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WO2008031105A1 - Germicides à base de sel d'un polymère de guanidine - Google Patents

Germicides à base de sel d'un polymère de guanidine Download PDF

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Publication number
WO2008031105A1
WO2008031105A1 PCT/US2007/078057 US2007078057W WO2008031105A1 WO 2008031105 A1 WO2008031105 A1 WO 2008031105A1 US 2007078057 W US2007078057 W US 2007078057W WO 2008031105 A1 WO2008031105 A1 WO 2008031105A1
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WIPO (PCT)
Prior art keywords
composition
agent
agents
antimicrobial
teat
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PCT/US2007/078057
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English (en)
Inventor
Fahim U. Ahmed
Alex Skender
Chris Foret
Thomas C. Hemling
N. Camelia Traistaru
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Delaval Holdings Ab
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Publication of WO2008031105A1 publication Critical patent/WO2008031105A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention pertains to biocide compositions of the type that may be used to control or destroy pathogenic microorganisms. More particularly, various antimicrobial agents are shown to work with cooperative effects against microorganisms in a wide variety of applications.
  • Antimicrobial compositions are used to reduce the risk of infection.
  • antimicrobials are used to disinfect surfaces in hospitals, lavatories, food preparation facilities, and offices.
  • Other uses include the control of pathogenic organisms on skin. They may be used on human skin to reduce the transmission of disease or infection, as surgical scrub solutions, or hand sanitizers.
  • the compositions may also be used in veterinary applications for the control or prevention of hoof diseases and mastitis. Prevention of mastitis is also a major goal of the dairy industry. Contact of the bovine or ovine mammary gland with pathogenic microorganisms, usually bacteria but occasionally yeast or fungi, can result in the disease of mastitis.
  • Mastitis is the single most costly disease affecting the dairy industry. Annual economic losses due to mastitis approximate $185 per dairy animal. This totals to approximately $1.7 billion annually for the entire United States market. Mastitis is always a potentially serious infection. Severe cases may cause death to the dairy animal. Milder cases are more common, but may have serious consequences, such as long term damage to the animal, loss of milk production for the dairy farmer and an unacceptable increase in veterinary costs.
  • commercial teat dips have been developed which are usually administered to the teat by dipping, foaming, or spraying the teat prior to milking as well as after removal of the milking cup. Teat dips applied subsequent to milking may form a thick composition, film or barrier that remains on the teat until the next milking, which is generally 8 to 12 hours later.
  • non-barrier teat dips may be divided into two primary classifications, namely, non-barrier and barrier dips.
  • the non-barrier teat dips are strictly antimicrobial and are applied to kill microorganisms on the surface of the teat skin.
  • the barrier dips may also be antimicrobial and are applied to form a prophylactic film or coating that may prevent microbes from contacting the teat.
  • Teat dips have used a variety of antimicrobial agents.
  • United States Patent No. 2,739,922 issued to Shelanski describes the use of polymeric N- vinyl pyrrolidone in combination with iodophors.
  • United States Patent No. 3,993,777 issued to Caughman et al. describes the use of halogenated quaternary ammonium compounds.
  • United States Patent No. 4,199,602 issued to Lentsch describes the use of iodophors, chlorine releasing compounds (e.g. alkali hypochlorite), oxidizing compounds (e.g. hydrogen peroxide, peracids), protonated carboxylic acids (e.g.
  • teat dip agents suffer from serious drawbacks.
  • iodine, hypochlorite, chlorine dioxide, and hypochlorous acid are powerful disinfectants and strong oxidants, but they are also particularly noxious for both humans and animals. Additionally, the use of overly powerful disinfectants may contribute to the mastitis problem by causing irritation of the teat skin, thus providing an opportunistic site which promotes infection.
  • the Lentsch '602 patent recognizes that iodophors and such chlorine-based biocides as hypochlorite, chlorine dioxide, and hypochlorous acid have achieved the widest commercial acceptance; however, teat dips of the future may have to be iodine- free.
  • iodine-based and chlorine-based compositions may induce sensitized reactions in cow teats.
  • Other biocides including chlorhexidine have become the focus of regulatory concern.
  • teat dip agents such as fatty acids and anionic surfactants, are often not broad enough in their antibacterial spectrum to provide complete germicidal protection.
  • the invention is an antimicrobial composition
  • a polymeric-guanidine salt-based antimicrobial agent In one embodiment the composition is adapted for topical applications on an animal. In another embodiment, the formulation is used as part of a teat-dip process.
  • an antimicrobial liquid composition that contains a cationic guanidine agent.
  • the agent includes at least one polymeric cationic guanidine salt.
  • the positively charged polymer includes at least one of Poly(HexaMethylenediamine) Guanidinium hydrochloride (PHMG) and Poly[2-(2-Ethoxy)-Ethyl] Guanidinium hydrochloride (PEEG).
  • the agent includes both PHMG and PEEG as a mixture.
  • PHMG and PEEG mixtures in some embodiments, can be in weight ratios from of 1 : 100 PHMG to PEEG to 100:1 PHMG to PEEG.
  • the ratios can be from 1 :20 PHMG versus PEEG to 20: 1 PHMG to PEEG. In still other embodiments, the PHMG versus PEEG weight ratios could be from 1 : 10 to 10: 1.
  • the biocides are a mixture of about a 3:1 ratio of PHMG salts and PEEG salts, and the mixture is readily commercially available under the trade name Akacid Plus ® .
  • Akacid Plus ® is manufactured and commercially available from P. O. C. Oil Industry Technology officialssges m.b.H. in Vienna, Austria. General support for biocide polymers based on guanidine salts can be found in U.S. Patent No. 7,001,606.
  • the antimicrobial liquid composition is applied topically. In other embodiments, the composition is applied as part of a teat-dip application. In yet further embodiments, the activity of the compositions is enhanced by maintaining pH levels higher than 8. In other embodiments, the compositions are used along with a surfactant. In still further embodiments, the compositions are used with a surfactant, and the pH level is enhanced to be between 8 and 10. In still further embodiments, the compositions are used with pH higher than 10 in hard surface applications.
  • the Akacid Plus ® biocide product is advantageous in that it is supported by European Biocidal Products Directive (BPD). Further, it has a broad antimicrobial spectrum covering hundreds of important strains of pathogens, fungi, and possibly viruses.
  • BPD European Biocidal Products Directive
  • the product is particularly useful because it is non-toxic for humans, animals, and plants at moderate doses. Additionally, it is neutralized in anionic surroundings or soil, and thus, is biodegradable. Further, it is not irritating to the body surfaces, mucosa, or the eyes. Additionally, the product is easy to handle and store, and can be used in nebulizers.
  • the antimicrobial is included in a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may, for example, be water.
  • the antimicrobial may be included in a carrier-reduced or carrier-free concentrate.
  • the carrier may include one or more additives selected from a buffering agent, an emollient, a humectant, a preservative, a barrier forming agent, a surfactant or wetting agent, a viscosity control agent, a colorant, an opacifying agent, and any combinations thereof.
  • the antimicrobial compositions provide a substantial reduction in Gram positive and Gram negative bacteria, as well other numerous classes of microbes.
  • the reduction may be on the order of a three or four log reduction or a substantially complete kill that is greater than a five log (99.999%) reduction.
  • the kill counts could be higher or lower.
  • a broader object of the disclosed instrumentalities is to provide biocide compositions that may be used, for example, according to any purpose for antibacterial or bactericidal properties.
  • the composition is intended to be used as a teat dip.
  • the composition is intended to be used as a foaming agent, hand sanitizer, a skin cleanser, a surgical scrub, a wound care agent, a disinfectant, a mouthwash, bath/shower gel, a hard surface sanitizer and the like.
  • the compositions for skin applications have a pH of about 4 to about 12.
  • the composition could have a pH in the range of about 5 to 11.
  • the compositions are adapted to have pH's in the range of about 6 to 10. Different uses, however, may make pH targets stray significantly from these ranges in other embodiments.
  • Methods of preparing compositions may involve dissolving a desired concentration of the antimicrobial and, optionally, any desired additives in a selected pharmaceutical carrier. The solution is then mixed, for example in a mixer, to form a final antimicrobial composition.
  • the composition is useable on a subject.
  • the term "subject” shall include humans and terrestrial animals.
  • the subject can be a domestic livestock species, a laboratory animal species, a zoo animal, a companion animal or a human.
  • "subject” refers more specifically to any lactating animal.
  • the subject is a cow.
  • terapéuticaally effective amount is intended to qualify the amount of the topical composition which will achieve the goal of decreased microbial concentration. “Therapeutically effective” may also refer to improvement in disorder severity or the frequency of incidence over no treatment.
  • additive shall mean any component that is not an antimicrobial agent or a pharmaceutical carrier.
  • a pharmaceutical carrier is generally a bulk solvent used to dilute or solubilize the components of the composition. In embodiments, this carrier is water.
  • pan dip or "teat dipping” shall be interpreted broadly and in accordance with the terminology used in the art of dairy farming.
  • the composition is not only intended for dipping of the teats but it can, of course, be applied in other ways, such as by spraying or foaming and still fall within the recognized terms teat dip or teat dipping composition or agent.
  • the term "antimicrobial” describes a biocidal effect that may be, for example, an antibacterial, antifungal, antiviral, bacteriostatic, disinfecting, or sanitizing effect.
  • the polymeric guanidine salt- based agent e.g., Akacid Plus ®
  • the polymeric guanidine salt- based agent can be used to make effective biocide compositions suitable for topical applications.
  • This antimicrobial may be formulated using additional antimicrobial agents, barrier-forming agents, viscosity control agents, pH adjusting agents, wetting agents, opacifying agents, and carriers to make a wide variety of products.
  • antimicrobial ingredients may be formulated using additional antimicrobial agents, barrier-forming agents, foaming agents, viscosity control agents, pH adjusting agents, wetting agents, opacifying agents, chelating agents, skin conditioning agents and carriers to make a wide variety of products.
  • Traditional antimicrobial agents are the components of a composition that destroy microorganisms or prevent or inhibit their replication.
  • the polymeric guanidine salt-based antimicrobial embodiments discussed above may be used to replace or eliminate the need for traditional antimicrobial agents in a wide variety of applications.
  • antimicrobial compositions according to the disclosed embodiments below may be used in combination with these traditional antimicrobial agents, for example, to achieve an effective kill at lower concentrations of traditional antimicrobial agents.
  • Traditional antimicrobial agents include iodophors, quaternary ammonium compounds, hypochlorite releasing compounds (e.g. alkali hypochlorite, hypochlorous acid), oxidizing compounds (e.g. peracids and hypochlorite), protonated carboxylic acids (e.g. heptanoic, octanoic, nonanoic, decanoic, undecanoic acids), acid anionics (e.g.
  • Phenolic antimicrobial agents may be chosen from 2,4,4 '-trichloro-2'- hydroxydiphenylether, which is known commercially as Triclosan and may be purchased from Ciba Specialty Chemicals as IRGASANTM and IRGASAN DP 300TM.
  • Another such antimicrobial agent is 4-chloro-3,5-dimethyl phenol, which is also known as PCMX and is commercially available as NIPACIDE PX and NIPACIDE PX-P.
  • Other traditional germicides include formaldehyde releasing compounds such as glutaraldehyde and 2-bromo-2-nitro-l,3-propanediol (Bronopol), polyhexamethyl biguanide (CAS 32289-58-0), guanidine salts such as polyhexamethylene guanidine hydrochloride (CAS 57028-96-3), polyhexamethylene guanidine hydrophosphate (89697-78-9), and poly[2-(2-ethoxy)-ethoxyethyl]-guanidinium chloride (CAS 374572-91-5) and mixtures thereof.
  • the disclosed germicides may be used in combination with traditional germicides such as copper sulfate, zinc sulfate, sulfamethazine, quaternary ammonium compounds, hydrogen peroxide and/or peracetic acid, for example, to achieve an effective kill at lower concentrations of traditional germicides.
  • traditional germicides such as copper sulfate, zinc sulfate, sulfamethazine, quaternary ammonium compounds, hydrogen peroxide and/or peracetic acid, for example, to achieve an effective kill at lower concentrations of traditional germicides.
  • Barrier and film forming agents are those components of a teat dipping composition that remain in contact with the teat between milking cycles. Barrier and film forming agents coat the teat skin and, optionally, the udder. Barrier agents may form a plug at the end of the open teat canal.
  • Typical barrier and film forming agents include thick creams or emollients (made with viscosity control agents), films, polymers, latex and the like.
  • Some nonionic surfactants may help further enhance the barrier properties of a composition, in addition to contributing to surface wetting. Examples of such surfactants may include, without limitation, polyoxyethylene-polyoxypropylene glycol (marketed as Pluronic F 108). Another commonly used barrier agent is marketed as Pluronic P 105.
  • Suitable barrier forming agents include, for example, latex, arabinoxylanes, glucomannanes, guar gum, johannistree gums, cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, starch, modified starch, hydrolyzed starch, hydroxyethyl starch, gum arabic, curdlan, pullulan, dextran, polysulfonic acid, polyacrylamide, high molecular weight polyacrylate, high molecular weight cross-linked polyacrylate, carbomer, glycerol, sodium alginate, sodium alginate cross-linked with calcium salt, xanthan gum, poly( vinyl alcohol) (PVA) and poly(N-vinylpyrrolidone) (PVP).
  • PVA vinyl alcohol
  • PVP poly(N-vinylpyrrolidone
  • Preferred embodiments for barrier- forming agents include xanthan gum, carboxymethyl cellulose, sodium alginate, sodium alginate cross-linked with calcium salt, PVA, hydroxyethyl cellulose, PVP, and (2,5-dioxo-4-imidazolidinyl)-urea (Allantoin).
  • a foaming agent may be used in the disclosed antimicrobial compositions.
  • a foaming agent aerates a liquid composition to produce foam that may increase surface area of the composition and improve contact with the surface to be treated (e.g., an animal hoof).
  • a foaming agent is in the form of a compressed gas, or a material that will decompose to release gas under certain conditions. Suitable gases include but are not limited to nitrogen, argon, air, carbon dioxide, helium and mixtures thereof.
  • solid carbon dioxide (dry ice), liquid nitrogen, hydrogen peroxide and other substances that release gas via a change in state or through decomposition are contemplated for use with the present compositions.
  • a high foaming surfactant such as sodium lauryl sulfate, dodecylbenzene sulfonic acid, sodium alkylaryl polyether sulfate, sodium lauryl ether sulfate, sodium decyl sulfate, cocamine oxide, Ci 2 - Ci 4 whole coconut amido betaines can be used to generate a stable foam.
  • the foam is produced when agitation in the form of a compressed gas is mixed with the solution either by bubbling the gas into the solution or spraying the solution or solution-gas mixture through spray equipment.
  • gases include but are not limited to nitrogen, air, carbon dioxide and mixtures thereof.
  • Foam can also be generated by the mechanical action of animals walking through the composition, or by other mechanical means that mix atmospheric air with the composition.
  • the composition can be applied by having animals walk through an area containing the foam or by having the animal walk through a footbath solution that has foam floating on top of the solution.
  • Surfactants are well known for foaming and are widely used as foaming agents in hand soap and manual/hand dishwashing detergents and such surfactants can be used as foaming agents in applications where foaming can boosts the performance and increase contact time of the composition to a particular substrates.
  • Suitable anionic surfactants can be chosen from a linear alkyl benzene sulfonic acid, a linear alkyl benzene sulfonate, an alkyl ⁇ -sulfomethyl ester, an ⁇ -olefm sulfonate, an alcohol ether sulfate, an alkyl sulfate, an alkylsulfo succinate, a dialkylsulfo succinate, and alkali metal, alkaline earth metal, amine and ammonium salts thereof.
  • linear Ci O -Ci 6 alkyl benzene sulfonic acid linear Ci 0 -Ci 6 alkyl benzene sulfonate or alkali metal, alkaline earth metal, amine and ammonium salt thereof e.g. sodium dodecylbenzene sulfonate, sodium Ci 4 - Ci 6 ⁇ -olefm sulfonate, sodium methyl ⁇ -sulfomethyl ester and disodium methyl ⁇ - sulfo fatty acid salt.
  • Suitable nonionic surfactants can be chosen from an alkyl polyglucoside, an alkyl ethoxylated alcohol, an alkyl propoxylated alcohol, an ethoxylatedpropoxylated alcohol, sorbitan, sorbitan ester, an alkanol amide.
  • Amphoteric surfactants can be chosen from alkyl betaines and alkyl amphoacetates.
  • Suitable betaines include cocoamidopropyl betaine, and suitable amphoacetates include sodium cocoamphoacetate, sodium lauroamphoacetate and sodium cocoamphodiacetate.
  • Alkyl amine oxides based on C 12-Cl 4 alkyl chain length feedstock such as those derived from coconut oil, palm kernel oil are also suitable foaming agents.
  • Viscosity control agents may be added to formulate the antimicrobial compositions according to an intended environment of use.
  • This type of viscous product especially one having a suitable thixotropic, pseudoplastic or viscoelastic gel strength, minimizes dripping of the product to avoid wastage and is particularly advantageous in teat dip compositions.
  • Teat dip compositions may benefit from a preferred dynamic viscosity ranging from 1 cPs to 3000 cPs.
  • Other applications including hard surface disinfectants have a preferred dynamic viscosity ranging from about 1 cPs to 300 cPs.
  • the amount of viscosity control agents may be substantially reduced or even eliminated in other compositions, such as surface or floor disinfectants where easy cleanup is desired.
  • An intermediate or medium viscosity composition may be useful in a hand cleaner or personal care product. It is seen from these examples that the antimicrobial compositions may be formulated for a wide variety of applications by altering the amount of viscosity control agents.
  • the viscosity referred to throughout this application is Brookfield viscosity measured in cPs by a Brookfield LV viscometer at ambient temperature (25 0 C) with a spindle # 2 @ 3 to 30 rpm.
  • a thickener may be added to achieve a viscosity range of from 50 cPs to 10000 cPs, or from 100 cPs to 4000 cPs.
  • Suitable viscosity control agents include hemicellulose, for example arabinoxylanes and glucomannanes; plant gum materials, for example guar gum and johannistree gums; cellulose and derivatives thereof, for example methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose; starch and starch derivatives, for example hydroxyethyl starch or cross linked starch; microbial polysaccharides, for example xanthan gum, sea weed polysaccharides, for example sodium alginate, carrageenan, curdlan, pullulan or dextran, dextran sulfate, whey, gelatin, chitosan, chitosan derivatives, polysulfonic acids and their salts, polyacrylamide, and glycerol.
  • plant gum materials for example guar gum and johannistree gums
  • cellulose and derivatives thereof for example methyl
  • Preferred viscosity controlling agents are, different types of cellulose and derivatives thereof, particularly hydroxyalkyl cellulose, methyl cellulose, and glycerol.
  • High molecular weight (MW > 1,000,000) cross-linked polyacrylic acid type thickening agents are the products sold by B. F. Goodrich (now Lubrizol) under their Carbopol ® trademark, especially Carbopol 941, which is the most ion-insensitive of this class of polymers, and Carbopol ® 940 and Carbopol ® 934.
  • the Carbopol ® resins, also known as "Carbomer” are reported in U.S. Pat. No. 5,225,096, and are hydrophilic high molecular weight, cross-linked acrylic acid polymers.
  • Carbopol ® 941 has a molecular weight of about 1,250,000
  • Carbopol ® 940 has a molecular weight of approximately 4,000,000
  • Carbopol 934 has a molecular weight of approximately 3,000,000.
  • the Carbopol ® resins are cross-linked with polyalkenyl polyether, e.g. about 1 % of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each molecule of sucrose. Further detailed information on the Carbopol ® resins is available from B.F. Goodrich (Lubrizol), see for example, the B. F. Goodrich catalog GC-67, Carbopol ® Water Soluble Resins.
  • Clays and modified clays such as bentonite or laponite can also be used as thickeners. Co-thickeners are often added to improve the stability of the gel matrix, for example, colloidal alumina or silica, fatty acids or their salts may improve gel stability.
  • Typical viscosity control ingredients include xanthan gum, carboxymethyl cellulose, sodium alginate, sodium alginate cross-linked with calcium salt, polysulfonic acids and their salts, polyacrylamide, polyvinyl alcohol (PVA), hydroxyethyl cellulose and polyN-vinylpyrrolidone (PVP).
  • a composition pH value may be selectively adjusted by the addition of acidic or basic ingredients.
  • an acidic pH is preferred.
  • Suitable acids for use as pH adjusting agents may include, for example, lactic acid, citric acid, phosphoric acid, phosphorous acid, sulfamic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid and hydrochloric acid.
  • Mineral acids may be used to drastically lower the pH.
  • the pH may be raised or made more alkaline by addition of an alkaline agent such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or combinations thereof.
  • Traditional acid buffering agents such as citric acid, lactic acid, phosphoric acid may also be used to maintain a desired pH, e.g., within the desired ranges discussed above.
  • wetting agent(s) or surface active agent(s) are also known as surfactants. Typical wetting agents are used to wet the surface of application, reduce surface tension of the surface of application so that the product can penetrate easily on the surface and remove unwanted soil.
  • the wetting agents or surfactants of the composition increase overall detergency of the formula, solubilize or emulsify some of the organic ingredients that otherwise would not dissolve or emulsify, and facilitate penetration of active ingredients deep onto the surface of the intended application surfaces, such as teat skin.
  • Suitably effective surfactants used for wetting may include anionic, cationic, nonionic, zwitterionic and amphoteric surfactants.
  • Wetting agents and surfactants used in the inventive applications can be high foaming, low foaming and non foaming type.
  • Suitable anionic surfactants can be chosen from a linear alkyl benzene sulfonic acid, a linear alkyl benzene sulfonate, an alkyl ⁇ -sulfomethyl ester, an ⁇ -olefin sulfonate, an alcohol ether sulfate, an alkyl sulfate, an alkylsulfo succinate, a dialkylsulfo succinate, and alkali metal, alkaline earth metal, amine and ammonium salts thereof.
  • linear Ci 0 -Ci 6 alkyl benzene sulfonic acid linear CiQ-Ci 6 alkyl benzene sulfonate or alkali metal, alkaline earth metal, amine and ammonium salt thereof e.g. sodium dodecylbenzene sulfonate, sodium Q 4 - C] 6 ⁇ -olefin sulfonate, sodium methyl ⁇ -sulfomethyl ester and disodium methyl ⁇ - sulfo fatty acid salt.
  • Suitable nonionic surfactants can be chosen from an alkyl polyglucoside, an alkyl ethoxylated alcohol, an alkyl propoxylated alcohol, an ethoxylatedpropoxylated alcohol, sorbitan, sorbitan ester, an alkanol amide.
  • Pluronic ® poloxamers commercialized by BASF Chemical Co.
  • Amphoteric surfactants can be chosen from alkyl betaines and alkyl amphoacetates.
  • Suitable betaines include cocoamidopropyl betaine
  • suitable amphoacetates include sodium cocoamphoacetate, sodium lauroamphoacetate and sodium cocoamphodiacetate.
  • An opacifying agent or dye is optionally included in the present compositions.
  • color on a teat tells a farmer that a particular cow has been treated.
  • FD&C Certified (food grade) dyes There are many FD&C dyes available which are FD&C Red #40, FD&C Yellow #6, FD&C Yellow #5, FD&C Green #3 and FD&C Blue #1. Dyes used either alone or in combination are preferred.
  • D&C Orange #4 can also be used. Titanium dioxide (TiO 2 ) is widely used as an opacifier and can also be used in combination with various colorants.
  • Some known teat dips and hand sanitizers include ethylenediaminetetraacetic acid (EDTA) and/or its alkali salts which can act as a chelating agent to remove metal ions from hard water.
  • EDTA ethylenediaminetetraacetic acid
  • the metal ions if not removed from the composition, serve as reaction sites for enzymes within the bacteria; the metalloenzyme reactions produce energy for bacterial cell replication.
  • Other traditional preservatives are widely used, for example, paraban, methyl paraban, ethyl paraban, glutaraldehyde, etc.
  • Preservatives such as an alcohol can also be added.
  • the alcohol in embodiments, may be benzyl alcohol.
  • Skin conditioning agents may also be optionally used in the disclosed compositions. Skin conditioning agents may provide extra protection for human or animal skin prior to or subsequent to being exposed to adverse conditions.
  • skin conditioning agents may include moisturizers, such as glycerin, sorbitol, propylene glycol, D-Panthenol, Poly Ethylene Glycol (PEG) 200-10,000, Poly Ethylene Glycol Esters, Acyl Lactylates, Polyquaternium-7, Glycerol Cocoate/Laurate, PEG-7 Glycerol Cocoate, Stearic Acid, Hydrolyzed Silk Peptide, Silk Protein, Aloe Vera Gel, Guar Hydroxypropyltrimonium Chloride, Alkyl Poly Glucoside/Glyceryl Luarate, shea butter and coco butter; sunscreen agents, such as titanium dioxide, zinc oxide, octyl methoxycinnamate (OMC), 4-methylbenzylidene camphor (4-MBC), oxybenzone and homo
  • sunscreen agents
  • a typical carrier or matrix for an antimicrobial composition is deionized water, although one skilled in the art will readily understand that other solvents or compatible materials other than water may be used to achieve the effective concentrations of germicidal agents.
  • a composition may contain at least about 60% water and preferably at least about 70% water by weight based on the total weight of the composition.
  • Propylene glycol, glycol ethers and/or alcohols can also be used as a carrier either alone or in combination with water.
  • test bacteria were Escherichia coli (ATCC 11229), which were originally isolated from mastitis infection and obtained on commercial order from Mastitlaboratoriet, SVA, and Staphylococcus aureus (ATCC6538 from Microbiologies, St. Cloud, MN), which was also isolated from mastitis infection.
  • Blood Cell Irritation tests were performed to determine if some particular representative compositions would be mild enough for topical applications. These tests involved separating red blood cells and then exposing them to the compositions.
  • the tests used for the compositions addressed in Tables 1 -2 included two measurements made on cow's blood. In the tests, fresh calf blood samples were obtained; 50 mL of sodium citrate buffer was added to every 450 mL of blood and mixed. The blood was then centrifuged to isolate red blood cells (RBC), which were then washed with sodium citrate buffer, and centrifuged several times to remove white cells and plasma, according to a known method. The red blood cells were placed into containers for use in testing the disclosed antimicrobial compositions.
  • RBC red blood cells
  • Red blood cells were treated with water, centrifuged and then, using a UV spectrophotometer, the absorption at 560 nm was measured in order to determine complete cell denaturation (Hi 00 ).
  • the product to be tested was then diluted in the range of 5000 ppm to 60000 ppm, blood cells were added to these dilutions, centrifuged and the absorption at 560 nm was measured by UV spectrometry.
  • Haemolysis Values H 50
  • the H 5 o value represents the product concentration (expressed in ppm) at which half of the blood cells are denatured.
  • a 1000 ppm solution of sodium lauryl sulfate solution was used as a reference.
  • the overall irritation value for a product was determined by the ratio of the H 50 /DI which is referred to as the lysis/denaturation quotient.
  • H 50 score which measures haemolysis alone usually shows a similar irritation correlation to the L/D ratio. The higher the ppm value for H 50 the less irritating the product.
  • a crude scale is H 50 > 500ppm (non-irritant); 120-500 (slight irritant), 30 - 120 (moderate irritant), 10 - 30 (irritant), 0-10 (strong irritant).
  • the DI score which measures denaturation of protein also shows a correlation to the L/D ratio.
  • a crude scale is DI 0-5% (non- irritant); 5 - 10% (slight irritant), 10 - 75% (moderate irritant), 75 - 100% (irritant), and >100% (strong irritant).
  • the H 50 and DI values may be of use in the interpretation of the results, the L/D ratio is the primary value used to determine irritation. This method is best suited to comparing two or more products and determining which product is likely to cause the least irritation to skin and eyes.
  • an L/D value greater than 100 is an indication that the composition is a non-irritant; levels between 10 and 100 are considered slight irritants; levels between 1 and 10 are considered moderate irritants; level between 0.1 to 1 are considered irritants; and levels lower than 0.1 are considered strong irritants.
  • polymeric guanidine agents when used with certain additives in an aqueous solution are capable of in are capable of effectively killing bacteria (e.g., producing five-log reductions or higher) while avoiding skin irritation, and maintaining sufficient viscosity for use in a teat dip or other like applications.
  • Tables I- VI below Shown in Tables I- VI below are the results of experiments carried out to determine the efficacy of various antimicrobial compositions against E. coli and S. aureus.
  • the formulations below all use a polymeric guanidine salt-based antimicrobial agent which includes Poly-(HexaMethylendiamineGuanidinium hydrochloride) (PHMG) and Poly- [2-(2-Ethoxy) Ethyl Guanidinium hydrochloride] in a mixture of about a 3:1 ratio of PHMG salts and PEEG salts, and the mixture is readily commercially available under the trade name Akacid Plus .
  • Akacid Plus® is commercially available in a concentration of 25% (Akacid Plus 25%), meaning that only a quarter of the amounts listed in the Tables are actually active ingredient.
  • Neodol 91-8 is included as a potential barrier and/or film forming agent which, in one embodiment, adapts the formulation for teat-dip applications.
  • NaOH sodium hydroxide
  • Table V below shows the use of a variety of other components intended to adapt the product for topical use.
  • skin conditioners such as glycerine and sorbitol.
  • barrier agents such as Maltrin M40, Propylene Glycol, PVP K30, and Pluronic 108. Results for viscosities, look, and film qualities are also shown in addition to L/D ratios.
  • Table VI shows that for some formulations using the skin-conditioner sorbitol, significant kill numbers were obtained using a number of well-known barrier agents.
  • the activity of germicidal compositions was tested by a procedure involving preparing a test tube containing 1 g (10%) or 2 g (20%) of manure, 9.9 mL of germicide and 0.1 mL of ⁇ lxl O 7 bacteria.
  • the reagents within the test tube were mixed for 30 seconds and then 0.1 mL of the mixture was added to a 6 mL well of a microwell plate containing 0.9 mL neutralizer. After mixing with the neutralizer, 4.5 mL of agar was added to the well. The microwell plate was then incubated for 24 hr to 48 hr. A visual score for the concentration of bacteria was recorded. A score of 5 indicated complete kill of bacteria when no colonies of growth were observed in the well.

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  • Dermatology (AREA)
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Abstract

L'objet de la présente invention est une composition liquide antimicrobienne qui contient au moins un ou bien un ensemble de Poly (HexaMéthylènediamine) chlorhydrate de guanidine (PHMG) et de Poly [2- (2- Éthoxy) -Éthyl] chlorhydrate de guanidine (PEEG). Dans certains modes de réalisation, la composition est utilisée comme élément d'une application de trempage du trayon. Dans certains autres modes de réalisation, l'action de la composition est augmentée en maintenant des niveaux de pH supérieurs à 8. Dans d'autres modes de réalisation, on ajoute un surfactant.
PCT/US2007/078057 2006-09-08 2007-09-10 Germicides à base de sel d'un polymère de guanidine WO2008031105A1 (fr)

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US97080007P 2007-09-07 2007-09-07
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CN109221223A (zh) * 2018-10-15 2019-01-18 陕西嘉禾药业有限公司 一种安全高效的复合消毒液
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WO2019194757A1 (fr) * 2018-04-07 2019-10-10 Ucar Dilek Protection alimentaire de fruits, de céréales et de légumes et dérivés
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CN102217588B (zh) * 2010-04-15 2014-07-16 上海于泽生物科技有限公司 一种组织标本保存液及聚六亚甲基胍水溶性衍生物的应用
CN103141469A (zh) * 2013-03-18 2013-06-12 广东海洋大学 聚六亚甲基胍作为动物标本防霉剂的用途
KR20160097202A (ko) * 2013-11-03 2016-08-17 더 리전츠 오브 더 유니버시티 오브 캘리포니아 경피 약물 전달용 이온성 액체
US11786597B2 (en) 2013-11-03 2023-10-17 The Regents Of The University Of California Ionic liquids for transdermal drug delivery
KR102286115B1 (ko) 2013-11-03 2021-08-04 더 리전츠 오브 더 유니버시티 오브 캘리포니아 경피 약물 전달용 이온성 액체
WO2015066647A3 (fr) * 2013-11-03 2015-06-18 The Regents Of The University Of California Liquides ioniques pour administration transdermique de médicaments
US10449254B2 (en) 2013-11-03 2019-10-22 The Regents Of The University Of California Ionic liquids for transdermal drug delivery
US10912834B2 (en) 2016-08-29 2021-02-09 The Regents Of The University Of California Topical formulations based on ionic species for skin treatment
WO2018060101A1 (fr) * 2016-09-30 2018-04-05 Flechsig Patent Company Llc Procédé pour protéger des plantes contre les organismes nuisibles en utilisant une composition pesticide à persistance et dégradabilité réglables
CN109982568A (zh) * 2016-09-30 2019-07-05 弗莱克西格专利有限责任公司 使用具有可调节的持久性和降解性的杀虫剂组合物保护植物免受有害生物侵害的方法
US10828265B2 (en) 2016-12-09 2020-11-10 The Regents Of The University Of California Formulations of propranolol and analogs as an amorphous melt or ionic liquid for transdermal drug delivery
EP3524055A1 (fr) * 2018-02-08 2019-08-14 BCSK Biocid GmbH Agent lubrifiant antibactérien et spermicide
WO2019154983A1 (fr) 2018-02-08 2019-08-15 Bcsk Biocid Gmbh Lubrifiant antibactérien et spermicide
JP2021513569A (ja) * 2018-02-08 2021-05-27 ベーツェーエスカー バイオシッド ゲゼルシャフト ミット ベシュレンクテル ハフツング 抗菌及び殺精子潤滑剤
CN111787802A (zh) * 2018-02-08 2020-10-16 Bcsk百盛有限责任公司 抗细菌杀精润滑剂
AT521125A1 (de) * 2018-03-23 2019-10-15 Bcsk Biocid Gmbh Flüssige Zusammensetzung
WO2019178632A1 (fr) * 2018-03-23 2019-09-26 Bcsk Biocid Gmbh Composition liquide contenant une guanidine polymère
CN112218532A (zh) * 2018-04-07 2021-01-12 优卡健康有限公司 水果、谷物和蔬菜及衍生物的食物保护
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EP3790391A4 (fr) * 2018-04-07 2022-03-02 UCAR Health GmbH Protection alimentaire de fruits, de céréales et de légumes et de dérivés
WO2019203740A1 (fr) * 2018-04-19 2019-10-24 Ucar Dilek Surface, air, textile, peinture, plastique, silicone et bois, polyéthylène; propriétés antimicrobiennes de métal et de dérivés
US20210145004A1 (en) * 2018-04-19 2021-05-20 Ucar Health Gmbh Surface, air, textile, paint, plastic, silicone and wood, polyethylene; metal and derivatives antimicrobial properties
CN109221223A (zh) * 2018-10-15 2019-01-18 陕西嘉禾药业有限公司 一种安全高效的复合消毒液
CN113026361A (zh) * 2021-02-26 2021-06-25 石家庄学院 一种戊二醛偶联聚六亚甲基盐酸盐制备长效抗菌聚酯纤维的方法及反应装置
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