US20200276149A1 - Antimicrobial, disinfecting and wound healing compositions and methods for producing and using same - Google Patents

Antimicrobial, disinfecting and wound healing compositions and methods for producing and using same Download PDF

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US20200276149A1
US20200276149A1 US16/736,546 US202016736546A US2020276149A1 US 20200276149 A1 US20200276149 A1 US 20200276149A1 US 202016736546 A US202016736546 A US 202016736546A US 2020276149 A1 US2020276149 A1 US 2020276149A1
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composition
acid
wound
hydroperoxide
rsdl
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Edwin Neas
Scott Noblitt
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Armis Biopharma Inc
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Armis Biopharma Inc
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Priority to US16/736,546 priority Critical patent/US20200276149A1/en
Priority to US16/900,816 priority patent/US20210077438A1/en
Publication of US20200276149A1 publication Critical patent/US20200276149A1/en
Assigned to Armis Biopharma, Inc. reassignment Armis Biopharma, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOBLITT, Scott, NEAS, Edwin
Priority to JP2022541784A priority patent/JP2023509515A/ja
Priority to EP21738304.1A priority patent/EP4087557A4/fr
Priority to EP21738256.3A priority patent/EP4087691A4/fr
Priority to PCT/US2021/012536 priority patent/WO2021142148A1/fr
Priority to US17/758,452 priority patent/US20230030675A1/en
Priority to PCT/US2021/012540 priority patent/WO2021142152A1/fr
Priority to US17/326,507 priority patent/US20220023174A1/en
Priority to US18/108,940 priority patent/US11969399B2/en
Priority to US18/339,096 priority patent/US20230404962A1/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/327—Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
    • 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
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • 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
    • A01N37/42—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 within the same carbon skeleton a carboxylic group or a thio analogue, or a derivative thereof, and a carbon atom having only two bonds to hetero atoms with at the most one bond to halogen, e.g. keto-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
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • 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
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides
    • 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
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0076—Sprayable compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/11—Peroxy compounds, peroxides, e.g. hydrogen peroxide

Definitions

  • the present invention relates to antimicrobial, disinfecting, and wound healing compositions and methods for producing and using the same.
  • the compositions may comprise one or more of a peracid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the skin is the body's largest organ and serves as the primary protective barrier to the outside world. Any physical disruption (i.e., wound) to this organ must therefore be quickly and efficiently repaired in order to restore tissue integrity and function. Quite often proper wound healing is impaired with devastating consequences such as severe morbidity, amputations, or death.
  • protection from mechanical injury, chemical hazards, and bacterial invasion is provided by the skin because the epidermis is relatively thick and covered with keratin. Secretions from sebaceous glands and sweat glands also benefit this protective barrier.
  • the body triggers a wound healing cascade of events.
  • the classical model of wound healing is divided into three or four sequential, yet overlapping, phases: (1) hemostasis, (2) inflammatory, (3) proliferative and (4) remodeling.
  • the hemostasis phase involves platelets (thromboctytes) to form a fibrin clot to control active bleeding.
  • the inflammatory phase involves migration of phagocytes to the wound to kill microorganisms and release of subsequent signaling factors to involve the migration and division of cells involved in the proliferative phase.
  • the proliferative phase involves vascular cell production for angiogenesis, fibroblast cells to excrete collagen and fibronectin to form an extracellular matrix, and epithelial cells to reform the external epidermis.
  • the wound is made smaller by myofibroblasts.
  • collagen is remodeled and cells that are no longer needed are removed by programmed cell death (i.e., apoptosis).
  • the process of wound healing can be divided into two major phases: early phase and cellular phase. See FIG. 1 .
  • the early phase involves hemostasis which involves vasoconstriction, temporary blockage of a break by a platelet plug, and blood coagulation, or formation of a clot that seals the hole until tissues are repaired.
  • the early phase also involves the generation of stimuli to attract the cellular responses needed to instigate inflammation.
  • white blood cells, or leukocytes are attracted to the wound site by platelet-derived growth factor (PDGF), and these cells of the immune system are involved in defending the body against both infectious disease and foreign materials.
  • PDGF platelet-derived growth factor
  • IL-4, IL-10, and IL-13 are potent activators of B lymphocytes.
  • IL-4, IL-10, and IL-13 are also potent anti-inflammatory agents.
  • the phagocytic cells engulf and then digest cellular debris and pathogens and stimulate lymphocytes and other immune cells to respond to the wound area.
  • the skin proceeds through the proliferative and remodeling stage by a complex cascade of biochemical events orchestrated to repair the damage. This involves the formation of a scab within several hours. The scab temporarily restores the integrity of the epidermis and restricts the entry of microorganisms.
  • Impediments to wound healing include hypoxia, infection, presence of debris and necrotic tissue, use of inflammatory medications, a diet deficient in vitamins or minerals or general nutrition, tumors, environmental factors, and metabolic disorders such as diabetes mellitus.
  • the primary impediments to acute wound healing are hypoxia, infection, wound debris, and anti-inflammatory medications.
  • the molecular events in the wound healing process of acute, chronic and burn wounds continues to be studied and exhibits an extremely complex array of biochemical events imposing a regulated cascade of inter and intra cellular events.
  • a rapidly growing field of wound healing research is centered around cellular growth factors and the use of these factors for the treatment of wounds.
  • the biochemical response at the cellular level is a process involving intricate interactions among different cell functions which include energy production, structural proteins, growth factors, and proteinases.
  • the treatment of wounds with known cellular growth factors has the potential ability to help heal wounds by stimulating the cellular processes involved in angiogenesis, cellular proliferation, regulating the production and degradation of the extracellular matrix, and being the signal for attracting the inflammatory cells and fibroblasts.
  • this complexity requires a plethora of biochemical reactions to provide the functions necessary to accomplish healing of the wound and is not completely understood at this point.
  • U.S. Pat. No. 6,329,343 discloses the use of a composition of salts of pyruvic acid and/or salts of pyruvic acid and alpha keto glutaric acid, a mixture of fatty acids, and an effective amount of an antibacterial agent as a bioadhesive antibacterial wound healing composition.
  • MRSA Methicillin-Resistant Staphylococcus aureus
  • VRE Vancomycin-resistant enterococci
  • Acinetobacter baumanni accounts for 6% of Gram-negative infections in intensive care facilities in the USA, with mortality rates as high as 54% having been reported.
  • MRSA and C. difficile are the leading causes of nosocomial infection in most parts of the world.
  • S. aureus was the leading pathogen associated with skin and soft tissue infections.
  • MRSA has moved from an exclusively hospital-acquired pathogen (HA-MRSA) to another type known as a community-acquired pathogen, CA-MRSA.
  • H-MRSA hospital-acquired pathogen
  • CA-MRSA community-acquired pathogen
  • silver containing dressings do not kill spores or biofilms and require long exposure times that may become cytotoxic over time.
  • the major cause of sepsis in burn wounds, Aspergillus niger has a 70% fatality and is not susceptible to silver compounds.
  • the cytotoxic effect would explain, in part, the clinical observation of delayed wound healing or inhibition of wound epithelialization after the use of certain topical silver dressings.
  • hypochlorous acid which is formed by PMN by myeloperoxidase-mediated peroxidation of chloride ions, is easily neutralized at physiological pH by nitrite, a major end-product of cellular nitric oxide (NO) metabolism, and its bactericidal effects subsequently diminished and it is not as effective as silver sulfadiazine, a common topical wound sanitizer.
  • hypochlorous acid does not inhibit wound healing at the concentrations for the effective biocidal levels used. That may be because it is a natural compound found in the inflammatory phase of wound healing.
  • Peracetic acid is used mainly in the food industry, where it is applied as a cleanser and as a disinfectant. Since the early 1950's, acetic acid was applied for bacteria and fungi removal from fruits and vegetables. It was also used for the disinfection of recycled rinsing water for foodstuffs.
  • peracetic acid is applied for the disinfection of medical supplies and to prevent biofilm formation in pulp industries. It can be applied during water purification as a disinfectant and for plumbing disinfection.
  • Peracetic acid is produced by a reaction between hydrogen peroxide and acetic acid or it can also be produced by oxidation of acethaldehyde. Peracetic acid is a very powerful oxidant; the oxidation potential outranges that of chlorine and chlorine dioxide. Peracetic acid has not been tested in wound healing. However, it is not known to be involved in any significant cellular metabolism and is typically produced with toxic sulfuric acid catalyst. Thus, many conventional topical wound sanitizers have various limitations.
  • a drawback of the peroxyacid-based chemical disinfectants is their inherent lack of stability, which poses a challenge for shelf-life when used for long term applications.
  • the present invention is directed toward overcoming one or more of the problems discussed above.
  • the present invention relates to novel antimicrobial, disinfecting, and/or wound healing compositions and methods for producing and using the same.
  • the compositions may comprise one or more of a keto acid, a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the present invention provides a wound healing composition made by a method comprising contacting a keto acid or a salt or anhydride thereof with an oxidizing agent while stirring and under conditions sufficient to produce one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the conditions are sufficient to produce a peroxyacid and a bis(hydroperoxide).
  • the conditions are sufficient to produce a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide.
  • the keto acid may be an alpha-, beta-, or gamma-keto acid. In other embodiments, the keto acid is an alpha-keto acid. In some embodiments, the keto acid is pyruvic acid or a salt or anhydride thereof. In other embodiments, the keto acid is parapyruvuc acid or a salt or anhydride thereof. In other embodiments, the keto acid is acetoacetic acid or a salt or anhydride thereof. In some embodiments, the keto acid salt may be a lithium, sodium, potassium, rubidium, cesium, zinc, magnesium, or calcium salt, or a mixture thereof. In other embodiments, the process further comprises contacting the keto acid or salt thereof and the oxidizing agent with maleic acid or anhydride, citraconic acid or anhydride, or a mixture thereof.
  • the reaction temperature is about 10° C. or less. In other embodiments, the reaction temperature ranges from about ⁇ 10° C. to 10° C. In some embodi-ments, the molar ratio of oxidizing agent to keto acid typically ranges from 1:1 to about 4:1.
  • the method comprises stirring the oxidizing agent at a shear rate between 150 s ⁇ 1 and 850 s ⁇ 1 , cooling the oxidizing agent to between ⁇ 10° C. to 0° C., and adding the keto acid at a rate sufficient to maintain the temperature between ⁇ 10° C. to 0° C. during addition of the keto acid to form a reaction solution.
  • a shear rate between about 150 and about 850 sec ⁇ 1 equates to stirring at a rate between about 90 and about 500 RPM.
  • the method further comprises continually stirring the reaction solution for 10 to 12 hours at a temperature ⁇ 10° C. to 0° C.
  • the method further comprises warming the reaction solution to between 14° C. and 27° C.
  • the method further comprises cooling the reaction solution to maintain this temperature for 30 days.
  • the oxidizing agent is hydrogen peroxide and the keto acid is pyruvic acid.
  • the present invention provides a wound healing composition made by a method comprising contacting citramalic acid or a salt thereof with an oxidizing agent while stirring under conditions sufficient to produce one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the conditions are sufficient to produce a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide.
  • the citramalic acid salt may be a lithium, sodium, potassium, rubidium, cesium, zinc, magnesium, or calcium salt, or a mixture thereof.
  • the process further comprises contacting citramalic acid or salt thereof and the oxidizing agent with acetic acid or anhydride thereof, maleic acid or anhydride thereof, citraconic acid or anhydride thereof, or a mixture thereof.
  • the present invention provides a wound healing composition made by a method comprising contacting an acetoacetate ester or a salt thereof with an oxidizing agent while stirring under conditions sufficient to produce one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the conditions are sufficient to produce a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide.
  • the acetoacetate ester may be methyl acetoacetate or ethylacetoacetate, or a mixture thereof.
  • the acetoacetate ester salt may be a lithium, sodium, potassium, rubidium, cesium, zinc, magnesium, or calcium salt, or a mixture thereof.
  • the process further comprises adding citramalic acid.
  • typical oxidizing agents may comprise hydrogen peroxide, barium peroxide, sodium carbonate peroxide, potassium superoxide, or a mixture thereof.
  • the oxidizing agent is hydrogen peroxide.
  • the present invention provides a wound healing composition comprising a peroxyacid and a bis(hydroperoxide).
  • the composition further comprises a hydroperoxide.
  • the composition further comprises an epoxide.
  • the composition comprises peracetic acid and 3,3-bis(hydroperoxy)butanoic acid.
  • the composition comprises peracetic acid and 3,3-bis(hydroperoxy)butaneperoxoic acid.
  • the composition further comprises at least one of methylhydroperoxide and hydroxymethyl hydroperoxide.
  • the composition further comprises 5-hydroperoxy-5-methyl-1,2-diox-olan-3-one.
  • the composition further comprises hydrogen peroxide.
  • the wound healing composition further comprises peroxycitraconic acid.
  • the peroxycitraconic acid may be either (2Z)-4-hydroperoxy-3-methyl-4-oxobut-2-enoic acid, (2Z)-4-hydroperoxy-2-methyl-4-oxobut-2-enoic acid, or a mixture thereof.
  • the compositions may comprise diperoxycitraconic acid, i.e., (2Z)-2-methylbut-2-enediperoxoic acid.
  • the composition further comprises peroxycitramalic acid.
  • the peroxycitramalic acid may be either 4-hydro-peroxy-2-hydroxy-2-methyl-4-oxobutanoic acid, 4-hydroperoxy-3-hydroxy-3-methyl-4-oxo-butanoic acid, or a mixture thereof.
  • the present invention provides a wound healing composition
  • a wound healing composition comprising 3,3-bis(hydroperoxy)butanoic acid, 3,3-bis(hydroperoxy)butaneperoxoic acid, or 3-oxobutaneperoxoic acid, or a mixture thereof.
  • the composi-tions further comprise 5-hydroperoxy-5-methyl-1,2-dioxolan-3-one.
  • the composition further comprises one or more of hydrogen peroxide, an organic hydroper-oxide, an organic peroxide, an organic peracid, an inorganic peracid, an organic acid, or an inorganic acid.
  • the composition further comprises hydrogen peroxide.
  • the present invention provides a wound healing composition
  • acetoacetic acid or a salt of acetoacetic acid.
  • the salt of acetoacetic acid may be a lithium, sodium, potassium, rubidium, cesium, zinc, magnesium, or calcium salt.
  • the composition may further comprise a hydroperoxide, including hydrogen peroxide and/or an organic hydroperoxide.
  • the composition may further comprise a keto acid.
  • the keto acid may be an alpha-, beta- or gamma-keto acid.
  • the composition may further comprise pyruvic acid, parapyruvic acid, or citramalic acid, any of their salts, or mixtures thereof.
  • the composition may further comprise an acetoacetate ester such as methyl acetoacetate, ethyl acetoacetate, or acetoacetic anhydride.
  • the composition further comprises hydrogen peroxide.
  • the present invention provides a wound healing composition comprising hydroperoxyacetic acid.
  • the composition further comprises hydrogen peroxide.
  • the present invention provides an antimicrobial, chemical oxidizer, or disinfecting products comprising one or more of the above-described composi-tions.
  • the antimicrobial product is a household care product.
  • the house hold care product is selected from the group consisting of hard surface cleaners, deodorizers, fabric care compositions, fabric cleaning compositions, manual dish detergents, automatic dish detergents, floor waxes, kitchen cleaners, bathroom cleaners, and combinations thereof.
  • the anti-microbial product is selected from the group consisting of hard surface cleaners, deodorizers, fabric care compositions, fabric cleaning compositions, manual dish detergents, automatic dish detergents, floor waxes, kitchen cleaners, bathroom cleaners, and combinations thereof.
  • Antimicrobial products of the invention can be used in a wide variety of settings including, but not limited to, in health care facilities such as hospitals, rehabilitation, assisted living facilities, etc.
  • the antimicrobial product is a medical device disinfect-ant. Still in other embodiments, the antimicrobial product is used as a disinfectant for aseptic filling equipment. Yet in other embodiments, the antimicrobial product is used in an aseptic food processing system. In other embodiments, the antimicrobial product is used as a disin-fectant for biofilms in water systems. Still in other embodiments, the antimicrobial product is used as a disinfectant for waste water treatment.
  • the present invention provides a method of making a wound healing composition
  • a method of making a wound healing composition comprising contacting a keto acid or a salt or anhydride thereof with an oxidizing agent while stirring and under conditions sufficient to produce one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the conditions are sufficient to produce a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide.
  • the keto acid may be an alpha-, beta-, or gamma-keto acid.
  • the keto acid is pyruvic acid or a salt or anhydride thereof.
  • the keto acid is parapyruvuc acid or a salt or anhydride thereof.
  • the keto acid is acetoacetic acid or a salt or anhydride thereof.
  • the keto acid salt may be a lithium, sodium, potassium, rubidium, cesium, zinc, magnesium, or calcium salt, or a mixture thereof.
  • the process further comprises contacting the keto acid or salt thereof and the oxidizing agent with maleic acid or anhydride, citraconic acid or anhydride, or a mixture thereof.
  • the reaction temperature is about 10° C. or less. In other embodiments, the reaction temperature ranges from about ⁇ 10° C. to 10° C. In some embodiments, the molar ratio of oxidizing agent to keto acid typically ranges from 1:1 to about 4:1. In some embodiments, the stirring is at a shear rate between 150 s ⁇ 1 and 850 s ⁇ 1 .
  • the method comprises stirring the oxidizing agent at a shear rate between 150 s ⁇ 1 and 850 s ⁇ 1 , cooling the oxidizing agent to between ⁇ 10° C. to 0° C., and adding the keto acid at a rate sufficient to maintain the temperature between ⁇ 10° C. to 0° C. during addition of the keto acid to form a reaction solution.
  • a shear rate between about 150 and about 850 sec ⁇ 1 equates to stirring at a rate between about 90 and about 500 RPM.
  • the method further comprises continually stirring the reaction solution for 10 to 12 hours.
  • the method further comprises warming the reaction solution to between 14° C. and 27° C.
  • the method further comprises cooling the reaction solution to maintain this temperature for 30 days.
  • the temperature is room temperature (between 20° C. and 22° C.)
  • the oxidizing agent is hydrogen peroxide and the keto acid is pyruvic acid.
  • the present invention provides a method of making a wound healing composition
  • a method of making a wound healing composition comprising contacting citramalic acid or a salt thereof with an oxidizing agent while stirring under conditions sufficient to produce one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the conditions are sufficient to produce a peroxyacid, a hydroperoxide, a bis(hydroperoxide) and an epoxide.
  • the citramalic acid salt may be a lithium, sodium, potassium, rubidium, cesium, zinc, magnesium, or calcium salt, or a mixture thereof.
  • the process further comprises contacting citramalic acid or salt thereof and the oxidizing agent with acetic acid, maleic acid or anhydride, citraconic acid or anhydride, or a mixture thereof.
  • the present invention provides a method of making a wound healing composition
  • a method of making a wound healing composition comprising contacting an acetoacetate ester or a salt thereof with an oxidizing agent while stirring under conditions sufficient to produce one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the conditions are sufficient to produce a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide.
  • the acetoacetate ester may be methyl acetoacetate or ethylacetoacetate, or a mixture thereof.
  • the acetoacetate ester salt may be a lithium, sodium, potassium, rubidium, cesium, zinc, magnesium, or calcium salt, or a mixture thereof.
  • the process further comprises adding citramalic acid.
  • typical oxidizing agents may comprise hydrogen peroxide, barium peroxide, sodium carbonate peroxide, potassium superoxide, or a mixture thereof.
  • the oxidizing agent is hydrogen peroxide.
  • the present invention provides a method of making a wound healing composition comprising combining one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide in an aqueous solution.
  • the method comprises combining a peroxyacid and bis(hydroperoxide) in an aqueous solution.
  • the peroxyacid is peracetic acid.
  • the bis(hydro-peroxide) is 3,3-bis(hydroperoxy)butanoic acid or 3-bis(hydroperoxy)butaneperoxoic acid.
  • the method further comprises adding a hydroperoxide to the aqueous solution.
  • the hydroperoxide is one of methylhydro-peroxide and hydroxymethyl hydroperoxide.
  • the method further comprises adding an epoxide to the aqueous solution.
  • the epoxide is 5-hydroperoxy-5-methyl-1,2-dioxolan-3-one.
  • the method further comprises adding hydrogen peroxide to the aqueous solution.
  • the peroxyacid is peroxycitraconic acid.
  • the peroxycitraconic acid may be either (2Z)-4-hydroperoxy-3-methyl-4-oxobut-2-enoic acid, (2Z)-4-hydroperoxy-2-methyl-4-oxobut-2-enoic acid, or a mixture thereof.
  • the peroxyacid is diperoxycitraconic acid, i.e., (2Z)-2-methylbut-2-enediperoxoic acid.
  • the peroxyacid is peroxycitramalic acid.
  • the peroxycitramalic acid may be either 4-hydroperoxy-2-hydroxy-2-methyl-4-oxobutanoic acid, 4-hydroperoxy-3-hydroxy-3-methyl-4-oxobutanoic acid, or a mixture thereof.
  • the present invention provides methods of making antimicrobial, chemical oxidizer, and disinfecting solutions comprising any of the above-described methods.
  • present invention provides methods for treating a wound infection in a subject comprising contacting the infected wound in the subject with a therapeutically effective amount of an above-described composition.
  • Methods of the invention can be used to treat surgical wound, battle wound, accidental wound, thermal burn wound, chemical burn wound, chronic wound, decubitus ulcer, foot ulcer, venous ulcer, laser treatment wound, sunburn, and/or an abrasion.
  • the composition is applied to the infected wound at least once, often at least twice a day initially.
  • the composition is formulated as a gel, a liquid, lotion, skin patch, irrigation gel, a liquid, lotion, skin patch, a spray, application granules, or a combination thereof.
  • the present invention provides methods for reducing the number of microbes on a surface. Such methods typically include contacting the surface with an antimicrobial product comprising an above-described composition. Yet other aspects of the invention provide a method for reducing the number of infectious vegetative bacteria on a substrate comprising contacting the substrate with an antimicrobial solution comprising an effective amount of an above-described composition. Other aspects of the invention provide a method for reducing the number of bacterial spores on a substrate comprising contacting the substrate with an antimicrobial solution comprising an effective amount of an above-described composition.
  • the microbe comprises vegetative bacteria.
  • the microbe comprises bacterial spores, mycobacteria, gram-negative bacteria, vegetative gram-positive bacteria, or a combination thereof.
  • Yet other aspects of the invention provide methods for preventing and/or reducing bacteria-related diseases in a mammal that result from the mammal's contact with a bacteria-infected substrate. Such methods can include contacting the substrate with an above-described composition.
  • FIG. 1 is a graphic illustration of phases of wound healing.
  • FIG. 2 is a schematic illustration of inflammatory phases of wound healing.
  • FIG. 3 is a reaction scheme for a reaction comprising pyruvic acid and hydrogen peroxide according to an embodiment of the present invention.
  • FIG. 4 is a reaction scheme for a reaction comprising acetoacetic acid and hydrogen peroxide according to an embodiment of the present invention.
  • FIG. 5 is a reaction scheme for a reaction comprising maleic acid and hydrogen peroxide according to an embodiment of the present invention.
  • FIG. 6 is a reaction scheme for a reaction comprising citraconic acid and hydrogen peroxide according to an embodiment of the present invention.
  • FIG. 7 is a graph of the VX dose lethality curves in animals decontaminated with either RSDL or a composition according to the invention after cutaneous exposure.
  • FIG. 8 is a depiction of the proton NMR spectrum of a composition according to the invention.
  • FIG. 9 is a depiction of a pulse sequence of modified gradient 1 H—X 1D-HSQC for chemical warfare agents (CWAs).
  • FIG. 10 is a depiction of an NMR spectrum of (a) chemical warfare agent VX and (b) its decontamination product.
  • FIG. 11 is a graph showing decontamination (DC) of chemical wafare agent HD by various concentrations of a composition according to the invention fit to a one-phase decay curve.
  • FIG. 12 is a graph showing decontamination of chemical wafare agent VX by various concentrations of a composition according to the invention fit to a one-phase decay curve.
  • FIG. 13 a depiction of RSDL and a composition according to the invention (2%) skin decontamination (DC) efficacy following topical application of agent VX. Decontamination was performed 2 min after agent application.
  • the graph shows the probit-predicted dose-lethality curves based on 24 hr mortality.
  • the table shows calculated probit estimates, group sizes, and estimated protective ratios (PR).
  • FIG. 14 is a depiction of skin decontamination efficacy of various materials using a 3-step decontamination method mimicking mass casualty procedures, following topical application of VX.
  • the DC was performed 2 min after agent application.
  • the graph shows the probit-predicted dose-lethality curves from 24 hr mortality.
  • the table shows calculated probit estimates for LD 50 , 95% CI, slope, group sizes, and estimated protective ratios (PR).
  • the present invention relates to antimicrobial, disinfecting, and/or wound healing compositions and methods for producing and using the same.
  • the compositions may comprise one or more of a keto acid, a peracid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • Some aspects of the present invention provide methods for treating a wound on a subject comprising contacting the wound with a therapeutically effective amount of a composition comprising a peracid and a bis(hydroperoxide).
  • the present invention also relates to compositions comprising a peracid and a bis(hydroperoxide), as well as methods for making and using such compositions and mixtures thereof.
  • the composition further comprises a hydroperoxide, an epoxide, or both.
  • peracids are compounds of oxidized form of a base organic acid (generally a carboxylic acid) that exist in equilibrium with an oxidizer (generally hydrogen peroxide) and water.
  • a base organic acid generally a carboxylic acid
  • an oxidizer generally hydrogen peroxide
  • PKCA peroxy alpha-keto acid
  • PKCA compounds would generally be composed of an ⁇ -keto carboxylic acid, the anion of that ⁇ -keto acid, a buffer, and hydrogen peroxide, and the oxidized form of the carboxylic acid.
  • Peroxy pyruvate acid (PPA) may be in equilibrium with pyruvic acid, acetic acid and peracetic acid and other peracids.
  • Peracids may be oxidized from other carboxylic acids, e.g. citric acid, succinic acid, short chain fatty acids, etc.
  • peracid As used herein, “peracid,” “peroxyacid,” “percarboxylic,” and “peroxy-carboxylic acid,” and are used interchangeably herein and refer to a compounds generally have the formula R(CO 3 H) n , where, for example, R is an alkyl, arylalkyl, cycloalkyl, aromatic, or heterocyclic group, and n is one, two, or three, and named by prefixing the parent acid with “peroxy-.”
  • the R group can be saturated or unsaturated as well as substitut-ed or unsubstituted.
  • Peroxycarboxylic acids can be made by the direct action of an oxidizing agent on a carboxylic acid, by autoxidation of aldehydes, or from acid chlorides, and hydrides, or carboxylic anhydrides with hydrogen or sodium peroxide.
  • Peroxycarboxylic acids useful in the compositions and methods of the present invention include peroxyformic, peroxyacetic, peroxypropionic, peroxybutanoic, peroxy-pentanoic, peroxyhexanoic, peroxyheptanoic, peroxyoctanoic, peroxynonanoic, peroxy-decanoic, peroxyundecanoic, peroxydodecanoic, or the peroxyacids of their branched chain isomers, peroxylactic, peroxymaleic, peroxyascorbic, peroxyhydroxyacetic, peroxyoxalic, peroxymalonic, peroxysuccinic, peroxyglutaric, peroxyadipic, peroxypimelic and peroxy-suberic acid and mixtures thereof.
  • the compositions of the invention utilize a combination of several different peroxycarboxylic acids.
  • the composition includes one or more C1 to C4 peroxycarboxylic acids and one or more C5 to C11 peroxycarboxylic acids.
  • the peroxycarboxylic acid is peracetic acid (C2), peroxy propionic acid (C3), peroxybutanoic acid (C4), peroxysuccinic and peroxymalonic acid.
  • C2 peracetic acid
  • C3 peroxy propionic acid
  • C4 peroxybutanoic acid
  • peroxysuccinic and peroxymalonic acid may come from the alpha-keto dicarboxylic acids.
  • these acids exist in the Krebs cycle they are metabolically active.
  • compositions and methods of the present invention include peroxyacetic acid.
  • Peroxyacetic (or peracetic) acid is a peroxycarboxylic acid having the formula: CH 3 COOH.
  • peroxyacetic acid is a liquid having an acrid odor at higher concentrations and is freely soluble in water, alcohol, ether, and sulfuric acid.
  • wt % refers to the weight percent relative to the total weight of the solution or dispersion.
  • Microorganism is meant to include any organism comprised of the phylogenetic domains of bacteria and archaea, as well as unicellular (e.g., yeasts) and filamentous (e.g., molds) fungi, unicellular and filamentous algae, unicellular and multicellular parasites, viruses, virinos, and viroids.
  • unicellular e.g., yeasts
  • filamentous e.g., molds
  • Frm-forming agent or “water soluble or water dispersible coating agent,” which may be used interchangeably herein, refer to agents that form a film and are employed to provide protective coating to the surface of interest. These agents are either water soluble or water dispersible. These agents are described in further detail below.
  • Antimicrobial agent refers to a compound or substance having antimicrobial properties
  • Biocide refers to a chemical agent, typically broad spectrum, which inactivates or destroys microorganisms.
  • a chemical agent that exhibits the ability to inactivate or destroy microorganisms is described as having “biocidal” activity.
  • Biofilm refers to a structured community of microorganisms encapsulated within a self-developed polymeric matrix and adherent to a living or inert surface.
  • Drying refers to a process by which the inert solvent or any other liquid present in the formulation is removed by evaporation.
  • Disinfectant as used herein is a chemical that kills 99.9% of the specific test microorganisms in 10 minutes under the conditions of the test. (Germicidal and Detergent Sanitizing Action of Disinfectants, Official Methods of Analysis of the Association of Official Analytical Chemists, paragraph 960.09 and applicable sections, 15th Edition, 1990 (EPA Guideline 91-2)).
  • Standardization or “sterilant” as used herein refers to the inactivation of all bio-contamination.
  • “Locus” as used herein, comprises part or all of a target surface suitable to be coated.
  • Some methods of the invention include contacting a keto acid and oxidizing agent while stirring and under conditions sufficient to produce one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the conditions are sufficient to produce a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide.
  • stir or “stirring” refers to agitating or act of causing a mixing of the reagents by using an external force such as by using a mechanical stirrer, a magnetic stirrer, a shaker, or any other mechanical, electrical, magnetic, or manual force including simply mixing the reagents manually.
  • the yield of the reaction is affected by a variety of reaction conditions and reagents used.
  • One of the factors influencing the yield is the reaction temperature.
  • the rate of reaction increases as the temperature increases, however, a higher reaction temperature can also increase the yield of side-product(s) and/or decomposi-tion to the non alpha-keto peroxyacid. Therefore, the reaction temperature is typically kept at about 0° C. or below, often at about 10° C. or below, and more often at about ⁇ 20° C. or below. In some embodiments, the reaction temperature is between ⁇ 10° C. to 10° C.
  • the concentration of the reagents can also affect the rate and the yield of the reaction.
  • the initial concentration of the oxidizing agent is generally about 12 M or less, typically about 7 M or less, and often about 1 M or less.
  • reaction time can also affect the yield. Typically the reaction time ranges from about 4 hours to about 12 hours, often from about 6 hours to about 8 hours, and more often from about 10 hours to about 12 hours.
  • Methods of the invention are applicable to a wide variety of keto acids, and in particular alpha-keto carboxylic acids.
  • any alpha-keto carboxylic acid can be used as long as any reactive functional group within the alpha-keto carboxylic acid is properly protected.
  • Suitable protection groups for various chemical reactions are well known to one skilled in the art. See, for example, Protective Groups in Organic Synthesis, 3rd ed., T. W. Greene and P. G. M.
  • alpha-keto carboxylic acids include, but are not limited to, pyruvic acid, alpha-keto butyric acid, alpha-keto valeric acid, alpha-keto glutaric acid, 2-oxo cylopental acetic acid, etc.
  • Exemplary oxidizing agents that are useful in methods of the invention include, but are not limited to, hydrogen peroxide, barium peroxide, sodium carbonate peroxide, calcium peroxide, sodium perborate, lithium peroxide, magnesium peroxide strontium peroxide, zinc peroxide, potassium superoxide, and the like.
  • the methods may comprise additional reagents such as acetic acid or anhydride, maleic acid or anhydride, citraconic acid or anhydride, or a mixture thereof.
  • the method comprises contacting a mixture of pyruvic acid, maleic acid, and citraconic acid with hydrogen peroxide while stirring at a reaction conditions sufficient to produce the reaction products shown in the reaction schemes of FIGS. 3-6 .
  • the terms “treating,” “contacting,” and “reacting” are used interchangeably herein, and refer to adding two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
  • the reaction is generally conducted in an aqueous solution.
  • Other solvents such as an organic solvent can also be used in addition to or in place of the aqueous solution. Because it is inexpensive and commercially available in an aqueous solution, typically hydrogen peroxide is used as an oxidizing agent.
  • the molar ratio of oxidizing agent to keto acid typically ranges from about 0.5:1 to about 2:1, often about 2:1 to about 6:1. A molar ratio above 1:1 is preferred.
  • compositions according to this embodiment contain hydrogen peroxide, a peracid, such as peracetic acid, and one or more optional com-pounds selected from tartaric acid, formic acid, cis-epoxysuccinic acid, methyltartaric acid, acetic acid, cis-epoxymethylsuccinic acid, maleic acid, citramalic acid and citraconic acid.
  • Compositions according to this embodiment of the present invention may also optionally include oxidized acetoacetate compounds.
  • Some aspects of the invention disclose a process for forming a stable aqueous composition containing one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the invention discloses a process for forming a stable aqueous composition comprising a peroxyacid and bis(hydroperoxide).
  • the invention discloses a process for forming a stable aqueous composition comprising a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide.
  • an antimicrobial containing one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide be available for use as a single, stable gel or a viscous solution (sol), although a solid would be satisfactory if it were biodegradable, easily soluble in water, and did not contain significant inorganic dis-solved solids such as are provided by sodium persulfate or sodium perborate. It is also desirable for the antimicrobial to have less odor, be non-corrosive and promote wound healing.
  • an aqueous composition comprising stable sols, gels and solids one or more of a peroxyacid, a hydroperoxide, a bis(hydroperoxide), or an epoxide.
  • the aqueous composition comprises stable sols, gels and solids comprising a peroxy acid and a bis(hydroperoxide).
  • the peroxyacid is a C2 to C6 peroxycarboxylic acids.
  • the compositions of the invention provide a combination of several different peroxycarboxylic acids.
  • the composition includes one or more C1 to C4 peroxycarboxylic acids and one or more C5 to C11 peroxycarboxylic acids.
  • the peroxycarboxylic acid is peracetic acid (C2) peroxy propionic acid (C3) peroxybutanoic acid (C4), peroxysuccinic and peroxymalonic acid.
  • Such compositions form carriers for delivering peroxycarboxylic acids for applications related to high level disinfectants/sterilants of vegetative bacteria, spores and biofilms.
  • compositions are particularly useful for killing vegetative bacteria and spores at the level acceptable to be called disinfectants.
  • disinfectants Unlike most peroxy carboxylic compounds, it was discovered that the non alpha-keto peroxyacid compounds in combination with keto peroxyacids do not require an acid catalyst for efficient synthesis and are effective against biofilms. Without the need for a toxic catalyst for synthesis, the mixture of the embodiments disclosed herein typically contains water, hydrogen peroxide, a peroxyacid, a hydroperoxide, a bis(hydroperoxide), and an epoxide, all of which work synergistically and are beneficial to healing of a wound.
  • the parent compounds i.e., the corresponding carboxylic acids
  • the parent carboxylic acid compounds of peroxypyruvic acid, peroxy oxaloacetate, peroxy alpha-keto glutarate are key compounds within the TCA cycle, the predominant energy producer for cellular metabolism.
  • the parent compound of peroxy alpha keto butyric acid, i.e. alpha keto butyric acid is in-volved in the metabolic production of succinyl-CoA which is also used in the TCA cycle and thus contributes to cellular energy production.
  • Alpha keto valeric acid the parent compound of peroxy alpha keto valeric acid, is an intermediate in protein synthesis and the biosynthesis of the amino acids such as leucine and valine.
  • Alpha keto valeric acid is involved in gluco-neogenesis in cells.
  • Pyruvate is involved in producing energy for hypoxic cells during wound healing through glycolysis. The potential harmful effects of the ROS can be mediated by alpha-keto acids.
  • pyruvate is involved in protecting DNA during hypoxia and is an indirect metabolic contributor to collagen deposition and angiogenesis in wound healing.
  • pyruvic acid accelerates the debridement of dead skin in both wounds and burns.
  • the compositions comprise acetoacetic acid.
  • Acetoacetic acid is one of the ketone bodies (along with 3-hydroxybutyric acid and acetone, although acetone is just a byproduct), which are major energy sources for the body, particu-larly during starvation.
  • Ketone bodies are involved in pathways related to the Kreb's cycle, lipogenesis, sterol biosynthesis, glucose metabolism, ⁇ -oxidation of fatty acids, mitochondrial electron transport chain, intracellular signal transduction pathways, hormonal signaling, and the microbiome (Cotter, D. G., et al., Am. J. Physiol, Heart Circ. Physiol., 2013, 304, H1060-H1076).
  • acetoacetic acid can be converted into acetyl-CoA in vivo, its ability to affect biological processes is extremely high. However, its presence in the solution is unexpected because acetoacetic acid is an unstable compound that reacts intramolecularly and irreversibly, producing acetone and carbon dioxide. Thus, it is expected to be unstable in all solvents and even as a solid compound.
  • acetoacetic acid represents a rather unique case where a compound is stabilized by the addition of hydrogen peroxide, whereas normally the addition of a per-oxide leads to chemical oxidation/degradation.
  • This stabilization is caused by the formation of a range of possible peroxide “adducts” with its ketone functionality and possibly its carboxylic acid. Because both moieties are required for intramolecular “self-destruction”, the formation of these other forms slows down the decomposition of the compound.
  • Peroxide adducts may include 3,3-bis(hydroperoxy)butanoic acid, 3,3-bis(hydroperoxy)butaneperoxoic acid, 3-oxobutane-peroxoic acid, and 5-hydroperoxy-5-methyl-1,2-dioxolan-3-one. This stabilization is shown in the reaction scheme of FIG. 4 .
  • the compositions may be further stabiliz-ed by citramalic acid or an acetoacetate ester, such as methyl or ethyl acetoacetate.
  • the compositions may comprise peroxycitraconic acid.
  • the peroxycitraconic acid may be either (2Z)-4-hydroperoxy-3-methyl-4-oxobut-2-enoic acid, (2Z)-4-hydroperoxy-2-methyl-4-oxobut-2-enoic acid, or a mixture thereof.
  • the compositions may comprise diperoxycitraconic acid, i.e., (2Z)-2-methyl-but-2-enediperoxoic acid.
  • the antimicrobial composition further comprises peroxycitramalic acid.
  • the peroxycitramalic acid may be either 4-hydroperoxy-2-hydroxy-2-methyl-4-oxobutanoic acid, 4-hydroperoxy-3-hydroxy-3-methyl-4-oxobutanoic acid, or a mixture thereof.
  • a “stable” composition is one which maintains sufficient physical properties and active oxygen content long enough to be useful, about twelve months.
  • “stable” does not imply static. That is, compositions of the present invention may be constantly undergoing a series of internal reactions. This is true of all liquid solutions to a degree, particularly for aqueous ones. However, this is especially true for compositions of the present invention, which have a large number of reversible and effectively irreversible reactions occurring at all times.
  • topical antiseptics should be toxic to bacteria but should have no significant toxicity to underlying tissues, and ideally, they should also preserve or enhance host defense against infection.
  • the present invention provides a method for treating wounds including, but not limited to, surgical, traumatic, chronic and burn wounds. Methods of the invention promote wound healing and typically rapidly kill high levels of viruses, vegetative bacteria, fungi, mycobacteria and spores. Unlike many conventional antiseptics available today, compositions and methods of the invention eliminate bacteria, enhance body's defense system, and enhance the healing process.
  • the combination of the peracids and bis(hydroperoxides) disclosed in the present embodiments can kill high levels of bacteria and spores in biofilms and in high protein environments without being corrosive and having virtually no cellular toxicity issues.
  • the compositions may be useful for at least one of dental cleaning, wound decontamination after exposure to chemical biological warfare agents, or wound healing decontamination after exposure to chemical biological warfare agents. Use of the composition for the latter two uses is particularly important as the skin is a primary route of exposure to chemical agents that may be used as weapons of mass destruction.
  • the composition may include at least one peroxyacetic acid at an equilibrium concentration of from 0.1 ppm to 10 weight percent, based on the weight of the composition.
  • the peroxyacid may be present at a concentration of less than 5 weight percent.
  • the peroxyacid may be a ready-to-use solution or a dilatable solution, which enables easy distribution of the composition.
  • compositions of the invention can include the presence of the parent carboxylic acid.
  • parent carboxylic acid refers to the corresponding carboxylic acid in which the peracid is derived from or is degraded into under a typical storage or production conditions.
  • the parent carboxylic acid is present in the composition of the invention in an amount of about 120.4 mM or less, typically, about 12.4 mM or less, more typically, about 6.2 mM or less, often about 2.5 mM or less, more often, about 1.2 mM or less, still more often about 0.62 mM or less, yet more often about 0.31 mM or less, and most often about 0.062 mM or less.
  • compositions of the invention can include hydrogen peroxide.
  • the amount of hydrogen peroxide present in the wound healing compositions of the invention is about 715 mM or less, typically about 71.5 mM or less, more typically about 35.8 mM or less, often about 14.3 mM or less, more often about 7.2 mM or less, still more often about 3.6 mM or less, yet more often about 1.8 mM or less, and most often about 0.35 mM or less.
  • compositions according to the present invention have a tendency to lose their antimicrobial activity over time, which is believed to be the result of evaporation of the neat peracid.
  • One aspect of the present invention adds a magnesium salt to the composition to form a salt of the peracid, which testing has shown to retain antimicrobial activity over a lengthy accelerated aging test.
  • compositions according to the present invention optionally further include a magnesium salt.
  • the magnesium salt can be a salt of the keto acid, or a magnesium salt such as magnesium, hydroxide, magnesium carbonate, magnesium acetate tetrahydrate, and the like.
  • reaction products were measured by HPLC analysis several times during the first 40 days after the reaction.
  • the first measurement was performed just 2.4 hr after the final pyruvic acid addition.
  • compositions capable of forming shelf-stable coatings containing the magnesium salt of peroxyacetic acid were prepared by drying solutions containing a magnesium salt, acetic acid, hydrogen peroxide, peracetic acid, and poly(ethylene glycol) (PEG).
  • the starting magnesium salt was magnesium hydroxide, magnesium carbonate, or magnesium acetate tetrahydrate (an anhydrous magnesium acetate salt would also be effective since it is being dissolved in a water-containing mixture).
  • the acetic acid/hydrogen peroxide/peracid source was an aqueous solution (called “PAA Source” in this document) usually containing 8-12 wt % peracid (peracetic acid), 15-22 wt % hydrogen peroxide, and 14-20 wt % acetic acid.
  • a typical coating-solution mixture consisted of the following, which was used immediately after mixing:
  • the composition of the present invention have utility in numerous household products.
  • the present invention thus also provides an antimicrobial product containing the compositions of the present invention.
  • the product is a household care product.
  • the house hold care product is selected from hard surface cleaners, deodorizers, fabric care compositions, fabric cleaning compositions, manual dish detergents, automatic dish detergents, floor waxes, kitchen cleaners, bathroom cleaners, and combinations thereof.
  • the antimicrobial product is selected from hard surface cleaners, deodorizers, fabric care compositions, fabric cleaning composi-tions, manual dish detergents, automatic dish detergents, floor waxes, kitchen cleaners, bath-room cleaners, and combinations thereof.
  • Antimicrobial products of the invention can be used in a wide variety of settings including, but not limited to, in health care facilities such as hospitals, rehabilitation, assisted living facilities, etc.
  • the antimicrobial product is a medical device disinfectant. Still in other embodiments, the antimicrobial product is used as a disinfectant for aseptic filling equipment. Yet in other embodiments, the antimicrobial product is used in an aseptic food processing system. In other embodiments, the antimicrobial product is used as a disinfectant for biofilms in water systems. Still in other embodiments, the antimicrobial product is used as a disinfectant for waste water treatment.
  • This example compared the effectiveness of the composition of the invention as a decontamination (DC) product after skin exposure to the chemical warfare agent VX, as compared to that of Reactive Skin Decontamination Lotion (RSDL), which is a mixture of potassium 2,3-butanedione monoximate (KBDO) and diacetylmonoxime (DAM) in a solvent of polyethylene glycol monomethyl ether (MPEG) and water.
  • RSDL Reactive Skin Decontamination Lotion
  • MPEG polyethylene glycol monomethyl ether
  • mice Male guinea pigs [Hartley, Crl(HA)BR] ranging in weight from 340-503 gm at the time of experimentation were obtained from Charles River (Canada). After arrival, the animals were maintained in quarantine for at least 5 days prior to use in an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALACI) accredited animal care and use facility. On the morning of an experiment, around 0800 hr, animals were weighed, the fur was carefully removed from the left side with electric clippers, and excess loose fur was removed with a vacuum. An exposure site was outlined with an indelible marker at approximately the same location on the left side of each animal midway between the spine and the ventral midline. The animals remained unanesthetized during the entire experiment.
  • AAALACI Laboratory Animal Care International
  • Neat VX was applied in a fume hood to the marked exposure site of each animal, using either a 5 pl Hamilton syringe for volumes greater than 1 pl, or a 0.5 pl or 1.0 pl Hamilton digital syringe for volumes less than 1 pl. Animals were hand restrained by a trained technician for exposure.
  • RSDL was applied with an applicator made by stapling 1 ⁇ 4 (25 mm ⁇ 50 mm) of a RSDL sponge pad to a wooden tongue depressor. Applicators for the composition were made by stapling a similar size folded gauze pad to wooden tongue depressors. A fresh applicator of each DC product was used on each animal. The RSDL applicators were made just before the start of the experiment and were placed into small plastic bags until use. The composition applicators were wetted with 10 ml of the diluted composition solution just before DC.
  • VX dose-lethality curves were generated for RSDL and the composition, based on 24 hr responses. After exposure and DC, each animal was monitored continuously until the onset of toxic signs, and then at 2 and 4 hr after DC, and again 24 hr after exposure. A modified stage-wise adaptive dose design was used to generate the VX dose-lethality curves for each DC product. The first stage utilized the classic up-down dose design of Dixon to estimate the LD 50 of VX for each DC product. Briefly, one animal at a time was challenged with a dose of VX for each DC product during Stage1.
  • the next animal in each DC product group received a higher (if alive at 24 hr) or lower (if dead at 24 hr) dose of VX, depending on the response of the previous animal.
  • the up-down procedure continued until four response reversals were observed.
  • the 24 hr responses for each DC product from Stage 1 were analyzed by probit analysis using SAS NLIN and special purpose probit programs developed by Battelle (Columbus, Ohio) to generate an interim LD 50 estimate.
  • the next stages of the experiment used 3-8 animals per stage and various doses of VX in each stage for each DC product to improve the LD 50 estimate and generate 95% confidence intervals (CI) by both the Fieller's and the delta methods.
  • VX doses in each stage were selected to improve the LD 50 estimate and 95% CI based from all stages.
  • Interim probit analyses were run after each stage, and the experiment was stopped when the ratio of the upper delta 95% CI minus the lower delta 95% CI divided by 2 times the LD 50 estimate was ⁇ 0.4.
  • a total of 15 and 26 animals were used to generate the RSDL and composition dose-lethality curves, respectively.
  • a final probit analysis was conducted on all stages from the 24 hr responses for RSDL and the composition.
  • the slopes, LD 50s as well as the LD 1 , LD 10 , LD 16 , LD 30 , LD 70 , LD 84 , LD 90 , and LD 99 with their respective 95% CI were calculated by both Fieller's and delta methods. Probit estimates were calculated using both target and actual doses of VX and were not statistically different; therefore, the target doses were used for all statistical comparisons and in the graphs and tables.
  • LD 50 estimates for RSDL and the composition were compared using SAS and another specialized probit program, which determined whether the ratio of the LD 50 s was statistically different at p ⁇ 0.05.
  • the PR expresses the magnitude of the increase in the LD 50 by the DC product.
  • the AER was defined as the LD 10 of VX in animals treated with a DC product divided by the dermal LD 90 of VX in untreated animals.
  • the AER expresses the magnitude of the increase in the LD 10 relative to the untreated LD 90 , and is a more operationally relevant measure of efficacy than the PR, especially if the slopes of the dose-lethality curves are significantly different.
  • Military requirements documents prescribe 80-90% survival for acceptance of new medical countermeasures against nerve agent intoxication.
  • FIG. 7 graphs the probit dose-lethality curves for VX in composition and RSDL-decontaminated animals, and Table 2 summarizes the results based on LD 50 s.
  • a total of 15 and 26 animals were needed to generate the dose-lethality curves for RSDL and the composition, respectively, using the stopping criteria described in the methodology.
  • the 24 hr dermal LD 50 of VX was 5959 ⁇ g/kg in animals decontaminated with the composition and 3380 ⁇ g/kg in animals decontaminated with RSDL.
  • the composition was 1.8-fold (p ⁇ 0.05) more effective than RSDL.
  • the slope of the composition dose-lethality curve was significantly (p ⁇ 0.05) different from the slope of the RSDL dose-lethality curve.
  • the estimated PR (treated to untreated) was 42.6 for the Composition® and 24.1 for RSDL.
  • VX LD50 Twenty-four hour VX LD50 Estimates in Guinea Pigs Decontaminated with the Composition or RSDL 2 Min After Dermal Exposure Slope of the 24 hr VX LD 50 , Estimated Number of Dose-Lethality ⁇ g/kg, p.c.
  • Ratio 1 Composition 26 6.4 5959 42.6 (4858-7309) RSDL 15 12.7 3380 24.1 (2921-3910) Efficacy Ratio Composition/RSDL 1.8 p ⁇ 0.05 50% Survival Estimated using a 24-hour dermal VX LD 50 of 140 ⁇ g/kg in fur-clipped unanesthetized guinea pigs (Clarkson, personal communication)
  • Table 3 summarizes the results based on LD 10 s.
  • the 24 hr dermal LD 10 of VX was 3755 ⁇ g/kg in animals decontaminated with the composition and 2681 ⁇ g/kg in animals decontaminated with RSDL.
  • the composition was 1.4-fold more effective than RSDL; this difference was not significant.
  • presented in Table 3 is the ratio of the VX LD 10 in animals receiving DC to the VX LD 90 in animals that were not treated with a DC product.
  • the LD 10 /LD 90 ratio for the composition was 20 and the ratio for RSDL was 14.
  • the ratio of the LD 10 in the animals receiving DC to LD 90 in animals not receiving DC provides another way of comparing efficacy which is independent of the slope. This ratio value represents the number of LD 90 s of exposure that can be tolerated without sustaining more than 10% lethality. This value was 20 for the composition and 14 for RSDL.
  • This example involved an In vitro evaluation of the composition of the invention by nuclear magnetic resonance (NMR) evaluation
  • a decontamination (DC) solution containing the composition was examined for its ability to breakdown intact chemical warfare agents (CWAs) in vitro using nuclear magnetic resonance spectroscopy (NMR).
  • Agents examined were HD, GD, VX, VR and A-232.
  • HSQC heteronuclear spin quantum correlation
  • FIG. 8 shows the 1H spectrum of the composition using presat sequence for water suppression; the inset (a) shows 1000 ⁇ vertical expansion of the region with trace impurities and inset (b) shows the two major peaks of the composition at 1.92 and 1.88 ppm, respectively.
  • CWAs were provided in deuterated solvents by the MRICD Chemical Exclusion Area where the concentrations of each of the CWAs were determined independently. For all experiments, 100 ⁇ L of CWA was mixed with 500 ⁇ L of the composition. For kinetic determinations, the peak area at time zero was set equal to the final amount of CWA after dilution with the composition. Time zero amounts were 912.8, 175.7, 95.3, 88.0 and 77.7 ⁇ g for HD, GD, VX, VR and A-232, respectively.
  • NMR data on VX, VR, GD and A-232 were collected on a 3-channel Bruker Avance III Ultrashield 500 MHz NMR spectrometer (Bruker Biospin, Billerica, Mass.) equipped with a Z-gradient 5 mm BBO probe head at 25° C. Topspin (Bruker 3.2pl6) was used for data acquisition and processing. Dynamics Center v2.2 was used for kinetic analysis, and results were exported to PDF and Excel formats, which later were analyzed using GraphPad's Prism5 for Windows.
  • NMR data on HD were collected on an Agilent (Agilent Systems, Santa Clara, Calif.) 4-channel DD2 Actively Shielded 600 MHz NMR instrument equipped with a 5 mm PFG Penta probe at 25° C. VNMRJ 3.2 was used for data collection and processing, and the results were exported to Excel for kinetic analysis.
  • Proton one-dimensional pulse sequence (s2pul) was used in HD, and modified gradient 1 H—X 1D-HSQC ( FIG. 9 ) was used for all other CWAs.
  • a representation of the gHSQC1D experiment is presented in FIGS. 10 a and 10 b showing expansion of the region of interest of methyl resonances —P—CH 3 at 1.96 and 1.20 ppm, respectively.
  • the ratio of G1/G2 gradient strength was also optimized to give an optimum signal, and this is based on the gyromagnetic ratio of proton and phosphorus.
  • LB exponential weighting function line broadening
  • Peak integrals were manually defined based on methyl peaks from starting material and methyl peaks from intermediate compound. These methyl peaks were identified by using an edited version of (gradient heteronuclear single quantum coherence with adiabatic pulses) gHSQCAD two-dimensional experiment and the peaks' chemical shifts. Total acquisition time for all kinetic experiments was adjusted to 1 hour. Triplicate data sets were collected for each of the four CWA and blank runs. Blank runs were done in 99.8% D2O without the composition and monitored for a total of 1 hr. Kinetic data are summarized in Tables 5 and 6.
  • the gHSQC method was used, and the peak corresponding to the starting material was manually integrated. This integration area was then applied to all spectra to obtain the change in concentration over time. In the case of HD, one-dimensional proton spectra were used. The peak corresponding to the methylene (—CH2-) peak of the starting material was integrated manually and then was applied to all spectra collected.
  • This example involved an initial skin DC efficacy evaluation of the composition and its comparison to RSDL following skin application of VX in guinea pigs.
  • VX vial of neat VX was obtained from the USAMRICD Chemical Exclusion Area each exposure day and placed in a fume hood at room temperature. VX was applied with a Hamilton 0.5 ul, 1 ul or 5 ul syringe equipped with a blunt tip needle and digital dispenser to the outlined exposure area.
  • FIG. 13 graphs the probit predicted dose-lethality curves for VX in the composition- and RSDL-decontaminated animals and tabulates the probit estimates at 24 hr for the LD 50 , 95% CI and slope.
  • a total of 15 and 26 animals were needed to generate the dose lethality curves for RSDL and the composition, respectively, using the stopping criteria described above.
  • the 24 hr dermal LD 50 of VX was 5959 ⁇ g/kg in the composition-decontaminated animals and 3380 ⁇ g/kg in RSDL-decontaminated animals.
  • the composition was 1.8-fold (p ⁇ 0.05) more effective than RSDL.
  • the estimated PR (treated/untreated) was 42.6 for the composition and 24.1 for RSDL. Since the gauze used with the composition was more abrasive than the sponge used with RSDL, the possibility that the higher level of protection provided by the composition may have been due to increased physical removal.
  • This example analyzed delayed skin DC efficacy of the composition and RSDL following topical A-232 application in guinea pigs.
  • DC Procedure RSDL and composition applicators and DC procedures were the same as described in previous studies. Water was applied with gauze applicators saturated with 10 ml using the same procedures utilized for RSDL and the composition. A fresh applicator of each DC product was used on each animal.
  • mice were randomly allocated into three DC treatment groups of 10; the groups were RSDL, 2% composition, and water.
  • animals were exposed topically to 5 ⁇ LD 50 s of neat A-232, and skin DC was performed at 3 hr after agent application or at the onset of signs, whichever occurred first.
  • animals were exposed topically to 10 ⁇ LD 50 of neat A-232, and skin DC was performed at 1 hr after agent application or at the onset of signs, whichever occurred first.
  • the clinical condition of each animal was evaluated at 2 hr and 4 hr after DC, early the next morning (0700-0800) and at 24 hr after exposure.
  • Experiment 1 Six of the 30 animals developed signs of nerve agent intoxication prior to the three-hour DC time. All but one of these six animals were decontaminated at the onset of signs with their assigned DC product, and all subsequently died prior to 24 hr. The one animal that was not decontaminated developed signs within 10 min after exposure and was dead by 13 min after exposure. The remaining 23 animals reached the 3 hr DC time without exhibiting any visible signs of nerve agent intoxication. Each was decontaminated, and the survival results are summarized in Table 7. The survival rates for the RSDL, composition (2%), and water DC groups were 9/9 (100%), 7/8 (88%) and 4/6 (67%), respectively. One animal in the composition DC group was removed from the study due to a technical error.
  • Table 8 shows the clinical assessment scores at 2 and 4 hr after DC, the next morning, and at 24 hr after exposure in the subset of 23 animals that were sign-free when DC was performed 3 hr after dermal exposure. Only one animal exhibited signs at 2 hr; this was an RSDL animal. The remaining animals that developed signs did so between 4 hr after DC and the next morning, at which time one composition animal was found dead, and two of the animals in the water group were severely affected. At 24 hr, 4/9 RSDL-decontaminated animals were normal and the remaining animals were scored as mild to moderately affected; 4/7 surviving composition animals were normal looking, and the remaining animals were mild to moderately affected. In the water DC group at 24 hr, 1/4 surviving animals appeared normal, two animals died, and three were mild to moderately affected.
  • Table 10 shows the clinical assessment scores at 2 and 4 hr after DC, the next morning, and at 24 hr after exposure in the subset of animals that were sign-free when DC was performed 1 hr after exposure.
  • 5 of 9 RSDL animals, 6 of 10 composition animals and 6 of 8 water animals displayed signs of nerve agent poisoning of varying severity and time to onset.
  • none of the RSDL animals had died, one was very severely intoxicated, and 8 of 9 were normal looking.
  • In the composition group one animal died, two other animals had mild or moderate signs and 7 of 10 were normal looking.
  • the water-decontaminated animals at 24 hr were clearly sicker than the animals in the composition and RSDL groups. Only 2 of 8 animals were normal looking, two had died, two were severely or very severely affected and two had mild to moderate signs.
  • the water DC group was included in the study as a control to evaluate the role of physical removal. Survival rate (83%) at 24 hr in the water group was not different from the RSDL and composition animals; however, more of the water-decontaminated animals died, showed signs of intoxication, and were more severely affected the day after exposure.
  • This example analyzed skin decontamination efficacy of the composition and RSDL in guinea pigs following topical VX application, using methods that mimic mass casualty DC procedures
  • Agent Exposure method was the same as in previous VX studies.
  • DC Decontamination
  • step 1 the DC material was applied by swiping an applicator containing the DC material 10 times quickly in short strokes across the exposure site in a head-to-tail direction; the DC material remained on the skin for 2 min.
  • step 2 the DC material was removed by wiping the exposure site 5 times quickly in short strokes in a head-to-tail direction with an applicator wetted with 10 ml of water.
  • step 3 the exposure area was dried with 5 swipes with a dry gauze applicator.
  • RSDL gauze applicator
  • RSDL-G gauze applicator saturated with 10 ml of RSDL
  • RSDL-S commercial sponge pad applicator
  • VX dose-lethality curves were generated for all DC materials using a modified stage-wise adaptive dose design.1 Each stage consisted of a number of agent doses and animals per dose to establish the range of lethality from 0-100% and to define the response relationship in the projected middle (30-70%) of the DLC.
  • a specialized probit analysis program (Battelle, Columbus, Ohio) and SAS NLIN were used on the cumulative results (survival/lethality) after each stage to estimate the LD 50 and 95% confidence intervals (CI) and to assess stopping criteria to limit animal use.
  • stage process continued with additional challenge doses and animals per agent dose until the ratio of the upper 95% CI minus the lower 95% CI (delta or Fieller's limits) divided by two times the MLD estimate from the latest stage was less than 0.4 (stopping criteria) or up to 40 animals were used.
  • each animal was monitored continuously for up to 2 hr until the onset of toxic signs appeared, then at 4 hr after DC and again at 24 hr after exposure.
  • FIG. 14 graphs the 24 hr probit-predicted VX dose-lethality curves for skin decontamination at 2 min after agent application with water, 1% DawnTM, RSDL-G, RSDL-S and 2% composition using a 3-step DC procedure as well as the probit estimates at 24 hr for the LD 50 , 95% CI and slope for each DC material.
  • the composition was significantly more effective than any of the other DC materials, with an estimated PR of 108.
  • the composition was more than 4 times more effective than tap water or soapy water, and more than 2 times more effective than RSDL applied with the commercial sponge pad (RSDL-S) or with the gauze (RSDL-G) applicator. There was a trend suggesting that the RSDL-S was more effective than RSDL-G.
  • composition was at least 2-fold more effective than RSDL and 4- to 4.5-fold more effective than tap water or soapy water using a 3-step skin DC methodology that mimics mass DC procedures against topically applied VX in guinea pigs. Since the composition was applied and left on the skin for only 2 min prior to rinsing and drying of the skin, the results suggest that the composition neutralized VX on skin.
  • This example analyzed Skin DC efficacy of the composition and RSDL following topical VX application in swine.
  • mice Gottingen mini-pigs were acclimated to being in a transfer sling and in a cage in a fume hood. Animals were trained to respond to Gatorade, which was used to entice the animal to approach the edge of the cage with its head down so that agent could be applied to the scalp and decontamination solution could be rubbed across the exposure site. On the day of exposure, the animals were weighed, the hair on the scalp was clipped and a 1-inch diameter circle was drawn on the scalp.

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US16/900,816 US20210077438A1 (en) 2017-07-07 2020-06-12 Compositions and methods for remediating chemical warfare agent exposure and surface decontamination
PCT/US2021/012540 WO2021142152A1 (fr) 2020-01-07 2021-01-07 Compositions et procédés pour remédier à une exposition d'agent de guerre chimique et à une décontamination de surface
US17/758,452 US20230030675A1 (en) 2017-07-07 2021-01-07 Solid state antimicrobial compositions and methods for producing and using same
EP21738304.1A EP4087557A4 (fr) 2017-07-07 2021-01-07 Compositions antimicrobiennes à l'état solide et leurs procédés de production et d'utilisation
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US17/326,507 US20220023174A1 (en) 2017-07-07 2021-05-21 Compositions and methods for remediating chemical warfare agent exposed skin
US18/108,940 US11969399B2 (en) 2017-07-07 2023-02-13 Compositions and methods for remediating chemical warfare agent exposed skin
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US11839213B2 (en) 2008-11-20 2023-12-12 Armis Biopharma, Inc. Antimicrobial, disinfecting, and wound healing compositions and methods for producing and using the same
US11969399B2 (en) 2017-07-07 2024-04-30 Armis Biopharma, Inc. Compositions and methods for remediating chemical warfare agent exposed skin

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WO2019010465A1 (fr) * 2017-07-07 2019-01-10 Armis Biopharma, Inc. Compositions antimicrobiennes, désinfectantes et cicatrisantes et leurs procédés de production et d'utilisation
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