WO2019077336A1 - Double distributeur contenant de l'eau et une composition antimicrobienne - Google Patents

Double distributeur contenant de l'eau et une composition antimicrobienne Download PDF

Info

Publication number
WO2019077336A1
WO2019077336A1 PCT/GB2018/052977 GB2018052977W WO2019077336A1 WO 2019077336 A1 WO2019077336 A1 WO 2019077336A1 GB 2018052977 W GB2018052977 W GB 2018052977W WO 2019077336 A1 WO2019077336 A1 WO 2019077336A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
water
substrate
enzyme
chamber
Prior art date
Application number
PCT/GB2018/052977
Other languages
English (en)
Inventor
Thomas Hall
Sophie Constance COX
Liam Michael Grover
David Kershaw
Mark BROUGHTON
Original Assignee
Matoke Holdings Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1716984.8A external-priority patent/GB201716984D0/en
Priority claimed from GBGB1806001.2A external-priority patent/GB201806001D0/en
Application filed by Matoke Holdings Limited filed Critical Matoke Holdings Limited
Publication of WO2019077336A1 publication Critical patent/WO2019077336A1/fr

Links

Classifications

    • 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
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • A01N25/06—Aerosols
    • 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
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/50—Isolated enzymes; Isolated proteins
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • A61K35/644—Beeswax; Propolis; Royal jelly; Honey
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
    • C12Y101/03004—Glucose oxidase (1.1.3.4)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
    • B05B11/0005—Components or details
    • B05B11/0078—Arrangements for separately storing several components
    • B05B11/0081—Arrangements for separately storing several components and for mixing the components in a common container as a mixture ready for use before discharging the latter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00—Containers or packages with special means for dispensing contents
    • B65D83/14—Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
    • B65D83/68—Dispensing two or more contents, e.g. sequential dispensing or simultaneous dispensing of two or more products without mixing them
    • B65D83/682—Dispensing two or more contents, e.g. sequential dispensing or simultaneous dispensing of two or more products without mixing them the products being first separated, but finally mixed, e.g. in a dispensing head

Definitions

  • the present invention relates to devices for dispensing compositions, particularly compositions that can provide antimicrobial activity.
  • compositions that are able to release hydrogen peroxide at the site of a microbial infection are particularly effective at preventing or inhibiting the infection.
  • SurgihoneyTM also known as SurgihoneyRO
  • SurgihoneyRO is a chemical engineered honey that has the ability to deliver variable and sustained doses of reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • Engineered Honey In Vitro Antimicrobial Activity of a Novel Topical Wound Care Treatment. Journal of Global Antimicrobial Resistance, 2, 168-172). It was also shown to be effective against fungi and prevented or reduced the seeding of biofilms (Dryden, M., Halstead, F., & Cooke, J. (2015). Engineered Honey to Manage Bacterial Bioburden and Biofilm in Chronic Wounds. EWMA Free Paper Session: Infection and Antimicrobials). Engineered honeys, such as honey with added glucose oxidase, and related compositions, are described in WO
  • Surgihoney is available in the form of a sachet or tube for topical administration.
  • administration of Surgihoney in these forms may be inconvenient. For example, applying a viscous composition evenly to a wound can be difficult and may require the applier to physically spread the composition on the wound.
  • the invention concerns a dispensing device for dispensing a composition that is able to generate hydrogen peroxide.
  • the composition may comprise an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme.
  • the composition may comprise a precursor-substrate that can be converted to a substrate for the enzyme.
  • the composition may not comprise sufficient free water to allow the enzyme to convert the substrate.
  • the composition may not comprise sufficient free water to allow the precursor-substrate to be converted to the substrate.
  • a dispensing device comprising: a first chamber having or containing a composition comprising an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme, the composition not having sufficient free water to allow the enzyme to convert the substrate; and a second chamber having or containing water.
  • a dispensing device comprising: a first chamber having or containing a composition comprising an enzyme that is able to convert a substrate to release hydrogen peroxide, and a precursor-substrate that can be converted to a substrate for the enzyme, the composition not having sufficient free water to allow the precursor-substrate to be converted to the substrate or to allow the enzyme to convert the substrate; and a second chamber having or containing water.
  • a dispensing device comprising: a first chamber having or containing a composition comprising an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme, the composition not having sufficient free water to allow the enzyme to convert the substrate; and a second chamber having or containing water; and at least one outlet for dispensing the composition and the water from the device.
  • a dispensing device comprising: a first chamber having or containing a composition comprising an enzyme that is able to convert a substrate to release hydrogen peroxide, and a precursor-substrate that can be converted to a substrate for the enzyme, the composition not having sufficient free water to allow the precursor-substrate to be converted to the substrate or to allow the enzyme to convert the substrate; and a second chamber having or containing water; and at least one outlet for dispensing the composition and the water from the device.
  • the water may be distilled or deionised water or the water may be provided as an aqueous solution.
  • the water may be provided as a saline solution.
  • the composition does not contain sufficient free water to allow the enzyme to convert the substrate (or for the precursor-substrate to be converted to the substrate), the composition, whilst it is present in the first chamber, may not be able to produce hydrogen peroxide.
  • the composition When the composition is dispensed from the device with the water, the water and the composition may mix to form a mixture in which the enzyme is able to convert the substrate to release hydrogen peroxide (and/or such that the precursor-substrate may be converted to the substrate). Consequently, dispensing the water and the composition on to a dry wound, for instance, may allow production of hydrogen peroxide at the wound site.
  • a dispensing device may remove the necessity of direct physical contact with, for example, a wound site.
  • a composition of the invention does not comprise sufficient free water to allow the enzyme to convert the substrate, it may contain trace amounts of free water that may allow trace amounts, or substantially no hydrogen peroxide to be produced.
  • hydrogen peroxide may present at a concentration less than 1 ppm.
  • Hydrogen peroxide may be present at a concentration less than 0.5 ppm.
  • Hydrogen peroxide may be present at a concentration less than 0.1 ppm.
  • Hydrogen peroxide may be present in the composition at a concentration of 120 ⁇ or less, preferably 100 ⁇ or less, more preferably 80 ⁇ or less.
  • compositions used in devices of the invention may separate (or compartmentalise) water from the enzyme and the substrate, such that the enzyme and the substrate are not in contact with sufficient free water to allow the enzyme to convert the substrate.
  • the composition may be a double emulsion, in which, for instance, droplets containing the enzyme and the substance (but without sufficient free water to allow the enzyme to convert the substrate) may be dispersed within globules of oil, and the globules of oil may be dispersed within an aqueous phase (e.g. water).
  • the composition and the water may be dispensed separately from the device.
  • the device may comprise a first outlet for the composition and a second outlet for water.
  • the first outlet may comprise a first tube through which the composition can be transported from the first chamber to a first exit hole or aperture.
  • the second outlet may comprise a second tube through which the water can be transported from the second chamber to a second exit hole or aperture.
  • the device may be arranged to separately dispense the composition and the water under pressure.
  • the device may be arranged to dispense both the composition and the water as a spray or atomised liquid.
  • the device is arranged such that the composition and the water are pre-mixed, i.e. mixed prior to dispensing from the device.
  • the device may comprise a mixing chamber having a first inlet for receiving the composition, a second inlet for receiving the water, and an outlet for dispensing a mixture of the composition and the water out of the mixing chamber.
  • the first inlet may comprise a tube through which the composition from the first chamber can flow to the mixing chamber;
  • the second inlet may comprise a tube through which the water from the second chamber can flow to the mixing chamber;
  • the outlet may comprise a tube through which the mixture from the mixing chamber can flow out of the device through an exit hole or aperture.
  • Pre-mixing the composition and the water may be
  • the addition of water to the composition may reduce the viscosity of the composition and make it easier to dispense from the device. This may be particularly advantageous if the device is arranged to dispense under pressure, such as a spray.
  • the device is arranged to dispense a mixture of the composition and the water under pressure.
  • the device may be arranged to dispense the mixture of the composition and water as a spray, such as a pump action or trigger spray, an atomiser or an aerosol.
  • devices of the invention may comprise a means for varying the amount or volume of the composition and/or the amount or volume of the water that can be dispensed from the device.
  • the first outlet and/or second outlet may comprise a variable restriction for restricting the volume of the composition and/or the volume of the water dispensed from the device.
  • the device of the invention permits the pre-mixing of a variable amount or volume of the composition and/or a variable amount or volume of the water.
  • Varying the relative amounts or volumes may allow the user to control the properties of the mixture. For example, increasing the ratio of the volume of water to the volume of composition may reduce viscosity and alter the properties of the spray dispensed from the device. A reduced viscosity may result in a spray with finer droplets, for instance.
  • the first inlet and/or second inlet may comprises a variable restriction for restricting the volume of the composition and/or the volume of the water entering the mixing chamber.
  • US Pat. No. 4,355,739 describes a spraying device which allows the ratio of the quantities of liquid components from the chambers to be varied. Another example of a device which allows variation of the relative voiumes of fluids entering a mixing chamber from two distinct chambers is shown in US pat. No. 5,152,461.
  • the first outlet and second outlet may comprise a variable restriction for restricting the amount or volume of the composition and/or the amount or volume of the water dispensed from the device.
  • the device may be configured or configurable to dispense, a composition: water volume ratio of 5:1 or lower.
  • the composition: water volume ratio may be 5:1 to 1 :1 ; 2:1 to 1 :1 or 1.5:1 to 1 :1.
  • the device may be configured or configurable to dispense, a composition: water volume ratio of 1 :5 or higher.
  • the composition: water volume ratio may be 1 :1 to 1 :5 1 :1 to 1 :2 or 1 :1 to 1 :1.5
  • the composition in the first chamber is a liquid, it is conceivable that it could be a powder. If the composition is a liquid, it is preferable that the composition comprises a non-aqueous or organic solvent. This may be particularly advantageous if the composition would otherwise be viscous.
  • the composition may comprise a honey-based composition. Honey, has a high viscosity and is sticky, which can make it difficult to incorporate into spraying devices. Therefore, the viscosity of honey may be reduced by using a non-aqueous solvent. The use of a non-aqueous solvent may mean that the viscosity can be reduced without using water, which would initiate hydrogen peroxide production and may affect the storage stability of the composition.
  • the non-aqueous solvent may comprise (or consist of) a mixture of more than one non-aqueous solvent.
  • non-aqueous solvent thus includes one or more, or at least one, nonaqueous solvent.
  • the non-aqueous solvent may comprise (or consist of) only one non-aqueous solvent.
  • the non-aqueous solvent may comprise an alcohol.
  • the non-aqueous solvent may comprise ethanol, dimethyl sulphoxide, glycerol, ethylene glycol and/or propylene glycol.
  • Solubility parameters and viscosity parameters for various non-aqueous solvents are shown in the following table.
  • non-aqueous solvents may be selected so that they have solubility parameters in the range of the non-aqueous solvents exemplified in the tables above.
  • 6 t /MPa 1 ' 7 may be from 26 to 50, such as 26.5 to 47.8.
  • 8d/MPa 1/2 may be from 15 to 19, such as 15.6 to 18.1.
  • ⁇ /MPa 1 ' 2 may be from 8 to 16, such as 8.8 to 16.
  • 5 h /MPa 1 ' 2 may be from 10 to 45, such as 10.2 to 42.3.
  • the non-aqueous solvent may be selected depending on the desired viscosity. For example, if a greater viscosity is desired, glycerol may be preferred.
  • a suitable viscosity for a composition of the invention may be 100 mPa.s. or less at 20°C. In some embodiments, a suitable viscosity may be 75 mPa.s. or less at 20°C. In some embodiments, a suitable viscosity may be 75 mPa.s. or less at 20°C.
  • compositions comprising a non-aqueous solvent may comprise at least 2% by weight of the non-aqueous solvent. In some embodiments of compositions comprising a non-aqueous solvent, the compositions may comprise at least 5% by weight of the non-aqueous solvent. In some embodiments of compositions comprising a non-aqueous solvent, the compositions may comprise at least 10% by weight of the nonaqueous solvent. In other embodiments, the composition may comprise at least 20% by weight of the non-aqueous solvent. In other embodiments, the composition may comprise at least 25% by weight of the non-aqueous solvent. In other embodiments, the composition may comprise at least 50% by weight of the non-aqueous solvent.
  • the composition may comprise at least 75% by weight of the non-aqueous solvent. In some embodiments, the amount of non-aqueous solvent in the composition may be 50-90%, by weight. In some embodiments, the amount of non-aqueous solvent in the composition may be 1-50, 5-50 or 10- 50%, by weight.
  • the composition is not, or does not comprise, honey and glycerol.
  • compositions in devices of the invention may be in the form of an emulsion.
  • emulsions are disclosed in WO 2017/013448 A1 and WO 2018/091890 A1.
  • the inventors have appreciated that emulsions may be particularly suitable for devices of the invention because application of shear and exposure to water can cause phase inversion, which initiates hydrogen peroxide production. Before application of shear and exposure to water, the emulsions may remain stable for long periods of time.
  • compositions in devices of the invention may comprise a first phase (or first liquid, or first component) and a second phase (or second liquid, or second component), an enzyme that is able to convert a substrate to release hydrogen peroxide; and a substance that includes a substrate for the enzyme.
  • the first phase and the second phase may be immiscible.
  • the first phase may be less polar than the second phase.
  • the first phase may be a non-polar phase such as a lipophilic phase or a hydrophobic phase e.g. an oil.
  • the second phase may be a polar phase, such as an aqueous phase.
  • the second phase may comprise a non-aqueous solvent. Droplets or micelles of the second phase may be dispersed within the first phase.
  • the lipophilic phase may be an oil.
  • the oil is selected from olive oil, corn oil, vegetable oil, sunflower oil or paraffin oil.
  • the oil may be paraffin oii.
  • the second phase may comprise water and/or non-aqueous solvent.
  • the enzyme and the substance of the composition may be dissolved in the water and/or non-aqueous solvent. Suitable non-aqueous solvents are described above.
  • Glycerol may be a particularly preferred non-aqueous solvent for emulsions.
  • the second phase may not comprise water or may comprise substantially no water.
  • the second phase may be described as non-aqueous.
  • the enzyme and the substance comprising a substrate for the enzyme may be dissolved in a non-aqueous solvent.
  • the non-aqueous solvent may be immiscible with respect to the first phase e.g. lipophilic phase.
  • the enzyme that is able to convert a substrate to release hydrogen peroxide and the substance that includes a substrate for the enzyme may be contained within micelles dispersed within the first phase, e.g. lipophilic phase.
  • the composition may comprise an emulsifying agent (or emulsifier).
  • suitable emulsifying agents include: Surfactants: Sodium lauryl sulphate, Cetrimide, Cetomacrogol 1000, PEG 1000 monostearate, Triethanolamine stearate, Sodium stearate; Fatty amphiphiles: Cetostearyl alcohol, Cetyl alcohol, Stearyl alcohol, Glyceryl monostearate, Stearic acid, Phosphatidylcholine.
  • Surfactants for use in compositions of the invention may include one or more of TWEEN (e.g. TWEEN 80), SPAN (e.g. SPAN 80), Poloxamer (e.g. Poloxamer 407) and Polyglycerol polyricinoleate (PGPR).
  • a preferred surfactant may be Poloxamer, such as Poloxamer 407. Another preferred surfactant may be PGPR.
  • the ratio of the first phase to the second phase may be from 9:1 to 1 :9, 8:1 to 1 :8, 7:1 to 1 :7, 6:1 to 1 :6, 5:1 to 1 :5, 4:1 to 1 :4, 3:1 to 1 :3, or 2:1 to 1 :2 (v/v), for example from 4:1 to 1 :4.
  • the composition may comprise 5-95%, 10-95%, 15-95%, 20-95%, 25-95%, 30-95%, 35-95%, 40-95%, 45-95%, 50-95%, 55-95%, 60-95%, 65-95%, 70-95%, 75-95%, 80-95%, 85-95%, or 90-95% (v/v) lipophilic phase, or first phase (including any emulsifying agent present).
  • the composition may comprise 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, or 5-10% (v/v) lipophilic phase, or first phase (including any emulsifying agent present).
  • the composition may comprise 5-95%, 10-95%, 15-95%, 20-95%, 25-95%, 30-95%, 35-95%, 40-95%, 45-95%, 50-95%, 55-95%, 60-95%, 65-95%, 70-95%, 75-95%, 80-95%, 85-95%, or 90-95% (v/v) aqueous phase, or second phase.
  • the composition may comprise 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, or 5-10% (v/v) aqueous phase, or second phase.
  • the composition may comprise 1-60%, 1-50%, 1-40%, 1-30%, 1-20%, or 1-10% (w/v) of the substance, for example a honey or a sugar substance.
  • a sugar substance may comprise the substrate for the enzyme, e.g. a purified substrate for the enzyme.
  • the sugar substance may comprise one or more sugars.
  • the sugar substance may comprise glucose and fructose.
  • the composition may comprise 1-60%, 5-60%, 10-60%, 15-60%, 20-60%, 25-60%, 30-60%, 35-60%, 40-60%, 45-60%, or 50-60% (w/v) of the substance.
  • the composition may comprise 10-60% (w/w) of non-aqueous solvent.
  • a composition of the invention may comprise 20-50% (w/w) of a non-aqueous solvent.
  • a composition of the invention may comprise 35-40% (w/w) of a non-aqueous solvent.
  • the composition may comprise 10-40 % (w/w) of the first phase, e.g. lipophilic phase (such as oil).
  • the composition may comprise 20-30% (w/w) of the first phase, e.g. lipophilic phase (such as oil).
  • the composition may comprise 1-10% (w/w) emulsifier.
  • the composition may comprise 1-5% (w/w) emulsifier.
  • the emulsifier is preferably a surfactant.
  • the composition may comprise 0-50% (w/w) of a sugar substance (e.g. glucose and fructose).
  • the composition may comprise 20-40% (w/w) of the substance. In some embodiments, the composition may comprise 25 to 35% (w/w) of the substance.
  • the composition may comprise 20-50% (w/w) of non-aqueous solvent, 20-30% (w/w) of the first phase e.g. lipophilic phase (such as oil), 1 -5% (w/w) emulsifier and 20-40% (w/w) of the substance which comprises a substrate for the enzyme.
  • the first phase e.g. lipophilic phase (such as oil)
  • 1 -5% (w/w) emulsifier such as oil
  • 20-40% w/w of the substance which comprises a substrate for the enzyme.
  • the composition may comprise 10-60% (w/w) of non-aqueous solvent, 10-40% (w/w) of the first phase e.g. lipophilic phase (such as oil), 1-10% (w/w) emulsifier and 10-50% (w/w) of the substance which comprises a substrate for the enzyme.
  • the first phase e.g. lipophilic phase (such as oil)
  • 1-10% (w/w) emulsifier e.g. lipophilic phase (such as oil)
  • 10-50% w/w of the substance which comprises a substrate for the enzyme.
  • the composition may comprise 35-45% (w/w) of non-aqueous solvent, 20-30% (w/w) of the first phase e.g. lipophilic phase (such as oil), 1-5% (w/w) emulsifier and 25-35% (w/w) of the substance which comprises a substrate for the enzyme.
  • the first phase e.g. lipophilic phase (such as oil)
  • 1-5% (w/w) emulsifier emulsifier
  • 25-35% (w/w) of the substance which comprises a substrate for the enzyme e.g. lipophilic phase (such as oil)
  • composition may comprise 30-60% (v/v) solvent, such as a non-aqueous, polar solvent.
  • composition may comprise 30-60% (v/v) first phase, such as a lipophilic phase (e.g. oil),
  • a lipophilic phase e.g. oil
  • composition may comprise 1-10% (v/v) emulsifier such e.g. surfactant.
  • emulsifier such e.g. surfactant.
  • compositions of the invention may comprise 1 -5% (v/v) emulsifier.
  • the composition may comprise 30-70% or 40-60% (w/w) of the substance that comprises a substrate for the enzyme, for example honey.
  • the ratio of the first phase to the second phase in the composition may be ⁇ 1 :1 (v/v), for example 0.1-1 :1 (v/v). In some embodiments, the ratio of the first phase to the second phase is ⁇ 0.6:1 (v/v), for example 0.1- ⁇ 0.6:1 (v/v). In some embodiments, the ratio of the first phase to the second phase is ⁇ 0.4:1 (v/v), for example 0.1-0.4:1 (v/v).
  • the first phase in the composition may be present at less than 60% (v/v) of the composition. In some embodiments, the first phase is present at 10% to less than 60% (v/v) of the composition. In some embodiments, the first phase is present at 10% to less than 50% (v/v) of the composition. In some embodiments, the first phase is present at 10% to less than 40% (v/v) of the composition. In some embodiments, the first phase is present at 10% to less than 30% (v/v) of the composition. In some embodiments, the first phase is present at 10% to less than 25% (v/v) of the composition.
  • the composition may comprise an emulsifier.
  • the emuisifier is present at up to 25% (v/v) of the composition, for example 1-25% (v/v) of the composition, 5-25% (v/v) of the composition, or 10-25% (v/v) of the composition.
  • the composition may comprise 1-5% (v/v) of emulsifier.
  • the ratio of the amount of the substance that includes a substrate for the enzyme to the volume of the second phase in the composition may be from 0.5:1 to 2:1 , for example 1 :1.
  • the amount of the substance that includes a substrate for the enzyme in the composition may be up to 70% (w/v) of the composition, for example 5-70% (w/v), 10-70% (w/v), 20-70% (w/v), or 30-70% (w/v), or up to 60% (w/v) of the composition, for example 5-60% (w/v), 10-60% (w/v), 20-60% (w/v), or 30-60% (w/v), of the composition.
  • Emulsions may comprise paraffin oil and PGPR ⁇
  • Emulsions may comprise paraffin oil, PGPR and glycerol.
  • Emulsions may comprise an organic salt such as magnesium sulfate heptahydrate.
  • Honey is a natural product, so its composition can vary greatly depending on its source. For example, the difference in antimicrobial potency among honeys can be more than one hundred-fold, depending on the geographical, seasonal and botanical source of the honey, as well as the harvesting, processing and storage conditions. Consequently, the antimicrobial efficacy may also vary depending on the type of honey used.
  • honey may also contain other components, such as allergens e.g. trace amounts of pollen, which may cause adverse reactions when applied to certain subjects and make it unsuitable for certain pharmaceutical applications.
  • Honey may require processing such that it is in a suitable form for application to subjects, which can add cost and complexity to the production process. Such processing may include creaming or pasteurisation. Furthermore, for certain pharmaceutical applications, it may be difficult to get regulatory approval for honey-based compositions.
  • compositions comprising unrefined natural substances, such as honey, may be used in devices of the invention, other compositions may be used which may provide some of the antimicrobial benefits provided by honey, but which also overcome some of its disadvantages.
  • Unrefined is used herein to refer to substances that have not been processed into a pure form. Unrefined substances include substances that may have been concentrated, for example by drying or boiling.
  • the substance may include one or more substrates from a natural source (termed herein a "natural substance").
  • natural substances include substances from a plant source, including from sap, roots, nectar, flowers, seeds, fruit, leaves, or shoots.
  • composition does comprise an unrefined natural substance such as honey, it is preferable that the substance is pasteurised.
  • composition does comprise an unrefined natural substance, such as honey, it is preferable that the substance does not contain catalase activity or contains essentially no catalase activity.
  • composition does comprise an unrefined natural substance, such as honey, the substance may be creamed.
  • the unrefined natural substance may account for at least 10% by weight of the composition.
  • the unrefined natural substance may account for at least 25 % by weight of the composition.
  • the unrefined natural substance may account for at least 50% by weight of the composition.
  • the unrefined natural substance may account for at least 75% by weight of the composition, such as at least 80% or at least 90% by weight of the composition.
  • devices of the invention do not comprise compositions formed from unrefined natural substances, such as honey.
  • the compositions of devices of the invention may comprise a purified enzyme that is able to convert a substrate to release hydrogen peroxide; and a purified substrate for the enzyme (and/or a purified precursor substrate that can
  • compositions may be formed by mixing a purified enzyme with purified substrate for the enzyme (and or a purified precursor substrate).
  • compositions comprising a purified enzyme and a purified substrate can be more effective at killing microorganisms than known honey-based compositions that can generate hydrogen peroxide.
  • the enzyme in compositions of devices of the invention may thus be a purified enzyme.
  • compositions of devices the invention may comprise a plurality of enzymes that are able to convert a substrate to release hydrogen peroxide.
  • compositions of devices the invention may comprise only one enzyme that is able to convert a substrate to release hydrogen peroxide.
  • purified enzyme is used herein to include an enzyme preparation in which the enzyme has been separated from at least some of the impurities originally present when the enzyme was produced.
  • impurities that have been removed or reduced include those that would otherwise interfere with the ability of the enzyme to convert the substrate to release hydrogen peroxide.
  • the purified enzyme is at a high level of purity provided that the enzyme is able to convert the substrate to release hydrogen peroxide. In some circumstances, it may be desirable to use a relatively crude enzyme preparation.
  • suitable purity levels include at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% pure (mass purity).
  • the enzyme is at least 90% pure. Even more preferably, the enzyme is at least 99% pure.
  • the enzyme may have been produced by recombinant or non-recombinant means, and may be a recombinant or non-recombinant enzyme.
  • the enzyme may be purified from a microbial source, preferably from a non-genetically modified microbe.
  • the level of purity of the enzyme may be selected as appropriate depending on the intended use of the composition.
  • a medical grade or medical device grade of purity may be used.
  • a pharmaceutical grade of purity may be used.
  • the enzyme is an oxidoreductase enzyme.
  • oxidoreductase enzymes that can convert a substrate to release hydrogen peroxide include glucose oxidase, hexose oxidase, cholesterol oxidase, galactose oxidase, pyranose oxidase, choline oxidase, pyruvate oxidase, glycollate oxidase, and aminoacid oxidase.
  • the corresponding substrates for these oxidoreductase enzymes are D-glucose, hexose, cholesterol, D-galactose, pyranose, choline, pyruvate, glycollate and aminoacid, respectively.
  • the oxidoreductase enzyme may be glucose oxidase, and the substrate may be D-glucose.
  • a mixture of one or more oxidoreductase enzymes and one or more substrates for the oxidoreductase enzymes may be present in compositions of devices of invention.
  • compositions may comprise sufficient enzyme and substrate to provide for sustained release of hydrogen peroxide at a specific level or concentration.
  • the compositions may comprise sufficient enzyme and substrate to provide for sustained release of hydrogen peroxide at a level of less than 2 mmol/iitre for a period of at least twenty four hours, following dilution of the composition.
  • compositions may comprise sufficient enzyme and substrate to provide for sustained release of at least 0.02, 0.03, 0.04, 0.05, 0.1 , 0.2, 0.3, 0.4, 0.5, 1 or 1.5 mmol/litre hydrogen peroxide for a period of at least 24 hours, more preferably 48 hours.
  • compositions may comprise sufficient enzyme and substrate to provide for sustained release of 0.1 to 2 mmol/litre hydrogen peroxide for a period of at least 24 hours, more preferably 48 hours.
  • the compositions may provide for sustained release of hydrogen peroxide at a concentration of at least 2 ppm, at least 5 ppm, at least 10 ppm, at least 20 ppm or at least 50 ppm.
  • the level may be at least 2 ppm.
  • the concentration may be, at the most, 500 ppm, 200 ppm, 100 ppm, 50 ppm, 20 ppm or 10 ppm.
  • the level may be 20 ppm or less. In even more preferred embodiments, the level may be 10 ppm or less.
  • the concentration may be 10 to 500 ppm, 20 to 200 ppm or 50 to 100 ppm, 2 to 50 ppm, 2 to 20 ppm or 5 to 10 ppm. If the composition does not comprise sufficient free water to allow the enzyme to convert the substrate, hydrogen peroxide production may only occur once it has been diluted by water and there is sufficient free water to allow the enzyme to convert the substrate. Addition of water may thus initiate hydrogen peroxide production.
  • Compositions may provide for sustained release of hydrogen peroxide for at least 1 hour, at least 12 hours, at least 24 hours, at least 2 days, or at least 4 days. Preferably, the level of hydrogen peroxide is sustained for at least 4 days.
  • the level of hydrogen peroxide is sustained at 10 to 500 ppm for at least 1 hour, at least 12 hours, at least 24 hours, at least 2 days, or at least 4 days. In other embodiments, the level of hydrogen peroxide is sustained at 50 to 100 ppm for at least 1 hour, at least 12 hours, at least 24 hours, at least 2 days, or at least 4 days. In other embodiments, the level of hydrogen peroxide is sustained at 2 to 50 ppm for at least 12 hours, at least 24 hours, at least 2 days, or at least 4 days. In other embodiments, the level of hydrogen peroxide is sustained at 5 to 10 ppm for at least 12 hours, at least 24 hours, at least 2 days, or at least 4 days. In some embodiments, compositions may provide for sustained release of 2 to 500 ppm hydrogen peroxide for at least 24 hours.
  • compositions may comprise 750 to 2000 ppm of the enzyme.
  • Compositions of devices the invention may comprise at least 500 ppm of the enzyme.
  • the compositions may comprise 250 to 1500 of the enzyme.
  • the enzyme activity may range, for example, from 1- 400 lU/mg, or 1-300 lU/mg, for example 250-280 lU/mg.
  • the amount of enzyme used is likely to depend on several factors, including the desired use of the composition, the desired level of hydrogen peroxide release, and the desired length of time for hydrogen peroxide release.
  • a suitable amount of enzyme can readily be determined by a person of ordinary skill in the art, if necessary using a well diffusion assay, to determine the extent of hydrogen peroxide release for different amounts of enzyme.
  • Suitable amounts of enzyme (such as glucose oxidase) may be from 0.0001 % to 0.5% w/w of the composition.
  • the amount of enzyme used may be selected so as to produce a composition for generating antimicrobial activity that is equivalent to a selected phenol standard (for example a 10%, 20%, or 30% phenol standard).
  • compositions of devices of the invention may comprise at least 1 unit, and preferably up to 1500 units, of the enzyme per gram of the composition.
  • a “unit” is defined herein as the amount of enzyme (e.g. glucose oxidase) causing the oxidation of 1 micromole of substrate (e.g.
  • the composition may comprise more than 15 units, for example at least 30 units, at least 50 units, or at least 100 units, and suitably less than 685 units, for example 100-500 units, of enzyme (e.g. glucose oxidase) per gram of the composition.
  • enzyme e.g. glucose oxidase
  • the composition may comprise at least 500 units, for example 500-1000 units, or 685-1000 units, of enzyme (e.g. glucose oxidase) per gram of the composition.
  • enzyme e.g. glucose oxidase
  • references herein to "substrate” or precursor-substrate” may refer to one or more substrates.
  • the compositions may comprise a plurality of substrates or precursor-substrates.
  • the compositions may comprise only one substrate or only one precursor substrate.
  • purified substrate or “purified precursor-substrate” is used herein to include a substrate or precursor-substrate preparation in which the substrate or precursor-substrate has been separated from at least some of the impurities originally present when the substrate or precursor-substrate was obtained or produced.
  • the purified substrate or precursor-substrate may be obtained from a natural source or may be synthetically produced.
  • the purified substrate or precursor-substrate may be a processed, extracted, or refined substrate or precursor- substrate (i.e. a substrate or precursor-substrate in which impurities or unwanted elements have been removed by processing).
  • the purified substrate or precursor-substrate is at a high level of purity provided that the enzyme is able to convert the substrate to release hydrogen peroxide. In some circumstances, it may be desirable to use a relatively crude substrate or precursor-substrate preparation. Examples of suitable purity levels include at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% pure. Preferably the purity level is at least 90%, even more preferably at least 99% pure. However, in some embodiments, it may be desirable that the purified substrate or purified precursor-substrate is a medical grade, medical device grade, or pharmaceutical grade substrate or precursor-substrate.
  • the purified substrate or precursor-substrate is or comprises a purified sugar.
  • the term "sugar” is used herein to refer to a carbohydrate with the general formula C m (H20) n .
  • the purified sugar may be obtained from a natural source (for example a processed, extracted, or refined natural sugar), or be synthetically produced.
  • the purified sugar may be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% pure.
  • the purity level is at least 90%. Even more preferably, the purity level is at least 99%.
  • the purified sugar may be a medical grade, medical device grade, or pharmaceutical grade sugar.
  • the sugar may include, for example purified D -glucose, hexose, or D-galactose.
  • the purified sugar may be medical grade, medical device grade, or
  • the enzyme and the substrate are purified, for example purified glucose oxidase and purified D-glucose, suitably medical grade, medical device grade, or pharmaceutical grade glucose oxidase and D-glucose.
  • compositions which comprise a precursor-substrate preferably comprises one or more enzymes (preferably purified enzymes) for converting the precursor-substrate to the substrate for the enzyme.
  • the precursor-substrate may not necessarily be converted to the substrate enzymatically.
  • addition of water may be enough for conversion.
  • compositions of devices of the invention may comprise non-enzymatic catalysts.
  • compositions of devices of the invention which comprise a precursor-substrate may comprise a first enzyme that is able to convert the substrate to release hydrogen peroxide, and a second enzyme that is able to convert the precursor-substrate to the substrate for the first enzyme.
  • the precursor-substrate is preferably a carbohydrate, such as a polysaccharide, or a sugar e.g. a disaccharide, or sugar derivative,
  • the precursor-substrate may be sucrose
  • the first enzyme may be glucose oxidase
  • the second enzyme may be invertase
  • the precursor-substrate may be maltose
  • the first enzyme may be glucose oxidase
  • the second enzyme may be maltase
  • compositions of devices of the invention which comprise a precursor-substrate may comprise an enzyme (preferably a purified enzyme) that is able to convert the substrate to release hydrogen peroxide, and at least two enzymes (e.g. second and third enzymes, preferably purified enzymes) that are able to convert the precursor-substrate to the substrate for the first enzyme.
  • an enzyme preferably a purified enzyme
  • at least two enzymes e.g. second and third enzymes, preferably purified enzymes
  • the precursor-substrate may be starch
  • the first enzyme may be glucose oxidase
  • the second and third enzymes may be amylase and maltase.
  • the precursor-substrate may be cellulose
  • the first enzyme may be glucose oxidase
  • the second and third enzymes may be cellulose and beta-glucosidase.
  • the composition may comprise both a substrate that can be converted by the enzyme to generate hydrogen peroxide, and a precursor-substrate that can be converted to the substrate.
  • compositions and water in the device of the invention are preferably sterile. Sterilisation may occur by any suitable means. Preferably the composition and/or water compositions are sterilised by irradiation.
  • the Applicant has found that compositions can retain glucose oxidase activity (and, therefore, the ability to release hydrogen peroxide on dilution) following sterilisation by exposure to gamma radiation or electron beam radiation.
  • a suitable level of gamma irradiation is 10-70 kGy, preferably 25-70 kGy, more preferably 35-70 kGy.
  • a suitable level or dose of irradiation e.g.
  • the composition and/or water may be sterilised by irradiation that is not gamma irradiation. Since ozone has not been authorised by the US FDA for sterilisation of honey-based products for use in wound healing, compositions in devices of the invention preferably have not been sterilized by ozonation, and do not include ozone, or any components that have been subjected to sterilisation by ozonation. In particular, the compositions in devices of the invention should not comprise ozonized honey or ozonated oil.
  • composition in the device of the invention is may be a medical grade or medical device grade composition.
  • composition in the device of the invention may be a pharmaceutical grade composition.
  • compositions of devices of the invention preferably comprise essentially no catalase, or substantially no catalase.
  • compositions of devices of the invention preferably comprises essentially no peroxidase, or substantially no peroxidase.
  • compositions of devices of the invention preferably comprises essentially no zinc oxide, or contain substantially no zinc oxide.
  • compositions of the devices of the invention may comprise an antioxidant.
  • compositions can be stored at ambient temperature for at least several days, preferably at least a week, more preferably at least one or two months, whilst retaining the ability to generate antimicrobial activity following dilution of the composition.
  • a preferred storage temperature is below 37°C, preferably 20-25°C.
  • compositions are stored away from exposure to light.
  • Hydrogen peroxide is generally unstable at ambient temperature.
  • the lack of sufficient free water in compositions of the devices of the invention prevents the enzyme converting the substrate to release hydrogen peroxide, and thus helps to maintain the stability of the composition for extended periods at ambient temperature.
  • a storage-stable composition for use in devices of the invention may include some water provided that there is not sufficient free water to allow the enzyme to convert the substrate (or to allow the precursor-substrate to be converted to the substrate for the enzyme). Suitable amounts of water will vary depending on the precise components of the composition. However, typically, a storage-stable composition for use in devices of the invention preferably comprises less than 20% (by weight) total water content, for example, 10%- 19%, water. Compositions in devices the invention may comprise 12% or less (by weight) of water.
  • compositions in devices of the invention may comprise 10% or less (by weight) of water.
  • Compositions in devices of the invention may comprise 5% or less (by weight) of water.
  • Compositions in devices of the invention may comprise 3% or less (by weight) of water.
  • Compositions in devices of the invention may have a water activity (a w ) of 0.7 or lower.
  • compositions of the invention may have an a w of 0.6 or lower, such as 0.5 or lower.
  • the compositions in the devices of the invention comprise substantially no hydrogen peroxide, or no detectable hydrogen peroxide.
  • hydrogen peroxide is preferably not detectable using a hydrogen peroxide test strip, such as a Quantofix® peroxide test stick (Sigma Aldrich, UK).
  • hydrogen peroxide may present at a level less than 1 ppm or at a level less than 0.5 ppm.
  • Hydrogen peroxide may be at a level less than 0.1 ppm.
  • compositions in the devices of the invention may comprise an additional component which is preferably a solute.
  • references herein to "solute" may refer to one or more solutes.
  • compositions of devices of the invention may comprise a plurality of solutes.
  • the composition may only comprise one solute.
  • the solute is soluble in water.
  • the solute may be distinct from the substrate, or in some examples, the substrate may be same as the solute.
  • the composition may comprise fructose and fructose oxidase: the fructose being both the solute and the substrate for enzyme.
  • the substrate may be glucose and the solute may be fructose.
  • the solute is preferably purified, meaning that the solute has been separated from at least some of the impurities originally present when the solute was obtained or produced.
  • the purified solute may be obtained from a natural source or may be synthetically produced.
  • the purified solute may be a processed, extracted, or refined substrate (i.e. a solute in which impurities or unwanted elements have been removed by processing).
  • the purified solute is at a high level of purity. In some circumstances, it may be desirable to use a relatively crude solute preparation. Examples of suitable purity levels include at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% pure. Preferably, the purity level is at least 90%. Even more preferably, the purity level is at least 99%. However, in some embodiments, it may be desirable that the solute is a medical grade, medical device grade, or pharmaceutical grade solute.
  • the solute may be a carbohydrate.
  • the solute may be a polysaccharide.
  • the solute is a sugar or sugar derivative. More preferably, the solute is a sugar.
  • Suitable sugars include oligosaccharides, disaccharides or monosaccharides.
  • the sugar is a disaccharide or a monosaccharide.
  • the sugar is a monosaccharide.
  • Suitable sugars may include fructose, glucose, galactose, sucrose and maltose. In a particularly preferred embodiment, the sugar is fructose.
  • sugar derivative is used herein to refer to a sugar that has been modified by addition of one or more substituents other than a hydroxy I group.
  • Sugar derivatives thus encompass amino sugars, acidic sugars, deoxy sugars, sugar alcohols, glycosylamines and sugar phosphates.
  • sugar derivatives may include glucose-6-phosphateglucosamine, glucoronate, gluconate, galactosamine, glucosamine, sialic acid, deoxyribosefucose, rhamnose glucuronic acid, polyols (e.g. sorbitol, erythritol, xylitol, mannitol, lactitol and maltitol) and sucralose.
  • polyols e.g. sorbitol, erythritol, xylitol, mannitol, lactitol and maltitol
  • compositions in devices of the invention may comprise two or more solutes, as described herein.
  • compositions in devices of the invention may comprise two or more sugars or sugar derivatives.
  • the composition may comprise a maximum of two solutes, e.g. two sugars or sugar derivatives; or a maximum of three solutes, e.g. three sugars or sugar derivatives.
  • compositions in devices of the invention may comprise glucose, fructose and sucrose.
  • the solute preferably has a high solubility in water, for example a solubility which is greater than glucose.
  • Glucose has a solubility of 90g/100g water at 20°C and 1 atm.
  • the solute has a solubility greater than or equal to 100g/100g water at 20°C and 1 atm, in a more preferred embodiment, the solute has a solubility greater than or equal to 200g/100g water at 20°C and 1 atm, in an even more preferred embodiment, the solute has a solubility greater than 300g/1 OOg water at 20°C and 1 atm.
  • a solute with a high solubility may be advantageous because a high concentration of solutes may provide a high osmolarity or osmotic strength.
  • Compositions with a high osmolality or osmotic strength may assist with the antimicrobial efficacy of the composition because they may reduce the amount of water available for microbes or draw water away from microbes, and may assist in wound healing and wound debridement.
  • Fructose is a particularly preferred solute because it has a solubility of about 375g/100g water at 20°C and 1 atm. Consequently, the solute may be fructose.
  • the solute with a solubility of at least 100g/1 OOg water at 20°C and 1 atm, at least 200g/100g water at 20°C and 1 atm or at least 300g/1 OOg water at 20°C and 1 atm may be the purified substrate.
  • the composition may comprise fructose and fructose oxidase.
  • the composition may comprise only one sugar or sugar derivative which is both the solute and the substrate, and one enzyme for converting the substrate and generating hydrogen peroxide.
  • the solute with the solubility of at least 100g/100g water at 20°C and 1 atm, at least 200g/100g water at 20°C and 1 atm or at least 300g/1 OOg water at 20°C and 1 atm may be distinct from the purified substrate.
  • a composition of the invention may comprise glucose, glucose oxidase and fructose.
  • the purified substrate is a sugar or sugar derivative ⁇ e.g. glucose) and the solute is a sugar or sugar derivative (e.g. fructose).
  • the composition comprises at least two sugars or sugar derivatives (e.g. including glucose and fructose).
  • the composition may comprise a maximum of two sugars or sugar derivatives (e.g. only glucose and fructose).
  • compositions in the devices of the invention may comprise at least 5% by weight of sugars and/or sugar derivatives.
  • Compositions in devices of the invention may comprise at least 10% by weight of sugars and/or sugar derivatives.
  • Compositions in devices of the invention may comprise at least 25% by weight of sugars and/or sugar derivatives.
  • Compositions in devices of the invention may comprise at least 50% by weight of sugars and/or sugar derivatives.
  • compositions in devices of the invention may comprise 95% by weight or less of sugars or sugar derivatives.
  • Compositions in devices of the invention may comprise at least 75% by weight or less of sugars and/or sugar derivatives.
  • compositions in devices of the invention may comprise 10% to 95% by weight sugars and/or sugar derivatives.
  • Compositions in devices of the invention may comprise 25% to 75% by weight sugars and/or sugar derivatives.
  • Compositions in devices of the invention may comprise 50 to 95% by weight sugars and/or sugar derivatives.
  • compositions in devices of the invention may comprise 5 to 50% by weight of substrate for the enzyme (e.g. glucose) or 5 to 50% by weight of the precursor-substrate that can be converted to the substrate for the enzyme.
  • substrate for the enzyme e.g. glucose
  • the compositions of the devices of the invention may comprise 5 to 25% by weight of substrate for the enzyme (e.g. glucose) or 5 to 25% by weight of the precursor substrate that can be converted to the substrate for the enzyme
  • compositions in devices of the invention may comprise 5 to 75% by weight of solute (e.g. fructose).
  • solute e.g. fructose
  • the compositions in the devices of the invention may comprise 10 to 50% by weight of solute.
  • the compositions in the devices of the invention may comprise at least 50% by weight of substrate and solute combined and at least 5% by weight of non-aqueous solvent.
  • the compositions may comprise 50% to 95% by weight of substrate and solute combined and 5% to 50% by weight non-aqueous solvent.
  • compositions in devices of the invention may comprise at least 50% by weight of sugar and at least 5% by weight of non-aqueous solvent.
  • the compositions may comprise 50% to 95% by weight sugar and 5% to 50% by weight non-aqueous solvent.
  • compositions in devices of the invention may comprise at least 5% by weight of substrate for the enzyme ⁇ or precursor-substrate) and at least 5% by weight of non-aqueous solvent.
  • compositions in devices of the invention may comprise 5 to 50% substrate (or precursor-substrate) and 5 to 50% by weight non-aqueous solvent.
  • compositions in devices of the invention may comprise a buffer, or a component that may be capable of acting as act as a buffer in an aqueous solution.
  • a suitable buffer is a citric acid/NaOH buffer, such as a 50 mmol citric acid NaOH buffer.
  • the compositions of devices of the invention may be buffered (or may be capable of being buffered in an aqueous solution) at a pH of 5 or less, e.g. 3 to 5 (such as about pH 4).
  • compositions of devices the invention may be buffered (or may be capable of being buffered in an aqueous solution) at a pH greater than 5, e.g. 6 to 8 (such as about pH 7).
  • compositions in devices of the invention may comprise a salt.
  • a method comprising applying a composition and water, the composition and water either being applied sequentially or simultaneously, the composition comprising an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme, the composition not comprising sufficient free water to allow the enzyme to convert the substrate.
  • a method of dispensing from a device comprising a first chamber comprising a composition, the composition having an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme, the composition not comprising sufficient free water to allow the enzyme to convert the substrate; a second chamber comprising water; the method comprising: a) dispensing separately from the device, the composition from the first chamber and the water from the second chamber; or b) pre-mixing the composition from the first chamber and the water from the second chamber to form a mixture, and then dispensing the mixture from the device.
  • a method of dispensing from a device comprising a first chamber comprising a composition, the composition having an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme, the composition not comprising sufficient free water to allow the enzyme to convert the substrate; a second chamber comprising water; and at least one outlet for dispensing the composition and the water from the device; the method comprising: a) dispensing separately from the device, the composition from the first chamber and the water from the second chamber; or b) pre-mixing the composition from the first chamber and the water from the second chamber to form a mixture, and then dispensing the mixture from the device.
  • composition and water are dispensed separately (e.g. through distinct holes or apertures).
  • the method may comprise dispensing the composition and the water concurrently or sequentially.
  • compositions, water or devices of methods of the invention may be as described herein,
  • the composition comprising the enzyme and substrate may be applied first (e.g. to a wound site) and the water may be applied second.
  • the water may be applied first and the composition comprising the enzyme and the substrate may be applied second.
  • the composition and the water may be applied concurrently or simultaneously.
  • Methods of the invention may comprise dispensing or applying on to a wound.
  • the method may comprise dispensing on to a surface which is not on a human or animal body.
  • the method may comprise dispensing on to, or in, a human or animal body.
  • the method comprise treating a wound, treating inflammation, stimulating tissue growth, debriding a wound, deodorising a wound, which comprises administering a composition of the invention to a wound in need of deodorising, or treating, or ameliorating a microbial infection.
  • the microbial infection may comprise a biofilm.
  • kits comprising a) a first device comprising: i) a chamber, the chamber comprising a composition having an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme, the composition not comprising sufficient free water to allow the enzyme to convert the substrate; and ii) an outlet for the composition, and separately, b) a second device comprising: i) a chamber, the chamber comprising water; and ii) an outlet for the water.
  • composition, water or devices of the invention may be as described herein,
  • a device according to the invention may be configurable such that the contents of the first chamber can be mixed with the contents of the second chamber, prior to dispensing from the device.
  • a device comprising: a first chamber comprising a composition, the composition having an enzyme that is able to convert a substrate to release hydrogen peroxide, and a substrate for the enzyme, the composition not having sufficient free water to allow the enzyme to convert the substrate; and a second chamber comprising water; wherein prior to dispensing, the device is configurable from a first arrangement in which the composition cannot mix with the water, to a second arrangement in which the composition can mix with the water.
  • the device may be configurable from a first arrangement in which the composition in the first chamber cannot pass to the second chamber and/or the water in the second chamber cannot pass to the first chamber, and a second arrangement in which the composition in the first chamber can pass to the second chamber and/or the water in the second chamber can pass to the first chamber.
  • the device may be configurable to provide an opening, such as an opening between the first chamber and second chamber, to permit mixing of the composition and the water.
  • the device may comprise a barrier, seal or septum. In one example, there may be a barrier, seal or septum separating the first chamber and second chamber. In another example there may be a barrier, seal or septum separating both the first and second chambers from a mixing chamber.
  • the barrier, seal or septum may be openable, for example it may be breakable or frangible.
  • the mixing of the water and the composition may occur manually, for example, by a user applying pressure, such as by massaging and/or shaking the device, to open the barrier, seal or septum.
  • the barrier, seal or septum may be positioned between the first chamber and the second chamber. It may comprise a wall separating the first chamber and the second chamber.
  • the device may be a sachet or a pouch.
  • the sachet or pouch may be manufactured from a plastics or polymer material.
  • the sachet or pouch may be flexible or deformable to enable a user to squeeze the sachet or pouch. Squeezing the sachet or pouch may allow breaking of the barrier, seal or septum between the first chamber and the second chamber.
  • the barrier, seal or septum may be configured to break or rupture at a predetermined pressure, for example if a user applies sufficient pressure to a wall of the first and/or second chamber. Squeezing the sachet or pouch may allow the diluted composition to be dispensed from the device.
  • the device may have an outlet, such as a nozzle, to allow the diluted composition to be dispensed from the device, it may not be necessary. This is because a user may manually create an outlet once the composition and the water have mixed.
  • An outlet may be created, for instance, by cutting, piercing or tearing a wall of the first and/or second chamber. The outlet may be formed by breaking a seal.
  • the device may thus not contain a nozzle or other such pre-formed dispensing means.
  • burstpouch.com a division of Eastern States Packaging, Inc., 27 Glen Street, Suite 6, Stoughton, MA 02072 USA.
  • a frangible membrane seal is installed across the pouch separating a first compartment from a second compartment, requiring deliberate pressure from a user to burst the frangible seal, allowing components of both compartments to mix.
  • Such mixing pouches are available both with or without dispensing tips.
  • composition and the water may form a gel or viscous liquid upon mixing.
  • Figure 1 shows a trigger spray device according to an embodiment of the invention
  • Figure 2 is a graph showing the effect of compositions for use in the invention comprising glucose, glucose oxidase and fructose (SyntheticRO) on the growth of planktonic MRSA, compared to SurgihoneyROTM, at various concentrations;
  • SyntheticRO glucose oxidase and fructose
  • Figure 3 is a graph showing the effect of sterile and non-sterile compositions for use in the invention comprising glucose, glucose oxidase and fructose (SyntheticRO) (buffered at pH
  • Figure 4 is a graph showing the effect of sterile and non-sterile compositions for use in the invention comprising glucose, glucose oxidase and fructose (SyntheticRO) (unbuffered) on the growth of planktonic MRSA, at various concentrations;
  • SyntheticRO glucose oxidase and fructose
  • Figure 5 is a graph showing the effect of sterile and non-sterile compositions for use in the invention comprising glucose, glucose oxidase and fructose (SyntheticRO) (buffered at pH
  • Figure 6 is a table showing the effect of sterile and non-sterile compositions for use in the invention comprising glucose, glucose oxidase and fructose, on the MIC and MBC of planktonic MRSA, at various concentrations;
  • Figure 7 shows the effect of compositions for use in the invention comprising glucose, glucose oxidase and fructose (SyntheticRO) on the growth of planktonic MRSA, compared to
  • Figure 8 shows the effect of SyntheticRO on the MIC and MBC of planktonic MRSA, compared to SurgihoneyRO, at various concentrations;
  • Figure 9 shows a schematic drawing of a pouch comprising a frangible septum positioned between a first chamber and a second chamber.
  • a device 1 as shown in Figure 1 has a first chamber 3 and a second chamber 7.
  • a composition 5 comprising 50% by weight SurgihoneyROTM (a commercially- available antimicrobial product formed from pasteurised honey with added glucose oxidase) and 50% by weight glycerol.
  • SurgihoneyROTM a commercially- available antimicrobial product formed from pasteurised honey with added glucose oxidase
  • glycerol 50% by weight glycerol
  • a first tube 11 connects the first chamber 3 to a mixing chamber 15 in a neck 14 of the device, and a second tube 13 connects the second chamber to the mixing chamber.
  • the mixing chamber is connected to a nozzle 17, which defines an outlet hole (not shown).
  • a trigger 19 is located on the neck of the device.
  • the user operates the trigger 17, which draws the composition 5 from the first chamber 3 through the first tube 11 to the mixing chamber 15, and simultaneously draws the deionised water 9 from the second chamber 7 through the second tube 13 to the mixing chamber 15.
  • the composition and the water mix in the mixing chamber to form a mixture and the mixture is ejected through the hole defined in the nozzle 17, as a spray.
  • the composition having been diluted by the water to form the mixture, produces hydrogen peroxide.
  • Samples with batch number "RO" contain no glucose oxidase.
  • Samples with batch number "R01" contain 50 ppm glucose oxidase.
  • Samples with batch number "R02" contain 1000 ppm glucose oxidase.
  • Non sterile base buffered R02 saccharide solution A6. Batch no N B01 p43R02
  • MIC and MBC were assessed for the R01 samples (containing 50 ppm glucose oxidase) and compared to SurgihoneyROTM (also containing 50 ppm glucose oxidase). See Andrews J. M, Journal of Antimicrobial Chemotherapy (2001 ) 48, suppl. S1, 5-16.
  • the synthetic composition buffered at pH7.04 had the most effective MIC. Sterilised compositions were more effective than non-sterilised compositions, and synthetic composition buffered at pH7.04 synthetic had the most effective MBC when compared to other synthetic compositions and even when compared to SurgihoneyRO.
  • FFiigguurreess 77 ((aa ttoo dd)) aanndd 88 sshhooww MMIICC aanndd MMBBCC rreessuullttss iinncclluuddiinngg SSuurrggiihhoonneeyyRROO ((RR0022)) ssaammpplleess aanndd ssyynntthheettiicc RR0022 ssaammpplleess..
  • a dispensing device 20 in the form of a flexible pouch formed from a plastics material has a first compartment 3 and a second compartment 7.
  • a composition 5 comprising 50% by weight SurgihoneyRO and 50% by weight glycerol.
  • the second compartment is deionised water.
  • the dispensing device comprises a frangible septum 22 positioned between the first compartment and the second compartment, and one outlet 21 in the form of a closed nozzle, which is in connection with the second compartment.
  • a user applies pressure to the first compartment 3 and/or the second compartment 7.
  • the resulting pressure causes the frangible septum 22 to rupture and open, allowing the composition and the water to mix and initiate hydrogen peroxide production. Mixing may be assisted by the user massaging the pouch.
  • the user then opens the nozzle 21 and squeezes the pouch such that the diluted composition may be dispensed from the pouch to the desired site, such as a wound.

Abstract

L'invention concerne un dispositif de distribution (1) comportant une première chambre (3) comprenant une composition (5). La composition comprend une enzyme apte à convertir un substrat pour libérer du peroxyde d'hydrogène, et un substrat pour l'enzyme. La composition ne contient pas suffisamment d'eau libre pour permettre à l'enzyme de convertir le substrat. Le dispositif comprend également une seconde chambre (7) comprenant de l'eau (9).
PCT/GB2018/052977 2017-10-16 2018-10-16 Double distributeur contenant de l'eau et une composition antimicrobienne WO2019077336A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB1716984.8A GB201716984D0 (en) 2017-10-16 2017-10-16 Antimicrobial compositions
GB1716984.8 2017-10-16
GB1806001.2 2018-04-11
GBGB1806001.2A GB201806001D0 (en) 2018-04-11 2018-04-11 Antimicrobial device

Publications (1)

Publication Number Publication Date
WO2019077336A1 true WO2019077336A1 (fr) 2019-04-25

Family

ID=64049452

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2018/052977 WO2019077336A1 (fr) 2017-10-16 2018-10-16 Double distributeur contenant de l'eau et une composition antimicrobienne

Country Status (1)

Country Link
WO (1) WO2019077336A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021186165A1 (fr) * 2020-03-16 2021-09-23 Matoke Holdings Limited Compositions antimicrobiennes

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5607681A (en) * 1990-02-03 1997-03-04 The Boots Company Plc Anti-microbial compositions
US20100189707A1 (en) * 2007-05-10 2010-07-29 Barnett Christopher C Stable Enzymatic Peracid Generating Systems
WO2017013448A1 (fr) * 2015-07-23 2017-01-26 Matoke Holdings Limited Compositions antimicrobiennes et formulations libérant du peroxyde d'hydrogène
US20170049111A1 (en) * 2014-04-30 2017-02-23 Matoke Holdings Limited Antimicrobial compositions
US20170266240A1 (en) * 2014-11-24 2017-09-21 Matoke Holdings Limited Prevention and treatment of microbial infections

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5607681A (en) * 1990-02-03 1997-03-04 The Boots Company Plc Anti-microbial compositions
US20100189707A1 (en) * 2007-05-10 2010-07-29 Barnett Christopher C Stable Enzymatic Peracid Generating Systems
US20170049111A1 (en) * 2014-04-30 2017-02-23 Matoke Holdings Limited Antimicrobial compositions
US20170266240A1 (en) * 2014-11-24 2017-09-21 Matoke Holdings Limited Prevention and treatment of microbial infections
WO2017013448A1 (fr) * 2015-07-23 2017-01-26 Matoke Holdings Limited Compositions antimicrobiennes et formulations libérant du peroxyde d'hydrogène

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021186165A1 (fr) * 2020-03-16 2021-09-23 Matoke Holdings Limited Compositions antimicrobiennes

Similar Documents

Publication Publication Date Title
KR101004551B1 (ko) 조직유착 방지액 및 조직유착 방지방법
EP3522717B1 (fr) Compositions antimicrobiennes
EP2156738B1 (fr) Compositions antiseptiques et procédés d'utilisation
BRPI0608690B1 (pt) uso de uma composição antimicrobiana
US20180318399A1 (en) Antimicrobial compositions and formulations releasing hydrogen peroxide
ES2275076T3 (es) Composicion parasiticida de larga duracion que contiene un compuesto de salicilanilida, una especie polimerica y al menos otro compuesto an tiparasitos.
ES2764506T3 (es) Composición que contiene cineol para administración nasal
CN115154619A (zh) 受控释放和层状的环糊精包合物媒介物
US20200069777A1 (en) Antimicrobial compositions and formulations
CN102159198A (zh) 皮肤感染的局部治疗
EP2555784B1 (fr) Composition de gel à base de miel
US20220175829A1 (en) Antimicrobial Compositions
WO2019077336A1 (fr) Double distributeur contenant de l'eau et une composition antimicrobienne
JP2018158890A (ja) 消毒用組成物
US20240108697A1 (en) Antimicrobial compositions
WO2018065789A1 (fr) Compositions antimicrobiennes
RU2162699C1 (ru) Водно-дисперсная лекарственная форма ивермектина для лечения экто- и эндопаразитозов
RU2148371C1 (ru) Биологически активная добавка к пище и напиткам
WO2016008999A1 (fr) Compositions pharmaceutique et/ou cosmetique decontaminees par haute pression
EP4247329A1 (fr) Composition antimicrobienne de soin de la peau comprenant du bêta-glucane et une huile naturelle
AT508949B1 (de) Antimikrobielles, viruzides und fungizides gemisch
OA18691A (en) Antimicrobial Compositions and Formulations Releasing Hydrogen peroxide
JP2021088509A (ja) 医薬品

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18795730

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18795730

Country of ref document: EP

Kind code of ref document: A1