WO2010136792A2 - Antibacterial composition - Google Patents

Antibacterial composition Download PDF

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Publication number
WO2010136792A2
WO2010136792A2 PCT/GB2010/050859 GB2010050859W WO2010136792A2 WO 2010136792 A2 WO2010136792 A2 WO 2010136792A2 GB 2010050859 W GB2010050859 W GB 2010050859W WO 2010136792 A2 WO2010136792 A2 WO 2010136792A2
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Prior art keywords
formula
compound
nanoparticles
composition
range
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PCT/GB2010/050859
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French (fr)
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WO2010136792A3 (en
Inventor
Selvaraj Subbiah
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Intrinsiq Materials Limited
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Publication of WO2010136792A3 publication Critical patent/WO2010136792A3/en

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    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION 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
    • A01N59/00Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16Heavy metals; Compounds thereof
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION 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
    • A01N59/00Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/06Aluminium; Calcium; Magnesium; Compounds thereof
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION 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
    • A01N59/00Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16Heavy metals; Compounds thereof
    • A01N59/20Copper

Definitions

  • the invention relates to antibacterial compositions, to processes for the preparation of these compositions and to uses thereof.
  • the invention relates to a nanoparticulate bactericidal composition comprising a metal oxide.
  • micro-organisms there is increasing concern about the presence of micro-organisms in the environment which could be damaging to human health. Of particular concern is the transmission of virulent pathogenic micro-organisms including bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile (C. difficile), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli).
  • MRSA Methicillin-resistant Staphylococcus aureus
  • C. difficile Clostridium difficile
  • Pseudomonas aeruginosa P. aeruginosa
  • Escherichia coli Escherichia coli
  • metals have bactericidal properties. For instance silver and copper ions are used in water treatment where they cause lysis of gram-negative bacteria such as Legionella, through disruption of the cell walls. These metals are often used in fine particulate form to maximise the surface area of the metal exposed to the environment. This minimises the amount of metal which must be used to achieve the desired bactericidal effect.
  • silver, copper and gold are known to migrate from their site of intended activity, leaching into their surrounds. This is undesirable as not only is the bactericidal benefit of the metal lost, but neighbouring materials become contaminated. It is further known that silver can be toxic in solution. As a result, these elements are prohibited from use as bactericides in some jurisdictions.
  • Nanoparticles have found use in pharmaceutical formulations to improve the solubility and/or biological activity of drug substances. Nanoparticles have also been used for medical purposes. For example, silver nanoparticles have been used to kill bacteria (Furno et al J. Antimicrob Chemother, 54(6), 1019-24 (2004)).
  • WO 2007/093808 (Ren et al.) describes compositions including nanoparticles of formula M n X y (in particular tungsten carbides), having antiviral activity.
  • WO 2007/023558 (Seto et al.) describes compositions which can have a deodorising effect when exposed to light.
  • the compositions described in Seto et al comprise nanoparticulate tungsten oxides supported on an inorganic material.
  • the repertoire of antibacterial compositions available to defend against infection remains limited, and it would be advantageous to provide a composition which is effective in the prevention and/or transmission of a wide range of different bacteria, and a composition that is effective without depending on high illumination.
  • an antibacterial composition comprising nanoparticles, the nanoparticles comprising a compound of formula M n O y where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
  • the above composition provides a biocide which is active against a range of different bacteria, including gram positive and gram negative bacteria and which can be used in a wide range of conditions.
  • the bactericidal compositions of the invention have activity across a wide range of temperatures, humidities, and may be used in both the dark and the light.
  • the antibacterial effect of the compositions is observed on contact with a wide range of materials including wood, metal, plastics materials, fabrics (both natural, such as cotton or wool, and synthetic, such as nylon or viscose), masonry and glass.
  • the active ingredients are inexpensive, providing an economical solution to the problem of reducing and/or preventing the transmission of bacteria.
  • the inventive compositions comprise nanoparticles.
  • nanoparticle is meant a particle having nanometric dimensions, and nanoparticles may have, for example, dimensions in the order of a few nanometres to a few micrometres.
  • the nanoparticles may be of average particle size equal to or less than 2 ⁇ m, equal to or less than 200 nm, in many instances equal to or less than 20 nm.
  • the composition will consist of nanoparticles with substantially all of the particles falling within the size range less than 2 ⁇ m, or the size range less than 200 nm, or the size range less than 20 nm.
  • a common size range would be in the range about 1 nm to about 100 nm, often this will be in the range about 10 nm to about 40 nm, preferably about 20 to about 30 nm.
  • the term "substantially all” is intended to mean 90% or above, typically 95% or above, most often 98% or above of the particles or other feature being described.
  • the average particle size relates to the diameter at the widest point of the particle.
  • the specific surface area of the particles described may be in the range of from 150 m 2 /g to about 1000 m 2 /g, often, from 200 m 2 /g to about 500 m 2 /g.
  • the nanoparticles are generally in the form of dry powders, but may also be in the form of liquids, sol-gels or polymers, as well as nanotubes.
  • the particles may be agglomerated or in free association.
  • the compound of formula M n O y will be non- stoichiometric, the non- stoichiometry will typically be introduced by the presence of dopants. However, in many instances it will be preferred that the compound of formula M n O y be stoichiometric, in these cases n is equal to 1, 2 or 3 and y is equal to 1, 2, 3 or 4. In stoichiometric compounds, the values of n and y may vary depending upon the relative valencies of M and Y.
  • M will be selected to provide a compound of formula M n O 5 , which is physically robust and stable to high temperature.
  • M will be a transition metal, although group I and II metal oxides may also be used.
  • M is selected from aluminium, zinc, calcium, nickel, iron, cobalt, tungsten, copper, and combinations thereof. The oxides of these metals have been found to offer good antibacterial activity, at a reasonable cost. It will often be the case that M comprises tungsten as tungsten compounds are stable to high temperature and have been found by the inventors to have a substantial bactericidal effect even when exposed to harsh conditions during processing.
  • the compound of formula M n O 5 is selected from aluminium oxide (Al 2 O 3 ), zinc oxide (ZnO), calcium oxide (CaO), tungsten oxide(s) (WO, WO 2 , WO 3 ), nickel oxide (NiO), iron oxide(s) (FeO, Fe 2 O 3 , Fe 3 O 4 ), cobalt oxide(s) (CoO, Co 3 O 4 ), copper oxide(s) (Cu 2 O, CuO), and combinations thereof.
  • the compound of formula M n O 5 is a tungsten oxide selected from tungsten oxide (WO), tungsten dioxide (WO 2 ) tungsten trioxide (WO 3 ), and combinations thereof. In most instances the compound of formula M n O y will be tungsten trioxide.
  • the nano form is not only highly anti-bacterial, but contains a significant triclinic crystalline fraction.
  • the micron form of the tungsten oxide is substantially monoclinic and includes no triclinic crystals. Without being bound by theory, it is possible that this difference in crystalline structure leads to the difference in antibacterial activity. It is also possible that increasing the percentage of triclinic crystals in the composition, may also increase the activity thereof.
  • the composition may comprise nanoparticles of more than one compound of formula M n O y .
  • Such compositions may comprise a mixture of nanoparticles where each nanoparticle comprises one compound of formula M n O y only, or nanoparticles where each nanoparticle comprises more than of compound of formula M n O y .
  • the compositions may comprise nanoparticles comprising the compound of formula M n O 5 , and particles (micro or nanoparticles) of an antimicrobial, antifungal and/or antiviral agent.
  • the composition may comprise tungsten carbide (WC) particles, for instance as described in WO 2009/022100.
  • Mixed particle compositions may be produced by any suitable method, such as, for example, tumble-mixing, co-deposition or mechanical alloying, or by co-production.
  • the W n O 5 , particles may be also prepared as layered (core/shell) particles, comprising a core of one compound of formula W n O 5 , and one or more shells of one or more other compounds of formula W n O y , or vice versa.
  • compositions of the invention generally do not include nanoparticles of pure metals.
  • carbonates, silicates, carbides and/or phosphates are absent as the oxides of formula M n O 5 , are preferred.
  • an article coated or impregnated with an antibacterial composition as described in the first aspect of the invention may comprise a wide range of materials and in many embodiments will comprise more than one material.
  • the materials may be natural or synthetic, hard or soft, permeable or impermeable.
  • the materials from which the article can be formed include wood, metal, plastics materials, fabrics and other materials comprising fibres.
  • the fibres may be coated with the antibacterial composition.
  • the article will be an article used in a medical environment, so that the transmission of bacteria via that article will be prevented or reduced.
  • the article may be selected from face masks, surgical masks, respirator masks, hats, hoods, trousers, shirts, gloves, skirts, boiler-suits, surgical gowns, and filters.
  • the surface may be permeable or impermeable, where the surface is permeable it will typically be the case that the surface is impregnated with the antibacterial composition, when the surface is impermeable, it will typically be the case that the antibacterial composition will be applied as a coating.
  • the term "coated" is intended to include surfaces where the substrate from which the surface is made has the antibacterial composition incorporated therein. For instance, where the surface is of a polymeric material, the polymer beads from which the surface is formed may be coated with the antibacterial composition before the surface is formed. In such surfaces the antibacterial composition will be integral to the polymeric material, by virtue of the starting material (such as beads) being coated before manufacture.
  • a bactericide of nanoparticles comprising a compound of formula M n O y where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
  • the use may be for the prevention and/or transmission of gram positive bacteria, gram negative bacteria or a combination thereof. It will generally be the case that the prevention and/or transmission is of both gram positive and gram negative bacteria. It is intended that the use be for the prevention and/or transmission of bacteria including bacteria selected from Escherichia coli, Staphylococcus aureus, Clostridium difficile, Pseudomonas aeruginosa, and combinations thereof. Further, it is an important advantage of the invention that the antibacterial composition described be usable regardless of the lighting conditions. In particular, the composition of the invention maybe used in the substantial absence of light (the dark), or in low lighting conditions as may be found in cupboards, under tables/working areas and behind sink and toilet units. In addition, the efficacy of the antibacterial composition of the invention is independent of the lighting conditions.
  • a fifth aspect of the invention provides for the use of a composition, article or surface according to any of the first three aspects of the invention for reducing and/or preventing bacterial transmission.
  • a sixth aspect of the invention offers a method for the reduction and/or prevention of bacterial transmission, comprising applying to an article or a surface, a composition of nanoparticles of a compound of formula M n O y where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
  • the nanoparticulate compositions of the invention can be prepared by, for instance, gas phase synthesis or sol-gel processing.
  • Gas phase synthesis will generally be used.
  • particles, often nanoparticles may be generated by evaporation and condensation (nucleation and growth) in a subatmospheric inert-gas environment.
  • Various aerosol processing techniques may be used to improve the production yield of nanoparticles. These include synthesis by combustion flame, plasma, laser ablation, chemical vapour condensation, spray pyrolysis, electrospray and plasma spray.
  • Ball and other forms of milling can also be used to produce particles, including nanoparticles.
  • the ultimate particle size depends upon factors including the size, morphology and composition of the grinding medium, process variables, design, and operation of the mill.
  • gas phase synthesis is a reliable way of achieving this.
  • the uniformity of particle size is typically achieved by using a combination of rigorous control of nucleation-condensation growth and avoidance of coagulation by diffusion and turbulence as well as by the effective collection of particles and their handling afterwards.
  • the stability of the collected particle powders against agglomeration, sintering, and compositional changes can be ensured by collecting the particles in liquid suspension.
  • One production method that is suitable for the production of nanoparticles is the Tesima® process (described in WO 01/78471 and WO 01/58625) where a high temperature DC plasma (a plasma torch) is used to a generate plasma stream within a gas envelope.
  • the gas envelope may be inert, comprising argon or helium for instance; or may contain a reactive gas, for instance hydrogen. Hydrogen may be present in the range 0 to 20 wt%, 1 to 10 wt%, or 2 to 5 wt%. Materials (either pre-produced feedstock or mixed feedstock), or liquids, can be placed into the plasma causing rapid vaporisation. The resultant vapour then exits the plasma where it may be cooled by quantities of cold gas. These gases can be inert (such as argon or helium), air, or can include trace components to develop the chemistry/morphology/size that is required.
  • the rapid cooling (greater than 100,000 degree per second) then freezes the particle for subsequent cooling and collection using a combination of techniques that can include solid or fabric filters, cyclones and liquid systems.
  • the materials can also be collected directly into containers under either inert gas or into various liquids.
  • a process for the preparation of a nanoparticulate antibacterial composition comprising inserting a compound of formula M n O y into a plasma stream and cooling a resultant vapour upon exit from the plasma stream, wherein M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
  • M is a metal
  • n is in the range 1 - 3
  • y is in the range 1 - 4.
  • the plasma may be in a gaseous envelope and the vapour may be cooled by gas.
  • more than one compound of formula M n O y is co-fed into the plasma stream in the process, thereby producing nanoparticles which are composites of more than one compound of formula M n O y .
  • the raw materials from which the particles are created will be in fine particulate form. This may require a pre-treatment step, such as a grinding step, to prepare the raw materials for reaction.
  • particles of the raw materials will be of size less than 10 ⁇ m diameter, often in the range 1 ⁇ m - 5 ⁇ m, or the range 2 ⁇ m - 4 ⁇ m.
  • Utilising the raw materials in fine particulate form increases the surface area available for reaction and hence reaction rate.
  • particles of size less than 1 ⁇ m or 2 ⁇ m can impair processing as the new materials begin to bind or clump together. This reduces the flow rate of material through the processing equipment and increases the risk that pipe work will become clogged causing production to cease whilst the processing equipment is cleaned.
  • An important aspect of the invention is the realisation by the applicant that the processing of raw materials of formula M n O y from fine or microparticulate dimensions to nanoparticulate dimensions confers on the resulting nanoparticles antibacterial properties. These are not observed when the same compounds are present in fine or microparticulate form. Without being bound by theory, this may be because the nanoparticles cause a change in the pH local to the surface of the bacteria, disrupting and causing lysis of the bacterial cell walls.
  • thermal plasma torch facilitates the production of particles of substantially uniform size with a high surface area which is stable to high temperature. This allows the resulting bactericidal composition to be used in applications where the processing is at high temperature, for instance, it provides a possible application in the incorporation of the bactericidal composition into plastics products creating a product with surfaces which are intrinsically hostile to bacteria.
  • composition may be formulated for use in an appropriate carrier, coating or solvent such as water, methanol, ethanol, acetone, water soluble polymer adhesives, such as polyvinyl acetate, epoxy resin, polyesters etc. as well as coupling agents and antistatic agents.
  • solutions of biological materials may also be used such as phosphate buffered saline (PBS) or simulated biological fluid (SBF).
  • the nanoparticles of formula M n O y are present in "free" particulate form, by which it is meant that the nanoparticles are present in the composition in unbound form.
  • the compositions of the invention include support structures, or that the nanoparticles be supported within a matrix or other framework before they will be effective. It is preferred that the nanoparticles be "free” within the composition so that their entire surface area is available to interact with the bacteria, thereby maximising the antibacterial effect of the compositions of the invention.
  • the term "free” is intended to mean substantially unbound or free to act chemically as though they were not bound; it is often important to ensure that the nanoparticles are not detachable as they may become an unwanted airborne or waterborne contaminant, where they would be a perceived or possibly an actual hazard to health or equipment.
  • the concentration of particles may lie in the range of 0.001 - 20 wt%, often 0.01 - 10 wt%, on occasion 0.1 - 5 wt%.
  • the particles may be included in a composition in powder form. They may be coated onto or impregnated into a surface or article, or mixed with an absorbent powder such as Fuller's earth or sand.
  • the reduction and/or prevention of the spread of pathogenic micro-organisms includes the prevention of infection of a subject with the bacterium; in addition to the prevention of transmission from a first location to a second location, or the prevention of transmission through a barrier material.
  • the subject may be a human or a non-human animal, suitably a non-human mammal.
  • the invention may therefore find application in the field of human medicine and animal veterinary medicine as well as in the field of infection control in a non- medical context, such as a prophylactic against the transmission and/or spread of bacteria.
  • compositions described can be applied to enclosed ventilation fabrics for public buildings, hospitals, and to vehicles such as cars, trains, ships and aeroplanes.
  • the compositions may also find use in medical applications, such as in filtering materials, i.e. in filtration of biological fluids such as plasma, blood, milk or semen to inactivate any bacteria present.
  • the antibacterial particles may be coated onto fabrics and surfaces of different products such as furniture, paints/coatings, book covers and computer keyboards to produce products with antibacterial properties. Such products will provide a low cost route to a safer environment for hospitals, children, patients and the elderly. Further uses may include air ventilation systems for enclosed environments such as passenger aeroplanes, for instance preventing the entry or outlet of airborne bacteria.
  • An article of the invention may be coated or impregnated with the antibacterial composition described above.
  • the composition will work most effectively where at least one coated or impregnated surface of the article comes into direct contact with the bacteria to be removed.
  • protective clothing may comprise fabrics and/or fibres coated with the antibacterial composition and the exposed surfaces of filters may be coated with the composition.
  • a counter top could be impregnated with or coated in the antibacterial composition to produce a surface which is intrinsically hostile to microorganisms. Such a surface could be used in hospitals to help improve the safety of surgical procedures or domestically to reduce the transmission of disease through the presence of pathogenic micro-organisms around the home.
  • the coating and impregnation processes which may be used are those common in the art and would be well known to the person skilled in the art. They include spray coating, extrusion- lamination, co-extrusion, electro-spray coating, dipping or plasma coating.
  • an article may be composed of fibres coated with the bactericidal composition.
  • Such articles will often be selected from filters, face masks, surgical masks, respirator masks, hats, hoods, trousers, shirts, gloves, boiler-suits and surgical gowns. Medical and veterinary devices and prophylactic devices may also be used.
  • surfaces that are routinely contacted by people, especially in communal areas such as toilets, doors, switches etc. may be coated and/or impregnated with the composition.
  • areas of food preparation and utensils or equipment used therein may be coated with a composition according to the invention.
  • Filters may be prepared from any suitable natural or artificial material.
  • the filter may be an air filter.
  • An air filter is a device which removes contaminants, often solid particles from air. Air filters are often used in diving air compressors, ventilation systems and any other situation in which air quality is important, such as in air-conditioning units.
  • An air filter includes devices which filter air in an enclosed space such as a building or a room, as well as apparatus or chambers for handling viral materials. Other articles which perform a protective function such as curtains or screens may therefore also be considered as air filters.
  • Air filters may be composed of paper, foam, cotton filters, or spun fibreglass filter elements. Alternatively, the air filter may use fibres or elements with a static electric charge. There are four main types of mechanical air filters: paper, foam, synthetics and cotton.
  • Polyester fibre can be used to make web formations used for air filtration. Polyester can be blended with cotton or other fibres to produce a wide range of performance characteristics. In some cases polypropylene may be used. Tiny synthetic fibres known as micro-fibres may be used in many types of high efficiency particulate air (HEPA) filters. High performance air filters may use oiled layers of cotton gauze.
  • HEPA high efficiency particulate air
  • the filter may be used to filter liquids.
  • Such filters may be composed of any suitable fibre as described above. Filters used to filter liquids may be used to filter potable liquids for human or animal consumption, water for general domestic use, fluids for medical use, such as plasma or saline solutions, or pharmaceutical formulations for injection, or other biological liquids which may come into contact with a patient.
  • Articles of protective clothing are suitable composed of fibres which are coated with a composition of particles as defined above.
  • the article of protective clothing may be a face mask. Such masks may cover the whole face of the user of a part thereof, suitably the external areas of the nose and/or mouth of the wearer.
  • the article of protective clothing may be prepared from any suitable fibre or fabric and may comprise natural and/or artificial fibres.
  • Suitable natural fibres include cotton, wool, cellulose (including paper materials), silk, hair, jute, hemp, sisal, flex, wood, bamboo, metal or carbon.
  • Suitable artificial fibres include polyester, rayon, nylon, Kevlar®, lyocell (Tencel®), polyethylene, polypropylene, polyimide, polymethyl methacrylate, poly(carboxylato phenoxy) phosphazene (PCPP), fibre glass (glass) or ceramics.
  • the article of clothing may be selected from the group consisting of face masks (surgical masks, respirator masks), hats, hoods, trousers, shirts, gloves, skirts, boiler suits and surgical gowns (scrubs). Such clothing may find particular use in a hospital where control of infection is of paramount importance.
  • the articles of clothing or filters may be made of mixed fibres from any source as described above.
  • the reduction and/or prevention of bacterial transmission may be defined as a reduction on bacterial titre of at least 90% following administration of a composition of nanoparticles as defined herein to a preparation of bacteria.
  • the reduction on titre is at least 93%, 94% or 95%, most preferably 98%, 99% or 100%. Reduction and/or prevention of transmission is demonstrated by the inactivation of the bacteria upon contact with the particles.
  • a reduction in titre of 70% or less is not an effective reduction sufficient to avoid infection.
  • the present invention provides a means for reducing titre such that infection is prevented or avoid to a significant extent.
  • the titre is a quantification of the number of bacteria in a given sample
  • a bioluminescent assay may be used to quantify the number of bacteria/titre.
  • the bacterial contamination of water may be determined by incubation of the water, filtration of the resulting bacterial suspension, release of bacterial ATP using a reagent such as dimethyl sulfoxide and detection of ATP concentration using luminescent techniques.
  • the titre may also be determined using a ⁇ -D-glucan assay. This assay is performed on incubated blood or plasma samples. A limulus amebocyte lysate is added to the sample and the change in optical density determined using spectro -photometric techniques. Other methods include disinfectant test methods such as that outlined in EN 1040 and performed upon dispersions of bacteria.
  • Figure 1 illustrates the particle size distribution of a tungsten trioxide feedstock (RQN 173) and a nanoparticulate tungsten trioxide for use in the compositions of the invention (PQN).
  • Figure 2 is a comparison of the activity (log 10 reduction) under low and high illumination against Staphylococcus aureus; at 1 hr contact time in suspension testing (EN1040);
  • Figure 3 is a comparison of the activity (log 10 reduction) under low and high illumination against Escherichia coli; at 1 hr contact time in suspension testing ( EN 1040);
  • Figure 4 is a comparison of the activity (log 10 reduction) under low and high illumination against Staphylococcus aureus; at 0.5 hr contact time in surface testing (ISO 22196);
  • Figure 5 is a comparison of the activity (log 10 reduction) under low and high illumination against Escherichia coli; at 0.5 hr contact time in surface testing (ISO 22196);
  • Figure 6 gives the XRD (X-Ray Diffraction) results for the micron- sized feedstock material (RQN 173, and for processed nanopowders PQN 952 and for PQN 956.
  • Raw material of micron sized tungsten trioxide was processed into nanosized tungsten trioxide in accordance with the methods used in granted patent EP 1904146.6 .
  • PQN 956 was prepared using at reducing atmosphere to get the composition of tungsten trioxide with elemental tungsten as shown in the X-ray diffraction pattern of Figure 6.
  • Nanoparticles of above mentioned composition were dispersed by adding a known amount of dispersant, in this case Tween-80 (CAS no. 9005-65-6) and water. This mixture was stirred using a high shear mixture (Silverson model L5T) for about 60 minutes and then the particles sizes were measured using Mastersizer 2000 from Malvern Instruments. Dispersion formulations of bacteria were prepared and tested according to EN 1040 against the microorganisms listed in Table 1. The products were tested undiluted (90% in test) and the solutions were equilibrated 20 ⁇ I 0 C for 1 hour prior to use.
  • the solutions were held as primary stock cultures at 4 0 C prior to use.
  • a secondary sub-culture of each species was prepared on Trypticase Soya Agar and incubated at 37 0 C.
  • cell suspensions of each of the test species were prepared in a tryptone based diluent as described in EN1040 to achieve a cell density of 1.5 - 5.0 x 108 cells ml-1. All cell densities were measured using a counting chamber (Thoma 1/400 mm2 x 0.02 mm depth) under 400 X magnification and phase contrast illumination. Where too low a cell count was achieved, further cells were added and the suspension was recounted. Where too high a cell count was achieved, the cells suspension was diluted in tryptone based diluent as appropriate to achieve the cell densities specified above.
  • E. coli here is virtually unaffected by light level, and is thus clearly not photochemical. It origin may be chemical or physical, but is clearly not proportionate to or directly dependent upon incident light. It is also notable how quickly the bactericide takes effect.
  • Example 3 Use of the Compositions as Coatings
  • the samples were prepared by taking a known amount of the above-mentioned dispersion and drawing this onto a surface using k-bar (s) in order to vary the thickness of coating. Solvent used to prepare the dispersion was evaporated immediately after the coating. Substrates used for this study are representation of flexible substrate (polypropylene), printing paper, stainless steel and filter elements. Binders may be used in order to improve the adhesion properties of the dispersion onto the given substrates.
  • Antibacterial activity was determined using a method based on that described in ISO 22196 but using a contact interval of 0.5 hour. Samples were tested either in subdued lighting (Dark) or under illumination (Light) for the duration of the contact period. For the subdued lighting, all additions and the actual exposure was performed under subdued amber lighting (400 Lux) in a photographic darkroom to minimise any potential photo-catalytic activity. For the illuminated study, all additions and the actual exposure was performed under constant illumination (2370 Lux) under a light-bank to stimulate any photo-catalytic activity.
  • Table 5 shows the Escherichia coli efficacy against the paper coated with control dispersion and other two material (RQN 173) and PQN 952.
  • PQN 952 showed the log reduction of 1.83 (in dark) and 3.27 (in light) respectively.
  • the control dispersion showed no efficacy; also the micron-sized raw material RQN 173 showed no efficacy in dark conditions, and barely any effect in light conditions.
  • the highly anti-bacterial nano form contains significant triclinic crystalline fraction (PQN 952 and PQN 956), in stark contrast with the ineffective, micron form feedstock which shows no presence of triclinic, being substantially monoclinic in form (RQN 173).
  • RQN 173 feedstock has sharp peaks showing a highly crystalline structure in which any triclinic peaks would be clearly visible.
  • the nanoform PQN's show as more broad curve, with triclinic peaks at around 42 two theta/degrees. a tungsten peak is visible in the PQN 956 graph at around 40 two theta/degrees.
  • compositions, methods and uses of the invention are capable of being incorporated into a variety of embodiments, only a few of which have been described above.

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Abstract

The invention relates to an antibacterial composition comprising nanoparticles, the nanoparticles comprising a compound of formula MnOy where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4. An article and a surface coated or impregnated with the antibacterial composition is also provided. The preparation of the composition, together with the use of the composition as a bactericide, and a method for the reduction and/or prevention of bacterial transmission using the composition are also provided.

Description

Antibacterial Composition
Field
The invention relates to antibacterial compositions, to processes for the preparation of these compositions and to uses thereof. In particular, the invention relates to a nanoparticulate bactericidal composition comprising a metal oxide.
Background
There is increasing concern about the presence of micro-organisms in the environment which could be damaging to human health. Of particular concern is the transmission of virulent pathogenic micro-organisms including bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile (C. difficile), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli).
Accordingly, there is an ongoing desire for new methods of preventing the growth of such micro-organisms and their transmission through the provision of new biocidal and/or biostatic products. Such products would beneficially have utility in reducing the transmission of pathogenic micro-organisms through direct contact; or indirect contact as a result of interaction with surfaces in our surroundings, organisms in found in water, airborne organisms or organisms carried in vectors such as mosquitoes or meat.
It is known that some metals have bactericidal properties. For instance silver and copper ions are used in water treatment where they cause lysis of gram-negative bacteria such as Legionella, through disruption of the cell walls. These metals are often used in fine particulate form to maximise the surface area of the metal exposed to the environment. This minimises the amount of metal which must be used to achieve the desired bactericidal effect.
However, there are problems associated with these products, for instance, it is necessary to balance the amount of metal used with the rate of consumption. The more metal is present, the higher the cost of the product, yet the less metal present the greater the rate of consumption or passivation by reaction with other chemicals. The problem of passivation is intrinsic to the use of such metals as they are often naturally reactive and prone to forming salts. These side reactions inhibit the bactericidal effect of the metals. In addition, it is difficult to thermally process silver and copper containing materials without degradation or reaction and as such their utility in articles which require high temperature processing is limited.
Further, silver, copper and gold are known to migrate from their site of intended activity, leaching into their surrounds. This is undesirable as not only is the bactericidal benefit of the metal lost, but neighbouring materials become contaminated. It is further known that silver can be toxic in solution. As a result, these elements are prohibited from use as bactericides in some jurisdictions.
It is important to destroy hazardous bacteria quickly as well as effectively. This is to prevent their spread while most readily capable of transfer person to person through contact with a surface or material. It is also to kill them while in the liquid suspension state and before they have changed into the spore state in which they are much harder to destroy. This is particularly important for such species as C. difficile, whose spread in hospitals has been a major cause for concern. Accordingly, the provision of an antibacterial composition which acts rapidly on contact with the bacteria would be of use.
It would be advantageous to overcome or ameliorate some or all of the above problems.
Nanoparticles have found use in pharmaceutical formulations to improve the solubility and/or biological activity of drug substances. Nanoparticles have also been used for medical purposes. For example, silver nanoparticles have been used to kill bacteria (Furno et al J. Antimicrob Chemother, 54(6), 1019-24 (2004)).
As a result, research has begun on the use of nanoparticulate compositions as biocides. WO 2007/093808 (Ren et al.) describes compositions including nanoparticles of formula MnXy (in particular tungsten carbides), having antiviral activity. WO 2007/023558 (Seto et al.) describes compositions which can have a deodorising effect when exposed to light. The compositions described in Seto et al comprise nanoparticulate tungsten oxides supported on an inorganic material. However, the repertoire of antibacterial compositions available to defend against infection remains limited, and it would be advantageous to provide a composition which is effective in the prevention and/or transmission of a wide range of different bacteria, and a composition that is effective without depending on high illumination.
Summary
There is provided in a first aspect of the invention an antibacterial composition comprising nanoparticles, the nanoparticles comprising a compound of formula MnOy where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
The above composition provides a biocide which is active against a range of different bacteria, including gram positive and gram negative bacteria and which can be used in a wide range of conditions. For instance, the bactericidal compositions of the invention have activity across a wide range of temperatures, humidities, and may be used in both the dark and the light. Further, the antibacterial effect of the compositions is observed on contact with a wide range of materials including wood, metal, plastics materials, fabrics (both natural, such as cotton or wool, and synthetic, such as nylon or viscose), masonry and glass. Further, the active ingredients are inexpensive, providing an economical solution to the problem of reducing and/or preventing the transmission of bacteria.
The inventive compositions comprise nanoparticles. By nanoparticle is meant a particle having nanometric dimensions, and nanoparticles may have, for example, dimensions in the order of a few nanometres to a few micrometres. The nanoparticles may be of average particle size equal to or less than 2 μm, equal to or less than 200 nm, in many instances equal to or less than 20 nm. In many cases the composition will consist of nanoparticles with substantially all of the particles falling within the size range less than 2 μm, or the size range less than 200 nm, or the size range less than 20 nm. A common size range would be in the range about 1 nm to about 100 nm, often this will be in the range about 10 nm to about 40 nm, preferably about 20 to about 30 nm.
For the purposes of this application the term "substantially all" is intended to mean 90% or above, typically 95% or above, most often 98% or above of the particles or other feature being described. The average particle size relates to the diameter at the widest point of the particle.
The specific surface area of the particles described may be in the range of from 150 m2/g to about 1000 m2/g, often, from 200 m2/g to about 500 m2/g.
The applicants have realised that when the compounds of formula MnOy are present in nanoparticulate form, that they exhibit antibacterial activity. Such activity is not observed with larger particles. Accordingly, it is an important aspect of the invention that the compounds of formula MnOy are present in nanoparticulate form.
The nanoparticles are generally in the form of dry powders, but may also be in the form of liquids, sol-gels or polymers, as well as nanotubes. The particles may be agglomerated or in free association.
In some embodiments the compound of formula MnOy will be non- stoichiometric, the non- stoichiometry will typically be introduced by the presence of dopants. However, in many instances it will be preferred that the compound of formula MnOy be stoichiometric, in these cases n is equal to 1, 2 or 3 and y is equal to 1, 2, 3 or 4. In stoichiometric compounds, the values of n and y may vary depending upon the relative valencies of M and Y.
In many examples M will be selected to provide a compound of formula MnO5, which is physically robust and stable to high temperature. Often M will be a transition metal, although group I and II metal oxides may also be used. Typically, M is selected from aluminium, zinc, calcium, nickel, iron, cobalt, tungsten, copper, and combinations thereof. The oxides of these metals have been found to offer good antibacterial activity, at a reasonable cost. It will often be the case that M comprises tungsten as tungsten compounds are stable to high temperature and have been found by the inventors to have a substantial bactericidal effect even when exposed to harsh conditions during processing.
Often the compound of formula MnO5, is selected from aluminium oxide (Al2O3), zinc oxide (ZnO), calcium oxide (CaO), tungsten oxide(s) (WO, WO2, WO3), nickel oxide (NiO), iron oxide(s) (FeO, Fe2O3, Fe3O4), cobalt oxide(s) (CoO, Co3O4), copper oxide(s) (Cu2O, CuO), and combinations thereof. In some embodiments the compound of formula MnO5, is a tungsten oxide selected from tungsten oxide (WO), tungsten dioxide (WO2) tungsten trioxide (WO3), and combinations thereof. In most instances the compound of formula MnOy will be tungsten trioxide.
It has been found that where the compound of formula MnOy is a tungsten oxide, the nano form is not only highly anti-bacterial, but contains a significant triclinic crystalline fraction. In contrast, the micron form of the tungsten oxide is substantially monoclinic and includes no triclinic crystals. Without being bound by theory, it is possible that this difference in crystalline structure leads to the difference in antibacterial activity. It is also possible that increasing the percentage of triclinic crystals in the composition, may also increase the activity thereof.
In some examples the composition may comprise nanoparticles of more than one compound of formula MnOy. Such compositions may comprise a mixture of nanoparticles where each nanoparticle comprises one compound of formula MnOy only, or nanoparticles where each nanoparticle comprises more than of compound of formula MnOy. In addition, the compositions may comprise nanoparticles comprising the compound of formula MnO5, and particles (micro or nanoparticles) of an antimicrobial, antifungal and/or antiviral agent. Additionally, the composition may comprise tungsten carbide (WC) particles, for instance as described in WO 2009/022100.
Mixed particle compositions may be produced by any suitable method, such as, for example, tumble-mixing, co-deposition or mechanical alloying, or by co-production. The WnO5, particles may be also prepared as layered (core/shell) particles, comprising a core of one compound of formula WnO5, and one or more shells of one or more other compounds of formula WnOy, or vice versa.
It is intended that the compositions of the invention generally do not include nanoparticles of pure metals. In many cases, carbonates, silicates, carbides and/or phosphates are absent as the oxides of formula MnO5, are preferred.
According to a second aspect of the invention there is provided an article coated or impregnated with an antibacterial composition as described in the first aspect of the invention. The article may comprise a wide range of materials and in many embodiments will comprise more than one material. The materials may be natural or synthetic, hard or soft, permeable or impermeable. The materials from which the article can be formed include wood, metal, plastics materials, fabrics and other materials comprising fibres. Where the article comprises fibres, the fibres may be coated with the antibacterial composition. Often the article will be an article used in a medical environment, so that the transmission of bacteria via that article will be prevented or reduced. For instance, the article may be selected from face masks, surgical masks, respirator masks, hats, hoods, trousers, shirts, gloves, skirts, boiler-suits, surgical gowns, and filters.
Also considered in this application is surface coated or impregnated with an antibacterial composition according to the first aspect of the invention, and this surface provides a third aspect of the invention. The surface may be permeable or impermeable, where the surface is permeable it will typically be the case that the surface is impregnated with the antibacterial composition, when the surface is impermeable, it will typically be the case that the antibacterial composition will be applied as a coating. As used herein the term "coated" is intended to include surfaces where the substrate from which the surface is made has the antibacterial composition incorporated therein. For instance, where the surface is of a polymeric material, the polymer beads from which the surface is formed may be coated with the antibacterial composition before the surface is formed. In such surfaces the antibacterial composition will be integral to the polymeric material, by virtue of the starting material (such as beads) being coated before manufacture.
In a fourth aspect of the invention there is provided the use as a bactericide of nanoparticles comprising a compound of formula MnOy where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
As described above, the use may be for the prevention and/or transmission of gram positive bacteria, gram negative bacteria or a combination thereof. It will generally be the case that the prevention and/or transmission is of both gram positive and gram negative bacteria. It is intended that the use be for the prevention and/or transmission of bacteria including bacteria selected from Escherichia coli, Staphylococcus aureus, Clostridium difficile, Pseudomonas aeruginosa, and combinations thereof. Further, it is an important advantage of the invention that the antibacterial composition described be usable regardless of the lighting conditions. In particular, the composition of the invention maybe used in the substantial absence of light (the dark), or in low lighting conditions as may be found in cupboards, under tables/working areas and behind sink and toilet units. In addition, the efficacy of the antibacterial composition of the invention is independent of the lighting conditions.
A fifth aspect of the invention provides for the use of a composition, article or surface according to any of the first three aspects of the invention for reducing and/or preventing bacterial transmission. A sixth aspect of the invention offers a method for the reduction and/or prevention of bacterial transmission, comprising applying to an article or a surface, a composition of nanoparticles of a compound of formula MnOy where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
The nanoparticulate compositions of the invention can be prepared by, for instance, gas phase synthesis or sol-gel processing. Gas phase synthesis will generally be used. In gas phase synthesis, particles, often nanoparticles, may be generated by evaporation and condensation (nucleation and growth) in a subatmospheric inert-gas environment. Various aerosol processing techniques may be used to improve the production yield of nanoparticles. These include synthesis by combustion flame, plasma, laser ablation, chemical vapour condensation, spray pyrolysis, electrospray and plasma spray.
Ball and other forms of milling can also be used to produce particles, including nanoparticles. In milling techniques the ultimate particle size depends upon factors including the size, morphology and composition of the grinding medium, process variables, design, and operation of the mill.
Where it is desirable to minimise the size variation between particles produced, gas phase synthesis is a reliable way of achieving this. The uniformity of particle size is typically achieved by using a combination of rigorous control of nucleation-condensation growth and avoidance of coagulation by diffusion and turbulence as well as by the effective collection of particles and their handling afterwards. The stability of the collected particle powders against agglomeration, sintering, and compositional changes can be ensured by collecting the particles in liquid suspension. One production method that is suitable for the production of nanoparticles is the Tesima® process (described in WO 01/78471 and WO 01/58625) where a high temperature DC plasma (a plasma torch) is used to a generate plasma stream within a gas envelope. The gas envelope may be inert, comprising argon or helium for instance; or may contain a reactive gas, for instance hydrogen. Hydrogen may be present in the range 0 to 20 wt%, 1 to 10 wt%, or 2 to 5 wt%. Materials (either pre-produced feedstock or mixed feedstock), or liquids, can be placed into the plasma causing rapid vaporisation. The resultant vapour then exits the plasma where it may be cooled by quantities of cold gas. These gases can be inert (such as argon or helium), air, or can include trace components to develop the chemistry/morphology/size that is required. The rapid cooling (greater than 100,000 degree per second) then freezes the particle for subsequent cooling and collection using a combination of techniques that can include solid or fabric filters, cyclones and liquid systems. The materials can also be collected directly into containers under either inert gas or into various liquids.
In a seventh aspect of the invention there is provided a process for the preparation of a nanoparticulate antibacterial composition, the process comprising inserting a compound of formula MnOy into a plasma stream and cooling a resultant vapour upon exit from the plasma stream, wherein M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4. In this process the plasma may be in a gaseous envelope and the vapour may be cooled by gas. Further, more than one compound of formula MnOy is co-fed into the plasma stream in the process, thereby producing nanoparticles which are composites of more than one compound of formula MnOy.
Typically, the raw materials from which the particles are created will be in fine particulate form. This may require a pre-treatment step, such as a grinding step, to prepare the raw materials for reaction. In many instances particles of the raw materials will be of size less than 10 μm diameter, often in the range 1 μm - 5 μm, or the range 2 μm - 4 μm. Utilising the raw materials in fine particulate form increases the surface area available for reaction and hence reaction rate. However, it has been found that using particles of size less than 1 μm or 2 μm can impair processing as the new materials begin to bind or clump together. This reduces the flow rate of material through the processing equipment and increases the risk that pipe work will become clogged causing production to cease whilst the processing equipment is cleaned.
An important aspect of the invention is the realisation by the applicant that the processing of raw materials of formula MnOy from fine or microparticulate dimensions to nanoparticulate dimensions confers on the resulting nanoparticles antibacterial properties. These are not observed when the same compounds are present in fine or microparticulate form. Without being bound by theory, this may be because the nanoparticles cause a change in the pH local to the surface of the bacteria, disrupting and causing lysis of the bacterial cell walls.
The use of a thermal plasma torch facilitates the production of particles of substantially uniform size with a high surface area which is stable to high temperature. This allows the resulting bactericidal composition to be used in applications where the processing is at high temperature, for instance, it provides a possible application in the incorporation of the bactericidal composition into plastics products creating a product with surfaces which are intrinsically hostile to bacteria.
The composition may be formulated for use in an appropriate carrier, coating or solvent such as water, methanol, ethanol, acetone, water soluble polymer adhesives, such as polyvinyl acetate, epoxy resin, polyesters etc. as well as coupling agents and antistatic agents. Solutions of biological materials may also be used such as phosphate buffered saline (PBS) or simulated biological fluid (SBF).
It is also desirable that the nanoparticles of formula MnOy are present in "free" particulate form, by which it is meant that the nanoparticles are present in the composition in unbound form. There is no requirement for the compositions of the invention include support structures, or that the nanoparticles be supported within a matrix or other framework before they will be effective. It is preferred that the nanoparticles be "free" within the composition so that their entire surface area is available to interact with the bacteria, thereby maximising the antibacterial effect of the compositions of the invention. As used herein, the term "free" is intended to mean substantially unbound or free to act chemically as though they were not bound; it is often important to ensure that the nanoparticles are not detachable as they may become an unwanted airborne or waterborne contaminant, where they would be a perceived or possibly an actual hazard to health or equipment. The concentration of particles may lie in the range of 0.001 - 20 wt%, often 0.01 - 10 wt%, on occasion 0.1 - 5 wt%.
Alternatively, the particles may be included in a composition in powder form. They may be coated onto or impregnated into a surface or article, or mixed with an absorbent powder such as Fuller's earth or sand.
The reduction and/or prevention of the spread of pathogenic micro-organisms includes the prevention of infection of a subject with the bacterium; in addition to the prevention of transmission from a first location to a second location, or the prevention of transmission through a barrier material. The subject may be a human or a non-human animal, suitably a non-human mammal. The invention may therefore find application in the field of human medicine and animal veterinary medicine as well as in the field of infection control in a non- medical context, such as a prophylactic against the transmission and/or spread of bacteria.
The compositions described can be applied to enclosed ventilation fabrics for public buildings, hospitals, and to vehicles such as cars, trains, ships and aeroplanes. The compositions may also find use in medical applications, such as in filtering materials, i.e. in filtration of biological fluids such as plasma, blood, milk or semen to inactivate any bacteria present.
The antibacterial particles may be coated onto fabrics and surfaces of different products such as furniture, paints/coatings, book covers and computer keyboards to produce products with antibacterial properties. Such products will provide a low cost route to a safer environment for hospitals, children, patients and the elderly. Further uses may include air ventilation systems for enclosed environments such as passenger aeroplanes, for instance preventing the entry or outlet of airborne bacteria.
An article of the invention may be coated or impregnated with the antibacterial composition described above. The composition will work most effectively where at least one coated or impregnated surface of the article comes into direct contact with the bacteria to be removed. For example, protective clothing may comprise fabrics and/or fibres coated with the antibacterial composition and the exposed surfaces of filters may be coated with the composition. Similarly, a counter top could be impregnated with or coated in the antibacterial composition to produce a surface which is intrinsically hostile to microorganisms. Such a surface could be used in hospitals to help improve the safety of surgical procedures or domestically to reduce the transmission of disease through the presence of pathogenic micro-organisms around the home.
The coating and impregnation processes which may be used are those common in the art and would be well known to the person skilled in the art. They include spray coating, extrusion- lamination, co-extrusion, electro-spray coating, dipping or plasma coating.
In addition to coating or impregnating the article itself, the components of the article may be pre-treated with the composition. For instance, an article may be composed of fibres coated with the bactericidal composition. Such articles will often be selected from filters, face masks, surgical masks, respirator masks, hats, hoods, trousers, shirts, gloves, boiler-suits and surgical gowns. Medical and veterinary devices and prophylactic devices may also be used. Alternatively, surfaces that are routinely contacted by people, especially in communal areas such as toilets, doors, switches etc. may be coated and/or impregnated with the composition. Similarly, areas of food preparation and utensils or equipment used therein may be coated with a composition according to the invention.
Filters may be prepared from any suitable natural or artificial material. The filter may be an air filter. An air filter is a device which removes contaminants, often solid particles from air. Air filters are often used in diving air compressors, ventilation systems and any other situation in which air quality is important, such as in air-conditioning units. An air filter includes devices which filter air in an enclosed space such as a building or a room, as well as apparatus or chambers for handling viral materials. Other articles which perform a protective function such as curtains or screens may therefore also be considered as air filters.
Air filters may be composed of paper, foam, cotton filters, or spun fibreglass filter elements. Alternatively, the air filter may use fibres or elements with a static electric charge. There are four main types of mechanical air filters: paper, foam, synthetics and cotton.
An example of pleated-paper air filters designed for in-duct use with home heating, ventilation and air-conditioning (HVAC) systems is the 3M "Filtrete" product. Polyester fibre can be used to make web formations used for air filtration. Polyester can be blended with cotton or other fibres to produce a wide range of performance characteristics. In some cases polypropylene may be used. Tiny synthetic fibres known as micro-fibres may be used in many types of high efficiency particulate air (HEPA) filters. High performance air filters may use oiled layers of cotton gauze.
Alternatively, the filter may be used to filter liquids. Such filters may be composed of any suitable fibre as described above. Filters used to filter liquids may be used to filter potable liquids for human or animal consumption, water for general domestic use, fluids for medical use, such as plasma or saline solutions, or pharmaceutical formulations for injection, or other biological liquids which may come into contact with a patient.
Articles of protective clothing are suitable composed of fibres which are coated with a composition of particles as defined above. The article of protective clothing may be a face mask. Such masks may cover the whole face of the user of a part thereof, suitably the external areas of the nose and/or mouth of the wearer.
The article of protective clothing may be prepared from any suitable fibre or fabric and may comprise natural and/or artificial fibres. Suitable natural fibres include cotton, wool, cellulose (including paper materials), silk, hair, jute, hemp, sisal, flex, wood, bamboo, metal or carbon. Suitable artificial fibres include polyester, rayon, nylon, Kevlar®, lyocell (Tencel®), polyethylene, polypropylene, polyimide, polymethyl methacrylate, poly(carboxylato phenoxy) phosphazene (PCPP), fibre glass (glass) or ceramics. The article of clothing may be selected from the group consisting of face masks (surgical masks, respirator masks), hats, hoods, trousers, shirts, gloves, skirts, boiler suits and surgical gowns (scrubs). Such clothing may find particular use in a hospital where control of infection is of paramount importance.
In aspects of the invention relating to articles of protective clothing or filters, it should be noted that the articles of clothing or filters may be made of mixed fibres from any source as described above. The reduction and/or prevention of bacterial transmission may be defined as a reduction on bacterial titre of at least 90% following administration of a composition of nanoparticles as defined herein to a preparation of bacteria. Preferably the reduction on titre is at least 93%, 94% or 95%, most preferably 98%, 99% or 100%. Reduction and/or prevention of transmission is demonstrated by the inactivation of the bacteria upon contact with the particles.
A reduction in titre of 70% or less is not an effective reduction sufficient to avoid infection. The present invention provides a means for reducing titre such that infection is prevented or avoid to a significant extent.
The titre is a quantification of the number of bacteria in a given sample, a bioluminescent assay may be used to quantify the number of bacteria/titre. For instance, the bacterial contamination of water may be determined by incubation of the water, filtration of the resulting bacterial suspension, release of bacterial ATP using a reagent such as dimethyl sulfoxide and detection of ATP concentration using luminescent techniques.
The titre may also be determined using a β-D-glucan assay. This assay is performed on incubated blood or plasma samples. A limulus amebocyte lysate is added to the sample and the change in optical density determined using spectro -photometric techniques. Other methods include disinfectant test methods such as that outlined in EN 1040 and performed upon dispersions of bacteria.
Unless otherwise stated each of the integers described in the invention may be used in combination with any other integer as would be understood by the person skilled in the art. Further, although all aspects of the invention preferably "comprise" the features described in relation to that aspect, it is specifically envisaged that they may "consist" or "consist essentially" of those features outlined in the claims.
Unless otherwise indicated all percentages appearing in the specification are percentages by weight of the element being described. In addition, unless otherwise stated, all numerical values appearing in this application are to be understood as being modified by the term "about". Examples
In order that the invention may be more readily understood, it will be described by way of example only, by reference to the accompanying figures, of which:
Figure 1 illustrates the particle size distribution of a tungsten trioxide feedstock (RQN 173) and a nanoparticulate tungsten trioxide for use in the compositions of the invention (PQN
952);
Figure 2 is a comparison of the activity (log 10 reduction) under low and high illumination against Staphylococcus aureus; at 1 hr contact time in suspension testing (EN1040);
Figure 3 is a comparison of the activity (log 10 reduction) under low and high illumination against Escherichia coli; at 1 hr contact time in suspension testing ( EN 1040); Figure 4 is a comparison of the activity (log 10 reduction) under low and high illumination against Staphylococcus aureus; at 0.5 hr contact time in surface testing (ISO 22196); Figure 5 is a comparison of the activity (log 10 reduction) under low and high illumination against Escherichia coli; at 0.5 hr contact time in surface testing (ISO 22196); and Figure 6 gives the XRD (X-Ray Diffraction) results for the micron- sized feedstock material (RQN 173, and for processed nanopowders PQN 952 and for PQN 956.
Example 1 : Preparation of a Compound of Formula MnOy
Raw material of micron sized tungsten trioxide was processed into nanosized tungsten trioxide in accordance with the methods used in granted patent EP 1904146.6 . PQN 956 was prepared using at reducing atmosphere to get the composition of tungsten trioxide with elemental tungsten as shown in the X-ray diffraction pattern of Figure 6.
Example 2: Antibacterial Activity of the Compositions of the Invention
Nanoparticles of above mentioned composition were dispersed by adding a known amount of dispersant, in this case Tween-80 (CAS no. 9005-65-6) and water. This mixture was stirred using a high shear mixture (Silverson model L5T) for about 60 minutes and then the particles sizes were measured using Mastersizer 2000 from Malvern Instruments. Dispersion formulations of bacteria were prepared and tested according to EN 1040 against the microorganisms listed in Table 1. The products were tested undiluted (90% in test) and the solutions were equilibrated 20 ± I0C for 1 hour prior to use.
Table 1
Figure imgf000016_0001
The solutions were held as primary stock cultures at 40C prior to use. One day prior to testing, a secondary sub-culture of each species was prepared on Trypticase Soya Agar and incubated at 370C. Immediately prior to use, cell suspensions of each of the test species were prepared in a tryptone based diluent as described in EN1040 to achieve a cell density of 1.5 - 5.0 x 108 cells ml-1. All cell densities were measured using a counting chamber (Thoma 1/400 mm2 x 0.02 mm depth) under 400 X magnification and phase contrast illumination. Where too low a cell count was achieved, further cells were added and the suspension was recounted. Where too high a cell count was achieved, the cells suspension was diluted in tryptone based diluent as appropriate to achieve the cell densities specified above.
All additions and the actual exposure was performed under constant illumination (2370 Lux) under a light-bank to stimulate any photo-catalytic activity. Two replicate aliquots (9 ml) of either dispersion formulations or sterile standard hard water were transferred to individual sterile containers (30 ml). Each aliquot was then inoculated with a sub-sample (1 ml) of the cell suspensions described above and then again thoroughly mixed. The inoculated aliquots were held at 2O0C in clear-sided tubes (30 ml) under constant agitation (roller-bed) for 60 minutes. After this contact interval an aliquot (1 ml) of each was transferred to individual subsamples (9 ml) of a neutraliser solution validated to be effective against the formulations under test and then thoroughly mixed. After a neutralising interval of 5 minutes the number of colony forming units present in both the neutralised mixture and a 1 : 99 dilution (in neutraliser) of them was determined by spiral dilution and pour plates as appropriate using Trypcase Soy Agar. The plates were incubated at 370C for 24 hours and then colony counts were performed. The geometric mean of the resulting counts was calculated. The average results are shown in Tables 2 - 3 and in Figure 3. A comparison of the effect under high and low levels of illumination are shown in Figures 1 and 2.
Figure imgf000017_0001
Table 3: Efficacy in loglO reduction (E. coli)
Figure imgf000017_0002
It can be seen from the results above that the populations of both E. coli and Staph aureus exposed to the water only control remained constant in size during the 1 hour contact interval.
In a study performed under a low level of light, the populations of Staph aureus exposed to RQN 173 remained relatively constant in size and the populations of E. coli was only reduced by around 0.5 orders of magnitude. In contrast, under a high level of illumination larger reductions in the size of the population of both Staph aureus and E. coli were observed (1.7 and 1.6 orders of magnitude). A reduction in the size of the populations of Staph aureus of 2.3 orders of magnitude was seen in the populations held in contact with PQN 952 and PQN 956. As table 2 shows, the reductions in Staph aureus in high light conditions due to exposure to PQN 952 and 956 were increased to 5.7 and 4.6 orders of magnitude respectively. However, in 'dark' (low amber light) conditions the equivalent results were still 2.4 and 2.3 respectively after 60 minutes.
For E. coli, it is particularly of note that a slightly larger reduction of 5.6 orders of magnitude was observed in the populations exposed to PQN952 in high light conditions, which reduced only a little to 5 in 'dark' conditions. Equally there was a large and remarkably similar sized reduction in the E. coli populations exposed to PQN 956 under higher light levels as under subdued lighting (4.88 vs. 4.85 respectively). This would indicate that the biocidal effect on
E. coli here is virtually unaffected by light level, and is thus clearly not photochemical. It origin may be chemical or physical, but is clearly not proportionate to or directly dependent upon incident light. It is also notable how quickly the bactericide takes effect.
Example 3: Use of the Compositions as Coatings
Some of the above materials were also prepared as coatings for surface testing against bacteria. The results of these are shown in figures 5 and 6. These figures clearly show a reduction in bacterial levels after just 30 minutes. In this case the "low tungsten metal" example, (PQN 952) which is chiefly tungsten oxides, clearly performs very well in both light and 'dark' conditions; the larger feedstock material and the control provided little to no bactericidal effect in either light or 'dark' conditions.
The samples were prepared by taking a known amount of the above-mentioned dispersion and drawing this onto a surface using k-bar (s) in order to vary the thickness of coating. Solvent used to prepare the dispersion was evaporated immediately after the coating. Substrates used for this study are representation of flexible substrate (polypropylene), printing paper, stainless steel and filter elements. Binders may be used in order to improve the adhesion properties of the dispersion onto the given substrates.
Antibacterial activity was determined using a method based on that described in ISO 22196 but using a contact interval of 0.5 hour. Samples were tested either in subdued lighting (Dark) or under illumination (Light) for the duration of the contact period. For the subdued lighting, all additions and the actual exposure was performed under subdued amber lighting (400 Lux) in a photographic darkroom to minimise any potential photo-catalytic activity. For the illuminated study, all additions and the actual exposure was performed under constant illumination (2370 Lux) under a light-bank to stimulate any photo-catalytic activity.
An aliquot (200 μl) of a log phase cell suspension of either E. coli (4.8 x 105 cells ml-1; ATCC 8739) or Staphylococcus aureus (4.9 x 105 cells ml-1; ATCC 6538p) prepared using the method described in ISO 22196 were held in intimate contact with each of 3 replicates of the test surfaces supplied using a 30 x 30 mm polyethylene film (cut from a sterile Stomacher bag) for up to 24 hours at 350C. The size of the surviving population was determined using the method described in ISO 22196. The viable cells in the suspension were enumerated by spiral dilution on to Trypcase Soya Agar and by the pour plate method described in ISO 22196. These plates were then incubated at 350C for 24 hours and then counted. An additional 3 replicate unfortified surfaces were also inoculated in the manner described above but were then analysed immediately for the size of microbial population present to provide 0- time control data. The results are shown in Tables 4 and5.
Table 4 Efficacy in loglO reduction {Staph aureus)
Figure imgf000019_0001
Table 5 Efficacy in loglO reduction (E. coli)
Figure imgf000019_0002
It can be seen from the results above that the population of Staphylococcus aureus exposed to the paper coated with control dispersion did not show any efficacy. In contrast the active materials (PQN 952) showed the log reduction of 2.40 (in dark) and 3.99 (in light). These efficacy is far higher than the feedstock (RQN 173) which hardly show any activity against Staphylococcus aureus. (Table 4).
Table 5 shows the Escherichia coli efficacy against the paper coated with control dispersion and other two material (RQN 173) and PQN 952. As observed the case of Staphylococcus aureus, PQN 952 showed the log reduction of 1.83 (in dark) and 3.27 (in light) respectively. In contrast, it can be clearly seen that the control dispersion showed no efficacy; also the micron-sized raw material RQN 173 showed no efficacy in dark conditions, and barely any effect in light conditions.
In the case of tungsten trioxide, it is notable that from the XRD analysis (Figure 6) that the highly anti-bacterial nano form contains significant triclinic crystalline fraction (PQN 952 and PQN 956), in stark contrast with the ineffective, micron form feedstock which shows no presence of triclinic, being substantially monoclinic in form (RQN 173). This correlation may explain the difference in behaviour between the micron feedstock and the processed nanopowder. Specifically, the RQN 173 feedstock has sharp peaks showing a highly crystalline structure in which any triclinic peaks would be clearly visible. The nanoform PQN's show as more broad curve, with triclinic peaks at around 42 two theta/degrees. a tungsten peak is visible in the PQN 956 graph at around 40 two theta/degrees.
It should be appreciated that the compositions, methods and uses of the invention are capable of being incorporated into a variety of embodiments, only a few of which have been described above.

Claims

Claims
1. An antibacterial composition comprising nanoparticles, the nanoparticles comprising a compound of formula MnOy where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
2. A composition according to claim 1 wherein the nanoparticles have an average particle size in the range about 1 nm to about 100 nm.
3. A composition according to claim 2 wherein the nanoparticles have an average particle size in the range about 20 nm to about 40 nm.
4. A composition according to any preceding claim wherein the compound of formula MnOy is stoichiometric.
5. A composition according to any preceding claim wherein M is selected from aluminium, zinc, calcium, nickel, iron, cobalt, tungsten, copper, and combinations thereof.
6. A composition according to any preceding claim wherein the compound of formula MnOy is selected from aluminium oxide (Al2O3), zinc oxide (ZnO), calcium oxide (CaO), tungsten oxide(s) (WO, WO2, WO3), nickel oxide (NiO), iron oxide(s) (FeO, Fe2O3, Fe3O4), cobalt oxide(s) (CoO, Co3O4), copper oxide(s) (Cu2O, CuO), and combinations thereof.
7. A composition according to claim 6 wherein the compound of formula MnOy is a tungsten oxide selected from tungsten oxide (WO), tungsten dioxide (WO2) tungsten trioxide
(WO3), and combinations thereof.
8. A composition according to claim 7 wherein the tungsten oxide includes a triclinic crystalline fraction.
9. A composition according to claim 7 or claim 8 wherein the compound of formula MnOy is tungsten trioxide.
10. A composition according to any preceding claim comprising nanoparticles of more than one compound of formula MnOy.
11. A composition according to any preceding claim wherein the nanoparticles each comprise more than one compound of formula MnOy.
12. A composition according to any preceding claim additionally comprising particles of an antimicrobial, antifungal and/or antiviral agent.
13. A composition according to any preceding claim additionally comprising tungsten carbide (WC) particles.
14. An article coated or impregnated with an antibacterial composition according to any of claims 1 to 13.
15. An article according to claim 14 comprising fibres coated with the antibacterial composition.
16. An article according to claim 14 or claim 15 selected from face masks, surgical masks, respirator masks, hats, hoods, trousers, shirts, gloves, skirts, boiler-suits, surgical gowns, and filters.
17. A surface coated or impregnated with an antibacterial composition according to any of claims 1 to 13.
18. Use as a bactericide of nanoparticles comprising a compound of formula MnOy where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
19. Use according to claim 18 for the prevention and/or transmission of gram positive bacteria, gram negative bacteria or a combination thereof.
20. Use according to claim 19 wherein the prevention and/or transmission is of both gram positive and gram negative bacteria.
21. Use according to claim 20 for the prevention and/or transmission of bacteria selected from Escherichia coli, Staphylococcus aureus, Clostridium difficile, Pseudomonas aeruginosa, and combinations thereof.
22. Use according to any of claims 18 to 21 in dark or low light conditions.
23. Use of a composition, article or surface according to any of claims 1 to 17 for reducing and/or preventing bacterial transmission.
24. A method for the reduction and/or prevention of bacterial transmission, comprising applying to an article or a surface, a composition of nanoparticles of a compound of formula MnOy where M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
25. A process for the preparation of a nanoparticulate antibacterial composition, the process comprising inserting a compound of formula MnOy into a plasma stream and cooling a resultant vapour upon exit from the plasma stream, wherein M is a metal, n is in the range 1 - 3, and y is in the range 1 - 4.
26. A process according to claim 25 wherein the plasma is in a gaseous envelope and the vapour is cooled by gas.
27. A process according to claim 25 or claim 26 wherein more than one compound of formula MnOy is co-fed into the plasma stream
28. A composition, article, surface, use, method or process substantially as described herein with reference to the examples and drawings.
29. A method for the reduction and/or prevention of bacterial transmission substantially as described herein.
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