EP2968686A1 - Polymerbeschichtungen mit antimikrobiellen eigenschaften - Google Patents

Polymerbeschichtungen mit antimikrobiellen eigenschaften

Info

Publication number
EP2968686A1
EP2968686A1 EP14762881.2A EP14762881A EP2968686A1 EP 2968686 A1 EP2968686 A1 EP 2968686A1 EP 14762881 A EP14762881 A EP 14762881A EP 2968686 A1 EP2968686 A1 EP 2968686A1
Authority
EP
European Patent Office
Prior art keywords
silver
polymer
iodate
article
antimicrobial
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP14762881.2A
Other languages
English (en)
French (fr)
Inventor
Amin A. OMAR
Patricia L. Nadworny
Janelle A. ROMANCHUK
Graeme PROSPERI-PORTA
Kevin R. UNRAU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innovotech Inc
Original Assignee
Innovotech Inc
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
Application filed by Innovotech Inc filed Critical Innovotech Inc
Publication of EP2968686A1 publication Critical patent/EP2968686A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • This invention relates to silver iodate compounds and their use in preventing or reducing microbial contamination.
  • the compositions and methods are suitable for treating or preventing microbial contamination on any surface (i.e. surfaces used for production, handling, transport, storage, processing, or packaging).
  • This invention also relates to antimicrobial compositions and the use of these compositions with various devices, preferably devices such as medical devices, in which having an antimicrobial property is beneficial.
  • the invention also relates to articles produced or formed using the antimicrobial compositions of the present invention.
  • these compositions may be used in the making of or coating of articles, such as medical devices.
  • the invention also relates to coatings and/or ingredients in the manufacture of devices where having an antimicrobial property is beneficial, e.g., a medical device or an implant.
  • Silver is known for its antimicrobial use with medical devices, such as catheters, cannulae, and stents.
  • medical devices such as catheters, cannulae, and stents.
  • One conventional approach for obtaining antimicrobial medical devices is the deposition of metallic silver directly onto the surface of the substrate, for example, by vapor coating, sputter coating, or ion beam coating.
  • these noncontact deposition coating techniques suffer many drawbacks, including poor adhesion, lack of coating uniformity, and the need for special processing conditions, such as preparation in darkness due to the light sensitivity of some silver salts.
  • One particular drawback of these coatings is that the processes by which the coatings are formed do not adequately coat hidden or enclosed areas, such as the interior lumen of a catheter or stent.
  • these methods produce coatings that are very much like metallic silver in that they do not release silver from the coating and require contact with the coating to provide antimicrobial action.
  • high concentrations of silver may be deposited on the substrate, very little free ionic silver is released on exposure to aqueous fluid.
  • these coatings provide only limited antimicrobial activity. They essentially retard colonization of microbial agents on the surface of the device. However, because they do not release sufficient silver ions into aqueous fluids, they offer little or no protection from bacteria carried into the body upon application of the device and do not inhibit infection in the surrounding tissue.
  • Another conventional approach for obtaining antimicrobial medical devices is the incorporation of silver, silver salts, and other antimicrobial compounds into the polymeric substrate material from which the article is formed.
  • An oligodynamic metal may be physically incorporated into the polymeric substrate in a variety of ways. For example, a liquid solution of a silver salt may be dipped, sprayed, or brushed onto the solid polymer, for example, in pellet form, prior to formation of the polymeric article. Alternatively, a solid form of the silver salt can be mixed with a finely divided or liquefied polymeric resin, which is then molded into the article. Further, the oligodynamic compound can be mixed with monomers of the material prior to polymerization.
  • a second disadvantage is that it is difficult to produce articles that allow the release of the oligodynamic material because most device polymers absorb little, if any, water to aid in the diffusion and release of the oligodynamic material, resulting in articles that provide only a limited antimicrobial effect.
  • oligodynamic agents incorporation of oligodynamic agents into a polymeric coating which is then applied to the surface of the article.
  • an oligodynamic agent is incorporated into the coating solution in the form of a solution or a suspension of particles of the oligodynamic agent. Problems associated with this approach include poor adhesion of the coating to the substrate, settling and agglomeration of the oligodynamic particles, and inadequate antimicrobial activity over time.
  • compositions which can be incorporated into articles to provide antimicrobial activity there is a need for compositions which can be employed as coatings for articles that exhibit improved adhesion.
  • compositions that overcome the solubility, settling, and agglomeration problems of conventional oligodynamic compositions, and exhibit enhanced, sustained release of oligodynamic agents There is further a need for compositions that allow delivery of one or more active agents to locations.
  • compositions and methods of the present invention comprise one or more silver iodate compounds or compositions and their use in or with polymers as
  • the invention also includes articles of manufacture that include one or more of these compounds incorporated into an article or as a polymeric layer or polymeric coating on the article.
  • compositions and methods of the present invention have applicability in a wide variety of agricultural, industrial, and medical environments, e.g., disinfecting any surface, particularly disinfecting work or processing surfaces (e.g., tables); in antimicrobial coatings; in medical devices and implants, particularly where having an antimicrobial property or characteristic would be beneficial; and in treating human, plant, and animal diseases and conditions.
  • any surface particularly disinfecting work or processing surfaces (e.g., tables); in antimicrobial coatings; in medical devices and implants, particularly where having an antimicrobial property or characteristic would be beneficial; and in treating human, plant, and animal diseases and conditions.
  • the compositions and methods may be used to treat or prevent one or more biofilms.
  • the compositions and methods may be used to treat and/or prevent one or more human, animal, or plant diseases, conditions, infections, or contaminations. Typically these diseases and infections, etc., are caused by microbes associated with or residing in the biofilm. IV. Detailed Description of the Invention
  • the present invention involves silver iodate compounds and their use as antimicrobial agents.
  • Some embodiments of the invention include one or more silver iodate compound as an active agent, imparting an antimicrobial property or properties on or in a polymer.
  • the active agent includes a family of silver (I) periodate compounds. All of the members of the family are silver (I) combined with a higher oxidation state iodine and coordinated with oxygen atoms.
  • compounds include but are not limited to silver (I) iodate; pentasilver hexaoxoiodate; Ag 5 l0 6 ; silver orthoperiodate; silver periodate (VII); silver iodate (VII); 5 Ag 2 O I 2 0 7 ;
  • the cation may be selected from the group consisting of K, Na, Mg, Ca, Au, Pt, Cu, and Fe.
  • the most preferred cations are potassium and sodium.
  • the inventors believe that the iodine facilitates silver transfer, in a form such as [Ag 2 l0 6 ] 3" , through the biofilm structure or matrix.
  • the inventors also believe that the silver ions, which are present in both the cation ([Ag3] 3+ ) and the anion ([Ag 2 IOe] 3" ), and iodine ions provide multiple antimicrobial mechanisms of action, thus providing improved antimicrobial activity as compared to conventional compounds, and potentially helping reduce the risk of microorganisms developing resistance to the active agents.
  • the compounds of the present invention may be used by themselves, may be an ingredient in a composition, or may be a part, element, coating, or layer of an article of manufacture (e.g., a wound dressing, a medical grade metal, or a catheter).
  • the compounds of the present invention may be combined with and/or formulated into a composition.
  • one or more active agents may be incorporated into the structure of substrate or as a coating or the like.
  • Exemplary substrates include metals; wound dressings; medical devices and instruments, including polymeric medical devices and instruments; and plants, including seeds and leaves.
  • Some embodiments of the invention include forming an article including an active agent of the present invention, thereby forming an article having one or more
  • the silver (I) periodate family of compounds of the present invention may be produced or synthesized by following processes already known to those skilled in the art. Examples of these processes include:
  • the silver compositions of the present invention may be used with or incorporated into an article where antimicrobial properties are desirable and/or beneficial.
  • examples include, but are not limited to, medical and surgical devices and/or environments, such as implants. Other examples are provided below.
  • Some embodiments of the present invention also include pharmaceutically acceptable salts, or solvates and hydrates, and compositions and formulations of silver iodate compounds, silver iodate reaction products, and active agents produced from a starting material such as sodium diperiodatoargentate (III) or potassium
  • the present invention also includes methods of coating a metal substrate with an active agent of the present invention, said methods resulting in imparting an antimicrobial characteristic to the substrate.
  • the present invention also includes methods of coating a wound dressing substrate with an active agent of the present invention, said methods resulting in imparting an antimicrobial characteristic to the substrate.
  • wound dressing substrate includes, but is not limited to, a wide variety of wound dressing substrates, including polymer-based substrates such as high density polyethylene and polyester, and organic based substrates such as cotton and rayon.
  • the present invention also includes methods of coating a substrate with an active agent of the present invention, said methods resulting in imparting an antimicrobial characteristic to the substrate.
  • the substrate may be any substrate; preferred substrates include but are not limited to polymers used in the manufacture of catheters and/or one or more monomers used to make a polymer.
  • compositions and methods may also include one or more other active agents.
  • the small grain size combined with a larger particle size contribute to enhanced or improved antimicrobial activity.
  • Ag 5 l0 6 has a grain size of about 15A (fifteen angstroms), that is, nano sized, and a particle size that is much larger (typically between about 2 and 20 ⁇ , that is, not nano).
  • the grain size may increase with some forms of processing or post- synthesis processing, e.g., heating, exposure to solvents or solutions, grains growing together, grains combining into a single larger grain, and the like.
  • Some embodiments of the invention include a coating, layer, or the like on an article, said coating, etc., comprising one or more active agents of the present invention (including but not limited to silver (I) iodate compounds, and imparting improved antimicrobial characteristics to the article or a portion of the article.
  • active agents of the present invention including but not limited to silver (I) iodate compounds, and imparting improved antimicrobial characteristics to the article or a portion of the article.
  • Some embodiments of the invention include incorporating one or more active agents of the present invention, e.g., a silver (I) iodate compound into or on the medical device.
  • the silver composition may be any form that does not inactivate the silver, including but not limited to a gel, ointment, or cream.
  • the active agent or a composition containing the active agent may be any form that does not inactivate the silver, including but not limited to a layer, or ingredient in a metal, a polymer, or a carrier.
  • the compositions and methods are used for treating a microbial contaminant using an antimicrobial agent comprising silver ions or silver-containing complexes.
  • the compositions and methods may also include one or more other active agents.
  • the compositions and methods are antimicrobial, e.g. against biofilm, similar structures, or precursors formed by bacteria, fungi, viruses, algae, parasites, yeast, and other microbes.
  • a microbial contaminant or infection may be found in a variety of species, including but not limited to humans, pigs, ruminants, horses, dogs, cats, and poultry.
  • the active agent(s) may be incorporated into or onto packaging for an article, such as a medical device or a needle.
  • one or more active agents or one or more starting materials may be used for the manufacture of a medicament intended to treat or prevent infections or contamination, particularly infections caused by bacteria, bacteria- like organisms, or biofilms.
  • the silver compositions of the present invention may be used to coat, or may be incorporated into, any article, including those comprising a metal or metal alloy.
  • Typical metals and alloys include, but are not limited to titanium, titanium containing alloys, aluminum, stainless steel, mild steel, and copper.
  • the metal is titanium (grade 2), titanium (grade 5), aluminum, stainless steel, stainless steel needles, titanium (grade 5) pins, and other titanium (grade 5) implants.
  • composition optionally contains additional
  • compositions optionally comprise additional noble metals or salts of one or more noble metals to promote galvanic action.
  • composition optionally comprises additional platinum group metals or salts of platinum group metals such as platinum, palladium, rhodium, iridium, ruthenium, osmium, and the like.
  • compositions optionally contain other components that provide beneficial properties to the composition, that improve the antimicrobial
  • compositions are also used to inhibit algal, fungal, mollusk, or microbial growth on surfaces.
  • compositions of the invention are also used as herbicides, insecticides, antifogging agents, diagnostic agents, screening agents, and antifoulants.
  • the composition may be applied as a coating to a preformed article, part of an article, a plant or portion thereof (e.g., a seed or a leaf), or a substrate.
  • the coating may be produced, for example, by dipping the article, etc., into the composition or by spraying the article with the composition and then drying the coated article.
  • the present invention relates to an article of manufacture which comprises the antimicrobial compositions of the present invention.
  • the composition is used to form an article or a portion of the article, for example by molding, casting, compounding, extruding, etc.
  • at least part of the formed article is composed of one or more of the compositions of the present invention, alone or in admixture with other components.
  • the composition is applied to a preformed article or part of an article as a coating.
  • the coated article may be produced, for example, by dipping the article into the composition or by spraying the article with the composition and then drying the coated article. This may be done in the presence of a solvent or a combination of solvents that promotes
  • a silver (I) iodate powder e.g., Ag 5 IOe
  • a polymer or monomer constituent
  • the polymer is allowed to swell, thereby allowing the silver (I) iodate to coat or be incorporated into or onto the polymer.
  • Some embodiments of the present invention include providing compositions that provide antimicrobial, antibacterial, antiviral, antifungal, or antibiotic activity, or any combination thereof. [0041] Some embodiments of the present invention include providing compositions that reduce encrustation, inhibit coagulation, improve healing, inhibit restenosis, or impart antiviral, antifungal, antithrombogenic, or other properties to coated substrates.
  • Some embodiments of the present invention include providing compositions that inhibit the growth of algae, mollusks, bacteria, bioslime, or some combination thereof on surfaces.
  • the methods and compositions of the present invention may be used wherever planktonic bacteria and/or biofilm or similar structures may be found, including but not limited to microorganisms growing and/or floating in liquid environments.
  • the antimicrobial or anti-biofilm effect may be biostatic or biocidal.
  • the present invention includes any method of contacting with an antimicrobial agent of the present invention.
  • Typical mechanisms of contacting include, but are not limited to, coating, spraying, immersing, wiping, and diffusing in liquid, powder, or other delivery forms (e.g., injection, tablets, washing, vacuum, or oral).
  • the compositions and methods may include applying the anti-biofilm agent to any portion of an article or an ingredient of an article.
  • any structure or hard surface e.g., tools or machinery surfaces associated with harvesting, transport, handling, packaging, or processing
  • the Examples provide experimental confirmation that the silver (I) periodate compounds of the present invention release silver over time, typically over fourteen or more days. These Examples therefore demonstrate that stable, slow release silver- containing compounds can be used as long-lasting antimicrobials against bacterial and fungal pathogens, including biofilms growing on a substrate or layer.
  • compositions exhibit antimicrobial activity and/or anti-biofilm activity against a variety of microbes, including both bacteria and fungi, and provide a sustained release of silver ions or silver containing complexes from silver compounds.
  • the preferred composition of the present invention comprises an active agent that results in slow release of an ionic silver species or silver-containing complex.
  • Silver complexes or compounds, as used herein, refers to a composition containing silver having a valent state of one.
  • the compositions of the present invention may be comprised of a silver-containing substance or a plurality of silver containing substances that may react over time to form other silver containing substances which may exhibit differing antimicrobial properties.
  • antimicrobial properties may be achieved by contacting an antimicrobially active silver species within or at the surface of a substrate, or diffusing from the surface of a substrate into an aqueous environment.
  • the silver compounds may be used in any of the following formats: silver deposition coatings, liquid, suspension, powder, capsule, tablet, coating, and similar configurations.
  • active agents are incorporated or coated directly onto or into a material, or may be incorporated or coated by sequentially adding components or precursors of the active agent to the material, and having the precursors of the active agent in or on the coating.
  • Other forms also include films, sheets, fibers, sprays, and gels.
  • antimicrobial agents examples include, but are not limited to: streptomycin, tetracycline, erythromycin, ciprofloxacin, doxycycline, ampicillin, penicillin, gentamicin, and heavy metals including, but not limited to, gold, platinum, silver, zinc, and copper, and their combined forms including salts, such as chloride, bromide, iodide, iodate, nitrate, sulphate, bisulphate, and periodate, complexes with carriers, and other forms.
  • inactive ingredients may be optionally incorporated in the formulations.
  • examples of such ingredients are emulsifiers, thickening agents, solvents, anti-foaming agents, preservatives, fragrances, coloring agents, emollients, fillers, and the like.
  • compositions and methods of the present invention may be used to treat planktonic microorganisms and/or biofilm in a wide range of environments and places.
  • Treating biofilm refers to contacting a biofilm or similar structure with an anti-biofilm agent wherever biofilm may be found, is expected to be found, or is postulated to be found.
  • an anti-biofilm agent wherever biofilm may be found, is expected to be found, or is postulated to be found.
  • the active agent(s) incorporated into the matrices and devices of the present invention may be used for a variety of applications where there is a need for or benefit from the presence of the active agent.
  • compositions and methods are suitable for treating against one or more microbial infections, including but not limited to diseases or conditions caused by Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, Clostridium difficile, Candida albicans, Staphylococcus epidermidis, Escherichia coli and other Escherichia spp, Streptococcus spp, Pseudomonads, and Xanthomonads.
  • the active agents of the present invention may also be used to treat plant pathogens, including but not limited to Pseudomonas syringae pv. syringae,
  • compositions may be used to coat substrate materials.
  • another aspect of the invention is a coating containing the composition of the invention.
  • These coatings may comprise either a single layer or multiple layers.
  • the compositions of the present invention are used alone or in combination with polymer coatings to provide
  • compositions are used, for example, to deliver pharmaceutical agents that, for example, prevent infection, reduce encrustation, inhibit coagulation, improve healing, inhibit restenosis, or impart antiviral, antifungal, antithrombogenic, or other properties to coated substrates.
  • Any polymer may be employed in the present invention, including hydrophilic polymers, hydrophobic polymers, and mixtures of these two types of polymers, provided that the active agent(s) retains all or a portion of its anti-microbial effectiveness.
  • hydrophilic polymers is preferred because such polymers have additional benefits. These benefits include increased lubricity for patient comfort, increased absorption of aqueous fluids from the body which aids in the release of oligodynamic ions from the composition, inhibition of bacterial attachment, and improved solubility for some metal salts.
  • Hydrophilic polymers best suited to the invention are those that are soluble in water or in organic solvents containing water. The ability to add water to the polymer
  • composition without precipitating the polymer facilitates the addition of water-soluble salts directly to the coating composition.
  • water is not limiting, as salt colloids can also be formed using alcohols, organic solvents, or both, that contain little or no water.
  • polymers which may be used to form the compositions include, but are not limited to, polyurethanes, including polyether polyurethanes, polyester
  • polyurethanes polyurethaneureas, and their copolymers
  • polyvinylpyrrolidones polyvinyl alcohols
  • polyethylene glycols and their copolymers polypropylene glycols and their copolymers
  • polyoxyethylenes and their copolymers polyacrylic acid; polyacrylamide; carboxymethyl cellulose; glycoproteins; proteoglycans; glycosaminoglycans; lipoproteins; liposaccharides; cellulose and its derivatives; dextrans and other polysaccharides;
  • starches starches; guar; xantham and other gums and thickeners; collagen; gelatins; other naturally occurring polymers; polytetrafluoroethylene; polyvinyl chloride (PVC);
  • polyvinylacetate poly(ethylene terephthalate); silicone; polyesters; polyamides;
  • polyureas polyureas; styrene-block copolymers; polymethyl methacrylate; acrylic-butadiene-styrene copolymers; polyethylene; polystyrene; polypropylene; natural and synthetic rubbers such as latex rubbers; acrylonitrile rubber; and mixtures and copolymers of any of the above.
  • the preferred polymer depends upon the substrate to be coated.
  • the polymer is a polyurethane, polyvinyl chloride, silicone, or natural latex rubber.
  • hydrophobic polymers that are chemically similar or identical to the substrate are used alone or in combination with hydrophilic polymers to form coatings that enhance adhesion of the coating to the substrate.
  • the silver species of the present invention may be incorporated into an article, medical device, implant, or the like.
  • incorporating refers to using an ionic silver species, such as pentasilver hexaoxoiodate, in the manufacture of the article, as a coating or layer of the article, or as a lubricant or the like when using the article.
  • Materials commonly used to make catheters include, but are not limited to natural rubber latexes, silicones, polyvinyl chlorides, polyurethanes, plastisols, polyvinyl acetate, and methacrylate copolymers. Natural rubber latexes, polyurethanes, polyvinyl chlorides, and silicones are preferred materials. Any combination of the foregoing materials may also be used in making catheters.
  • catheters of the present invention are not limited in terms of the number of layers of material.
  • one or more additional coatings may be applied to the surface of the catheters to provide lubricity, to reduce risk of infection, or for any other purpose. Any combination of layers can be used.
  • the compounds of the present invention and/or their reaction products may be incorporated into any metal article, e.g., a metallic medical device, including but not limited to various grades of titanium, titanium alloys, stainless steel, mild steel, aluminum, copper, etc.
  • the active agents of the present invention also exhibit good storage stability.
  • Ag 5 l06 powder is stable at 90°C for >28 days, which correlates to stability for greater than two years at room temperature.
  • the active agents of the present invention also exhibit good photostability. Ag 5 l0 6 powder is photostable, and therefore does not need to be stored in the absence of light.
  • the active agents of the present invention are also thermally stable. Ag 5 l06 powder is stable up to 440°C, indicating that the active agents of the present invention may be used under the high heat thermal processing required in the manufacture of some medical devices.
  • the active agents of the present invention may also be formulated into a composition comprising a solvent with short term stability.
  • exemplary solvents include, but are not limited to, water, saline (where some initial breakdown occurs but appears to be self-limited), methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, chloroform, 1 ,2,4-trichlorobenzene, and 3M Novec Engineered Fluids such as HFE-7100 and HFE- 71 DE.
  • the active agent can then be incorporated into or coated onto polymers by exposing the polymers to the active agents in slurried or solution form in these solvents within the time period for which the components are stable together.
  • the active agents of the present invention exhibit improved and commercially valuable antimicrobial activity and longevity.
  • silver(l) periodate exhibits bacteriostatic longevity on wound dressings for greater than 10 days in vitro using day-to-day transfer corrected zone of inhibition testing, and bactericidal longevity on wound dressings greater than 14 days in vitro with continuous exposure to saline followed by a challenge in human serum and media in saline.
  • the active agents of the present invention also exhibit broad range antimicrobial activity. As shown in the Examples, would dressings coated with an active agent of the present invention are antimicrobial against fungi, bacteria (Gram-positive and Gram- negative pathogens, including C. difficile), both against planktonic forms and as anti- adherent/anti-biofilm agents. Further, these active agents retain their antimicrobial activity in environments that reduce or eliminate the antimicrobial effect of some silver species, e.g., in the presence of bodily fluids such as human serum and physiological saline.
  • the active agents of the present invention may be used in the agricultural industry as an antimicrobial agent or composition.
  • One or more agents are suitable for use as an antimicrobial seed coating or in a foliar spray.
  • Agents have demonstrated bactericidal activity (anti-adherence and anti-planktonic) against plant pathogens, including after exposure to soil.
  • the compounds of the present invention and/or their reaction products may be incorporated into any gel, ointment, or cream.
  • active agent describes a silver-containing chemical substance, compound, or complex that exhibits antimicrobial activity, and is Ag (I) combined with higher oxidation state iodine and coordinated with oxygen atoms.
  • Active agent includes, but is not limited to, a silver(l) periodate; one or more reaction products of a sodium diperiodatoargentate, each of these reaction products containing silver and iodine; one or more reaction products of a potassium diperiodatoargentate, each of these reaction products containing silver and iodine; one or more reaction products of a combination of sodium and potassium diperiodatoargentate, each of these reaction products containing silver and iodine; pentasilver hexaoxoiodate; Ag 5 l0 6 ; silver orthoperiodate; silver periodate (VII); silver iodate (VII); 5 Ag 2 O°l 2 O 7 ; Ag 2 H 3 l0 6 ; and other combinations of Ag x
  • cation can be any of a large number of cations.
  • exemplary cations include but are not limited to K, Na, Mg, Ca, Au, Pt, Cu, and Fe.
  • the preferred cations are K and Na.
  • Active agent also includes compositions comprising one or more active agents.
  • Reaction product refers to any silver containing compound or complex in the silver iodate family, formed by a number of different reaction processes.
  • Exemplary reaction products include but are not limited to pentasilver hexaoxoiodate; Ag 5 IO 6 ; silver orthoperiodate; silver periodate (VII); silver iodate (VII); 5 Ag 2 O°l 2 O 7 ;
  • Medical device refers to any device, tool, instrument, implant, or the like, relating to medicine or the practice of human or veterinary medicine, or intended for use to heal or treat a disease or condition.
  • a medical device of the present invention may be used for the medical benefit of a human or animal, including laboratory or hospital equipment.
  • a medical device or a component of a medical device may include all natural and synthetic materials and both fibrous and non-fibrous materials.
  • the materials may be comprised of a metal, plastic, paper, glass, ceramic, textile, rubber, polymer, composite material or any other material or combination of materials.
  • Exemplary medical devices include, but are not limited to, any kind of catheter; cannulae; needles; stents; guide wires; implant devices; filters; endoscopes; surgical or medical instruments; stents of any size, shape, or placement; coils of any size, shape, or placement; contact lenses; lUDs; peristaltic pump chambers; endotracheal tubes;
  • gastroenteric feeding tubes arteriovenous shunts; condoms; oxygenator and kidney membranes; gloves; pacemaker leads; wound dressings; metallic pins, plates, and screws; metallic artificial hips; artificial knees; and gels, creams, and ointments.
  • sustained release or “sustainable basis” are used to define release of atoms, molecules, ions, or clusters of a noble metal that continues over time measured in hours or days, and thus distinguishes release of such metal species from the bulk metal, which releases such species at a rate and concentration which is too low to be effective, and from highly soluble salts of noble metals such as silver nitrate, which release silver ions virtually instantly, but not continuously, in contact with an alcohol, aqueous solution, or electrolyte.
  • the products of the present invention are superior to other commercially available silver containing compounds in part because of the slower release of silver.
  • Surface contamination refers to microorganisms growing on or relocated to a surface.
  • the microorganisms associated with surface contamination may be actively growing or dormant, but represent a viable inoculum that can reinitiate infection, disease, or other undesirable conditions.
  • Antimicrobial activity is art-recognized and may be biostatic and/or biocidal.
  • Biostatic materials are materials that inhibit the growth of all or some of the
  • biocide is a material that kills all or some of the microorganism.
  • the active agents of the present invention are sufficiently soluble to provide biostatic and/or biocidal activity.
  • coating generally includes coatings that completely cover a surface, or portion thereof, as well as coatings that may only partially cover a surface, such as those coatings that after drying leave gaps in coverage on a surface.
  • the latter category of coatings may include, but are not limited to a network of covered and uncovered portions (e.g., non-continuous covered regions of the surface).
  • the coating may be applied to a surface or impregnated within the material used to construct an item or a portion of an item.
  • substrate generally refers to a body or base layer or material (e.g., onto which other layers are deposited).
  • a substrate may be organic (e.g., cotton or wool), metal, a polymer (e.g., polyvinyl chloride, high density polyethylene, polyurethane, silicone, rubber, rayon or polyester), or cellular (e.g., a plant, a seed, leaves, skin, or hide).
  • Metal substrates include but are not limited to a wide variety of metals (e.g., titanium and stainless steel); metal alloys; and devices or products made using these metals (e.g., medical devices, needles, ports, implants, pins, etc.).
  • the substrate must not inactivate the silver compound, or inactivate it to the extent that the silver is no longer suitable for use as an antimicrobial agent.
  • the purpose of this study was to determine whether or not Ag 5 IO 6 interacts with methanol, tetrahydrofuran, acetone, and acetonitrile.
  • 2-3 mm of Ag 5 l06 was placed in a vial, 2 mL of the solvent was added, and the vial was placed in a TAM III for an isothermal run at room temperature for >24h with solvent only as the reference. The heat flow was measured. After the run was complete, the solvents were allowed to flash off and the solids collected were submitted to XRD. Samples exposed following essentially the same method for only 18h were also submitted for XRD.
  • Organisms P. aeruginosa, S. epidermidis, S. aureus, K. pneumoniae, C. albicans.
  • Inoculum was made up in 10% MHB/SDB in 0.9% saline + 25% human serum to determine ability of Ag 5 IO 6 coatings to act in the presence of human serum and saline. 24h was allowed for biofilm growth.
  • Dressings Coated Source Gauze Sponges - 100% cotton; 3 ply dressings - rayon/polyester core with upper and lower HDPE layers; and Tensoplast - rayon/cotton with adhesive
  • Organisms P. aeruginosa ATCC 9027, S. aureus ATCC 6538, K. pneumoniae ATCC
  • Coated dressings (all 3 types) demonstrated substantial bacteriostatic longevity against a wide range of clinically relevant bacteria (gram positive and gram negative pathogens). In some cases, the dressings were still active after 10 days. The dressings were also active against C. albicans, for a shorter time period (4 days).
  • the resulting material was submitted for XRD to determine whether the Ag 5 l0 6 had reacted with the silicones. For all 4 silicone samples, the only silver species detected was Ag 5 l0 6 .
  • Digestible silver content was determined by AAS. The silver released during nitric acid digest was: 0.55 mg/g GE silicone, 6.93 mg/g MED 6345, and 3.89 mg/g MED 9050. Silver release from MED 4870 was not determined.
  • the GE silicone and MED 4870 silicone did not generate zones of inhibition, even on the first day.
  • Method 1 Ag 5 IO 6 was incorporated into silicone (S), polyvinyl chloride (C), polyurethane (U), and latex rubber (R) using the following solvents: acetone (A), acetonitrile (B), ethanol (E), methanol (M), and tetrahydrofuran (T). Polymer tubing lengths were placed in a 5000 ppm slurry of Ag 5 l0 6 in each solvent and stirred for a maximum of 18 hours. The solvent was then allowed to flash off of the polymers, the tubing pieces were briefly rinsed in ddh ⁇ O to remove any poorly-adhered Ag 5 l0 6 , and then the tubing lengths were allowed to dry.
  • Method 2 This was performed using the same technique as Method 1 , except that polymers were first placed in the pure solvent and allowed to swell for up to 2 days or until swelling equilibrium was reached, and then transferred to the Ag 5 l0 6 slurry with agitation for 18h.
  • CZOI day-to-day corrected zone of inhibition
  • sample codes are based on (polymer)(solvent)-(method); i.e. for AgslOe incorporated into silicone using acetone via method 1, the code would be SA-1.
  • a sample of RB-1 was submitted for XRD analysis, and the only silver species detected in the polymer was AgslOe as a minor component relative to the polymer.
  • Method 1 caused higher incorporation of silver than Method 2.
  • Method 1 treated polymers contained more digestible silver than Method 2 treated polymers.
  • CZOI data indicated that Method 1 was more effective at generating an antimicrobially-active Ag 5 l0 6 -incorporated polymer than Method 2.
  • the ethanol swelled polyurethane using Method 1 had significantly larger zones than Method 2.
  • the acetonitrile and methanol swelled PVC using Method 1 had significantly larger zones than using Method 2.
  • the acetonitrile swelled silicone using Method 1 had significantly larger zones than using Method 2. It was only on Day 3 that the acetone swelled latex rubber tubing using Method 2 had significantly larger zones than using Method 1.
  • the maximum number of transfers achieved by any method was 3 days.
  • Improved results could be obtained by increasing the penetration of Ag 5 IO 6 into the polymers, increasing the quantity coated onto/incorporated into the polymers, or improving release of Ag 5 IO 6 after incorporation.
  • Chloroform, HFE-71 DE, and HFE-7100 were all considered appropriate solvents for potential use for incorporation of Ag 5 IO 6 into polymers, but 1 ,2,4-trichlorobenzene was not for the polymers tested.
  • Example 5 The purpose of this study was the same as Example 5 using additional solvents selected from Example 5.
  • the methods were the same as those described in Example 5, except that the following solvents were used: HFE-7100 3M Novec Engineered Fluid (H), HFE-71 DE 3M Novec Engineered Fluid (D), and chloroform (F). In addition, only Method 1 was performed.
  • CD had significantly more silver than the other PVC tubing pieces as well as the other tubing materials coated using the HFE-71 DE solvent (p ⁇ 0.05 or p ⁇ 0.01 for all cases).
  • RH had significantly more silver than other latex rubber tubing pieces as well as the other tubing materials coated using HFE-7100 (p ⁇ 0.001 for all cases).
  • Example 5 The purpose of this study was the same as Example 5 using blends of methanol and tetrahydrofuran (THF) rather than single solvents.
  • the methods used were the same as those described in Example 5 except that the following solvent blends (by volume) were used: 90% THF/10% methanol (9T1M), 70% THF/30% methanol (7T3M), 50% THF/30% methanol (5T5M), 30% THF/70% methanol (3T7M), and 10% THF/90% methanol (1T9M).
  • Method 1 was performed, and the only polymers used were silicone (S) and latex rubber (R).
  • the samples codes are based on (polymer)(solvent blend); i.e. for AgslOe incorporated into silicone using 90%THF/10% methanol, the code would be S9T1 M.
  • the R9T1M had significantly more silver deposited per unit area than all other latex rubber samples, and significantly more silver than the S9T1M.
  • Polyurethane sample H continued to prevent adherence of bacteria out to 30 days, but between 21 and 30 days lost the ability to eliminate the surrounding planktonic bacteria, suggesting insufficient silver release into the surrounding media by Day 30.
  • Polyurethane sample P generated anti-adherence activity and the ability to eliminate surrounding planktonic bacteria for 7 days, but failed by 14 days.
  • PVC sample G continued to prevent adherence of bacteria out to 21 days (failed at 30 days), but was able to eliminate surrounding planktonic bacteria out to 30 days, suggesting that the material may have lost its silver coating unevenly, such that there were bare patches that allowed for bacterial adherence, but that the silver was still able to be released from other areas to kill the planktonic organisms.
  • PVC sample J was the reverse - it was able to prevent adherence out to 30 days, but only eliminated
  • the remaining eight coated polymers (E, F, I, K, L, M, N, and O) showed bactericidal activity and anti-adherence (anti-biofilm) properties under the same
  • wound dressings were coated at different concentrations (similar to Example 3, except that the full amount of Ag 5 l0 6 was used for some dressings, 5x less material was used for others, and a third group was coated using 10x less Ag 5 l0 6 ).
  • Day-to-day transfer corrected zone of inhibition testing was performed using the same 5 organisms as Example 3, except that the Pseudomonas aeruginosa strain used was ATCC 27853.
  • using 5x less Ag 5 l0 6 to coat dressings did not impact the number of days that zones of inhibition could be generated.
  • using 10x less Ag 5 l06 in the coating process resulted in reduced longevity, suggesting that the dressings should be coated with at least that quantity of Ag 5 IOe to obtain good bacteriostatic longevity.
  • B-10x Ag 5 l0 6 treated 3 ply dressings treated at 10x less concentration
  • D-5x Ag 5 l0 6 treated 3 ply dressings treated at 5x less concentration
  • D-10x Ag 5 l0 6 treated 3 ply dressings treated at 10x less concentration
  • E Aquacel® (growth control for F)
  • a BESTTM assay used, with a challenge in 10% media+25% human serum in 0.9% saline - 24h biofilm growth. Both pianktonic and adhered bacteria (biofilm) recovery performed.
  • the Ag 5 l0 6 -coated dressings performed well against all three organisms (gram positive, gram negative, and yeast), and demonstrated both anti-adherence and anti- planktonic activity. Even after 14 days exposure to saline, the dressings demonstrated bactericidal activity and anti-adherence properties under most conditions.
  • the AgslOe- coated dressings out-performed the other dressings (with the exception of dressing J performing better than dressing H for adhered S. aureus and C. albicans at Day 14 only).
  • AgslOe-coated 3-ply dressings demonstrated activity against C. difficile, both killing the planktonic bacteria and preventing adherence with log reductions >3, and just under 3, respectively. This indicates that Ag 5 IO 6 may be an effective agent against C. difficile in appropriate formulations, where other commercial silver-containing dressings were not.
  • the purpose of this study was to test successful Ag 5 10 6 -coated polymers for antimicrobial efficacy against relevant clinical human pathogens, compared to uncoated control polymers against a selected strain over an evaluation window of up to 30 days.
  • Example 9 was repeated, except that the samples were tested against three different microorganisms: P. aeruginosa, ATCC 27853; C. albicans, ATCC 18804; and S. aureus, ATCC 29213.
  • the AgslO 6 coated catheters showed variable anti-adherence activity for all three strains tested. Despite the general presence of anti-adherence activity, it appears as though the Pseudomonas strain is more susceptible to the anti-microbial effects of the silver.
  • the silver coated catheters exposed to Pseudomonas aeruginosa resulted in higher log reductions for both planktonic and adhered biomass compared to its controls (un-coated catheters) and the other two strains at the different time points tested. Nevertheless, silver coated catheters exposed to Staphylococcus aureus showed significant log reduction for both planktonic and adhered biomass, specifically catheters F, G, H, J compared to its controls (uncoated catheters) on day 14 and 30.

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