K) to cause in said preparation.Thickening material is used to facilitate high viscosity, and this has stoped in the application process product " washing off " conversely.Usually the thickening effectiveness of expecting to use minimum as far as possible thickening material and aspiration level still being provided.In addition, thickening material must with other compositions in the preparation, comprise that alcoholic solvent is compatible with the tetravalence anti-microbial polymer.Carbomer (a kind of polyacrylic ester) is the thickening material that is usually used in the skin preparation; Yet, its incompatible with quaternary ammonium polymer (formation throw out).We have found that, use Natvosol (HEC) can obtain the compatible preparation that has the desirable viscosity characteristic and lack any physics of not expecting or aesthetic effect as thickening material.Select the HEC rank to optimize the physical property of expectation.Cellulose ethers for example methylcellulose gum or Methocel (Dow) is used to implement suitable thickening material of the present invention.The order that adds composition is important in to obtain useful preparation.
Prepare preparation according to following process: (Cellosize #QP-100M-H, solution Dow) prepared in 70 ℃ of vortexs on impeller by HEC is scattered in the water 1.07g Natvosol in 50mL water (" HEC ") then in 2 hours.The solution store overnight, and after storage, show and have more slick denseness.Then, the dehydrated alcohol of 100g (126.5mL) is added in the HEC solution altogether, then thorough mixing.Thus, formed and comprised approximate 0.65wt%HEC and 70% alcoholic acid solution.40% antimicrobial quaternary ammonium polymer solution in ethanol mixes this solution (105g) with 10g dehydrated alcohol and 15g, obtains being used to be applied to the antimicrobial barrier film preparation of skin.Employed antimicrobial quaternary ammonium polymer is substantially similar to those that describe in embodiment A 14.Said preparation is applied to human skin, with finger tip it is wiped into then, this does not cause untoward reaction.Preparation is dry suitably and when drying or be not viscosity afterwards.
Embodiment A 26: comprise the preparation of the free-standing polymeric film of pure solubility anti-microbial polymer and softening agent
By mixing 25 parts of polyvinyl chloride (MW=47,000; Aldrich Chemical Co, catalog number (Cat.No.) 389323), 0.3 part of Citroflex B-6 softening agent (Moreflex, Inc), 3.3 parts the antimicrobial quaternary ammonium polymer solution that is dissolved in 25 weight % in the tetrahydrofuran (THF) (THF) and 20 parts of tetrahydrofuran (THF)s (THF), dissolve fully and the mixture homogeneous up to composition, solution is prepared.Employed antimicrobial quaternary ammonium polymer is similar to described in the embodiment A 14 those basically.Solution is poured on the flat non-stick frying pan, and allows dried overnight.Frying pan is placed on the surface of level to promote to form the film thickness of homogeneous.The exsiccant film is peeled from pot.The contrast film prepares in a similar manner; Yet it does not comprise anti-microbial polymer.Use the antimicrobial validity of ASTM " vibrator fask oscillating method " (test of ASTM E2149-antimicrobial surface, " antimicrobial acivity of immobilization biocide is determined under the kinetics contact conditions ") testing film.Test organism is MRSA (ATCC# BAA-44), and be 30 minutes duration of contact.Compare with non-processing film, the film with antimicrobial content shows that the bacterium with 5.4log reduces (all killing).Two films are similar on outward appearance and physical property.
Embodiment A 27: injection with urethane ball of anti-microbial polymer solution
Prepare such solution, contain 10g basically with antimicrobial quaternary ammonium polymer like the polymer phase described in the embodiment A 15, it is dissolved in 350mL THF and the 50mL alcoholic acid mixture.The urethane resin that in this solution, adds the ball form of approximate 3mm of 100g diameter and length 3mm.Suspension mixed on impeller spend the night.Absorb all solution at this time durations ball.Ball is dry under the situation of decompression and mild heat.Except the ball of handling is the slight yellow, the exsiccant ball is similar substantially to untreated ball in appearance.The evidence that does not have tangible visible residual anti-microbial polymer or coating.Use the antimicrobial validity of ASTM " vibrator fask oscillating method " (test of ASTM E2149-antimicrobial surface, " antimicrobial acivity of immobilization biocide is determined under the kinetics contact conditions ") test ball.Test organism is MRSA (ATCC# BAA-44), and be 30 minutes duration of contact.Compare with non-processing ball, the ball with antimicrobial content shows that the bacterium with 2.5log reduces.
Embodiment A 28: with of the processing of anti-microbial polymer solution to substrate
Substrate for example comprises for example thermoplastic polymer film water-insoluble quaternary ammonium anti-microbial polymer solution-treated that is dissolved in the suitable solvent of polyvinyl chloride, polycarbonate, polyacrylic ester or polystyrene; Wherein, suitable solvent and/or polymers soln can dissolve (all or part of), absorb the surface that enters or infiltrate through in other mode substrate.Described substrate can be passed through any suitable way, comprises that for example brush is smeared, sprayed or floods, with described solution-treated.After described processing, handled substrate drying to remove described suitable solvent, is stayed described water-insoluble quaternary ammonium anti-microbial polymer and injects, applies, adheres to, adheres to or infiltrate into substrate, give substrate with antimicrobial property.
Film validity test (TFET):
Sum up: based on [Bhende, S; Rothenburger, S; Spangler, D.J; In Vitro Assessment of Microbial Barrier Properties of Dermabond Topical Skin Adhesive. Surgical Infections 3 (3), 251-257 page or leaf (2002)] and developed film validity test (TFET) to determine the bacteriostasis of antibacterium solution.The process steps of TFET is formed with permission solution complete drying to the suitable growth culture plate by using antibacterium solution.Then with flat board with～1 * 10 -6The desired organism inoculation of CFU/ml, next overnight incubation after inoculum is absorbed fully.Check the bacteriostatic activity of application region then.
Dull and stereotyped: the culture medium flat plate that is used for this mensuration is for each organism appropriate selection culture medium flat plate.For each
Organism is used 60 flat boards.
MSA:MSA (sweet dew alkoxide agar) is the selection substratum of streptococcus aureus and MRSA.
EMB: EMB agar is colibacillary selection substratum.
EA: enterococcosel agar is the selection substratum of VRE.
Coating: 100 μ l antibacterium solution are applied to each flat board and allow air-dry minimum in the Biosafety cupboard before inoculation
1 hour.
Inoculation: test organism grows in the suitable growth medium and overnight incubation, unless otherwise indicated.Inoculate
Reach 10 6The titre of CFU/ml.The flat board that will apply is inoculated with 1000 μ l bacterial solutions then, and is logical then
Cross and move flat board with circumferential motion inoculum is used equably.
Contact: sample is cultivated and be to spend the night duration of contact in 37 ℃ in the high humidity case, unless otherwise indicated.
Result: after cultivating, check each dull and stereotyped bacteriostatic activity of going up the application region.The result be expressed as by/failure.As
Fruit is growth not, then flat board be expressed as by, if in the zone growth is arranged, then flat board is expressed as failure.
TFET-result:
Embodiment T1
Film validity test (TFET) is used for determining the bacteriostasis of antimicrobial solutions.The process steps of TFET is made up of following: use used therein the selected antimicrobial solutions of 100 μ l at the growth medium flat board at dull and stereotyped center as carrier.Before inoculation, allow air-dry minimum 1 hour of antimicrobial solutions.Coated flat board with 1000 μ l inoculums with 10 6The titre inoculation of CFU/ml.By dull and stereotyped vortex is covered dull and stereotyped whole surface fully up to inoculum, inoculum is evenly used.Make the dull and stereotyped dry of inoculation then, next in 37 ℃ of following overnight incubation.After incubated overnight, check of the inhibition of antimicrobial solutions application region, and the result is expressed as by/failure to bacterial growth.If observe growth-inhibiting, then flat board be considered to by.If do not observe the inhibition of growth, then flat board is considered to failure.The substratum that uses for streptococcus aureus ATCC #6538 is that sweet dew alkoxide agar (MSA) and employed antimicrobial solutions are H3-C (from embodiment A 6).Result for streptococcus aureus is as follows:
Figure BPA00001216315000321
Embodiment T2:
Embodiment T2 uses X-1497 resistance streptococcus aureus (MRSA, ATCC #BAA-44) as test organism, and reuses MSA as growth medium.Result for MRSA is as follows:
Figure BPA00001216315000322
Embodiment T3:
Embodiment T3 use intestinal bacteria ATCC #15597 is as test organism and in addition, EMB agar is as growth medium.
As follows for colibacillary result:
Figure BPA00001216315000323
Embodiment T4:
Embodiment T4 uses vancomycin resistance faecalis (VRE, ATCC # 700221) as test organism, and uses enterococcosel agar as growth medium in addition.
Result for VRE is as follows:
Figure BPA00001216315000331
Embodiment T5:
Embodiment T5 uses H-1 preparation (seeing embodiment A 3) as antimicrobial solutions.
Result for streptococcus aureus is as follows:
Embodiment T6:
Embodiment T6 also uses the H-1 preparation as antimicrobial solutions.
As follows for colibacillary result:
Figure BPA00001216315000333
Comparing embodiment T7:
In order to compare with composition of the present invention, (Aquagen International is Inc.) as antimicrobial solutions for the hand hygiene sterilizing agent of embodiment T7 use trade mark Zero.
Result for streptococcus aureus is as follows:
Figure BPA00001216315000334
Comparing embodiment T8:
In order to compare with composition of the present invention, embodiment T8 also uses the hand hygiene sterilizing agent of trade mark Zero as antimicrobial solutions.
As follows for colibacillary result:
Figure BPA00001216315000335
Comparing embodiment T9:
In order to compare with composition of the present invention, (GOJO Industries is Inc.) as antimicrobial solutions for the hand hygiene sterilizing agent of embodiment T9 use trade mark Purell.
Result for streptococcus aureus is as follows:
Comparing embodiment T10:
In order to compare with composition of the present invention, embodiment T10 also uses the hand hygiene sterilizing agent of trade mark Purell, and (GOJO Industries is Inc.) as antimicrobial solutions.
As follows for colibacillary result:
Figure BPA00001216315000342
Carrier persistence test (CPT):
Sum up: the modification that this process is the standard openating procedure to EPA---test of the anti-streptococcus aureus of spraying sterilizing agent, Pseudomonas aeruginosa and Mycobacterium bovis (Mycobacterium bovis)---; It is to determine the validity as the anti-Mycobacterium bovis of sprays product (BCG), Pseudomonas aeruginosa and three kinds of test organisms of streptococcus aureus of crust sterilizing agent to the modification of AOAC method.
The process steps of CPT is made up of following: use antimicrobial test soln to selected carrier, and made carrier drying before with suitable test organism inoculation carrier.After inoculation, the carrier cultivation is reached specified duration of contact, next place neutralization solution, serial dilution and spread plate are used to use standard method that validity is carried out quantitatively then.
Carrier: carrier is 25cm 2And can comprise multiple material.By being suitable for carrier components
Method carrier is sterilized.Three kinds of bearer types that use in these are measured are borosilicates
Silicate glass, Vitro-Skin and pigskin skin; Yet, suitable use in the method
Carrier be not limited to above-mentioned these.
Borosilicate borosilicate glass slide glass cleans with ethanol and makes it air-dry.After drying, boron
Glass: the silicate glass slide glass placed culture dish and autoclaving 15 minutes.
Vitro-Skin: the specification sheets according to the manufacturer prepares Vitro-Skin.If Vitro-Skin becomes non-
Aseptic, then need alcohol sterilization, dry and according to manufacturer's specification sheets with 70%
Rehydration.Directly (IMS Inc., Orange CT) buy Vitro-Skin from the manufacturer.
VITRO-SKIN is the advanced test substrate of effective anthropomorphic dummy's skin surface characteristic.Its
Comprise the protein and the fat composition of optimization, and be designed to have similar to human skin
Pattern, pH, critical surface tension and ionic strength.
The pigskin skin: the pigskin skin is sterilized with 70% alcohol.This process comprises with 70% alcohol thoroughly wetting year
Body also makes carrier air-dry fully in Biosafety cupboard (BSC).As alternatives,
The pigskin skin can be exposed to UV light following 10 minutes.Fresh pigskin skin is from Tu of locality
Kill a purchase.
Use: antimicrobial solutions is applied to each carrier up to its complete moistening carrier.Liquor capacity
1000 μ l should be no more than and 20 μ l will be not less than.Then before inoculation,
Made antimicrobial solutions among the BSC air-dry minimum 1 hour.
Inoculation: test organism is grown in the suitable growth substratum and in 37 ℃ of following overnight incubation,
Unless otherwise indicated.Make inoculum produce 10 8The titre of CFU/ml.Then, take
The carrier of band antimicrobial solutions is with the inoculum inoculation of 10 μ l-20 μ l.Use is to connect
Planting the saturated sterile swab of thing is distributed inoculum.Duration of contact is upright after inoculation
Carve beginning.
The contact: be to spend the night duration of contact, unless otherwise indicated, and in the high humidity case in 37 ℃
Following culture sample.
Neutralization: before reclaiming organism, will neutralize to stop antimicrobial solutions through the carrier of inoculation
Antimicrobial acivity.All neutralizations all in the conical centrifuge tube of 50ml with
The 20ml aliquots containig of Letheen meat soup was carried out 10 minutes at least, unless say in addition
Bright.
Reclaim: the beginning organism is reclaimed in the neutralization pipe.Through neutral carrier vortex 1 minute, subsequently
Reclaim with standard series dilution and dull and stereotyped inoculation method.Flat board was cultivated under 37 ℃
Night, and in inferior ration colony forming unit.
Contrast: the carrier substrates of not using any antimicrobial overlay is used as negative control to determine
The baseline microorganism growth.Control substrate has with basic as test in each sample sets
The component that the end is identical.The colony count of record control substrate.
Calculate: use Microsoft Excel spreadsheet to pass through computer calculates.Electronic chart
The electronic edition of software and hard copy will keep.
Calculate the CFU/mL of each carrier:
[(for 10 -wAverage CFU)+(for 10 -xAverage CFU)+(for 10 -yAverage CFU)+(for 10 -zAverage CFU)]/(10 -w+ 10 -x+ 10 -y+ 10 -z)
Wherein 10 -w, 10 -x, 10 -yWith 10 -zIt is the extent of dilution that carries out dull and stereotyped coating.One or more extent of dilution obtain greater than 300 or situation less than 30 plate count under, the extent of dilution of these countings and their correspondences will not use in calculating.Reach under 300CFU or the situation still less at the counting that a flat board is only arranged in the middle of two flat boards, then this plate count and corresponding extent of dilution thereof will be included, but uncertain mean value.
Attention: be that 0 plate count is included in during all calculate.
Calculating Log reduces:
LR=Log[(is for the CFU/ml that handles carrier)/(for the CFU/ml of control vector)]
Carrier persistence test-result:
Embodiment C 1:
10% solution of H-1 anti-microbial polymer (seeing embodiment A 3) is applied to borosilicate glass slide glass carrier.Use head of pipette 250 μ l NimbuDerm H-1 to be applied in equably the 25cm of glass slide carrier 2On the surface.Before inoculation, with glass slide carrier drying at least 1 hour.With 10 of 10 μ l 8The inoculum inoculation carrier of CFU/ml is to guarantee 10 6The target heap(ed) capacity of CFU/ml.Employed organism is streptococcus aureus ATCC #6538, and be 30 minutes duration of contact that allows.After contact, the glass slide carrier of inoculation places 20ml Letheen meat soup neutralization solution to be no less than 10 minutes so that neutralization fully---before use Letheen meat soup is cooled to 4 ℃.After neutralization, carrier in and meat soup mesoscale eddies 1 minute to promote the recovery of organism.The recovery of live organism is undertaken by standard series dilution and dull and stereotyped inoculation method.
The result is as follows:
Streptococcus aureus control vector population: 3.20 * 10 6CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 30 minutes
Sample solution Log reduces
1 10％H-1 6.51 *
2 10％H-1 6.51 *
3 10％H-1 6.51 *
4 10％H-1 6.51 *
( *=all kill)
Embodiment C 2:
Except the duration of contact difference, Embodiment C 2 is identical with Embodiment C 1.Be 16 hours (contact of spending the night) duration of contact of using for Embodiment C 2.
The result is as follows:
Streptococcus aureus control vector population: 2.30E07CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 10％H-1 7.36 *
2 10％H-1 7.36 *
3 10％H-1 7.36 *
4 10％H-1 7.36 *
5 10％H-1 7.36 *
6 10％H-1 7.36 *
( *=all kill)
Embodiment C 3:
Except the organism difference, Embodiment C 3 is identical with Embodiment C 2.Employed organism is intestinal bacteria ATCC 15597.
The result is as follows:
Intestinal bacteria control vector population: 1.06E05CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 10％H-1 5.03 *
2 10％H-1 5.03 *
3 10％H-1 5.03 *
4 10％H-1 5.03 *
5 10％H-1 5.03 *
6 10％H-1 5.03 *
( *=all kill)
Embodiment C 4:
Except the carrier difference, Embodiment C 4 is identical with Embodiment C 3.Employed carrier is Vitro-Skin.
The result is as follows:
Intestinal bacteria control vector population: 2.87E06CFU/ml
Carrier: Vitro-Skin
Duration of contact: 16 hours
Sample solution Log reduces
1 10％H-1 6.46 *
2 10％H-1 6.46 *
3 10％H-1 6.46 *
4 10％H-1 6.46 *
5 10％H-1 6.46 *
6 10％H-1 6.46 *
( *=all kill)
Embodiment C 5:
10% solution of H-3 anti-microbial polymer (seeing embodiment A 6) is applied to borosilicate glass slide glass carrier.Use head of pipette 250 μ l H-3 (10% polymer content) to be applied in equably the 25cm of glass slide carrier 2On the surface.Before inoculation, with glass slide carrier drying at least 1 hour.With 10 of 10 μ l 8The inoculum inoculation carrier of CFU/ml is to guarantee 10 6The target heap(ed) capacity of CFU/ml.Employed organism is streptococcus aureus ATCC #6538, and be 30 minutes duration of contact that allows.After contact, the glass slide carrier of inoculation places 20ml Letheen meat soup neutralization solution to be no less than 10 minutes so that neutralization fully.Before use Letheen meat soup is cooled to 4 ℃.After neutralization, carrier in and meat soup mesoscale eddies 1 minute to promote the recovery of organism.The recovery of live organism is undertaken by standard series dilution and dull and stereotyped inoculation method.
The result is as follows:
Intestinal bacteria control vector population: 1.06E05CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 10％H-3 5.03 *
2 10％H-3 5.03 *
3 10％H-3 5.03 *
4 10％H-3 5.03 *
5 10％H-3 5.03 *
6 10％H-3 5.03 *
( *=all kill)
Embodiment C 6:
Except the carrier difference, Embodiment C 6 is identical with Embodiment C 5.Employed carrier is Vitro-Skin.
The result is as follows:
Intestinal bacteria control vector population: 2.87E06CFU/ml
Carrier: Vitro-Skin
Duration of contact: 16 hours
Sample solution Log reduces
1 10％H-3 6.46 *
2 10％H-3 6.46 *
3 10％H-3 6.46 *
4 10％H-3 6.46 *
5 10％H-3 6.46 *
6 10％H-3 6.46 *
( *=all kill)
Embodiment C 7:
Except skin health disinfectant solution concentration difference, Embodiment C 7 is identical with Embodiment C 5.Concentration with H3-C skin health sterilizing agent is reduced to 7% now.
The result is as follows:
Intestinal bacteria control vector population: 2.50E06CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 7％H3-C 6.40 *
2 7％H3-C 6.40 *
3 7％H3-C 6.40 *
4 7％H3-C 6.40 *
5 7％H3-C 6.40 *
6 7％H3-C 6.40 *
( *=all kill)
Embodiment C 8:
Except the carrier difference, Embodiment C 8 is identical with Embodiment C 7.Employed carrier is Vitro-Skin.
The result is as follows:
Intestinal bacteria control vector population: 2.08E06CFU/ml
Carrier: Vitro-Skin
Duration of contact: 16 hours
Sample solution Log reduces
1 7％H3-C 6.32 *
2 7％H3-C 6.32 *
3 7％H3-C 6.32 *
4 7％H3-C 6.32 *
5 7％H3-C 6.32 *
6 7％H3-C 6.32 *
( *=all kill)
Embodiment C 9:
Except skin health disinfectant solution concentration difference, Embodiment C 9 is identical with Embodiment C 7.The concentration of H3-C skin health sterilizing agent further is reduced to 1% now.
The result is as follows:
Intestinal bacteria control vector population: 2.77E04CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 1％H3-C 4.44 *
2 1％H3-C 4.44 *
3 1％H3-C 4.44 *
4 1％H3-C 4.44 *
5 1％H3-C 4.44 *
6 1％H3-C 4.44 *
( *=all kill)
Embodiment C 10:
Except the organism difference, Embodiment C 10 is identical with Embodiment C 9.Employed organism is streptococcus aureus ATCC #6538.
The result is as follows:
Streptococcus aureus control vector population: 1.25E03CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 1％H3-C 3.10 *
2 1％H3-C 3.10 *
3 1％H3-C 3.10 *
4 1％H3-C 3.10 *
5 1％H3-C 3.10 *
6 1％H3-C 3.10 *
Embodiment C 11:
Except the organism difference, Embodiment C 11 is identical with Embodiment C 10.Employed organism is Pseudomonas aeruginosa ATCC #15442.
The result is as follows:
Pseudomonas aeruginosa control vector population: 3.93E06CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 1％H3-C 6.59 *
2 1％H3-C 6.59 *
3 1％H3-C 6.59 *
4 1％H3-C 6.59 *
5 1％H3-C 6.59 *
6 1％H3-C 6.59 *
( *=all kill)
Embodiment C 12:
1% solution of H3-C anti-microbial polymer is applied to borosilicate glass slide glass carrier.By with the saturated non-woven cleaning material of disinfecting agent solution (polyester/cotton flower) at 25cm 2Use the disinfecting agent solution through twice on the slide surface.Make the glass slide carrier that now applied drying at least 1 hour before inoculation.Then, with 10 8The glass slide of the inoculum inoculation coating of CFU/ml is to guarantee 10 6The target heap(ed) capacity of CFU/ml.Employed organism is intestinal bacteria ATCC 15597, and be 16 hours duration of contact that allows.After contact, the glass slide carrier of inoculation places 20ml Letheen meat soup neutralization solution to be no less than 10 minutes so that neutralization fully.Before use Letheen meat soup is cooled to 4 ℃.After neutralization, carrier in and meat soup mesoscale eddies 1 minute to promote the recovery of organism.The recovery of live organism is undertaken by standard series dilution and dull and stereotyped inoculation method.
The result is as follows:
Intestinal bacteria control vector population: 1.57E06CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 1％H3-C 6.19 *
2 1％H3-C 6.19 *
3 1％H3-C 6.19 *
4 1％H3-C 6.19 *
5 1％H3-C 6.19 *
6 1％H3-C 6.19 *
( *=all kill)
Embodiment C 13:
Except the organism difference, Embodiment C 13 is identical with Embodiment C 12.Employed organism is Pseudomonas aeruginosa ATCC #15442.
The result is as follows:
Pseudomonas aeruginosa control vector population: 4.70E06CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 16 hours
Sample solution Log reduces
1 1％H3-C 6.67 *
2 1％H3-C 6.67 *
3 1％H3-C 6.67 *
4 1％H3-C 6.67 *
5 1％H3-C 6.67 *
6 1％H3-C 6.67 *
( *=all kill)
Comparing embodiment C14:
(GOJO Industries Inc.) is applied to borosilicate glass slide glass carrier to the instant hand hygiene disinfectant solution of trade mark Purell.Use head of pipette 250 μ l Purell to be applied in equably the 25cm of glass slide carrier 2On the surface.Before inoculation, with glass slide carrier drying at least 1 hour.With 10 of 10 μ l 8The inoculum inoculation carrier of CFU/ml is to guarantee 10 6The target heap(ed) capacity of CFU/ml.Employed organism is streptococcus aureus ATCC #6538, and be 30 minutes duration of contact that allows.After contact, the glass slide carrier of inoculation places 20ml Letheen meat soup neutralization solution to be no less than 10 minutes so that neutralization fully.Before use Letheen meat soup is cooled to 4 ℃.After neutralization, carrier in and meat soup mesoscale eddies 1 minute to promote the recovery of organism.The recovery of live organism is undertaken by standard series dilution and dull and stereotyped inoculation method.
Streptococcus aureus control vector population: 1.02E05CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 30 minutes
Sample solution Log reduces
1 Purell 1.07
2 Purell 1.22
3 Purell 1.17
4 Purell 1.07
5 Purell 1.19
6 Purell 1.14
Comparing embodiment C15:
Except the organism difference, Embodiment C 15 is identical with Embodiment C 14.Employed organism is intestinal bacteria ATCC #15597.
The result is as follows:
Intestinal bacteria control vector population: 4.70E06CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 30 minutes
Sample solution Log reduces
1 Purell 0.89
2 Purell 0.50
3 Purell -1.46
4 Purell -4.95
5 Purell 0.75
Comparing embodiment C16:
Except the organism difference, Embodiment C 16 is identical with Embodiment C 14.Employed organism is Pseudomonas aeruginosa ATCC #15442.
The result is as follows:
Pseudomonas aeruginosa control vector population: 4.70E06CFU/ml
Carrier: borosilicate glass slide glass
Duration of contact: 30 minutes
Sample solution Log reduces
1 Purell 0.37
2 Purell 0.33
3 Purell 0.37
Embodiment C 17:
The material of embodiment A 9 (SS-1C) is applied to pigskin skin carrier.Use head of pipette 1000 μ l SS-1C to be applied in equably the 25cm of pigskin skin carrier 2On the surface.Before inoculation, with pigskin skin carrier drying at least 1 hour.With 10 of 20 μ l 8The inoculum inoculation carrier of CFU/ml is to guarantee 10 6The target heap(ed) capacity of CFU/ml.Employed organism is serratia marcescens ATCC #13380, and be 4 hours duration of contact that allows.After contact, the pigskin skin carrier of inoculation places 20ml Letheen meat soup neutralization solution to be no less than 10 minutes so that neutralization fully---before use Letheen meat soup is cooled to 4 ℃.After neutralization, carrier in and meat soup mesoscale eddies 1 minute to promote the recovery of organism.The recovery of live organism is undertaken by standard series dilution and dull and stereotyped inoculation method.
The result is as follows:
Serratia marcescens control vector population: 1.18E07CFU/ml
Carrier: pigskin skin
Duration of contact: 4 hours
Sample solution Log reduces
1 10％SS-C 7.07
2 10％SS-C 7.07
3 10％SS-C 7.07
Embodiment C 18:
Except the organism difference, Embodiment C 18 is identical with Embodiment C 17.Employed organism is intestinal bacteria ATCC 8739.
The result is as follows:
Intestinal bacteria control vector population: 1.54E07CFU/ml
Carrier: pigskin skin
Duration of contact: 4 hours
Sample solution Log reduces
1 10％SS-C 7.19
2 10％SS-C 7.19
3 10％SS-C 7.19
Embodiment C 19:
Except the organism difference, Embodiment C 19 is identical with Embodiment C 17.Employed organism is MRSA (an X-1497 resistance streptococcus aureus).
The result is as follows:
MRSA control vector population: 2.63E07CFU/ml
Carrier: pigskin skin
Duration of contact: 4 hours
Sample solution Log reduces
1 10％SS-C 7.42
2 10％SS-C 7.42
3 10％SS-C 7.42
Embodiment C 20:
Except the organism difference, Embodiment C 20 is identical with Embodiment C 17.Employed organism is VRE (a vancomycin resistance faecalis).
The result is as follows:
VRE control vector population: 3.23E06CFU/ml
Carrier: pigskin skin
Duration of contact: 4 hours
Sample solution Log reduces
1 10％SS-C 6.51
2 10％SS-C 6.51
3 10％SS-C 6.51
Though described the present invention prevailingly, comprise the embodiment that it is best, skilled person in the art will appreciate that the present invention considers embodiment of the present invention and the equivalent thereof that limits as following claims.Yet, skilled person in the art will appreciate that scope of the present invention should judge by the appended claim book, rather than only judge by the particular of this paper institute illustration.Those skilled in the art will appreciate that also more the complicated technology progress might occur later on to Patent Office's proposition present specification.Improvement with regard to these back exploitations embodies disclosure core work principle, and these improvement considered to be within the scope of following claims equally.

Claims (52)

1. give the composition of substrate with lasting antimicrobial acivity, comprise the solvent that (1) is made up of glycol basically, the perhaps solvent of forming by the mixture of at least a two pure and mild at least a alcohol basically, (2) anti-microbial polymer, wherein said anti-microbial polymer comprises the monomer segment of the molecular structure that is covalently bond to described polymkeric substance, wherein said monomer segment has at least one quaternary ammonium group, wherein said anti-microbial polymer is easy dissolved in described solvent, but be undissolved in water, wherein said solvent serves as and is used for described anti-microbial polymer and described substrate bonded carrier, and wherein said antimicrobial acivity be can't help the antimicrobial metal material and provided.
2. the composition of claim 1, wherein said anti-microbial polymer comprises first kind of monomer segment and second kind of monomer segment, and wherein at least a described kind has at least one quaternary ammonium group.
3. the composition of claim 2, wherein said first kind of monomer segment are that the monomer segment and the described second kind of monomer segment that contain allyl group or vinyl are the monomer segments that contains allyl group or vinyl.
4. the composition of claim 1, wherein said monomer segment is the monomer segment that contains allyl group or vinyl.
5. the composition of claim 1, wherein said anti-microbial polymer use progressively polymerization synthetic.
6. the composition of claim 1, wherein said anti-microbial polymer is the polyether polyols with reduced unsaturation that comprises the monomer segment with at least one quaternary ammonium group, and described composition provides durable antimicrobial activity when described composition is applied to or is incorporated in the substrate thus.
7. the composition of claim 6, wherein for the described polyether polyols with reduced unsaturation of every 350g, at least one mole the described monomer segment with quaternary ammonium group is covalently bond to the molecular structure of polymkeric substance.
8. the composition of claim 1, wherein said anti-microbial polymer has 5 to 25,000 mean polymerisation degree.
9. the composition of claim 1, wherein said solvent are made up of one or more the glycol that is selected from glycerine, ethylene glycol, propylene glycol, butyleneglycol, pentanediol and their isomers and derivative basically.
10. the composition of claim 9, wherein said glycol accounts for the 60-95 weight % of described composition.
11. the composition of claim 1, wherein said solvent is made up of the mixture that comprises at least a two pure and mild at least a alcohol basically, wherein said alcohol is selected from methyl alcohol, ethanol and Virahol, and wherein said glycol is selected from glycerine, ethylene glycol, propylene glycol, butyleneglycol, pentanediol and their isomers and derivative.
12. the composition of claim 11, wherein said mixture account for the 60-95 weight % of described composition.
13. the composition of claim 1, wherein said anti-microbial polymer can not enter the contacting with fluid from substrate leaching, wash-out or release with the level that causes fluid disinfection.
14. the composition of claim 1, wherein said anti-microbial polymer are colourless, tasteless or not only colourless but also tasteless.
15. the composition of claim 1, wherein said composition has the pH between 5 and 9.
16. the composition of claim 1, wherein said composition is for being selected from liquid, gel, foam and aerocolloidal form.
17. the composition of claim 1 also comprises the biocide that can leach.
18. the composition of claim 17, wherein said biocide is selected from quaternary ammonium salt, biguanides and phenolic compound.
19. the composition of claim 18, wherein said biocide is selected from benzalkonium chloride, benzethonium chloride, didecyldimethylammonchloride chloride and composition thereof.
20. the composition of claim 18, wherein said biocide is selected from chlorhexidine and poly hexamethylene biguanide.
21. the composition of claim 18, wherein said biocide is selected from phenol and trichlorophenol.
22. the composition of claim 1 also comprises tenderizer.
23. the composition of claim 22, wherein said tenderizer are selected from glycerine (glycerol), ethylene glycol, propylene glycol, butyleneglycol, pentanediol, dipropylene glycol, polypropylene glycol, polyoxyethylene glycol, mineral oil, Fatty Alcohol(C12-C14 and C12-C18), lanolin, siloxanes, Wickenol 111, squalane, glycerine (glycerin), its isomers or derivative and above-mentioned mixture arbitrarily.
24. the composition of claim 23, wherein said lanolin are the ethoxylation ethanoyl alcohol derivate of lanolin or the surfactivity alcohol derivate of lanolin, and wherein said siloxanes is Simethicone, cyclomethicone or Simethicone.
25. the composition of claim 1, also comprise at least a additive that is selected from medicine, biocide, sanitas, thickening material, moistening agent, tenderizer, VITAMIN, interim dyestuff, permanent dyestuff and UV absorption agent, described thus composition is adapted at using on human or animal's skin.
26. the composition of claim 25, wherein said interim dyestuff or described permanent dyestuff are attached to described anti-microbial polymer by the covalent chemical bonding, prevent that thus dye migration from going out polymkeric substance.
27. the composition of claim 26, wherein said dyestuff is a fluorescein.
28. the composition of claim 1, wherein said composition also comprises thickening material.
29. the composition of claim 28, wherein said thickening material comprises Natvosol or ether of cellulose.
30. the composition of claim 1, wherein described composition produces the streptococcus aureus minimizing of 3-log at least when using the CPT testing method.
31. the composition of claim 1, wherein described composition produces the Pseudomonas aeruginosa minimizing of 3-log at least when using the CPT testing method.
32. the method for sterilization substrate comprises step:
A. the set of applications compound is to described substrate, wherein said composition comprises the solvent that (1) is made up of glycol basically, the perhaps solvent of forming by the mixture of at least a two pure and mild at least a alcohol basically, (2) anti-microbial polymer, wherein said anti-microbial polymer comprises the monomer segment of the molecular structure that is covalently bond to described polymkeric substance, wherein said monomer segment has at least one quaternary ammonium group, wherein said anti-microbial polymer is easy dissolved in described solvent, but be undissolved in water, described thus solvent serves as the carrier that the described antimicrobial polymer compositions of antimicrobial acivity is provided to described substrate, and wherein said antimicrobial acivity be can't help the antimicrobial metal material to be provided
B. make described substrate drying with remove described solvent and
C. on the surface of described substrate, stay described anti-microbial polymer, give described substrate durable antimicrobial activity thus.
33. the method for claim 32, wherein said substrate are human or animal's skin.
34. the method for claim 33, wherein said solvent is a glycol.
35. the method for claim 33, wherein the application of step a, b and c occurs in before medical procedures or the animal doctor's process.
36. the method for claim 33, wherein said substrate are the poly-units that is selected from medical treatment device and household supplies.
37. the method for claim 33, wherein said substrate are fabric, timber or paper.
38. make the method for antimicrobial article, comprise step:
A. prepare composition, wherein said composition comprises (1) basically by acetone, methyl ethyl ketone, tetrahydrofuran (THF), ethyl acetate, ether, ester, benzene, toluene, carbonic ether, hydrocarbon, chlorinated hydrocarbon, alcohol, the solvent that glycol or its mixture are formed, (2) anti-microbial polymer, wherein said anti-microbial polymer comprises the monomer segment of the molecular structure that is covalently bond to described polymkeric substance, wherein said monomer segment has at least one quaternary ammonium group, wherein said anti-microbial polymer is easy dissolved in described solvent, but be undissolved in water, and wherein said antimicrobial acivity can't help that the antimicrobial metal material provides and
B. use described composition to described substrate, the all or part of injection of wherein said composition, be absorbed into, infiltrate or mix described substrate in other mode, described thus anti-microbial polymer is impregnated, inject, apply, adhere to, adhere to or infiltrate into described substrate, and described thus anti-microbial polymer is given described article with antimicrobial acivity.
39. the method for claim 38, wherein said solvent are made up of ether and alcohol, glycol basically, perhaps described solvent is made up of the mixture of at least a two pure and mild at least a alcohol basically.
40. the method for claim 38, wherein the curable coating composition of UV is polymeric plate or film with the described substrate of combination of described antimicrobial composition and step b in step a.
41. the method for claim 38, wherein said substrate are the cosmetic formulations that comprises described anti-microbial polymer.
42. the method for claim 38 also comprises step:
Described substrate drying is desolvated to remove, and described anti-microbial polymer is retained in the described substrate when the contact aqueous fluids thus.
43. the method for claim 42, wherein said substrate are polymkeric substance, fabric, timber or paper.
44. the method for claim 42, wherein said substrate are suture line or wound dressing.
45. the method for claim 38 also comprises step:
C. form the article that are selected from film, fiber, gel, foam, tackiness agent, sealing agent, spackling, pipe, plate, rod, overlay or powder from described substrate, wherein said article comprise described anti-microbial polymer therein.
46. the method for claim 45, wherein said article are the wound dressings that comprise anti-microbial polymer.
47. the method for claim 45, wherein said article are the suture lines that comprise anti-microbial polymer.
48. the method for claim 45, wherein said article are the tackiness agents that comprise anti-microbial polymer.
49. improve the method for the validity of the composition comprise the basad anti-microbial polymer that rapid action and persistence antimicrobial acivity be provided, wherein said anti-microbial polymer comprises the monomer segment of the molecular structure that is covalently bond to described polymkeric substance, wherein said monomer segment has at least one quaternary ammonium group, wherein said anti-microbial polymer is also to comprise basically by alcohol, the composition of the composition of the solvent that glycol or its mixture are formed, and wherein said anti-microbial polymer is dissolving easily in described solvent, and wherein said antimicrobial acivity be can't help the antimicrobial metal material to be provided, and it comprises step: strengthen water-based solubleness until the total polymer weight of described anti-microbial polymer 50% solvable.
Mix hydrophilic unit 50. the method for claim 49, wherein said enhancing comprise in described anti-microbial polymer, described thus hydrophilic unit has increased the solubleness of described anti-microbial polymer in aqueous medium.
51. the method for claim 49, wherein said hydrophilic unit are by two (2-hydroxyethyl) ether and Toluene-2,4-diisocyanate, 4-vulcabond (TDI) reaction produces-CH 2-CH 2-O-CH 2-CH 2-unit.
52. the method for claim 49, wherein said enhancing comprises producing to have the anti-microbial polymer that can reach 100 mean polymerisation degree, and the solubleness of described thus anti-microbial polymer in aqueous medium is higher than the solubleness of the polymkeric substance with higher mean polymerisation degree.
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