WO2021183878A1 - Compositions et procédés d'inhibition d'endospores utilisant des polyphénols de thé vert - Google Patents

Compositions et procédés d'inhibition d'endospores utilisant des polyphénols de thé vert Download PDF

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Publication number
WO2021183878A1
WO2021183878A1 PCT/US2021/022095 US2021022095W WO2021183878A1 WO 2021183878 A1 WO2021183878 A1 WO 2021183878A1 US 2021022095 W US2021022095 W US 2021022095W WO 2021183878 A1 WO2021183878 A1 WO 2021183878A1
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Prior art keywords
green tea
tea polyphenol
spores
composition
compositions
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PCT/US2021/022095
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English (en)
Inventor
Stephen Hsu
Lee H. Lee
Tin-Chun Chu
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Augusta University Research Institute, Inc.
Seton Hall University
Montclair State University
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Priority claimed from US16/818,488 external-priority patent/US20200214290A1/en
Application filed by Augusta University Research Institute, Inc., Seton Hall University, Montclair State University filed Critical Augusta University Research Institute, Inc.
Publication of WO2021183878A1 publication Critical patent/WO2021183878A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A23B2/733—Compounds of undetermined constitution obtained from animals or plants
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • 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
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/12—Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • 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
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • 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
    • A01N65/00—Biocides, pest repellants or attractants, or plant growth regulators containing material from algae, lichens, bryophyta, multi-cellular fungi or plants, or extracts thereof
    • A01N65/08—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A23B2/742—Organic compounds containing oxygen
    • A23B2/75—Organic compounds containing oxygen with doubly-bound oxygen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A23B2/771—Organic compounds containing hetero rings
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the field of the invention is generally related to compositions and methods of use thereof for rapidly killing, inactivating, or otherwise reducing spores such as bacterial spores.
  • antimicrobial agents e.g., iodophors, peracids, hypochlorites, chlorine dioxide, ozone, etc.
  • antimicrobial agents e.g., iodophors, peracids, hypochlorites, chlorine dioxide, ozone, etc.
  • these agents are often ineffective against spores. Rapidly killing, inactivating, or otherwise reducing the active population of spores can be difficult.
  • Bacterial spores for example, have a unique chemical composition of spore layers that make them more resistant than vegetative bacteria to the antimicrobial effects of chemical and physical agents. This resistance can be particularly troublesome when the spores or fungi are located on surfaces such as food, food contact sites, ware, hospitals and veterinary facilities, surgical and other medical devices, and hospital and surgical linens and garments.
  • Bacillus cereus is frequently diagnosed as a cause of gastrointestinal disorders and has been suggested to be the cause of several food-home illness outbreaks. Due to its rapid sporulating capacity, Bacillus cereus easily survives in the environment. It is ever- present in nature, and consequently is often found in animal feed and fodder. Bacillus cereus can contaminate raw milk via feces and soil, and can survive intestinal passage in cows and the pasteurization process. In humans, Bacillus cereus can cause serious human illness via environmental contamination. For example, Bacillus cereus is known to cause post-traumatic injury eye infections, which can result in visual impairment or loss of vision within 12-48 hours after infection. Furthermore, it is believed that Bacillus cereus can be transmitted from washed surgical garments to patients.
  • compositions and methods of use thereof for rapidly killing, inactivating, or otherwise reducing spores are provided.
  • compositions and methods of reducing or prevent spore reactivation and germination It is also an object of the invention to provide compositions and methods for increasing the shelf-life or reducing spoilage of food and foodstuffs.
  • compositions and methods for rapidly killing, inactivating, or otherwise reducing spores are disclosed.
  • An exemplary composition includes alcohol, a modified green tea polyphenol, and other plant-derived ingredients.
  • One embodiment provides a sporicidal composition including 80% ethanol, 0.2% (-)-epigallocatechin-3-gallate esterified at the 4’ position with palmitic acid, 0.3% citrate, 5% glycerin and 15% water, wherein the composition achieves at least a 4-log reduction in bacterial spores within thirty seconds of contacting the bacterial spores.
  • the modified green tea polyphenol is (-)- epigallocatechin-3-gallate (EGCG) modified at the 4’ position with palmitic acid.
  • the compositions can also include one or more additional components selected from the group consisting of bioactive agents, therapeutic agents, excipients, carriers, fillers, additives, binders, disintegration agents, lubricants, flavoring agents, and combinations thereof.
  • compositions and methods of inactivating spores in as few as 60 seconds, or as few as 30 seconds from contact.
  • An exemplary method of rapidly killing, inactivating, or otherwise reducing spores includes steps of contacting spores with a composition having at least one modified green tea polyphenol and ethanol, in an amount effective to disrupt the spore coating and denature the inner biological molecules to prevent or reduce reactivation and germination of the spores.
  • compositions and methods of sterilizing objects or surfaces suspected of being contaminated with bacterial spores are also disclosed herein.
  • the methods include steps of contacting the object or surface with a composition having at least one modified green tea polyphenol and alcohol in an amount effective to sterilize the object or surface, wherein at least a 4-log reduction in bacterial spores is achieved within thirty seconds of contacting the object or surface with the composition.
  • compositions and methods can be used in a variety of applications, for example, to increase the shelf-life of a food or a foodstuff, to reduce or delay the spoilage of a food or a foodstuff, or to decontaminate a device or surface contaminated with spores.
  • Exemplary objects or surfaces that can be decontaminated or sterilized include but are not limited to a food item, a food preparation surface, a food contact surface, a surgical surface, a surgical tool, a medical device, a hospital or veterinary facility surface, hospital and surgical linens and garments, or a skin surface.
  • Figures 3A-3F are scanning electron microscope images showing B. cereus and C. sporogenes endospores untreated (Figs. 3A and 3D, respectively), Fl-treated (3B and 3E, respectively), or F-2 treated (Figs. 3C and 3F, respectively).
  • Figure 4 is a bar graph showing Log 10 reduction of spore re-germination by formulations #1 (FI) & #2 (F2) after 30 seconds.
  • “Acyloxy”, as used herein, refers to a substituent having the following chemical formula: wherein R is a linear, branched, or cyclic alkyl, alkenyl, or alkynyl group.
  • Alkoxy carbonyl refers to a substituent having the following chemical formula: wherein R is a linear, branched, or cyclic alkyl group.
  • alkenyl refers to a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkynyl refers to a monovalent, unbranched or branched hydrocarbon chain having one or more triple bonds therein.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • cell refers to a membrane-bound biological unit capable of replication or division.
  • emulsion refers to a mixture prepared from two mutually insoluble components. It is possible to generate mixtures of homogenous macroscopic appearance from these components through proper selection and manipulation of mixing conditions.
  • the most common type of emulsions are those in which an aqueous component and a lipophilic component are employed and which in the art are frequently referred to as oil-in-water and water-in-oil emulsions.
  • oil-in-water emulsions the lipophilic phase is dispersed in the aqueous phase
  • water-in-oil emulsions the aqueous phase is dispersed in the lipophilic phase.
  • Commonly known emulsion based formulations that are applied to the skin include cosmetic products such as creams, lotions, washes, cleansers, milks and the like as well as dermatological products comprising ingredients to treat skin conditions, diseases or abnormalities.
  • host refers to a living organism, including but not limited to a mammal such as a primate, and in particular a human.
  • Hydrophilic refers to substances that have strongly polar groups that readily interact with water.
  • Hydrophilic refers to substances that lack an affinity for water; tending to repel and not absorb water as well as not dissolve in or mix with water.
  • isolated when used to describe the various compositions disclosed herein, means a substance that has been identified and separated and/or recovered from a component of its natural environment.
  • an isolated polypeptide or polynucleotide is free of association with at least one component with which it is naturally associated. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide or polynucleotide and may include enzymes, and other proteinaceous or non-proteinaceous solutes.
  • An isolated substance includes the substance in situ within recombinant cells. Ordinarily, however, an isolated substance will be prepared by at least one purification step.
  • Green Tea Polyphenols and “GTP” refers to polyphenolic compounds present in the leaves of Camellia sinensis.
  • Green tea polyphenols include, but are not limited to (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), (-)- epigallocatechin-3-gallate (EGCG), proanthocyanidins, enantiomers thereof, epimers thereof, isomers thereof, combinations thereof, and prodrugs thereof.
  • Modified green tea polyphenols refers to a green tea polyphenol having one or more hydrocarbon chains, for example C 1 to C 30 and the compounds according to Formula I and II disclosed herein.
  • Lipid soluble refers to substances that have a solubility of greater than or equal to 5g / 100ml in a hydrophobic liquid such as castor oil.
  • lipid-soluble green tea polyphenol and “LTP” refers to a green tea polyphenol having one or more hydrocarbon chains having for example C 1 to C 30 groups linked to the polyphenol. C 1 to C 30 groups include for example cholesterol.
  • Representative lipid-soluble green tea polyphenols include those according to Formula I and Formula II disclosed herein. The term is used interchangeably with “modified green tea polyphenol”.
  • operably linked refers to a juxtaposition wherein the components are configured so as to perform their usual function.
  • control sequences or promoters operably linked to a coding sequence are capable of effecting the expression of the coding sequence, and an organelle localization sequence operably linked to protein will direct the linked protein to be localized at the specific organelle.
  • prodrug refers to an agent, including nucleic acids and proteins, which is converted into a biologically active form in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Harper, N.J. (1962). Drug Latentiation in Jucker, ed. Progress in Drug Research, 4:221-294; Morozowich et al. (1977). Application of Physical Organic Principles to Prodrug Design in E. B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APhA; Acad. Pharm. Sci. ; E.
  • substituted C 1 to C 30 refers to an alkyl, alkenyl, or alkynyl chain of one to thirty carbons wherein one or more carbons are independently substituted with one or more groups including, but not limited to, halogen, hydroxy group, aryl group, heterocyclic group, or alkyl ester.
  • the range C 1 to C 30 includes C 1 , C 2 , C 3 , C 4 , C 5 , 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 etc. up to C 30 as wells as ranges falling within C 1 to C 30 , for example, C 1 to C 29 , C 2 to C 30 , C 3 to C 28 , etc.
  • the range also includes less than C 30 , less than C 19 , etc.
  • treating or treatment refers to alleviating, reducing, or inhibiting one or more symptoms or physiological aspects of a disease, disorder, syndrome, or condition.
  • Water soluble refers to substances that have a solubility of greater than or equal to 5g /100ml water.
  • foodstuff refers to a substance with food value, and includes the raw material of food before or after processing.
  • foodstuff is intended to mean a substance which is suitable for human or animal consumption, and includes dairy products (e.g., milk and cheese), animal foods (e.g., dog and cat food), snack foods (e.g., pretzels, chips, crackers), sauces and gravies, soups, casseroles, fruits, vegetables, juices, prepared meat and meat spreads, cereals, margarine, salad dressings, condiments (e.g., ketchup and mustard), meat, fish and shellfish, and poultry.
  • dairy products e.g., milk and cheese
  • animal foods e.g., dog and cat food
  • snack foods e.g., pretzels, chips, crackers
  • sauces and gravies soups, casseroles, fruits, vegetables, juices, prepared meat and meat spreads, cereals, margarine, salad dressings, condiments (e.g., ketchup and mustard), meat, fish and
  • pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and the like.
  • sporicidal refers to the ability to kill spores.
  • the term “sterilization” refers to a process that destroys or eliminates all forms of microbial life, including bacterial spores. “Disinfection” refers to a process that eliminates many or all pathogenic microorganisms, except bacterial spores, on inanimate objects. Unlike sterilization, disinfection is not sporicidal. A few disinfectants will kill spores with prolonged exposure times (3-12 hours); these are called chemical sterilants.
  • Sterilization and disinfection are important techniques used in the medical field to prevent the transmission of microbes to patients.
  • hand hygiene is one of four standard precautions that are used in addition to disinfection and sterilization to prevent against disease transmission in a hospital or clinical setting.
  • Hand hygiene means cleaning ones hands by using either handwashing (washing hands with soap and water), antiseptic hand wash, antiseptic hand rub (i.e. alcohol- based hand sanitizer including foam or gel), or surgical hand antisepsis.
  • the Centers for Disease Control and Prevention state that alcohol-based hand sanitizers are the most effective products for reducing the number of germs on the hands of healthcare providers and are the preferred method for cleaning ones hands in most clinical situations.
  • Log reduction refers to the measurement of how thoroughly a decontamination process reduces the concentration of a contaminant.
  • green tea polyphenols and modified green tea polyphenols, combinations thereof, and compositions thereof can be used to rapidly kill, inactivate, or otherwise reduce spores.
  • Reactivation of the spores typically occurs when conditions are more favorable to vegetative cells.
  • the process of reactivation involves activation, germination, and outgrowth. Even if a spore is located in plentiful nutrients, it may fail to germinate unless activation has taken place. This may be triggered by heating the spore.
  • Germination which involves the dormant spore starting metabolic activity, can include rupture or absorption of the spore coat, swelling of the spore, an increase in metabolic activity, and loss of resistance to environmental stress.
  • Outgrowth follows germination and involves the core of the spore manufacturing new chemical components and exiting the old spore coat to develop into a fully functional vegetative bacterial cell, which can divide to produce more cells.
  • the disclosed modified green tea polyphenol compositions rapidly kill, inactivate, or otherwise reduce spores in as few as 30 seconds. In another embodiment, the disclosed modified green tea polyphenol compositions and methods achieve at least a 4-log reduction in bacterial spores within thirty seconds of contacting the object or surface with the composition.
  • Certain microorganisms are able to form spores which help them survive under harsh environmental conditions. For example, in spore-forming bacteria, when a bacterium detects environmental conditions are becoming unfavorable, it may initiate endosporulation. First, DNA is replicated and a membrane wall called a spore septum forms between it and the rest of the cell. The plasma membrane of the cell surrounds this wall and pinches off to leave a double membrane around the DNA. The developing structure is referred to as a forespore. Calcium dipicolinate is incorporated into the forespore and a peptidoglycan cortex forms between the two layers. The bacterium adds a spore coat to the outside of the forespore. The now mature endospore is released when the surrounding vegetative cell degrades.
  • Endospores are highly resistant to environmental challenges such as temperature differences, absence of air, water and nutrients, chemicals insults, heat, mechanical disruption, UV irradiation, and enzymes. Most agents that would normally kill the vegetative cells they formed from are ineffective against spores. For example, nearly all household cleaning products, alcohols, quaternary ammonium compounds and detergents have little effect endospores. Through sporulation, bacteria can adapt to unfavorable conditions surviving for years before reactivation via spore germination and outgrowth.
  • the disclosed modified green tea polyphenol compositions rapidly kill, inactivate, or otherwise reduce spores in as few as thirty seconds.
  • the disclosed modified green tea polyphenol compositions not only rapidly kill, inactivate, or otherwise reduce spores, they also rapidly disrupt the spore coat in as few as thirty seconds. Without being bound by any one theory, it is believed that the modified green tea polyphenol compositions compromise or collapse the spore coating, allowing alcohol to penetrate the outer layer of the spores, therefore denaturing the nucleic acids and proteins within the spore.
  • the disclosed modified green tea polyphenol compositions are formulated as a sterilization agent for use on objects and surfaces.
  • the compositions can also be formulated into sporicidal hand and skin hygiene products.
  • Hand wash with soap and water is the only recommended method to prevent the spread of C. cliff either in healthcare sehings or at home (CDC, C. cliff Prevent the spread of C. cliff). This is because commonly used hand sanitizers, hand rubs or scrubs, either containing alcohol or bactericidal agents, are not able to eradicate C. diff or other bacterial endospores, which are resistant to alcohol and other bactericidal agents.
  • the disclosed methods of rapidly killing, inactivating, or otherwise reducing spores typically includes contacting spores with an effective amount of one or more of the disclosed modified green tea polyphenol compositions to kill spores, thereby reducing or preventing spore reactivation and germination.
  • the one or more modified green tea polyphenol compositions can be part of a sporicidal composition that includes one or more additional inert or active ingredients. Therefore, in some embodiments, a method of preventing spore reactivation and germination includes contacting spores with an effective amount of a composition including one or more green tea polyphenols, one or more modified green polyphenols, or combinations thereof to reduce or prevent spore reactivation and germination.
  • the one or more green tea polyphenols, one or more modified green polyphenols, or combinations thereof, can be effective to reduce or prevent spore germination or to reduce or prevent spore outgrowth.
  • the contacting can be for minutes, hours, days, weeks or longer.
  • the contacting is for 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 12 minutes, 18 minutes, 24 minutes, 36 minutes, 48 minutes, or more minutes, hours, days, weeks, or months.
  • the disclosed modified green tea polyphenol compositions inhibits spore germination in as few as 30 seconds or 60 seconds.
  • the disclosed modified green tea polyphenol compositions and methods achieve at least a 4-log reduction in spores within at least thirty seconds of contacting the object or surface with the composition.
  • the compositions and methods can achieve a 4-log, 5-log, 6-log, 7-log, 8-log, 9-log, 10-log or more than 10-log reduction in spores.
  • the compositions kill, inactivate, or otherwise reduce the number of total spores or the number of active spores. In some embodiments, the compositions reduce or prevent one or more hallmarks of germination, outgrowth, or a combination thereof, including, but not limited to, an increase in metabolic activity of the spore/bacterium, rupture or absorption of the spore coat, swelling of the spore, loss of resistance to environmental stress, the core of the spore manufacturing new chemical components, exiting the old spore coat, formation of a fully functional vegetative bacterial cell, and vegetative bacterial cell division.
  • the effect of the one or more modified green tea polyphenol compositions, or sporicidal composition thereof can be compared to a control.
  • Controls are known and understood by one of skill in the art and can include, for example, untreated spores or spores treated with an alternative anti-spore composition.
  • An exemplary in vitro test that can used to measure spore reactivation in the presence or absence of modified green tea polyphenol compositions, or a sporicidal composition is described in the Examples below.
  • the methods disclosed herein typically include contacting a spore, or a surface thought to be infected with spores, with an effective amount of one or more modified green tea polyphenol compositions, or a sporicidal composition including one or more GTP, LTP, or a combination thereof.
  • modified green tea polyphenols, combinations thereof, and compositions thereof are provided below.
  • the spores can be contacted with a composition that is less than 1%, 1%, 2%, 5%, 10%, 25%, or more than 25% modified green tea polyphenol.
  • the amount of modified green tea polyphenol that is need to effectively reduce or prevent spore reactivation can depend on factors including the composition(s) of the modified green tea polyphenol, the species of spores to be contacted, and the environmental conditions (i.e., temperature, availability of nutrients, etc.).
  • the methods can include one or more additional steps or agents that further reduce spore reactivation.
  • the method includes a heat treatment.
  • the heat treatment can, for example, include maintaining the temperature at, or above, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, or 250°C.
  • the treatment can be for less than one hour, for one hour, or for more than one hour.
  • the treatment can be 1, 2, 3, 4, 5, 6, 12, 18, 24, 36, 48, or more hours.
  • the treatment can be before, after, or concurrent with contacting the spores with the compositions disclosed herein. It is therefore appreciated that the appropriate temperature and the duration of the temperature can be selected based on the intended use. For example, a mild heat treatment, such as to between about 30 and 100°C can be used to induce spore activation prior to or during treatment with the disclosed modified green tea polyphenol compositions. In some embodiments, a heat treatment, for example above 120°C is used during or after treatment with the disclosed modified green tea polyphenol compositions to increase the spore killing ability of the disclosed composition, for example, by further reducing germination, outgrowth, or a combination thereof.
  • a mild heat treatment such as to between about 30 and 100°C can be used to induce spore activation prior to or during treatment with the disclosed modified green tea polyphenol compositions.
  • a heat treatment for example above 120°C is used during or after treatment with the disclosed modified green tea polyphenol compositions to increase the spore killing ability of the disclosed composition, for example, by further reducing germination
  • the method can include adjusting the pH.
  • the pH can be adjusted to be around physiological pH (i.e. between about 7.2 and 7.6, or about 7.4).
  • the pH can also be adjusted to be more acidic, (i.e., a pH of about 1, 2, 3, 4, 5, or 6); or more basic (i.e., a pH of about 8, 9, 10, 11, 12, 13, 14).
  • the treatment can be for less than one hour, for one hour, or for more than one hour.
  • the treatment can be 1, 2, 3, 4, 5, 6, 12, 18, 24, 36, 48, or more hours.
  • the treatment can be before, after, or concurrent with contacting the spores with the compositions disclosed herein. Therefore, it will be appreciated as discussed above with respect to heat treatment, that the appropriate pH and the duration of the pH can be selected based on the intended use. For example, acidic pH, such as 4.5 or below can be selected to induce spore activation prior to or during treatment with the disclosed modified green tea polyphenol compositions. In another embodiment, pH adjustment is used during or after treatment with the disclosed modified green tea polyphenol compositions to increase the spore killing ability of the disclosed composition, for example, by further reducing germination, outgrowth, or a combination thereof.
  • the disclosed methods of using modified green tea polyphenol compositions can include a bleach, glutaraldehyde, or other disinfectant treatment.
  • a bleach treatment can include contacting spores with between about 1% and 15% bleach for between about 5 minutes and 15 minutes. In one embodiment, the spores are contacted with about 10% bleach for about 10 minutes.
  • Spore disinfectant treatments are known in the art, see for example, Heninger, et al., Appl Biosaf., 14(1): 7-10 (2009), which is specifically incorporated by reference herein in its entirety. The treatment can be before, after, or concurrent with contacting the spores with the compositions disclosed herein.
  • the disclosed compositions and methods are used to reduce or prevent reactivation and germination of spores, including but not limited to endospores.
  • the spores are fungal spores.
  • the compositions and methods disclosed herein are used to reduce or prevent reactivation of exospores, such as those formed by Methylosinus .
  • the difference between endospores and exospores is mainly in how they form. Endospores form inside the original bacterial cell, as described above. Exospores form outside by growing or budding out from one end of the cell. Exospores also do not typically have all the same components as endospores, but are similarly resistant to environment insults.
  • the spores are cysts.
  • Members of the Azotobacter, Bdellovibrio, Myxococcus and Cyanobacteria genera can form protective structures called cysts.
  • Cysts are thick-walled structures that, like spores, protect bacteria from harm. Cysts can be less durable than endospores and exospores.
  • the spores treated with the disclosed compositions and methods are typically protective spores.
  • the spores are formed by spore-forming bacteria.
  • spore-forming bacteria include the genera: Acetonema, Alkalibacillus, Ammoniphilus, Amphibacillus, Anaerobacter, Anaerospora, Aneurinibacillus, Anoxybacillus, Bacillus, Brevibacillus, Caldanaerobacter, Caloramator, Caminicella, Cerasibacillus, Clostridium, Clostridiisalibacter, Cohnella, Dendrosporobacter, Desulfotomaculum, Desulfosporomusa, Desulfosporosinus, Desulfovirgula, Desulfunispora, Desulfurispora, Filifactor, Filobacillus, Gelria, Geobacillus, Geosporobacter, Gracilibacillus,
  • Halonatronum Heliobacterium, Heliophilum, Laceyella, Lentibacillus, Lysinibacillus, Mahella, Metabacterium, Moorella, Natroniella, Oceanobacillus, Orenia, Ornithinibacillus, Oxalophagus, Oxobacter, Paenibacillus, Paraliobacillus, Pelospora, Pelotomaculum, Piscibacillus, Planifilum, Pontibacillus, Propionispora, Salinibacillus, Salsuginibacillus, Seinonella, Shimazuella, Sporacetigenium, Sporoanaerobacter, Sporobacter,
  • Sporobacterium Sporohalobacter, Sporolactobacillus, Sporomusa, Sporosarcina,
  • Tepidibacter Tepidibacter, Terribacillus, Thalassobacillus, Thermoacetogenium, Thermoactinomyces, Thermoalkalibacillus, Thermoanaerobacter, Thermoanaeromonas, Thermobacillus, Thermoflavimicrobium, Thermovenabulum, Tuberibacillus, Virgibacillus, and Vulcanobacillus.
  • the bacteria is Baceillus, Clostridium,
  • the spore forming microorganism is not bacteria.
  • the microorganism can b e Microsporidia.
  • Microsporidia constitute a phylum (Microspora) of spore-forming unicellular parasites with over 1,500 species. Microsporidia can cause chronic, debilitating diseases and in some cases lethal infections in humans. III. Applications of Rapidly Killing, Inactivating, and Reducing Spores
  • the disclosed compositions and methods can be used in various applications where it is desirable to kill, inactivate, or reduce the number of spores.
  • the disclosed compositions and methods can also be used in various applications where it is desirable to inhibit, reduce, or prevent spore reactivation and germination.
  • the one or more modified green tea polyphenol compositions can be added to or coated onto food to delay or prevent spoilage; they can be added to or coated onto equipment used to collect, process, prepare, or distribute food to reduce or prevent spore contamination of food; they can be added to or coated onto medical devices and surgical instruments to reduce or prevent infection associated with medical interventions; and they can be used as a hand hygiene product to reduce or prevent infection associated with medical interventions or daily subject to subject contact.
  • the modified green tea polyphenols, combinations thereof, and compositions thereof can be used to reduce or prevent food spoilage caused by spore forming bacteria. Therefore, the compositions can be used as a preservative to increase the half-life of foodstuffs.
  • the modified green tea polyphenol composition is used as a food additive to limit microbial activity and improve shelf life of a food or foodstuff.
  • the composition does not have an adverse effect on the flavor of the food or foodstuff (i.e., the organoleptic properties of the foodstuff are maintained or improved).
  • the modified green tea polyphenol compositions can be added or applied to the food or foodstuff in a form and method known to those skilled in the art.
  • the additive can be in the form of a powder, granular blend, or a liquid, and can be applied to or mixed with the food or foodstuff using marination, kneading, blending, tumbling, spraying, massaging, injecting, mixing and the like.
  • the modified green tea polyphenol compositions can be sprayed, injected, dipped or poured directly onto products.
  • the modified green tea polyphenol compositions are frozen and products are placed in contact with the frozen compositions.
  • the modified green tea polyphenol compositions can be spray dried, freeze-dried and/or powdered and then applied to products.
  • compositions can be added to a finished product or may be added at any step in the production processes of a product.
  • the compositions can be added to the final product or to what becomes the final product, or in a process of making the final product, either separately or all together at once.
  • Any food, foodstuff, beverage or medicine in need of increased or enhanced stability or shelf life can be treated with the disclosed methods and compositions.
  • the modified green tea polyphenol compositions can also be used on foods and plant species to reduce surface spore populations and used at manufacturing or processing sites handling such foods and plant species.
  • the product is one that is likely to be exposed to bacteria, particularly spore-forming bacteria, or spores thereof during its collection, processing, packaging, or distribution.
  • Some non-limiting examples of products that can be treated or supplemented with the disclosed methods and compositions include, but are not limited to, canned, frozen, dried, or fresh fruits and vegetables or products containing the same, wines (red or white), pet foods, fruit juices, food colorings and dyes, vegetable oils, butter, meats, cereals, chewing gum, baked goods, snack foods, dehydrated potatoes, beer, animal feed, food packaging, cosmetics, rubber products, and petroleum products, cookies, crackers, beet sugar, pie dough, rice, pasta, noodles, and beans.
  • the products can be fresh perishable materials such as meats, fish, mollusks, crustacean, poultry, dairy products, infant foods, soups, sauces wet dishes (i.e. ready meals), fruit and vegetables, eggs, seeds, leaves, etc.
  • Particular plant surfaces that can be treated include both harvested and growing leaves, roots, seeds, skins or shells, stems, stalks, tubers, corms, fruit, and the like.
  • the disclosed modified green tea polyphenol compositions be used at manufacturing or processing sites handling food or foodstuffs.
  • the modified green tea polyphenol composition can be used on food transport lines (e.g., as belt sprays); boot and hand-wash dip-pans; food storage facilities; anti-spoilage air circulation systems; refrigeration and cooler equipment; beverage chillers and warmers, blanchers, cutting boards, third sink areas, and meat chillers or scalding devices.
  • the modified green tea polyphenol compositions can be used to treat produce transport waters such as those found in flumes, pipe transports, cutters, sheers, blanchers, retort systems, washers, and the like.
  • the modified green tea polyphenol compositions can also be used on food packaging materials and equipment.
  • the modified green tea polyphenol compositions can also be used on or in ware wash machines, dishware, bottle washers, bottle chillers, warmers, third sink washers, cutting areas (e.g., water knives, sheers, cutters and saws) and egg washers.
  • Particular treatable surfaces include packaging such as cartons, bottles, films and resins; dish ware such as glasses, plates, utensils, pots and pans; ware wash machines; exposed food preparation area surfaces such as sinks, counters, tables, floors and walls; processing equipment such as tanks, vats, lines, pumps and hoses (e.g., dairy processing equipment for processing milk, cheese, ice cream and other dairy products); and transportation vehicles.
  • the modified green tea polyphenol compositions can also be used on or in other industrial equipment and in other industrial process streams such as heaters, cooling towers, boilers, retort waters, rinse waters, aseptic packaging wash waters, and the like.
  • the modified green tea polyphenol compositions can be used to treat microbes and odors in recreational waters such as in pools, spas, recreational flumes and water slides, fountains, and the like.
  • the disclosed modified green tea polyphenol compositions can be coated onto, or incorporated into, a medical device to reduce or prevent bacterial contamination of the device.
  • the device can be a device that is inserted into the subject transiently, or a device that is implanted permanently.
  • medical devices include, but are not limited to, needles, cannulas, catheters, shunts, balloons, and implants such as stents and valves.
  • the medical device is a vascular implant such as a stent.
  • Stents are utilized in medicine to prevent or eliminate vascular restrictions.
  • the implants may be inserted into a restricted vessel whereby the restricted vessel is widened.
  • the device is a surgical device.
  • Surgical devices include, but are not limited to articulator, bone chisel, cottle cartilage crusher, bone cutter, bone distractor, ilizarov apparatus, bone drill, bone extender, bone file, bone lever, bone mallet, bone rasp, bone saw, bone skid, bone splint, bone button, caliper, cannula, catheter, cautery, clamps, curette, depressor, dilator, dissecting knife, distractor, dermatome, forceps, acanthulus or acanthabolos, hemostat, hook, lancet (scalpel), luxator, lythotome, lythotript, mallet, mouth prop, mouth gag, mammotome, needle holder, occlude, osteotome, elevator, probe, retractor, rake, rib spreader, rongeur, scissors, spatula, speculum, sponge bowl, sterilization tray, tubes, knife, mesh, needle, snare
  • the modified green tea polyphenol compositions can be formulated to permit its incorporation onto the device.
  • the composition can be included within a coating on the device.
  • There are various coatings that can be utilized such as, for example, polymer coatings that can release the composition over a prescribed time period.
  • the composition can be embedded directly within the medical device.
  • the composition is coated onto or within the device in a delivery vehicle such as a microparticle or liposome that facilitates its release and delivery.
  • the disclosed modified green tea polyphenol compositions can be formulated into hand hygiene products for use in a hospital or clinical setting, schools, airports, cruise ships, nursing homes, or any other setting in which the transmission of microbes from one person to another, or a surface to a subject is possible.
  • the hand hygiene product is a gel, spray, foam, soap, wipe, lotion, sanitizer, or other product that can be applied to the skin.
  • the disclosed modified green tea polyphenol compositions are more effective than products currently available to healthcare professionals.
  • Methods of rapidly killing, inactivating or otherwise reducing the number of spores, or inhibiting, reducing, or preventing spore reactivation and germination typically include contacting spores, or a surface thought to be contaminated by spores, with one or more modified green tea polyphenol compositions described herein.
  • the modified green tea polyphenol compositions include one or more components or ingredients.
  • the additional components or ingredients can include additional active agents, carriers, fillers, etc., as discussed in more detail below.
  • compositions can be suitable for use as a food additive or preservative, as a pharmaceutical composition, or an antiseptic depending on the additional components or ingredients added to the composition, and one of skill in the art can select the additional components based on the intended use. For example, it will be appreciated that if the composition is to be used as a food additive or preservative any additional active or inert ingredients in the compositions should be edible. It will also be appreciated that if the composition is to be used for coating surgical or medical devices any additional active or inert components of the composition should be compatible with the intended use of the surgical or medical device, for example, introduction or implantation into or onto the body of the subject.
  • Green tea polyphenols preferably one or more green tea polyphenols modified with one or more hydrocarbon chains having C 1 to C 30 groups, as well as compositions having one or more green tea polyphenols, preferably one or more green tea polyphenols modified with one or more hydrocarbon chains having C 1 to C 30 groups, and combinations thereof are provided.
  • Representative green tea polyphenols include, but are not limited to (-)- epigallocatechin-3-gallate, (-)-epicatechin, (-)-epigallocatechin, and (-)-epicatechin-3-gallate.
  • Preferred modified GTPs include modified (-)-epigallocatechin-3-gallate, a pharmaceutically acceptable salt, prodrug, or derivative thereof.
  • a modified green tea polyphenol, a derivative or a variant of a green tea polyphenol includes green tea polyphenols having chemical modifications to increase solubility or bioavailability in a host.
  • these chemical modifications include the addition of chemical groups having a charge under physiological conditions.
  • the modifications include the conjugation of the green tea polyphenol to other biological moieties such as polypeptides, carbohydrates, lipids, or a combination thereof.
  • Preferred modifications include modifications with one or more hydrocarbon chains having C 1 to C 30 groups.
  • a sporicidal composition including one or more green tea polyphenols, modified green tea polyphenols, optionally in combination with one or more of a pharmaceutically acceptable carrier, diluent, excipient, filler, or other inert or active agents.
  • the active ingredient in the composition consists essentially of (-)-epigallocatechin-3-gallate, (-)-epigallocatechin-3-gallate modified with one or more hydrocarbon chains having C 1 to C 30 groups, or a combination thereof, a pharmaceutically acceptable salt or prodrug thereof.
  • the active ingredient can be in the form a single optical isomer.
  • one optical isomer will be present in greater than 85%, 90%, 95%, or 99% by weight compared to the other optical isomer. It will be appreciated that the composition can also include at least one additional active ingredient, for example a second therapeutic. Additional description of the disclosed pharmaceutical compositions is provided below.
  • Lipophilic tea polyphenols can be prepared by catalytic esterification of a green tea polyphenols (GTP).
  • Green tea polyphenols modified to increase the permeability of the green tea polyphenols to skin and cell membranes or increase their solubility in hydrophobic media relative to unmodified green tea polyphenols are therefore provided.
  • Green tea polyphenols that can be modified include, but are not limited to (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), (-)-epigallocatechin-3- gallate (EGCG), proanthocyanidins, enantiomers thereof, epimers thereof, isomers thereof, combinations thereof, and prodrugs thereof.
  • One embodiment provides a green tea polyphenol having an ester-linked C 1 to C 30 hydrocarbon chain, for example a fatty acid, at one or more positions.
  • Another embodiment provides a green tea polyphenol having one or more cholesterol groups linked to the polyphenol.
  • the cholesterol group can be linked for example by an ether linkage directly to the polyphenol or a C 1 to C 10 linker can connect the cholesterol group to the polyphenol.
  • Another embodiment provides a green tea polyphenol compound having one or more acyloxy groups, wherein the acyl group is C 1 to C 30 . It is believed that the addition of alkyl, alkenyl, or alkynyl chains, for example via fatty acid esterification, to green tea polyphenols increases the stability of the green tea polyphenols and increases the solubility of the green tea polyphenols in hydrophobic media including lipids, fats, soaps, detergents, surfactants or oils compared to unmodified green tea polyphenols.
  • Green tea polyphenols having one or more hydrocarbon chains for example ester-linked C 1 to C 30 groups or C 1 to C 30 acyloxy groups are believed to more permeable to skin or cell membranes and thereby enable the ester-linked hydrocarbon chain containing or acyloxy containing green tea polyphenol to readily enter a cell and have a biological effect on the cell, for example modulating gene expression, compared to unmodified green tea polyphenols.
  • one or more hydrocarbon chains can be linked to the green tea polyphenol using linkages other than ester linkages, for example thio-linkages.
  • Esterified green tea polyphenols can be combined with oils, detergents, surfactants, or combinations thereof to produce compositions which clean the skin and deliver green tea polyphenols to the skin.
  • the oils, detergents, or surfactants advantageously increase the stability of green tea polyphenols by reducing contact of the green tea polyphenols with aqueous media.
  • Certain embodiments provide single optical isomers, enantiomers, or epimers of the disclosed modified green tea polyphenols.
  • Other embodiments provide compositions containing single optical isomers, enantiomers, or epimers or the disclosed modified green tea polyphenols.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are each independently H, OH, wherein R 8 is a linear, branched or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 8 is cyclic, R 8 is a C 3 -C 30 group; and
  • R 6 is O, -NR 9 R 10 , or S, wherein R 9 and R 10 are independently hydrogen, or a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 9 and/or R 10 are cyclic, R 9 and/or R 10 are C 3 -C 30 groups; wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 9 , or R 10 is or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • R 8 is a linear or branched alkyl chain. In more preferred embodiments of Formula I, R 8 is a linear or branched C 16 -C 25 alkyl group. In particularly preferred embodiments of Formula I, R 8 is a C 17 H 35 group.
  • One embodiment provides a compound according to Formula I as described above, provided R 4 is not when R 1 , R 2 , R 3 , R 5 , and R 7 are OH; or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • One embodiment provides a compound according to Formula I as described above wherein at least two of R 1 , R 2 , R 3 , R 4 , R 5 , or R 7 are independently provided R 4 is not when R 1 , R 2 , R 3 , R 5 are OH, and R 7 is or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • Another embodiment provides a compound according to Formula I as described above wherein at least three of R 1 , R 2 , R 3 , R 4 , R 5 , or R 7 are independently or or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • Still another embodiment provides a compound according to Formula I as described above wherein at least four of R 1 , R 2 , R 3 , R 4 , R 5 , or R 7 are independently or or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are each independently H, OH,
  • R 11 is a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 11 is cyclic, R 11 is a C 3 -C 30 group;
  • R 5 and R 6 are independently O, -NR 12 R 13 or S, wherein R 12 and R 13 are independently hydrogen, or a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 12 and/or R 13 are cyclic, R 12 and/or R 13 are C 3 -C 30 groups; and wherein at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • R 11 is a linear or branched alkyl chain. In more preferred embodiments of Formula II, R 11 is a linear or branched C 16 -C 25 alkyl group. In particularly preferred embodiments of Formula II, R 11 is a C 17 H 35 group.
  • Another embodiment provides a compound according to Formula II wherein at least two of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • Another embodiment provides a compound according to Formula II as described above wherein at least three of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently , or optionally in combination with an excipient.
  • Another embodiment provides a compound according to Formula II as described above wherein at least four of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently , or optionally in combination with an excipient.
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are each independently H, OH, ⁇
  • R 11 is a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 11 is cyclic, R 11 is a C 3 -C 30 group;
  • R 5 and R 6 are independently O, -NR 12 R 13 or S, wherein R 12 and R 13 are independently hydrogen, or a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 12 and/or R 13 are cyclic, R 12 and/or R 13 are C 3 -C 30 groups; and wherein at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently , or . and wherein R 4 is not when R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , and R 10 are
  • compositions including a compound according to Formula II wherein at least two of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • compositions including a compound according to Formula II as described above wherein at least three of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are
  • compositions including a compound according to Formula II as described above wherein at least four of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are
  • compositions including a compound according to Formula II wherein R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are each independently H, OH,
  • R 11 is a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 11 is cyclic, R 11 is a C 3 -C 30 group;
  • R 5 and R 6 are independently O, -NR 12 R 13 or S, wherein R 12 and R 13 are independently hydrogen, or a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 12 and/or R 13 are cyclic, R 12 and/or R 13 are C 3 -C 30 groups; and wherein at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently a when R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , and R 10 are
  • One embodiment provides a compound according to Formula III: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are each independently H, OH, wherein R 8 is a linear or branched C 16 -C 25 alkyl group.
  • R 6 is O, -NR 9 R 10 , or S, wherein R 9 and R 10 are independently hydrogen, or a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 9 and/or R 10 are cyclic, R 9 and/or R 10 are C 3 -C 30 groups; wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 9 , or R 10 is or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • R 8 is a C 17 H 35 group.
  • One embodiment provides a compound according to Formula III as described above, wherein one or more of R 1 , R 2 , R 3 , R 4 , R 5 , or R 7 is or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • One embodiment provides a compound according to Formula III as described above, wherein at least two of R 1 , R 2 , R 3 , R 4 , R 5 , or R 7 are independently . or or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • Another embodiment provides a compound according to Formula III as described above wherein at least three of R 1 , R 2 , R 3 , R 4 , R 5 , or R 7 are independently . or or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • R 1 , R 2 , R 3 , R 4 , R 5 , or R 7 are independently . or or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are each independently H, OH,
  • R 11 is a linear or branched C 16 -C 25 alkyl group
  • R 5 and R 6 are independently O, -NR 12 R 13 or S, wherein R 12 and R 13 are independently hydrogen, or a linear, branched, or cyclic, saturated or unsaturated, substituted or unsubstituted C 1 -C 30 group, wherein if R 12 and/or R 13 are cyclic, R 12 and/or R 13 are C 3 -C 30 groups; and wherein at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • Rii is a C17H35 group.
  • One embodiment provides a compound according to Formula IV as described above, wherein one or more of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 is or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently 0 or or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • Another embodiment provides a compound according to Formula IV as described above wherein at least three of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently O O ⁇ O- C 17 H 35 optionally in combination with an excipient.
  • Another embodiment provides a compound according to Formula IV as described above wherein at least four of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently optionally in combination with an excipient.
  • compositions including a compound according to Formula IV wherein at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • compositions including a compound according to Formula IV wherein at least two of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient.
  • compositions including a compound according to Formula IV as described above wherein at least four of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are independently optionally in combination with an excipient.
  • a green tea polyphenol esterified with one fatty acid is provided.
  • Another embodiment provides a green tea polyphenol esterified with at least two fatty acids.
  • Certain embodiments provide a green tea polyphenol esterified with one or more fatty acids having a hydrocarbon chain greater than 16 carbons.
  • Some embodiments provide a green tea polyphenol esterified with one or more fatty acids having a hydrocarbon chain of between 17 and 25 carbons in length.
  • Particularly preferred embodiments provide a green tea polyphenol esterified with one or more stearic acid or palmitic acid chains.
  • Representative green tea polyphenols include, but are not limited to (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), (-)-epigallocatechin-3- gallate (EGCG).
  • Representative fatty acids include, but are not limited to butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid (palmitic acid), 9-hexadecenoic acid, octadecanoic acid (stearic acid), 9- octadecenoic acid, 11-octadecenoic acid, 9,12-octadecadienoic acid, 9,12,15-octadecatrienoic acid, 6,9,12-octadecatrienoic acid, eicosanoic acid, 9-eicosenoic acid, 5,8,11,14- eicosatetraenoic acid, 5,8,11, 14, 17-eicosapentaenoic acid, docosanoic acid, 13-docosenoic acid, 4,7,10,13,16,19-doc
  • Lipid esters of EGCG can be formed either enzymatically or chemically (Chen, et al., Journal of Zhejiang University Science. 2003; 6:714-718).
  • EGCG-ester was purified previously by Chen et al in China. This was accomplished from a catalytic esterification between green tea polyphenols and Cl 6-fatty acid. The esterification was obtained by mixing 4 grams of green tea polyphenols and 6.5 grams of hexadecanoyl chloride. Next, 50 mLs of ethyl acetate and a catalyst at 40°C were added to the mixture. After 3 hours of stirring, the solution was washed three times with 30 mLs of deionized water. The organic layer was then allowed to evaporate and further dried by using a vacuum at 40°C. This resulted in 8.7g of powder product. A schematic of the synthesis of a likely esterification between GTP and Hexadecanoyl Chloride is shown below. (Chen, et al., Journal of Zhejiang University Science, 2003; 6:714-718.)
  • EGCG is esterified at the 4' position according to the structure above with stearic acid (as shown) or palmitic acid.
  • compositions containing the disclosed modified green tea polyphenols optionally include one more bioactive agents or additional therapeutic agents.
  • one or more bioactive agents can be conjugated to the green tea polyphenol.
  • Bioactive agents include therapeutic, prophylactic and diagnostic agents. These may be organic or inorganic molecules, proteins, peptides, sugars, polysaccharides, tea saponin, vitamins, cholesterol, or nucleic acid molecules.
  • Representative vitamins include, but are not limited to lipid soluble vitamins such as vitamin D, vitamin E, or combinations thereof.
  • therapeutic agents include proteins, such as hormones, antigens, and growth effector molecules; nucleic acids, such as antisense molecules; and small organic or inorganic molecules such as antimicrobials, antihistamines, immunomodulators, decongestants, neuroactive agents, anesthetics, amino acids, and sedatives.
  • active agents that can be used in combination with the disclosed modified green tea polyphenol compositions are disclosed in U.S. Published Application Nos. 2012/0172423 and 2012/0076872 each of which are specifically incorporated by reference herein in their entities.
  • the active agents can be, for example, anti-fungal agents, anti- bacterial agents, antiseptic agents, skin protectants, anti-psoriasis agents, local anesthetics, antihistamines, and antioxidants.
  • the composition includes one or more additional antibacterial agents.
  • additional antibacterial agents can be used to prepare the described compositions.
  • a list of potential antibacterial agents can be found in “Martindale - The Complete Drug Reference”, 32nd Ed., Kathleen Parfitt, (1999) on pages 112-270.
  • Classes of useful antibacterials include aminoglycosides, antimycobacterials, cephalosporins and beta-lactams, chloramphenicols, glycopeptides, lincosamides, macrolides, penicillins, quinolones, sulphonamides and diaminopyridines, tetracyclines, and miscellaneous.
  • the antibacterial agent is selected from the group consisting of metronidazole, timidazole, secnidazole, erythromycin, bactoban, mupirocin, neomycin, bacitracin, cicloprox, fluoriquinolones, ofloxacin, cephalexin, dicloxacillin, minocycline, rifampin, famciclovir, clindamycin, tetracycline and gentamycin.
  • Suitable aminoglycosides include antibiotics derived from Streptomyces and other actinomycetales, including streptomycin, framycetin, kanamycin, neomycin, paramomycin, and tobramycin, as well as gentamycin, sissomycin, netilmycin, isepamicin, and micronomycin.
  • Suitable antimycobacterials include rifamycin, rifaximin, rifampicin, rifabutinisoniazid, pyrazinamide, ethambutol, streptomycin, thiacetazone, aminosalicylic acid, capreomycin, cycloserine, dapsone, clofazimine, ethionamide, prothionamide, ofloxacin, and minocycline.
  • Cephalosporins and beta-lactams generally have activity against gram-positive bacteria and newer generations of compounds have activity against gram-negative bacteria as well. Suitable cephalosporins and beta-lactams include:
  • cephalothin cephazobn, cephradine, cephaloridine, cefroxadine, cephadroxil, cefatrizine, cephalexin, pivcephalexin, cefaclor, and cefprozil.
  • cephamandole cefuroxime axetil, cefonicid, ceforanide, cefotiam, and cephamycin.
  • cefotaxime cefmenoxime, cefodizime, ceftizoxime, ceftriaxone, cefixime, cefdinir, cefetamet, cefpodoxime, ceftibuten, latamoxef, ceftazidime, cefoperazone, cefpiramide, and cefsulodin.
  • cephalosporins include cefoxitim, cefmetazole, cefotetan, cefbuperazone, cefminox, imipenem, meropenem, aztreonam, carumonam, and loracarbef.
  • Chloramphenicols inhibit gram positive and gram negative bacteria.
  • Suitable cloramphenicols include chloramphenicol, its sodium succinate derivative, thiamphenicol, and azidamfenicol.
  • Suitable glycopeptides include vancomycin, teicoplanin, and ramoplanin.
  • Suitable lincosamides include lincomycin and clindamycin, which are used to treat primarily aerobic infections.
  • Macrolides have a lactam ring to which sugars are attached.
  • Suitable macrolides include erytjhromycin, as well as spiromycin, oleandomycin, josamycin, kitamycin, midecamycin, rokitamycin, azithromycin, clarithromycin, dirithromycin, roxithromycin, flurithromycin, tylosin; and streptgramins (or synergistins) including pristinamycin, and virginiamycin; and combinations thereof.
  • Suitable penicillins include natural penicillin and the semisynthetic penicillins F, G, X, K, and V.
  • Newer penicillins include phenethicillin, propicillin, methicilin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, nafcillin, ampicillin, amoxicillin, bacampicillin, hetacillin, metampicillin, pivampicillin, carbenecillin, carfecillin, carindacillin, sulbenecillin, ticarcillin, azlocillin, mezlocillin, piperacillin, temocillin, mecillinam, and pivemecillinam.
  • Lactamase inhibitors such as clavulanic acid, sulbactam, and tazobacytam are often co- administered.
  • Suitable quinolones include nalidixic acid, oxolinic acid, cinoxacin, acrosoxacin, pipemedic acid, and the fluoroquinolones flumequine, ciprofloxacin, enoxacin, fleroxacin, grepafloxacin, levofloxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, trovafloxacin, danofloxacin, enrofloxacin, and marbofloxacin.
  • Sulphonamides and diaminopyridines include the original of the “sulfa” drugs, sulphanilamide, and a large number of derivatives, including sulfapyridine, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfadimethoxine, sulfadimethoxydiazine, sulfadoxine, sulfametopyrazine, silver sulfadiazine, mafenide acetate, and sulfasalizine, as well as related compounds including trimethoprim, baquiloprim, brodimoprim, ormetoprim, tetroxoprim, and in combinations with other drugs such as co-trimoxazole.
  • Tetracyclines are typically broad-spectrum and include the natural products chlortetracycline, oxytetracycline, tetracycline, demeclocycline, and semisynthetic methacycline, doxycycline, and minocycline.
  • Suitable antibacterial agents that do not fit into one of the categories above include spectinomycin, mupirocin, newmycin, fosfomycin, fusidic acid, polymixins, colistin, bacitracin, gramicidin, tyrothricin, clioquinol, chloroquinaldol, haloquinal, nitrofurantonin, nitroimidazoles (including metronizole, timidazole and secnidazole), and hexamine.
  • the antibiotic and antifungal agents may be present as the free acid or free base, a pharmaceutically acceptable salt, or as a labile conjugate with an ester or other readily hydrolysable group, which are suitable for complexing with the ion-exchange resin to produce the resinate.
  • the composition include one or more excipients, carriers, fillers, additives, binders, disintegration agents, lubricants, flavoring agents, and combinations thereof.
  • a composition can include one or more of the following: a binder, such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof; an excipient, such as, for example, dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate or combinations thereof; a disintegrating agent, such as, for example, com starch, potato starch, alginic acid or combinations thereof; a lubricant, such as, for example, magnesium stearate; a sweetening agent, such as, for example, sucrose, lactose, saccharin or combinations thereof; a flavoring agent, such as, for example peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc.; or combinations thereof.
  • a binder such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof
  • an excipient such as, for example
  • compositions of the invention generally may include vitamins, minerals, and other additives such as flavorings, preservatives, emulsifiers and humectants.
  • exemplary ingredients include animal protein, plant protein, farinaceous matter, vegetables, fruit, egg-based materials, undenatured proteins, food grade polymeric adhesives, gels, polyols, starches, gums, flavorants, seasonings, salts, colorants, time-release compounds, prebiotics, probiotics, aroma modifiers, textured wheat protein, textured soy protein, textured lupin protein, textured vegetable protein, breading, comminuted meat, flour, comminuted pasta, water, and combinations thereof.
  • the nutritional balance including the relative proportions of vitamins, minerals, protein, fat and carbohydrate, and other components can be determined according to dietary standards known in the veterinary and nutritional art.
  • a carrier can be a solvent or dispersion medium.
  • exemplary carriers include, but are not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids (e.g., triglycerides, vegetable oils, liposomes) and combinations thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in carriers such as, for example liquid polyol or lipids; by the use of surfactants such as, for example hydroxypropyl cellulose; or combinations thereof such methods.
  • isotonic agents such as, for example, sugars, sodium chloride or combinations thereof.
  • the filler can be a solid, a liquid or packed air.
  • the filler can be reversible (for example thermo-reversible including gelatin) and/or irreversible (for example thermo-irreversible including egg white).
  • Non limiting examples of the filler include gravy, gel, jelly, aspic, sauce, water, air (for example including nitrogen, carbon dioxide, and atmospheric air), broth, and combinations thereof.
  • Formulations of the compounds disclosed herein including modified green tea polyphenols can be prepared using pharmaceutically acceptable excipients composed of materials. It will be appreciated that the pharmaceutical compositions and formulations disclosed herein are considered safe and effective and can be administered to an individual without causing undesirable biological side effects or unwanted interactions. Therefore, in some embodiments, the pharmaceutical compositions are administered to a subject. In some embodiments, the pharmaceutical composition is added to a food or foodstuff to reduce or prevent spoilage or contamination of the food, or used applied in or onto equipment or devices to reduce or prevent contamination. Therefore, in some embodiments, the pharmaceutical compositions not intended to treat a disease or disorder in a subject. In some embodiments, the pharmaceutical compositions is not administered to a subject at all.
  • excipient includes, but is not limited to, surfactants, emulsifiers, emulsion stabilizers, emollients, buffers, solvents and preservatives.
  • Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol.
  • the oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers. a. Emollients
  • Suitable emollients include those generally known in the art and listed in compendia, such as the “Handbook of Pharmaceutical Excipients”, 4 th Ed., Pharmaceutical Press, 2003. These include, without limitation, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and combinations thereof.
  • the emollients are ethylhexylstearate and ethyl
  • Suitable surfactants include anionic surfactants, nonionic surfactants, cationic surfactants and ampholytic surfactants.
  • Anionic surfactants include alkaline salts, ammonium salts, amine salts, amino alcohol salts and magnesium salts of the following compounds: alkyl sulphates, alkyl ether sulphates, alkylamido ether sulphates, alkylaryl polyether sulphates, monoglyceride sulphates; alkyl sulphonates, alkylamide sulphonates, alkylaryl sulphonates, olefin sulphonates, paraffin sulphonates; alkyl sulphosuccinates, alkyl ether sulphosuccinates, alkylamide sulphosuccinates; alkyl sulphosuccinamates; alkyl sulphoacetates; alkyl phosphates, alkyl ether phosphates; acy
  • Suitable anionic surfactants include fatty acid salts such as oleic, ricinoleic, palmitic and stearic acid salts; coconut oil acid or hydrogenated coconut oil acid; acyl lactylates, in which the acyl group contains from 8 to 30 carbon atoms.
  • Surfactants considered as weakly anionic can also be used, such as polyoxyalkylenated carboxylic alkyl or alkylaryl ether acids or salts thereof, polyoxyalkylenated carboxylic alkylamido ether acids or salts thereof, and alkyl D- galactosiduronic acids or salts thereof.
  • Suitable amphoteric surfactants are secondary or tertiary aliphatic amine derivatives, in which the aliphatic radical is a linear or branched chain containing 8 to 22 carbon atoms and which contains at least one carboxylate, sulphonate, sulphate, phosphate or phosphonate water-solubilizing anionic group; (C 8 -C 20 ) alkylbetaines, sulphobetaines, (C 8 -C 20 ) alkyl - amido (C 1 -C 6 ) alkylbetaines or (C 8 -C 20 ) alkyl-amido (C 1 -C 6 ) alkylsulphobetaines.
  • the nonionic surfactants are chosen more particularly from polyethoxylated, polypropoxylated or polyglycerolated fatty acids or alkylphenols or alcohols, with a fatty chain containing 8 to 30 carbon atoms, the number of ethylene oxide or propylene oxide groups being between 2 and 50 and the number of glycerol groups being between 2 and 30.
  • Disodium cocoamphodiacetate, disodium lauroamphodiacetate, disodium capryloamphodiacetate, disodium caproamphodiacetate, disodium cocoampho-dipropionate, disodium lauroamphodipropionate, disodium caproamphodipropionate, disodium capryloamphodipropionate, lauroamphodipropionate acid, and cocoamphodipropionate acid can also be used.
  • Representative cationic surfactants are chosen in particular from optionally polyoxyalkylenated primary, secondary or tertiary fatty amine salts; quaternary ammonium salts; imidazoline derivatives; or amine oxides of cationic nature.
  • Suitable quaternary ammonium salts are tetraalkylammonium halides (for example chlorides) such as, for example, dialkyldimethylammonium or alkyltrimethylammonium chlorides, in which the alkyl radical contains from about 12 to 22 carbon atoms, in particular behenyltrimethylammonium, distearyl-dimethylammonium, cetyltrimethylammonium or benzyl-dimethylstearylammonium chloride or alternatively the stearamidopropyldimethyl(myristyl acetate)ammonium chloride.
  • tetraalkylammonium halides for example chlorides
  • dialkyldimethylammonium or alkyltrimethylammonium chlorides in which the alkyl radical contains from about 12 to 22 carbon atoms, in particular behenyltrimethylammonium, distearyl-dimethylammonium, cetyltrimethylammonium or benzyl-d
  • the acyl groups preferably contain 14 to 18 carbon atoms and are more particularly obtained from a plant oil such as palm oil or sunflower oil.
  • Additional surfactants that can be used include, but are not limited to sodium dodecylsulfate (SDS), sodium cholate, sodium deoxycholate (DOC), N-lauroylsarcosine sodium salt, lauryldimethylamine-oxide (LDAO), cetyltrimethylammoniumbromide (CTAB), and bis(2-ethylhexyl)sulfosuccinate sodium salt.
  • SDS sodium dodecylsulfate
  • DOC sodium deoxycholate
  • LDAO lauryldimethylamine-oxide
  • CTAB cetyltrimethylammoniumbromide
  • bis(2-ethylhexyl)sulfosuccinate sodium salt bis(2-ethylhexyl)sulfosuccinate sodium salt.
  • non-ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof.
  • the non-ionic surfactant is stearyl alcohol.
  • Representative detergents include but are not limited to alkylbenzyldimethylammonium chloride, alkyldimethylbenzylammonium chloride, sodium bis(2-ethylhexyl) sulfosuccinate, bis(2-ethylhexyl) sulfosuccinate sodium salt, 3-[(3- Cholamidopropyl)dimethylammonio] - 1 -propanesulfonate.
  • Emulsifiers include but are not limited to alkylbenzyldimethylammonium chloride, alkyldimethylbenzylammonium chloride, sodium bis(2-ethylhexyl) sulfosuccinate, bis(2-ethylhexyl) sulfosuccinate sodium salt, 3-[(3- Cholamidopropyl)dimethylammonio] - 1 -propanesulfonate.
  • Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, self- emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sul
  • Buffers preferably buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7.
  • the disclosed compositions can also contain at least one adjuvant chosen from the adjuvants usually used in cosmetics, such as fragrances, preserving agents, sequestering agents, wetting agents, sugars, amphoteric polymers, menthol, nicotinate derivatives, agents for preventing hair loss, foam stabilizers, propellants, dyes, vitamins or provitamins, acidifying or basifying agents or other well-known cosmetic adjuvants.
  • the modified green tea polyphenols can be incorporated into a polymeric component by encapsulation in a microcapsule.
  • the microcapsule can be fabricated from a material different from that of the bulk of the carrier, coating, or matrix. Suitable microcapsules are those which are fabricated from a material that undergoes erosion in the host, or those which are fabricated such that they allow the green tea polyphenol to diffuse out of the microcapsule. Such microcapsules can be used to provide for the controlled release of the encapsulated green tea polyphenol from the microcapsules.
  • microparticle sizes may range from about 0.2 pm up to about 100 pm.
  • Synthetic methods for gel microparticles, or for microparticles from molten materials are known, and include polymerization in emulsion, in sprayed drops, and in separated phases.
  • known methods include wet or dry milling or grinding, pulverization, size separation by air jet, sieve, and the like.
  • Microparticles can be fabricated from different polymers using a variety of different methods known to those skilled in the art. Exemplary methods include those set forth below detailing the preparation of polylactic acid and other microparticles. Polylactic acid microparticles are preferably fabricated using one of three methods: solvent evaporation, as described by Mathiowitz, et al. (1990) J. Scanning Microscopy 4:329; Beck, et al. (1979) Fertil. Steril. 31: 545; and Benita, et al. (1984) J. Pharm. Sci. 73: 1721; hot-melt microencapsulation, as described by Mathiowitz, et al., Reactive Polymers 6: 275 (1987); and spray drying. Exemplary methods for preparing microencapsulated bioactive materials are set forth below.
  • the microcapsule polymer is dissolved in a volatile organic solvent, such as methylene chloride.
  • a volatile organic solvent such as methylene chloride.
  • the green tea polyphenol (either soluble or dispersed as fine particles) is added to the solution, and the mixture is suspended in an aqueous solution that contains a surface active agent such as poly(vinyl alcohol).
  • the resulting emulsion is stirred until most of the organic solvent has evaporated, leaving solid microparticles.
  • the solution is loaded with the green tea polyphenol and suspended in vigorously stirred distilled water containing poly(vinyl alcohol) (Sigma). After a period of stirring, the organic solvent evaporates from the polymer, and the resulting microparticles are washed with water and dried overnight in a lyophilizer.
  • Microparticles with different sizes (1- 1000 pm) and morphologies can be obtained by this method.
  • This method is useful for relatively stable polymers like polyesters and polystyrene.
  • Labile polymers such as polyanhydrides, may degrade during the fabrication process due to the presence of water.
  • the following two methods which are performed in completely anhydrous organic solvents, are preferably used.
  • the polymer is first melted and then mixed with the solid particles of biologically active material that have preferably been sieved to less than 50 microns.
  • the mixture is suspended in a non-miscible solvent (like silicon oil) and, with continuous stirring, heated to about 5°C. above the melting point of the polymer.
  • a non-miscible solvent like silicon oil
  • the emulsion is stabilized, it is cooled until the polymer particles solidify.
  • the resulting microparticles are washed by decantation with a solvent such as petroleum ether to give a free-flowing powder.
  • Microparticles with sizes ranging from about 1 to about 1000 microns are obtained with this method.
  • the external surfaces of capsules prepared with this technique are usually smooth and dense. This procedure is preferably used to prepare microparticles made of polyesters and polyanhydrides.
  • the solvent removal technique is preferred for polyanhydrides.
  • the green tea polyphenol is dispersed or dissolved in a solution of the selected polymer in a volatile organic solvent like methylene chloride. This mixture is suspended by stirring in an organic oil (such as silicon oil) to form an emulsion. Unlike solvent evaporation, this method can be used to make microparticles from polymers with high melting points and different molecular weights. Microparticles that range from about 1 to about 300 pm can be obtained by this procedure.
  • the external morphology of spheres produced with this technique is highly dependent on the type of polymer spray drying, the polymer is dissolved in methylene chloride. A known amount of the green tea polyphenol is suspended or co-dissolved in the polymer solution. The solution or the dispersion is then spray-dried. Microparticles ranging between about 1 to about 10 pm are obtained with a morphology which depends on the type of polymer used.
  • the green tea polyphenol is encapsulated in microcapsules that comprise a sodium alginate envelope.
  • Microparticles made of gel-type polymers, such as alginate are produced through traditional ionic gelation techniques. The polymers are first dissolved in an aqueous solution, mixed with barium sulfate or some bioactive agent, and then extruded through a microdroplet forming device, which in some instances employs a flow of nitrogen gas to break off the droplet. A slowly stirred (approximately 100-170 RPM) ionic hardening bath is positioned below the extruding device to catch the forming microdroplets. The microparticles are left to incubate in the bath for about twenty to thirty minutes in order to allow sufficient time for gelation to occur. Microparticle size is controlled by using various size extruders or varying either the nitrogen gas or polymer solution flow rates.
  • Liposomes can aid in the delivery of the green tea polyphenol to a particular tissue and also can increase the half-life of green tea polyphenol. Liposomes are commercially available from a variety of suppliers. Alternatively, liposomes can be prepared according to methods known to those skilled in the art, for example, as described in Eppstein et ak, U.S. Pat. No. 4,522,811. In general, liposomes are formed from standard vesicle-forming lipids, which generally include neutral or negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of factors such as the desired liposome size and half-life of the liposomes in the blood stream.
  • the liposomes encapsulating the green tea polyphenol include a ligand molecule that can target the liposome to a particular cell or tissue at or near the site of HSV infection.
  • the liposomes encapsulating the green tea polyphenols of the present disclosure are modified so as to avoid clearance by the mononuclear macrophage and reticuloendothelial systems, for example by having opsonization-inhibition moieties bound to the surface of the structure.
  • a liposome can comprise both opsonization- inhibition moieties and a ligand.
  • Opsonization-inhibiting moieties for use in preparing the liposomes in one embodiment are large hydrophilic polymers that are bound to the liposome membrane.
  • an opsonization inhibiting moiety is “bound” to a liposome membrane when it is chemically or physically attached to the membrane, e.g., by the intercalation of a lipid-soluble anchor into the membrane itself, or by binding directly to active groups of membrane lipids.
  • These opsonization-inhibiting hydrophilic polymers form a protective surface layer which significantly decreases the uptake of the liposomes by the macrophage-monocyte system (“MMS”) and reticuloendothelial system (“RES”); e.g., as described in U.S. Pat. No. 4,920,016. Liposomes modified with opsonization-inhibition moieties thus remain in the circulation much longer than unmodified liposomes.
  • Stealth liposomes are sometimes called “stealth” liposomes.
  • Stealth liposomes are known to accumulate in tissues fed by porous or “leaky” microvasculature.
  • the reduced uptake by the RES lowers the toxicity of stealth liposomes by preventing significant accumulation in the liver and spleen.
  • Opsonization inhibiting moieties suitable for modifying liposomes are preferably water-soluble polymers with a molecular weight from about 500 to about 40,000 daltons, and more preferably from about 2,000 to about 20,000 daltons.
  • Such polymers include polyethylene glycol (PEG) or polypropylene glycol (PPG) derivatives; e.g., methoxy PEG or PPG, and PEG or PPG stearate; synthetic polymers such as polyacrylamide or poly N-vinyl pyrrolidone; linear, branched, or dendrimeric polyamidoamines; polyacrylic acids; polyalcohols, e.g., polyvinylalcohol and polyxylitol to which carboxylic or amino groups are chemically linked, as well as gangliosides, such as ganglioside GME Copolymers of PEG, methoxy PEG, or methoxy PPG, or derivatives thereof, are also suitable.
  • PEG polyethylene glycol
  • the opsonization inhibiting polymer can be a block copolymer of PEG and either a polyamino acid, polysaccharide, polyamidoamine, polyethyleneamine, or polynucleotide.
  • the opsonization inhibiting polymers can also be natural polysaccharides containing amino acids or carboxylic acids, e.g., galacturonic acid, glucuronic acid, mannuronic acid, hyaluronic acid, pectic acid, neuraminic acid, alginic acid, carrageenan; laminated polysaccharides or oligosaccharides (linear or branched); or carboxylated polysaccharides or oligosaccharides, e.g., reacted with derivatives of carbonic acids with resultant linking of carboxylic groups.
  • the opsonization-inhibiting moiety is a PEG, PPG, or derivatives thereof.
  • Liposomes modified with PEG or PEG-derivatives are sometimes called “PEGylated liposomes.”
  • the opsonization inhibiting moiety can be bound to the liposome membrane by any one of numerous well-known techniques. For example, an N-hydroxysuccinimide ester of PEG can be bound to a phosphatidyl-ethanolamine lipid-soluble anchor, and then bound to a membrane.
  • a dextran polymer can be derivatized with a stearylamine lipid- soluble anchor via reductive amination using Na(CN)BH3 and a solvent mixture such as tetrahydrofuran and water in a 30: 12 ratio at 60° C.
  • microparticles and liposomes and methods of preparing microparticles and liposomes are offered by way of example and are not intended to define the scope of microparticles or liposomes of use in the present disclosure. It will be apparent to those of skill in the art that an array of microparticles or liposomes, fabricated by different methods, are of use in the present invention.
  • the compositions contains 0.01% to 20% (v/v) epigallocatechin-3-gallate (EGCG) esterified at the 4’ position with EC16.
  • the composition can include 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0,7%, 0.8%, 0.9%, 1.0%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% EC16.
  • the modified green tea polyphenol composition includes 0.1% to 1% (-)-epigallocatechin-3- gallate (EGCG) esterified at the 4’ position with palmitic acid (referred to as EC16).
  • the modified green tea polyphenol composition includes 62% to 90% (v/v) alcohol.
  • the composition can include 62%, 63%, 64%, 65%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% (v/V) alcohol.
  • the alcohol is ethanol or isopropanol and is present in 62% to 90% (v/v).
  • the modified green tea polyphenol additionally includes 0% to 20% (v/v) glycerin.
  • the composition can include 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% glycerin.
  • the modified green tea polyphenol composition can also include citrate.
  • the composition includes 0% to 1% (v/v) citrate.
  • the composition can include 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% (v/v) citrate.
  • the modified green tea polyphenol composition additionally includes benzalkonium chloride.
  • the composition can include 0% to 1% benzalkonium chloride. In one embodiment, the composition includes 0%, 0.1%, 0.2%,
  • the composition can also optionally include 0% to 40% water.
  • the composition includes 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,
  • compositions contains 10% to 38%.(v/v) water.
  • Table 1 describes exemplary formulations.
  • Example 1 Effect of EGCG-P, different concentrations of ethanol and EGCG-P/alcohol combinations on the spore germination.
  • B. cereus was incubated on modified nutrient agar plates (supplemented with 0.06 g of MgSO 4 and 0.25 g of KH 2 PO 4 per liter) at 37 ° C for 10 days to enhance endospore formation. After 10 days, Schaeffer Fulton differential staining was conducted to observe the endospore and vegetative cells. The endospores were then purified by centrifugation at room temperature for 10 min at 10,000 rpm twice. The supernatant was discarded and the endospores were suspended in sterile deionized water and vortexed to create a homogenous suspension.
  • the suspension was heated for 20 min at 75°C to eliminate any remaining vegetative cells and obtain pure endospores.
  • Purified endospores from B. cereus were mixed for 1 min (60 sec) with the formulations #1, 2, 3, 4 or 5 (Table 1, above). After treatment, serial 10 X dilutions were made immediately, plated out and incubated for 24 hours. The CFU was counted, the % of inhibition and logio reduction were calculated, plated onto nutrient agar plates, and subsequently incubated at 37°C for 24 h.
  • CFU colony forming unit
  • the spore suspensions were treated with media (control), or different concentrations of EtOH (70%, 78% and 85 %) respectively for 60 seconds.
  • the combination of 0.2% EGCG-P with different concentrations of EtOH was also used to treat the spore suspension for 60 seconds. Results are shown in Figure 1.
  • the different concentrations of EtOH alone inhibited spore germination of B. cereus; the percentage inhibition in for all three concentrations was above 99%.
  • the average logio reduction for 70%. 78% and 85% EtOH was 2.43, 2.58 and 2.45, respectively.
  • the average logio reduction of EGCG-P+70% EtOH, EGCG-P+78% EtOH and EGCG-P+85% EtOH was 2.45, 2.94 and 2.77, respectively.
  • B. cereus was incubated on modified nutrient agar plates (supplemented with 0.06 g of MgSO 4 and 0.25 g of KH 2 PO 4 per liter) at 37°C for 10 days to enhance spore formation.
  • the spores were then purified by centrifugation at room temperature for 10 min at 10,000 rpm twice. The supernatant was discarded and the spores were suspended in sterile deionized water and vortexed to create a homogenous suspension. The suspension was heated for 20 min at 75 °C to eliminate any remaining vegetative cells and obtain pure spores.
  • Endospores were treated with FI and F2 for 60 seconds. Once the treatment time was up, 100 ⁇ L of the samples were dispensed and vacuum filtered using 0.2 pm polycarbonate membrane (EMD Millipore Isopore #GTTP01300). Samples were rinsed with PBS (pH 7.2) or 0.1 mol U 1 sodium cacodylate buffer [Na(CH 3 ) 2 AsO 2 -3H 2 O] three times for 5 min each; fixed with 2.5% glutaraldehyde in 0.1 mol-U 1 cacodylate buffer for 30 min at room temperature.
  • FI -treated spores of B. cereus exhibit altered morphology with smaller size and porous spore shell along with film-like appearance among the spores, while F2-treated spores show a complete destruction of spore structures (Figs. 3A-3C).
  • morphology changes are apparent after formula treatments in spores of C. sporogenes.

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Abstract

La présente divulgation concerne des compositions et des procédés d'élimination, d'inactivation, ou sinon de réduction rapide de spores telles que des spores bactériennes. Les procédés comprennent typiquement la réduction ou la prévention de la réactivation des spores comprenant la mise en contact des spores avec une quantité efficace d'un ou plusieurs polyphénols de thé vert (GTP), un ou plusieurs polyphénols de thé vert modifiés (LTP), ou une combinaison de ceux-ci. Dans un mode de réalisation préféré, le LTP est du (-)-épigallocatéchin-3-gallate (EGCG) estérifié à la position 4' avec de l'acide stéarique, de l'EGCG estérifié à la position 4' avec de l'acide palmitique, ou une combinaison de ceux-ci. Les compositions et les procédés peuvent être utilisés dans une diversité d'applications, par exemple, pour accroître la durée de conservation d'un aliment ou d'un produit alimentaire, pour réduire ou retarder l'altération d'un aliment ou d'un produit alimentaire, ou pour décontaminer un dispositif contaminé par des spores.
PCT/US2021/022095 2020-03-13 2021-03-12 Compositions et procédés d'inhibition d'endospores utilisant des polyphénols de thé vert WO2021183878A1 (fr)

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