WO2002085299A2 - Therapeutic treatments using the direct application of antimicrobial metal compositions - Google Patents

Therapeutic treatments using the direct application of antimicrobial metal compositions Download PDF

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Publication number
WO2002085299A2
WO2002085299A2 PCT/US2002/012690 US0212690W WO02085299A2 WO 2002085299 A2 WO2002085299 A2 WO 2002085299A2 US 0212690 W US0212690 W US 0212690W WO 02085299 A2 WO02085299 A2 WO 02085299A2
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WIPO (PCT)
Prior art keywords
tissue
treated
injection
atomic disorder
antimicrobial
Prior art date
Application number
PCT/US2002/012690
Other languages
French (fr)
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WO2002085299A3 (en
Inventor
Scott H. Gillis
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Nucryst Pharmaceuticals Corp.
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.)
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Publication date
Priority claimed from US09/840,637 external-priority patent/US7008647B2/en
Application filed by Nucryst Pharmaceuticals Corp. filed Critical Nucryst Pharmaceuticals Corp.
Priority to AU2002303438A priority Critical patent/AU2002303438B2/en
Priority to JP2002582875A priority patent/JP2005507368A/en
Priority to CA002443587A priority patent/CA2443587A1/en
Priority to EP02731461A priority patent/EP1390013A4/en
Publication of WO2002085299A2 publication Critical patent/WO2002085299A2/en
Publication of WO2002085299A3 publication Critical patent/WO2002085299A3/en

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    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • Y10T428/31855Of addition polymer from unsaturated monomers

Definitions

  • This invention relates to therapeutic treatments in general, and more particularly to therapeutic treatments using the direct application of antimicrobial metal compositions.
  • a common form of treatment for localized infections is oral antibiotic therapy.
  • this treatment is systemic, requires multiple dosages, frequently causes side effects, and can give rise to the evolution of antibiotic-resistant bacteria.
  • debates are common among healthcare professionals and the general population regarding the over-use of antibiotics.
  • Nucryst has determined that its antimicrobial metals with atomic disorder provide excellent therapeutic benefits. More particularly, antimicrobial metals with atomic disorder have been found to serve effectively as an antimicrobial agent, an anti- inflammatory agent, an immuno modulator agent, an enzyme modulator agent, and/or an anti-tumor agent, for human and/or animal use. Among other things, antimicrobial metals with atomic disorder have proven to be a broad spectrum (e.g., gram positive, gram negative, fungus and drug resistant) bacteriocidal agent with little likelihood of fostering resistant bacteria and having a sustained antimicrobial activity (for example, antimicrobial activity lasting over seven days has been consistently demonstrated with antimicrobial metals with atomic disorder) .
  • antimicrobial metals with atomic disorder have proven to be a broad spectrum (e.g., gram positive, gram negative, fungus and drug resistant) bacteriocidal agent with little likelihood of fostering resistant bacteria and having a sustained antimicrobial activity (for example, antimicrobial activity lasting over
  • Nucryst has recently discovered new ways of forming its antimicrobial metals with atomic disorder in free-standing powder form, solution form and suspension form.
  • the ability to form antimicrobial metals with atomic disorder in free-standing powder form, solution form and suspension form has greatly expanded the possibilities for using these selected nanocrystalline compositions for therapeutic purposes.
  • antimicrobial metals with atomic disorder in free-standing powder form, solution form and suspension form has lead to the further discovery that it is possible to utilize antimicrobial metals with atomic disorder in a radical new way, i.e., for direct application to a wide range of different tissues so as to therapeutically treat a wide range of different medical disorders.
  • therapeutic treatments may be applied to internal anatomy as well as to surface anatomy.
  • the present invention utilizes selected structures of antimicrobial metals.
  • the antimicrobial metals are preferably selected noble metals such as silver, gold, platinum, palladium, etc.
  • the structures are formed with atomic disorder, such that ions, clusters, atoms or molecules of the metals are released at a concentration sufficient to provide a localized therapeutic effect.
  • the structures are preferably in nanocrystalline form.
  • Antimicrobial metals with atomic disorder may be prepared in the manner taught in International Patent Publication No. WO 93/23092, published November 25, 1993; International Patent Publication No. WO 95/13704, published May 26, 1995; and International Patent Publication No. WO 98/41095, published September 24, 1998, which documents are incorporated herein by reference.
  • Metal or “metals” includes one or more metals whether in the form of substantially pure metals, alloys or compounds such as oxides, nitrides, borides, sulphides, halides or hydrides.
  • Antimicrobial metals are silver, gold, platinum, palladium, iridium, zinc, copper, tin, antimony, bismuth, or mixtures of these metals with same or other metals, silver, gold, platinum and palladium being preferred, and silver being most preferred.
  • Noble metals are silver, gold, platinum and palladium, or mixtures of such metals with same or other metals, with silver metal being the most preferred.
  • Antimicrobial effect means that atoms, ions, molecules or clusters of the antimicrobial or noble metal are released into the electrolyte which the coating contacts in concentration sufficient to inhibit microbial growth on and in the vicinity of the coating.
  • the most common methods of measuring an antimicrobial effect are a zone of inhibition test (which indicates an inhibitory effect, whether microbiostatic or microbiocidal) or a logarithmic reduction test (which indicates a microbiocidal effect) .
  • ZOI zone of inhibition test
  • the material to be tested is placed on a bacterial lawn (or a lawn of other microbial species) and incubated.
  • a relatively small or no ZOI (ex. less than 1 mm) indicates a non-useful antimicrobial effect, while a larger ZOI (ex. greater than 5 mm) indicates a highly useful antimicrobial effect.
  • the ZOI is generally reported as a corrected zone of inhibition (CZOI), wherein the size of the test sample is subtracted from the zone.
  • a logarithmic reduction test in viable bacteria is a quantitative measure of the efficacy of an antibacterial treatment; for example, a 5 log reduction means a reduction in the number of microorganisms by 100, 000-fold (e.g., if a product contained 100,000 pertinent microorganisms, a 5 log reduction would reduce the number of pertinent microorganisms to 1). Generally, a 3 log reduction represents a bactericidal effect.
  • the logarithmic reduction test involves combining the inoculum with the test treatment, recovering the bacteria or other microbial species, and enumerating the bacteria or other microbial species using serial dilutions.
  • Anti-inflammatory effect means a reduction in one or more of the symptoms of erythema (redness), edema (swelling) , pain and pruritus which are characteristic of inflammatory skin conditions.
  • Inflammatory skin conditions refers to those conditions of the skin in which inflammatory cells (e.g., polymorphonuclear neutrophils and lymphocytes) infiltrate the skin with no overt or known infectious etiology, but excluding psoriasis and its related conditions. Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, pruritus, increased surface temperature and loss of function.
  • inflammatory cells e.g., polymorphonuclear neutrophils and lymphocytes
  • Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, pruritus, increased surface temperature and loss of function.
  • inflammatory skin conditions include, but are not limited to, eczema and related conditions, insect bites, erythroderma, mycosis fungoides and related conditions, pyoderma gangrenosum, erythema multiforme, rosacea, onychomycosis, and acne and related conditions, but excluding psoriasis and its related conditions.
  • Biocompatible means generating no significant undesirable host response for the intended utility. Most preferably, biocompatible materials are non-toxic for the intended utility. Thus, for human utility, biocompatible is most preferably non-toxic to humans or human tissues.
  • sustained release or “sustainable basis” are used to define release of atoms, molecules, ions or clusters of a antimicrobial metal that continues over time measured in hours or days, and thus distinguishes release of such metal species from the bulk metal, which release such species at a rate and concentration which is too low to be therapeutically effective, and from highly soluble salts of antimicrobial metals such as silver nitrate, which releases silver ions virtually instantly, but not continuously, in contact with an alcohol or electrolyte.
  • Atomic disorder includes high concentrations of one or more of: point defects in a crystal lattice, vacancies, line defects such as dislocations, interstitial atoms, amorphous regions, grain and sub grain boundaries and the like relative to its normal ordered crystalline state. Atomic disorder leads to irregularities in surface topography and inhomogeneities in the structure on a nanometer scale.
  • Normal ordered crystalline state means the crystallinity normally found in bulk metal materials, alloys or compounds formed as cast, wrought or plated metal products. Such materials contain only low concentrations of such atomic defects as vacancies, grain boundaries and dislocations.
  • “Diffusion”, when used to describe conditions which limit diffusion in processes to create and retain atomic disorder, i.e. which freeze-in atomic disorder, means diffusion of atoms (adatom diffusion) and/or molecules on the surface or in the matrix of the material being formed.
  • Alcohol or water-based electrolyte is meant to include any alcohol or water-based electrolyte that the antimicrobial materials of the present invention might contact in order to activate (i.e. cause the release of species of the antimicrobial metal) into same.
  • the term is meant to include alcohols (short chain (C 6 or less) and preferably C 4 or less), water, gels, fluids, solvents, and tissues containing, secreting, or exuding water or water-based electrolytes, including body fluids (for example blood, urine, or saliva), and body tissue (for example skin).
  • Bioabsorbable as used herein in association includes substrates which are useful in medical devices, that is which are biocompatible, and which are capable of bioabsorption in period of time ranging from hours to years, depending on the particular application.
  • Bioabsorption means the disappearance of materials from their initial application site in the body (human or mammalian) with or without degradation of the dispersed polymer molecules.
  • Cold change is meant to include changes of intensity of light under monochromatic light as well as changes of hue from white light containing more than one wavelength.
  • An “interference colour” is produced when light impinges on two or more partly reflective surfaces separated by a distance which bears the right relationship to the wavelength of the light to be removed by destructive interference.
  • Partly reflective when used to describe the base or top layer materials, means that the material has a surface which reflects a portion of incident light, but which also transmits a portion of the incident light. Reflection occurs when a ray of incoming light encounters a boundary or interface characterized by a change in refractive index between two media.
  • That interface is with air.
  • the base layer the interface is with the top layer. The reflectance of the base and top layers is balanced so as to generate an interference colour.
  • Partly light trans issive when used to describe a thin film of the top layer material means that the thin film is capable of transmitting at least a portion of incident visible light through the thin film.
  • Detectable when used to describe a colour change means an observable shift in the dominant wavelength of the reflected light, whether the change is detected by instrument, such as a spectrophotometer, or by the
  • the dominant wavelength is the wavelength responsible for the colour being observed.
  • Cold working indicates that the material has been mechanically worked such as by 5 milling, grinding, hammering, mortar and pestle or compressing, at temperatures lower than the recrystallization temperature of the material. This ensures that atomic disorder imparted through working is retained in the material.
  • “Pharmaceutically- or therapeutically-acceptable” is used herein to denote a substance which does not significantly interfere with the effectiveness or the biological activity of the active ingredients (antimicrobial and anti-inflammatory activities) and L5 which has an acceptable toxic profile for the host to which it is administered.
  • “Therapeutically effective amount” is used herein to denote any amount of a formulation of the antimicrobial or noble metals which will exhibit either '0 or both of an antimicrobial and optionally an anti- inflammatory effect, or some other therapeutic effect, when applied to the affected area of the tissue.
  • a single application of the formulations of the present invention may be sufficient, or the formulations may be applied repeatedly over a period of time, such as several times a day for a period of days or weeks.
  • the amount of the active ingredient, that is the antimicrobial or noble metal in the form of a coating, powder or dissolved in liquid solution will vary with the conditions being treated, the stage of advancement of the condition, the age and type of host, and the type and concentration of the formulation being applied. Appropriate amounts in any given instance will be readily apparent to those skilled in the art or capable of determination by routine experimentation.
  • Carrier means a suitable vehicle including one or more solid, semisolid or liquid diluents, excipients or encapsulating substances which are suitable for administration to the skin.
  • Nanocrystalline is used herein to denote single-phase or multi-phase polycrystals, the grain size of which is less than about 100, more preferably ⁇ 50, even more preferably ⁇ 40, even more preferably ⁇ 30, and most preferably ⁇ 25 nanometers in at least one dimension.
  • WE i-i or flakes of the antimicrobial or noble metals, is not meant to restrict the particle size of the materials when used in a powder form.
  • Powder is used herein to include particulates of 5 the antimicrobial or noble metals ranging from nanocrystalline (less than 100 nm) to submicron sized powders up to flakes.
  • powders of the antimicrobial or noble metals used in the present invention are sized at less than 100 ⁇ m, and more
  • Gram size or “crystallite size” means the size of the largest dimension of the crystals in the antimicrobial metal coating or powder.
  • Hydrocolloid means a synthetically prepared or naturally occurring polymer capable of forming a thickened gel in the presence of water and polyols (swelling agent) .
  • the swelling agent must be capable of swelling the hydrocolloid chosen in order to form
  • Hydrogels means a hydrocolloid swollen with water or another hydrophilic liquid which is used for absorbing or retaining moisture or water.
  • Gel means a composition that is of suitable viscosity for such purposes, e.g., a composition that is of a viscosity that enables it to be applied and remain on the skin.
  • nanocrystalline antimicrobial metal and similar terminology, such as “nanocrystalline coatings or powders” is meant to refer to antimicrobial metals formed with atomic disorder and having a nanocrystalline grain size.
  • Antimicrobial metals with atomic disorder may be provided in free-standing powder form in a variety of different ways.
  • Patent Publication No. WO 95/13704 published May 26, 1995; and/or International Patent Publication No. WO 98/41095, published September 24, 1998, it was disclosed that antimicrobial metals with atomic disorder may be provided in free-standing powder form by "cold working".
  • antimicrobial metals with atomic disorder may be provided in free-standing powder form by vapor deposition on a fixed element, with the deposited material thereafter being stripped off so as to yield the desired free-standing powder.
  • antimicrobial metals with atomic disorder may be provided in free-standing powder form by vapor deposition on an NGRC ("next generation roll coater") apparatus. More particularly, a continuous belt is coated with antimicrobial metals with atomic disorder using vapor deposition techniques, with the antimicrobial metals with atomic disorder being scraped off the belt further down the line so as to yield the free-standing powder form of the antimicrobial metals with atomic disorder.
  • NGRC next generation roll coater
  • This last-mentioned method for making the free-standing powder form of the antimicrobial metals with atomic disorder is particularly advantageous, inasmuch as it can quickly and easily yield a relatively large supply of free-standing powder at a relatively low cost.
  • Crystalline powder forms of the antimicrobial or noble metals can be prepared as free standing powders, by coating powdered substrates, or from coatings on substrates which are then collected, for example by scraping and then sized.
  • the powders may be prepared as pure metals, metal alloys or compounds such as metal oxides or metal salts, by vapour deposition, mechanical working, or compressing to impart the atomic disorder.
  • the crystalline powders are formed with atomic disorder in accordance with the techniques set out above and as published in the prior patent applications of Burrell et al . , see for example WO 93/23092, published November 25, 1993, and WO 95/13704, published May 26, 1995.
  • the atomic disorder will most typically be formed in the metal powders during physical vapour deposition as set out above for coatings or by mechanically imparting the disorder, such as by milling, grinding, hammering, mortar and pestle or compressing, under conditions of low temperature (i.e., temperatures less than the temperature of recrystallization of the material) to ensure that annealing or recyrstallization does not take place.
  • the powders may be formed by inert- gas condensation techniques, which are modified to provide atomic disorder in the powder produced, as taught in WO 95/13704 to Burrell et al .
  • Powders of the antimicrobial or noble metals are preferably formed by physical vapour deposition (PVD) onto a substrate such as a cold finger, a silicon wafer, solid plates, a rotating cylinder, a continuous belt in a roll coater, or on steel collectors in known PVD coaters.
  • PVD physical vapour deposition
  • Preparation of powders of the present invention by sputtering onto a continuous belt in a roll coater, or other some other moving or rotating substrate surface is particularly advantageous, inasmuch as it can quickly and easily yield a relatively large supply of free-standing powder at a relatively low cost.
  • a stainless steel belt can be used in the roll coating process without the need to provide additional cooling of the substrate.
  • the powders or coatings are then scraped off to form a powder, and may be sized to avoid overly large particulates.
  • the powders are scraped off the moving surface with scrapers which contact the moving surface at an angle sufficient to remove the coating in flake or powder form.
  • the coating may be scraped off with scrapers angled for forward cutting of the coating from the moving surface, or with scrapers which remove the coating from the moving surface by reverse dragging action on the surface.
  • the scrapers may be suspended above the belt, and either weighted or spring loaded to apply pressure sufficient to remove the coating from the moving surface. With a continuous belt, the scrapers can conveniently be located above the end rollers to remove the coating with a reverse dragging action as the belt rounds the end roller.
  • the powders of the antimicrobial or noble metals may be formed on powdered substrates which are biocompatible, or otherwise compatible for the end use of the powder.
  • powdered substrates are hydrocolloids, particularly those which are bioabsorbable and/or hygroscopic powders such as chitin.
  • Exemplary bioabsorbable and/or hygroscopic powders are composed of : Synthetic Bioabsorbable Polymers: for example polyesters/polyactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers .
  • Synthetic Bioabsorbable Polymers for example polyesters/polyactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers .
  • Naturally Derived Polymers Proteins: albumin, fibrin, collagen, elastin; Polysaccharides : chitosan, alginates, hyaluronic acid; and Biosynthetic Polyesters: 3-hydroxybutyrate polymers.
  • the powders may be incorporated into or onto medical dressings or pharmaceutical formulations, by any methods known in the art.
  • the powders may be layered onto the substrates (dressings or powders) , mechanically fixed within the fibres of the dressings, impregnated into dressings by physical blowing, or added to topical pharmaceutical ingredients .
  • powders of the present invention are sized at less than 100 ⁇ m, and more preferably less than 40 ⁇ m, and most preferably about 3 - 5 ⁇ m in size.
  • antimicrobial metals with atomic disorder Once antimicrobial metals with atomic disorder have been provided in free-standing powder form, they can then be used therapeutically in that form, or the free-standing powder can be used to form solutions or suspensions of the antimicrobial metals with atomic disorder prior to being used to therapeutically treat tissue.
  • Antimicrobial metals with atomic disorder in free-standing powder form may be sprinkled lightly onto surface anatomy (e.g., the skin) in therapeutically effective amounts so as to provide an antimicrobial treatment to that surface anatomy, e.g., to an infected cut.
  • antimicrobial metals with atomic disorder may be mixed with one or more other materials prior to being sprinkled onto the skin, where these other materials may be biologically active materials (e.g., growth promoters) or biologically neutral materials acting as a "filler" to facilitate easier deployment of relatively small quantities of antimicrobial metals with atomic disorder.
  • antimicrobial metals with atomic disorder in free-standing powder form can be applied to the lungs using a so-called dry powder inhaler.
  • Antimicrobial metals with atomic disorder in freestanding powder form may also be injected, by small- needle or needle-less injection, into the interior of the body in therapeutically effective amounts so as to provide their therapeutic benefit to interior anatomy.
  • the antimicrobial metals with atomic disorder can be delivered to interior anatomy via a small-needle drug delivery system or via a needle-less drug delivery system.
  • Such systems are available from Powderject Research Limited of Oxford, United Kingdom (see, for example, U.S. Patents Nos. 5,899,880; 6,010,478 and 6,013,050, which patents are hereby incorporated herein by reference) and Bioject, Inc. of Portland, Oregon (see, for example, U.S. Patents Nos.
  • the particulate size be less than 2 microns, and preferably less than 1 micron, so as so minimize any adverse reaction to the presence of the particulate in the tissue.
  • Many health afflictions can be addressed by delivering antimicrobial metals with atomic disorder, in free-standing powder form, to an interior anatomical site with small-needle and/or needle-less drug delivery systems.
  • examples of some of these applications include: (1) dermal drug delivery for skin conditions such as, but not limited to, acne, psoriasis, eczema and skin infections; (2) localized infections such as, but not limited to, middle ear infections, endocardititis, pericarditis, prostatitis, sinusitis, osteomyelitis and onychomycosis; (3) mouth, gum and throat afflictions; (4) arthritis; and (5) direct-to- tumor chemotherapeutic delivery.
  • antimicrobial metals with atomic disorder may be injected directly into psoriatic plaques.
  • antimicrobial metals with atomic disorder may be injected by small-needle or needle-less injection through the eardrum (i.e., through the tympanic membrane) into the middle ear, whereby to provide a localized antimicrobial, anti-inflammatory treatment for middle ear infections.
  • long-acting antimicrobial metals with atomic disorder may be injected into the prostate gland for difficult-to-treat prostate infections.
  • antimicrobial metals with atomic disorder may be injected into the tissues of the oral cavity and throat to treat sore throats, thrush (Candida infections) and periodontal diseases such as gingivitis.
  • antimicrobial metals with atomic disorder may be injected into arthritic joints to reduce destructive inflammation.
  • long-acting antimicrobial metals with atomic disorder of platinum can be injected into tumors that are responsive to chemotherapy with platinum compounds.
  • Numerous advantages are achieved by delivering antimicrobial metals with atomic disorder to the interior anatomy using such drug delivery systems. For one thing, local treatment (versus systemic treatment) results in lower total doses being required and in fewer side effects. For another thing, the broad spectrum antimicrobial activity of the antimicrobial metals with atomic disorder results in faster infection fighting with low likelihood of bacterial resistance. Furthermore, due to the long-acting nature of the antimicrobial metals with atomic disorder, a single dose or relatively infrequent (e.g., weekly) doses results in an easier therapy regimen than many conventional treatment regimens.
  • antimicrobial metals with atomic disorder in solution form.
  • the solution form of antimicrobial metals with atomic disorder can be advantageous in many anatomical applications, since there is substantially no particulate present which might irritate tissue.
  • Antimicrobial metals with atomic disorder may be provided in solution form in a variety of different ways .
  • a solution of antimicrobial metals with atomic disorder is created by dissolving a f ee-standing powder of antimicrobial metals with atomic disorder in water.
  • the f ee-standing powder of antimicrobial metals with atomic disorder may be packaged in a "tea-bag” type pouch, such that undissolved antimicrobial metals with atomic disorder remain captured within the pouch.
  • a solution of antimicrobial metals with atomic disorder may be provided by immersing, in water, a substrate carrying deposited antimicrobial metals with atomic disorder.
  • a carrier strip may be coated with antimicrobial metals with atomic disorder by vapor deposition, and then the carrier strip may be immersed in water so as to create the solution of antimicrobial metals with atomic disorder.
  • a bandage may be coated with antimicrobial metals with atomic disorder by vapor deposition, and then the bandage may be immersed in water so as to create the solution of antimicrobial metals with atomic disorder.
  • the solution of antimicrobial metals with atomic disorder may be prepared in advance (e.g., at a manufacturing plant) or on site at the time of use. Where a solution of antimicrobial metals with atomic disorder is prepared in advance (e.g., at a manufacturing plant), it is preferred that the solution be created by immersing a "tea-bag" type pouch of the free-standing powder form of antimicrobial metals with atomic disorder in water and leaving it there until the time of use, or by immersing a substrate carrying deposited antimicrobial metals with atomic disorder in water and leaving it there until the time of use. Once a solution of antimicrobial metals with atomic disorder has been created, it may be applied to tissue as a liquid or as an aerosol.
  • the dosage is dependent, to at least some extent, on the concentration of antimicrobial metals with atomic disorder present in the solution.
  • concentration of antimicrobial metals with atomic disorder it may be desirable to raise the concentration of antimicrobial metals with atomic disorder in the solution.
  • the pH of the solution can be lowered by adding acid to the solution. In one preferred form of the invention, CO?
  • the C0 2 creates carbonic acid, thus lowering the pH of the solution and increasing the concentration of antimicrobial metals with atomic disorder in the solution.
  • a solution of antimicrobial metals with atomic disorder may be applied to tissue as a liquid or as an aerosol.
  • a solution of antimicrobial metals with atomic disorder may be applied, in liquid form, and in various viscosities, to a wide range of different tissues in therapeutically effective amounts so as to therapeutically treat a wide range of different medical disorders .
  • a solution of antimicrobial metals with atomic disorder can be applied as a rinse or bath or wash to treat a dermal condition such as, but not limited to, acne, psoriasis, eczema and skin infections.
  • a solution of antimicrobial metals with atomic disorder can be applied as a rinse or bath or wash to treat a wound or a surgical site.
  • a solution of antimicrobial metals with atomic disorder can be applied to mouth tissue (e.g., the gums) as an oral rinse.
  • a solution of antimicrobial metals with atomic disorder can be applied to throat tissue as a gargle.
  • a solution of antimicrobial metals with atomic disorder can be applied to nasal passages and the sinus, e.g., to treat sinusitis and allergic rhinitis.
  • a solution of antimicrobial metals with atomic disorder can be applied to the eyes as eyedrops.
  • a solution of antimicrobial metals with atomic disorder can be applied to the ears as ear drops. It is also possible to apply a solution of antimicrobial metals with atomic disorder, in liquid form, to internal anatomy using a small-needle and/or needle-less drug delivery systems, including catheter- based drug delivery systems.
  • a solution of antimicrobial metals with atomic disorder may be introduced by catheter into the bladder to treat a bladder infection; or injected into the middle ear to treat middle ear infections; or injected or instilled or otherwise introduced into the abdomen to treat a post-surgical abdominal abscess or to treat an infection from peritoneal dialysis; or injected or instilled or otherwise introduced into other internal anatomical structures, including body cavities, so as to treat conditions such as, but not limited to, endocardititis, pericarditis, prostatitis, sinusitis, osteomyelitis and onychomycosis; or injected into skin tissue to treat acne, psoriasis, eczema and/or or other skin conditions; etc.
  • a solution of antimicrobial metals with atomic disorder may also be applied, in aerosol form, to a wide range of different tissues in therapeutically effective amounts so as to therapeutically treat a wide range of different medical disorders.
  • a solution of antimicrobial metals with atomic disorder may be applied in aerosol form to surface tissues as a spray.
  • a solution of antimicrobial metals with atomic disorder can be applied as a spray to treat a dermal condition such as, but not limited to, acne, psoriasis, eczema and skin infections.
  • a solution of antimicrobial metals with atomic disorder can be applied as a spray to treat or clean a wound or a surgical site.
  • a solution of antimicrobial metals with atomic disorder, in aerosol form may be inhaled by a patient for deployment to the throat, the nasal and sinus passages and/or the lungs.
  • the aerosol of antimicrobial metals with atomic disorder may be created by passing a liquid solution of antimicrobial metals with atomic disorder through a mechanical mister (e.g., a simple spray bottle or nebulizer) and may be applied directly (e.g., via a hand inhaler) or through some other delivery system (e.g., an oxygen tent, etc.).
  • a mechanical mister e.g., a simple spray bottle or nebulizer
  • some other delivery system e.g., an oxygen tent, etc.
  • the droplet size of the aerosol can be important, for at least two reasons.
  • the droplet size of the aerosol can affect the dosage of antimicrobial metals with atomic disorder being applied to the tissue, i.e., a larger droplet size results in delivery of more antimicrobial metals with atomic disorder to the tissue.
  • the droplet size of the aerosol can also affect delivery of the antimicrobial metals with atomic disorder to the target tissue, e.g., where the aerosol is inhaled through the mouth, big droplets tend to stay in the throat whereas small droplets (e.g., approximately 10 microns or so) tend to travel to the lungs .
  • droplet size can be regulated, to at least some extent, by the device (e.g., the mechanical mister) which is used to produce the aerosol.
  • the device e.g., the mechanical mister
  • the aerosol's droplet size can be adjusted, to at least some extent, by modifying the surface tension of the solution.
  • the solution of antimicrobial metals with atomic disorder has water as its solvent, and water has a relatively high surface tension, so it is relatively straightforward to create an aerosol having a relatively small droplet size.
  • surfactants can be added to the solution so as to reduce the surface tension of the solution, whereby to create an aerosol having a relatively large droplet size.
  • surfactants may comprise phospholipids, e.g., lecithin, sphingomyelin, etc.
  • antimicrobial metals with atomic disorder in suspension form.
  • the suspension form of antimicrobial metals with atomic disorder can be advantageous in many applications, since it has a relatively long storage life and, perhaps even more importantly, has a relatively long- lasting therapeutic life.
  • Antimicrobial metals with atomic disorder may be provided in suspension form in a variety of different embodiments. More particularly, a suspension of antimicrobial metals with atomic disorder can be created in free-standing form or as a dried gel applied to a medical device.
  • a suspension of antimicrobial metals with atomic disorder can comprise a free-standing form, i.e., it can comprise a liquid such as a lotion; or a semi-solid such as a gel (i.e. a water-based hydrocolloid) or an emulsion (i.e., an oil-in-water or water-in-oil suspension) such as a cream or ointment.
  • Formulations can include carboxymethyl cellulose ("CMC"), polyvinyl alcohol, methyl parabin, proply parabin, and 0.1% antimicrobial metals with atomic disorder in powder form.
  • a suspension of antimicrobial metals with atomic disorder can comprise a dried gel applied to a medical device.
  • a hydrated form of the gel is created, applied to a medical device, and then dehydrated. During use, the gel becomes rehydrated, whereby the antimicrobial metals with atomic disorder are released to provide their therapeutic effect to tissue.
  • the suspension may also include biologically active agents such as cytoconductive agents, etc.
  • biologically active agents such as cytoconductive agents, etc.
  • betaglucan a complex carbohydrate which appears to have cytoconductive properties, may be added to the suspension.
  • glycerol can be deleterious to the therapeutic effect of the antimicrobial metals with atomic disorder, and should be avoided.
  • a suspension of antimicrobial metals with atomic disorder can comprise a freestanding form, i.e., it can comprise a liquid such as a lotion; or a semi-solid such as a gel (i.e. a water- based hydrocolloid) or an emulsion (i.e., an oil-in- water or water-in-oil suspension) such as a cream or ointment.
  • a free-standing form of the suspension are intended to be applied topically to the tissue which is to be treated, in therapeutically effective amounts, and can be used to treat a dermal condition such as, but not limited to, acne, psoriasis, eczema and skin infections.
  • the free-standing forms of the suspension can be applied topically to treat a wound or a surgical site, etc.
  • a suspension of antimicrobial metals with atomic disorder in the form of a dried gel applied to medical devices.
  • the hydrated form of the gel is created, applied to a medical device (e.g., during manufacture of the medical device), and then dehydrated. During use, the gel becomes rehydrated, whereby the antimicrobial metals with atomic disorder are released in therapeutically effective amounts so as to provide their therapeutic effect to tissue.
  • medical devices which are prime candidates for a dried gel coating include catheters (e.g., urological catheters, in-dwelling catheters, drainage catheters, etc.), bone screws, total joints, vascular grafts, hernia meshes, surgical dressings, surgical packing materials, etc.
  • the dried gel can be quite stable and easy to handle when dehydrated, but very slippery when rehydrated.
  • dried gels can be particularly advantageous with certain types of medical devices which might otherwise require lubrication during use, since the rehydrated gel automatically provides such lubrication.
  • Urological catheters are one example of a medical device which generally requires lubrication during use, and which would benefit from the natural lubrication provided by the rehydrated gel.
  • L5 6 milligrams of antimicrobial metals with atomic disorder, in free-standing powder form, are sprinkled lightly onto 6.5 cm 2 of burned tissue, and thereafter wet with a light spray of water or wound exudate or TDWL (Trans Dermal Water Loss) or other bodily fluids,
  • 0.5 milligrams of antimicrobial metals with atomic disorder, in free-standing powder form, are injected, using a small-needle drug delivery system or a needle- less drug delivery system, into gum tissue so as to treat gingivitis.
  • the treatment is repeated every 3 days until the therapeutic effects are no longer needed.
  • a solution of antimicrobial metals with atomic disorder is prepared by dissolving 6 milligrams of antimicrobial metals with atomic disorder in 1 gram of water.
  • the solution of antimicrobial metals with atomic disorder is applied as a rinse or bath or wash to a wound site so as to provide an antimicrobial treatment to the wound site. The treatment is repeated every 24 hours until the therapeutic effects are no longer needed.
  • a solution of antimicrobial metals with atomic disorder is prepared by dissolving 6 milligrams of antimicrobial metals with atomic disorder in 1 gram of water.
  • the solution of antimicrobial metals with atomic disorder is applied to the interior of the bladder via a catheter so as to provide antimicrobial treatment to the bladder. The treatment is repeated every 8 hours until the therapeutic effects are no longer needed.
  • a solution of antimicrobial metals with atomic disorder is prepared by dissolving 6 milligrams of antimicrobial metals with atomic disorder in 1 gram of water.
  • the solution of antimicrobial metals with atomic disorder is injected (using a small-needle or needle-less injection system) under the toenails or into the nail bed and/or the surrounding tissue of a person suffering from onychomycosis so as to provide an antimicrobial treatment to the tissue.
  • the treatment is repeated 2 times a day until the therapeutic effects are no longer needed.
  • the solutions were in turn placed in an ultrasonic nebulizer that created small droplets containing dissolved and suspended parts of the solution of nanocrystalline noble metals.
  • the output from the nebulizer was directed into a chamber made from a stainless steel frame and base.
  • Petri dishes containing Mueller Hinton agar streaked with 4 h old cultures of Pseudomonas aerugi ona and Staphyl ococcus aureus were exposed to nanocrystalline noble metal aerosols and the silver nitrate aerosols.
  • the delivery of antimicrobial materials may most expeditiously be accomplished by using aerosols (e.g., in the treatment of pneumonia).
  • aerosols e.g., in the treatment of pneumonia.
  • the drawback of aerosols is the requirement for a high concentration of the active ingredient to ensure that a sufficient amount is delivered to achieve the biological effect desired without causing problems with the carrier solvent (e.g., water).
  • the essential requirement of the equipment for producing an aerosol that contains dissolved and suspended components of antimicrobial metals with atomic disorder is that it must form droplets of aerosol directly from the liquid form, and the aerosol droplets must be small enough to reach the lungs. This means that the droplets should be preferably less than approximately 10 ⁇ m.
  • the aerosol cannot be created by first evaporating the liquid and then condensing it to form droplets, since this would remove the desired antimicrobial metals with atomic disorder from the aerosol.
  • a test chamber was constructed using a stainless steel frame with a transparent plastic covering. The frame was placed on a stainless steel plate. The output nozzle from the humidifier was modified so that the aerosol could be directed into the chamber at a height of approximately 30 cm from the base. The plates and other test samples were placed on the stainless steel plate and exposed to the aerosol for a prescribed length of time.
  • Solution 1 A solution of antimicrobial metals with atomic disorder was prepared by immersing 518 sq. inches of Acticoat ® burn dressing in IL of reverse osmosis water, which was treated with C0 2 to maintain a pH of 6.5. After 20 minutes the concentration of silver in the water was 85 ⁇ g/mL.
  • Solution 2 A solution containing 370 ⁇ g/mL of silver from a
  • Acticoat ® dressing was prepared as follows: 1 L of reverse osmosis water was purged with commercial grade carbon dioxide until the pH was 4.3. Sufficient Acticoat ® dressing was added to bring the pH up to 6.5. At that time, the silver concentration was 370 ⁇ g/mL.
  • Solution 3 Ag as AgNo 3 was prepared by dissolving 0.157 g of AgNo 3 into 1 L of reverse osmosis water and mixed until dissolved. The solution was analyzed by Atomic
  • Solution 4 Ag as AgN0 3 was prepared by dissolving 0.427 of AgN0 3 into 1 L of reverse osmosis water and mixed until dissolved. The solution was analyzed by Atomic
  • Aerosolization Petri dishes containing Mueller Hinton agar, were streaked with 4 h old cultures of Pseudomonas aeruginosa or Staphyl ococcus a ureus . The plates were then weighed and their exposed outer surfaces were coated with Parafilm to prevent condensation from occurring on these surfaces. These plates were placed in the aerosol chamber uncovered. The ultrasonic nebulizer was then started and run for 53 minutes. The plates were then removed from the chamber, the plastic was removed and the dishes re-weighed so that the amount of moisture loss/gain could be determined. The plates were then placed in a 35° C incubator for 16 h. After incubation the pattern and amount of growth was assessed on the plates for both organisms.
  • the Acticoat ® dressing generated silver was effective at controlling the growth of both organisms while the silver nitrate only prevented the growth of
  • both antimicrobial metals with atomic disorder 370 ⁇ g/mL
  • AgNo 3 300 ⁇ g/mL were effective at controlling P. aerugi nosa . Since no re-growth occurred, it is assumed that the agent at this concentration was bactericidal. Antimicrobial silver with atomic disorder was more effective than AgN0 3 at controlling S. aureus. No re- growth occurred on any plates or in the broth indicating a total kill of the organism while, in the AgN0 3 treatment, a large number of organisms grew at 16h.
  • a dose per unit area can be calculated. In each case for Solution 1, the dose was 8.5 ⁇ g/sq. inch, while for
  • the dose was 38 ⁇ g/sq. inch. These doses, on a per lung basis, would be less than 10 mg of silver per hour of treatment. Each hour of treatment with antimicrobial silver with atomic disorder aerosols appears to provide at least 48 h of protection. Therefore, the dose per day, from the high concentration treatment, would be about 5 mg or a little less than the silver released by 2 sq. inches of SSD per day.
  • the most significant advantage of using antimicrobial silver with atomic disorder may be the lack of a toxic action such as N0 3 or sulfadiazine.
  • Aerosols of antimicrobial metals with atomic disorder transmit the antimicrobial activity of the dressings to remote sites.
  • Aerosols of antimicrobial metals with atomic disorder are more effective than comparable concentrations of silver nitrate.
  • Gel products of antimicrobial metals with atomic disorder encompass both “wet” and “dry” materials.
  • a "wet" gel product of antimicrobial metals with atomic disorder is a product that provides moisture to a dry skin condition (psoriasis, eczema, acne, wound, etc.) and facilitates autolytic debridement of necrotic tissue. It also delivers the antimicrobial and anti-inflammatory properties of the suspended antimicrobial metals with atomic disorder powders.
  • biologically active molecules it is also beneficial to supply biologically active molecules to elicit a specific response such as cell migration, etc. Since these biologically active molecules are susceptible to microbial degradation if not protected, it is beneficial to include them in gels of antimicrobial metals with atomic disorder that will provide the necessary protection.
  • “Dry” gel products of antimicrobial metals with atomic disorder are physically stabilized (dry or cross-linked) materials that provide lubricious, antimicrobial, antithrombogenic, and anti-inflammatory properties to a variety of implantable, trancutaneous or topically applied devices.
  • the coatings may also provide other benefits such as accelerating or otherwise facilitating tissue integration by creating a favorable environment for cell proliferation. This favorable environment may be created by including cytoconductive agents or anti-adhesion agents such as bone morphogenetic proteins, B-glucan hyaluronic acids in the gel.
  • the gel may be stabilized by cross-linking the gel components (collagen, gelatin, etc.) or by drying the coated materials.
  • Examples of the primary gelling agents are listed in Table 3. Biologically active ingredients that may be used, in any combination with the primary gelling agents, are given in Table 4 . Materials that should not be used with gels of antimicrobial silver with atomic disorder are given in Table 5.
  • No. 1 A commercial carboxymethyl cellulose/pectin gel (Duoderm Convatec) was combined with antimicrobial metals with atomic disorder powder to produce a gel with 0.1% silver. A logarithmic reduction test was performed as follows in the gel using Pseudomonas aeruginosa .
  • the inoculum was prepared by placing 1 bacteriologic loopful of the organism in 5 mL of trypticase soy broth and incubating it for 3-4 h. The inoculum (0.1 mL) was then added to 0.1 mL of gel and vortexed (triplicate samples) . The mixture was incubated for one-half hour. Then 1.8 L of sodium thioglycollate-saline (STS) solution was added to the test tube and vortexed. Serial dilutions were prepared on 10 "1 to 10 "7 . A 0.1 mL aliquot of each dilution was plated in duplicate into Petri plates containing Mueller-Hinton agar. The plates were incubated for 48 h and then colonies were counted. Surviving members of organisms were determined and the logarithmic reduction compared to the initial inoculum was calculated.
  • STS sodium thioglycollate-saline
  • Carboxymethyl cellulose (CMC) fibers were coated directly to produce a defective nanocrystalline antimicrobial coating.
  • the CMC was then gelled in water by adding 2.9 g to 100 mL volume. This material was tested using the method of No. 1. The material generated a 5.2 logarithmic reduction of Pseudomonas aeruginosa, demonstrating that the gel had a significant bactericidal effect.
  • the well was filled with either 0.1 mL of the silver containing gel, a mupirocin containing cream or a mupirocin containing ointment.
  • the Petri plates were then incubated for 24 h and the diameter of the zone of inhibition was measured and recorded.
  • the silver containing gel produced 9 mm zones against both Pseudomonas aerugi nosa and Staphyl ococcus a ureus, while the mupirocin cream and ointment produced 42 and 48 mm zones against Staphylococcus a ureus and 0 mm zones against Pseudomonas aerugi nosa .
  • the silver containing gel reduced the Pseudomonas aeruginosa and Staphylococcus a ureus properties 4.4 and 0.6 logs, respectively, showing good bactericidal activity.
  • the mupirocin cream and ointment generated 0.4 and 0.8, and 0.8 and 1.6, log reductions against Staphyl ococcus a ureus and Pseudomonas aeruginosa , respectively.
  • the silver gel had both a greater bactericidal effect and spectrum of activity than the mupirocin containing products.
  • Zones of inhibitions were determined in No. 4 and log reductions were determined in No. 1. All formulae provided a broader spectrum of activity and a greater bactericidal effect than did mupirocin in a cream or ointment form.
  • the mupirocin cream produced zones of inhibition of 42 and 0, and log reduction of 0.4 and 0.8, against Staphyl ococcus a ureus and Pseudomonas aerugi nosa , respectively.
  • No. 11 A commercially available gel (glyceryl polymethacrylate) was blended with antimicrobial metals with atomic disorder powder to produce a gel with a silver content of 0.1%. This gel was tested as in Nos. 5-10 and was found to produce zones of 15 mm against both Staphyl ococcus a ureus and Pseudomonas aerugi nosa . Log reductions of 1.7 and >5 were produced against Staphyl ococcus a ureus and Pseudomonas aerugi nosa . This gel product had a greeted spectrum of activity than did mupirocin cream or ointment.
  • a gel coat for a urinary catheter was prepared using the formula in No. 6. The coating was applied to the catheter using a dipping method. The coating was air dried overnight.
  • the dried gel coat was smooth and easy to handle. It was not tacky to touch and had excellent abrasion and adhesion properties. Upon rewetting, the surface became extremely slippery indicating excellent lubricious properties.
  • a zone of inhibition test was performed against Pseudomonas aerugi nosa using an inoculum as prepared in No. 1.
  • the inoculum (0.1 mL) was spread over the surface of Mueller-Hinton agar in a Petri plate.
  • the catheter was cut into 1" segments which were laid on their side into the middle of the Petri plate. Petri plates were incubated for 24 h and then the zone of inhibitions was measured.
  • zones of inhibition were generated that ranged from 7-10 mm. This indicates that getting drying and rehydrating had no negative effect on the antimicrobial activity of the gel coat.

Abstract

Therapeutic treatments using the direct application of selected structures of antimicrobial metals in free-standing powder form, solution form and/or suspension form in therapeutically effective amounts. The selected structures of antimicrobial metals serve as an antimicrobial agent, an anti-inflammatory agent, an immuno modulator agent, an enzyme modulator agent, and/or an anti-tumor agent, for human and/or animal use.

Description

THERAPEUTIC TREATMENTS USING THE DIRECT APPLICATION OF ANTIMICROBIAL METAL COMPOSITIONS
Reference To Pending Prior Patent Applications This patent application:
(1) claims benefit of pending prior U.S. Provisional Patent Application Serial No. 60/285,884, filed April 23, 2001 by Robert E. Burrell et al . for THERAPEUTIC TREATMENTS USING THE DIRECT APPLICATION OF NOBLE METAL COMPOSITIONS (Attorney's Docket No. WEST-1 PROV) , which patent application is hereby incorporated herein by reference; and
(2) is a continuation-in-part of pending prior U.S. Patent Application Serial No. 09/840,637, filed April 23, 2001 by Robert E. Burrell et al. for
TREATMENT OF ACNE (Attorney's Docket No. 53-01), which patent application is also hereby incorporated herein by reference.
Field Of The Invention
This invention relates to therapeutic treatments in general, and more particularly to therapeutic treatments using the direct application of antimicrobial metal compositions.
Background Of The Invention Localized infections affect millions of people each year. If not timely treated, localized infections may spread, can result in unnecessary pain, may require increasingly more aggressive treatment, can result in developmental delays and permanent disability and, in severe cases, can even result in death.
A common form of treatment for localized infections is oral antibiotic therapy. However, this treatment is systemic, requires multiple dosages, frequently causes side effects, and can give rise to the evolution of antibiotic-resistant bacteria. Furthermore, debates are common among healthcare professionals and the general population regarding the over-use of antibiotics.
As a result, there is a significant need for an improved treatment for localized infections. Description Of The Invention
Overview
Nucryst Pharmaceuticals Corp. and its predecessors, all of Fort Saskatchewan, Alberta, Canada and sometimes collectively referred to herein as "Nucryst", have developed selected structures of antimicrobial metals such as silver, gold, platinum, palladium, etc. See, for example, International Patent Publication No. WO 93/23092, published November 25, 1993/ International Patent Publication No. WO 95/13704, published May 26, 1995/ and International Patent Publication No. WO 98/41095, published September 24, 1998, which documents are hereby incorporated herein by reference. These selected structures of antimicrobial metals will hereinafter sometimes be collectively referred to as "antimicrobial metals with atomic disorder" . Nucryst has determined that its antimicrobial metals with atomic disorder provide excellent therapeutic benefits. More particularly, antimicrobial metals with atomic disorder have been found to serve effectively as an antimicrobial agent, an anti- inflammatory agent, an immuno modulator agent, an enzyme modulator agent, and/or an anti-tumor agent, for human and/or animal use. Among other things, antimicrobial metals with atomic disorder have proven to be a broad spectrum (e.g., gram positive, gram negative, fungus and drug resistant) bacteriocidal agent with little likelihood of fostering resistant bacteria and having a sustained antimicrobial activity (for example, antimicrobial activity lasting over seven days has been consistently demonstrated with antimicrobial metals with atomic disorder) .
Furthermore, Nucryst has recently discovered new ways of forming its antimicrobial metals with atomic disorder in free-standing powder form, solution form and suspension form. The ability to form antimicrobial metals with atomic disorder in free-standing powder form, solution form and suspension form has greatly expanded the possibilities for using these selected nanocrystalline compositions for therapeutic purposes.
In particular, the ability to form antimicrobial metals with atomic disorder in free-standing powder form, solution form and suspension form has lead to the further discovery that it is possible to utilize antimicrobial metals with atomic disorder in a radical new way, i.e., for direct application to a wide range of different tissues so as to therapeutically treat a wide range of different medical disorders.
Furthermore, by combining the therapeutic benefits of antimicrobial metals with atomic disorder with recent advances in minimally invasive surgery, including small-needle and needle-less drug delivery systems, therapeutic treatments may be applied to internal anatomy as well as to surface anatomy.
Antimicrobial Metals With Atomic Disorder
The present invention utilizes selected structures of antimicrobial metals. The antimicrobial metals are preferably selected noble metals such as silver, gold, platinum, palladium, etc. The structures are formed with atomic disorder, such that ions, clusters, atoms or molecules of the metals are released at a concentration sufficient to provide a localized therapeutic effect. The structures are preferably in nanocrystalline form. Antimicrobial metals with atomic disorder may be prepared in the manner taught in International Patent Publication No. WO 93/23092, published November 25, 1993; International Patent Publication No. WO 95/13704, published May 26, 1995; and International Patent Publication No. WO 98/41095, published September 24, 1998, which documents are incorporated herein by reference.
As used herein, the terms and phrases set out below are intended to have the meanings as follows: "Metal" or "metals" includes one or more metals whether in the form of substantially pure metals, alloys or compounds such as oxides, nitrides, borides, sulphides, halides or hydrides.
"Antimicrobial metals" are silver, gold, platinum, palladium, iridium, zinc, copper, tin, antimony, bismuth, or mixtures of these metals with same or other metals, silver, gold, platinum and palladium being preferred, and silver being most preferred.
"Noble metals" are silver, gold, platinum and palladium, or mixtures of such metals with same or other metals, with silver metal being the most preferred. "Antimicrobial effect" means that atoms, ions, molecules or clusters of the antimicrobial or noble metal are released into the electrolyte which the coating contacts in concentration sufficient to inhibit microbial growth on and in the vicinity of the coating. The most common methods of measuring an antimicrobial effect are a zone of inhibition test (which indicates an inhibitory effect, whether microbiostatic or microbiocidal) or a logarithmic reduction test (which indicates a microbiocidal effect) . In a zone of inhibition test (ZOI) the material to be tested is placed on a bacterial lawn (or a lawn of other microbial species) and incubated. A relatively small or no ZOI (ex. less than 1 mm) indicates a non-useful antimicrobial effect, while a larger ZOI (ex. greater than 5 mm) indicates a highly useful antimicrobial effect. The ZOI is generally reported as a corrected zone of inhibition (CZOI), wherein the size of the test sample is subtracted from the zone. A logarithmic reduction test in viable bacteria is a quantitative measure of the efficacy of an antibacterial treatment; for example, a 5 log reduction means a reduction in the number of microorganisms by 100, 000-fold (e.g., if a product contained 100,000 pertinent microorganisms, a 5 log reduction would reduce the number of pertinent microorganisms to 1). Generally, a 3 log reduction represents a bactericidal effect. The logarithmic reduction test involves combining the inoculum with the test treatment, recovering the bacteria or other microbial species, and enumerating the bacteria or other microbial species using serial dilutions.
"Anti-inflammatory effect" means a reduction in one or more of the symptoms of erythema (redness), edema (swelling) , pain and pruritus which are characteristic of inflammatory skin conditions.
"Inflammatory skin conditions" refers to those conditions of the skin in which inflammatory cells (e.g., polymorphonuclear neutrophils and lymphocytes) infiltrate the skin with no overt or known infectious etiology, but excluding psoriasis and its related conditions. Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, pruritus, increased surface temperature and loss of function. As used herein, inflammatory skin conditions include, but are not limited to, eczema and related conditions, insect bites, erythroderma, mycosis fungoides and related conditions, pyoderma gangrenosum, erythema multiforme, rosacea, onychomycosis, and acne and related conditions, but excluding psoriasis and its related conditions. "Biocompatible" means generating no significant undesirable host response for the intended utility. Most preferably, biocompatible materials are non-toxic for the intended utility. Thus, for human utility, biocompatible is most preferably non-toxic to humans or human tissues.
"Sustained release" or "sustainable basis" are used to define release of atoms, molecules, ions or clusters of a antimicrobial metal that continues over time measured in hours or days, and thus distinguishes release of such metal species from the bulk metal, which release such species at a rate and concentration which is too low to be therapeutically effective, and from highly soluble salts of antimicrobial metals such as silver nitrate, which releases silver ions virtually instantly, but not continuously, in contact with an alcohol or electrolyte.
"Atomic disorder" includes high concentrations of one or more of: point defects in a crystal lattice, vacancies, line defects such as dislocations, interstitial atoms, amorphous regions, grain and sub grain boundaries and the like relative to its normal ordered crystalline state. Atomic disorder leads to irregularities in surface topography and inhomogeneities in the structure on a nanometer scale.
"Normal ordered crystalline state" means the crystallinity normally found in bulk metal materials, alloys or compounds formed as cast, wrought or plated metal products. Such materials contain only low concentrations of such atomic defects as vacancies, grain boundaries and dislocations.
"Diffusion", when used to describe conditions which limit diffusion in processes to create and retain atomic disorder, i.e. which freeze-in atomic disorder, means diffusion of atoms (adatom diffusion) and/or molecules on the surface or in the matrix of the material being formed.
"Alcohol or water-based electrolyte" is meant to include any alcohol or water-based electrolyte that the antimicrobial materials of the present invention might contact in order to activate (i.e. cause the release of species of the antimicrobial metal) into same. The term is meant to include alcohols (short chain (C6 or less) and preferably C4 or less), water, gels, fluids, solvents, and tissues containing, secreting, or exuding water or water-based electrolytes, including body fluids (for example blood, urine, or saliva), and body tissue (for example skin).
"Bioabsorbable" as used herein in association includes substrates which are useful in medical devices, that is which are biocompatible, and which are capable of bioabsorption in period of time ranging from hours to years, depending on the particular application.
"Bioabsorption" means the disappearance of materials from their initial application site in the body (human or mammalian) with or without degradation of the dispersed polymer molecules.
"Colour change" is meant to include changes of intensity of light under monochromatic light as well as changes of hue from white light containing more than one wavelength.
An "interference colour" is produced when light impinges on two or more partly reflective surfaces separated by a distance which bears the right relationship to the wavelength of the light to be removed by destructive interference.
"Partly reflective" when used to describe the base or top layer materials, means that the material has a surface which reflects a portion of incident light, but which also transmits a portion of the incident light. Reflection occurs when a ray of incoming light encounters a boundary or interface characterized by a change in refractive index between two media. For the top layer of the antimicrobial materials of this invention, that interface is with air. For the base layer, the interface is with the top layer. The reflectance of the base and top layers is balanced so as to generate an interference colour. "Partly light trans issive" when used to describe a thin film of the top layer material means that the thin film is capable of transmitting at least a portion of incident visible light through the thin film.
"Detectable" when used to describe a colour change means an observable shift in the dominant wavelength of the reflected light, whether the change is detected by instrument, such as a spectrophotometer, or by the
wr,D i' human eye. The dominant wavelength is the wavelength responsible for the colour being observed.
"Cold working" as used herein indicates that the material has been mechanically worked such as by 5 milling, grinding, hammering, mortar and pestle or compressing, at temperatures lower than the recrystallization temperature of the material. This ensures that atomic disorder imparted through working is retained in the material. 10 "Pharmaceutically- or therapeutically-acceptable" is used herein to denote a substance which does not significantly interfere with the effectiveness or the biological activity of the active ingredients (antimicrobial and anti-inflammatory activities) and L5 which has an acceptable toxic profile for the host to which it is administered.
"Therapeutically effective amount" is used herein to denote any amount of a formulation of the antimicrobial or noble metals which will exhibit either '0 or both of an antimicrobial and optionally an anti- inflammatory effect, or some other therapeutic effect, when applied to the affected area of the tissue. A single application of the formulations of the present invention may be sufficient, or the formulations may be applied repeatedly over a period of time, such as several times a day for a period of days or weeks. The amount of the active ingredient, that is the antimicrobial or noble metal in the form of a coating, powder or dissolved in liquid solution, will vary with the conditions being treated, the stage of advancement of the condition, the age and type of host, and the type and concentration of the formulation being applied. Appropriate amounts in any given instance will be readily apparent to those skilled in the art or capable of determination by routine experimentation.
"Carrier" means a suitable vehicle including one or more solid, semisolid or liquid diluents, excipients or encapsulating substances which are suitable for administration to the skin.
"Nanocrystalline" is used herein to denote single-phase or multi-phase polycrystals, the grain size of which is less than about 100, more preferably < 50, even more preferably <40, even more preferably <30, and most preferably < 25 nanometers in at least one dimension. The term, as applied to the crystallite or grain size in the crystal lattice of coatings, powders
WE, i-i or flakes of the antimicrobial or noble metals, is not meant to restrict the particle size of the materials when used in a powder form.
"Powder" is used herein to include particulates of 5 the antimicrobial or noble metals ranging from nanocrystalline (less than 100 nm) to submicron sized powders up to flakes. Preferably, powders of the antimicrobial or noble metals used in the present invention are sized at less than 100 μm, and more
10 preferably less than 40 urn, and most preferably less than 10 μm.
"Grain size", or "crystallite size" means the size of the largest dimension of the crystals in the antimicrobial metal coating or powder.
L5 "Hydrocolloid" means a synthetically prepared or naturally occurring polymer capable of forming a thickened gel in the presence of water and polyols (swelling agent) . The swelling agent must be capable of swelling the hydrocolloid chosen in order to form
:0 the gel phase.
"Hydrogels" means a hydrocolloid swollen with water or another hydrophilic liquid which is used for absorbing or retaining moisture or water. "Gel" means a composition that is of suitable viscosity for such purposes, e.g., a composition that is of a viscosity that enables it to be applied and remain on the skin. When used herein and in the claims, the term
"nanocrystalline antimicrobial metal" and similar terminology, such as "nanocrystalline coatings or powders" is meant to refer to antimicrobial metals formed with atomic disorder and having a nanocrystalline grain size.
Free-Standing Powder Form Of Antimicrobial Metals With Atomic Disorder
Antimicrobial metals with atomic disorder may be provided in free-standing powder form in a variety of different ways.
By way of example but not limitation, in International Patent Publication No. WO 93/23092, published November 25, 1993; and/or International
Patent Publication No. WO 95/13704, published May 26, 1995; and/or International Patent Publication No. WO 98/41095, published September 24, 1998, it was disclosed that antimicrobial metals with atomic disorder may be provided in free-standing powder form by "cold working".
Furthermore, in International Patent Publication No. WO 93/23092, published November 25, 1993; and/or International Patent Publication No. WO 95/13704, published May 26, 1995; and/or International Patent Publication No. WO 98/41095, published September 24, 1998, it was disclosed that antimicrobial metals with atomic disorder may be provided in free-standing powder form by vapor deposition on a fixed element, with the deposited material thereafter being stripped off so as to yield the desired free-standing powder.
In accordance with a further aspect of the present invention, it has recently been discovered that antimicrobial metals with atomic disorder may be provided in free-standing powder form by vapor deposition on an NGRC ("next generation roll coater") apparatus. More particularly, a continuous belt is coated with antimicrobial metals with atomic disorder using vapor deposition techniques, with the antimicrobial metals with atomic disorder being scraped off the belt further down the line so as to yield the free-standing powder form of the antimicrobial metals with atomic disorder.
This last-mentioned method for making the free-standing powder form of the antimicrobial metals with atomic disorder (i.e., vapor deposition on an NGRC apparatus) is particularly advantageous, inasmuch as it can quickly and easily yield a relatively large supply of free-standing powder at a relatively low cost.
Crystalline powder forms of the antimicrobial or noble metals (particularly preferred being Ag, Au, Pt, and Pd) can be prepared as free standing powders, by coating powdered substrates, or from coatings on substrates which are then collected, for example by scraping and then sized. The powders may be prepared as pure metals, metal alloys or compounds such as metal oxides or metal salts, by vapour deposition, mechanical working, or compressing to impart the atomic disorder. The crystalline powders are formed with atomic disorder in accordance with the techniques set out above and as published in the prior patent applications of Burrell et al . , see for example WO 93/23092, published November 25, 1993, and WO 95/13704, published May 26, 1995. The atomic disorder will most typically be formed in the metal powders during physical vapour deposition as set out above for coatings or by mechanically imparting the disorder, such as by milling, grinding, hammering, mortar and pestle or compressing, under conditions of low temperature (i.e., temperatures less than the temperature of recrystallization of the material) to ensure that annealing or recyrstallization does not take place.
Alternatively, the powders may be formed by inert- gas condensation techniques, which are modified to provide atomic disorder in the powder produced, as taught in WO 95/13704 to Burrell et al .
Powders of the antimicrobial or noble metals are preferably formed by physical vapour deposition (PVD) onto a substrate such as a cold finger, a silicon wafer, solid plates, a rotating cylinder, a continuous belt in a roll coater, or on steel collectors in known PVD coaters. Preparation of powders of the present invention by sputtering onto a continuous belt in a roll coater, or other some other moving or rotating substrate surface is particularly advantageous, inasmuch as it can quickly and easily yield a relatively large supply of free-standing powder at a relatively low cost. A stainless steel belt can be used in the roll coating process without the need to provide additional cooling of the substrate. The powders or coatings are then scraped off to form a powder, and may be sized to avoid overly large particulates. The powders are scraped off the moving surface with scrapers which contact the moving surface at an angle sufficient to remove the coating in flake or powder form. The coating may be scraped off with scrapers angled for forward cutting of the coating from the moving surface, or with scrapers which remove the coating from the moving surface by reverse dragging action on the surface. The scrapers may be suspended above the belt, and either weighted or spring loaded to apply pressure sufficient to remove the coating from the moving surface. With a continuous belt, the scrapers can conveniently be located above the end rollers to remove the coating with a reverse dragging action as the belt rounds the end roller. Alternatively, the powders of the antimicrobial or noble metals may be formed on powdered substrates which are biocompatible, or otherwise compatible for the end use of the powder. Particularly preferred powdered substrates are hydrocolloids, particularly those which are bioabsorbable and/or hygroscopic powders such as chitin. Exemplary bioabsorbable and/or hygroscopic powders are composed of : Synthetic Bioabsorbable Polymers: for example polyesters/polyactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers .
Naturally Derived Polymers: Proteins: albumin, fibrin, collagen, elastin; Polysaccharides : chitosan, alginates, hyaluronic acid; and Biosynthetic Polyesters: 3-hydroxybutyrate polymers.
The powders may be incorporated into or onto medical dressings or pharmaceutical formulations, by any methods known in the art. For example, the powders may be layered onto the substrates (dressings or powders) , mechanically fixed within the fibres of the dressings, impregnated into dressings by physical blowing, or added to topical pharmaceutical ingredients . Preferably, powders of the present invention are sized at less than 100 μm, and more preferably less than 40 μm, and most preferably about 3 - 5 μm in size. Once antimicrobial metals with atomic disorder have been provided in free-standing powder form, they can then be used therapeutically in that form, or the free-standing powder can be used to form solutions or suspensions of the antimicrobial metals with atomic disorder prior to being used to therapeutically treat tissue.
Use Of Antimicrobial Metals With Atomic Disorder In Free-standing Powder Form
Antimicrobial metals with atomic disorder in free-standing powder form may be sprinkled lightly onto surface anatomy (e.g., the skin) in therapeutically effective amounts so as to provide an antimicrobial treatment to that surface anatomy, e.g., to an infected cut. If desired, antimicrobial metals with atomic disorder may be mixed with one or more other materials prior to being sprinkled onto the skin, where these other materials may be biologically active materials (e.g., growth promoters) or biologically neutral materials acting as a "filler" to facilitate easier deployment of relatively small quantities of antimicrobial metals with atomic disorder. Or antimicrobial metals with atomic disorder in free-standing powder form can be applied to the lungs using a so-called dry powder inhaler.
Antimicrobial metals with atomic disorder in freestanding powder form may also be injected, by small- needle or needle-less injection, into the interior of the body in therapeutically effective amounts so as to provide their therapeutic benefit to interior anatomy. The antimicrobial metals with atomic disorder can be delivered to interior anatomy via a small-needle drug delivery system or via a needle-less drug delivery system. Such systems are available from Powderject Research Limited of Oxford, United Kingdom (see, for example, U.S. Patents Nos. 5,899,880; 6,010,478 and 6,013,050, which patents are hereby incorporated herein by reference) and Bioject, Inc. of Portland, Oregon (see, for example, U.S. Patents Nos. 4,596,556; 4,790,824; 5,064,413; 5,312,335; 5,383,851; 5,399,163; 5,520,639; 6,096,002; and Des. 349,958, which patents are also hereby incorporated herein by reference) . Delivery of antimicrobial metals with atomic disorder with such drug delivery systems provides local therapy to the interior anatomy. Where the antimicrobial metals with atomic disorder are to be applied to the tissue in free-standing powder form by inhalation and/or injection, it is preferred that the particulate size be less than 2 microns, and preferably less than 1 micron, so as so minimize any adverse reaction to the presence of the particulate in the tissue.
Many health afflictions can be addressed by delivering antimicrobial metals with atomic disorder, in free-standing powder form, to an interior anatomical site with small-needle and/or needle-less drug delivery systems. Examples of some of these applications include: (1) dermal drug delivery for skin conditions such as, but not limited to, acne, psoriasis, eczema and skin infections; (2) localized infections such as, but not limited to, middle ear infections, endocardititis, pericarditis, prostatitis, sinusitis, osteomyelitis and onychomycosis; (3) mouth, gum and throat afflictions; (4) arthritis; and (5) direct-to- tumor chemotherapeutic delivery.
For example, antimicrobial metals with atomic disorder may be injected directly into psoriatic plaques. Or antimicrobial metals with atomic disorder may be injected by small-needle or needle-less injection through the eardrum (i.e., through the tympanic membrane) into the middle ear, whereby to provide a localized antimicrobial, anti-inflammatory treatment for middle ear infections. Or long-acting antimicrobial metals with atomic disorder may be injected into the prostate gland for difficult-to-treat prostate infections. And antimicrobial metals with atomic disorder may be injected into the tissues of the oral cavity and throat to treat sore throats, thrush (Candida infections) and periodontal diseases such as gingivitis. Also, antimicrobial metals with atomic disorder may be injected into arthritic joints to reduce destructive inflammation. And long-acting antimicrobial metals with atomic disorder of platinum can be injected into tumors that are responsive to chemotherapy with platinum compounds. Numerous advantages are achieved by delivering antimicrobial metals with atomic disorder to the interior anatomy using such drug delivery systems. For one thing, local treatment (versus systemic treatment) results in lower total doses being required and in fewer side effects. For another thing, the broad spectrum antimicrobial activity of the antimicrobial metals with atomic disorder results in faster infection fighting with low likelihood of bacterial resistance. Furthermore, due to the long-acting nature of the antimicrobial metals with atomic disorder, a single dose or relatively infrequent (e.g., weekly) doses results in an easier therapy regimen than many conventional treatment regimens.
Solutions Of Antimicrobial Metals With Atomic Disorder
It is also possible to provide antimicrobial metals with atomic disorder in solution form. The solution form of antimicrobial metals with atomic disorder can be advantageous in many anatomical applications, since there is substantially no particulate present which might irritate tissue. Antimicrobial metals with atomic disorder may be provided in solution form in a variety of different ways .
In one form of the invention, a solution of antimicrobial metals with atomic disorder is created by dissolving a f ee-standing powder of antimicrobial metals with atomic disorder in water. The f ee-standing powder of antimicrobial metals with atomic disorder may be packaged in a "tea-bag" type pouch, such that undissolved antimicrobial metals with atomic disorder remain captured within the pouch.
In another form of the invention, a solution of antimicrobial metals with atomic disorder may be provided by immersing, in water, a substrate carrying deposited antimicrobial metals with atomic disorder. By way of example, a carrier strip may be coated with antimicrobial metals with atomic disorder by vapor deposition, and then the carrier strip may be immersed in water so as to create the solution of antimicrobial metals with atomic disorder. Alternatively, a bandage may be coated with antimicrobial metals with atomic disorder by vapor deposition, and then the bandage may be immersed in water so as to create the solution of antimicrobial metals with atomic disorder.
The solution of antimicrobial metals with atomic disorder may be prepared in advance (e.g., at a manufacturing plant) or on site at the time of use. Where a solution of antimicrobial metals with atomic disorder is prepared in advance (e.g., at a manufacturing plant), it is preferred that the solution be created by immersing a "tea-bag" type pouch of the free-standing powder form of antimicrobial metals with atomic disorder in water and leaving it there until the time of use, or by immersing a substrate carrying deposited antimicrobial metals with atomic disorder in water and leaving it there until the time of use. Once a solution of antimicrobial metals with atomic disorder has been created, it may be applied to tissue as a liquid or as an aerosol.
Regardless of how the solution of antimicrobial metals with atomic disorder is applied to tissue, the dosage is dependent, to at least some extent, on the concentration of antimicrobial metals with atomic disorder present in the solution. Thus, where it is necessary to apply a strong dose of antimicrobial metals with atomic disorder, it may be desirable to raise the concentration of antimicrobial metals with atomic disorder in the solution. In this respect it has been discovered that by lowering the pH of the solution, a higher concentration of antimicrobial metals with atomic disorder can be obtained and, significantly, the antimicrobial metals with atomic disorder go into solution faster. The pH of the solution can be lowered by adding acid to the solution. In one preferred form of the invention, CO? is added to the solution: the C02 creates carbonic acid, thus lowering the pH of the solution and increasing the concentration of antimicrobial metals with atomic disorder in the solution. As noted above, once a solution of antimicrobial metals with atomic disorder has been created, it may be applied to tissue as a liquid or as an aerosol.
Use Of Antimicrobial Metals With Atomic Disorder In Solution Form -Liquid Application
A solution of antimicrobial metals with atomic disorder may be applied, in liquid form, and in various viscosities, to a wide range of different tissues in therapeutically effective amounts so as to therapeutically treat a wide range of different medical disorders . By way of example, a solution of antimicrobial metals with atomic disorder can be applied as a rinse or bath or wash to treat a dermal condition such as, but not limited to, acne, psoriasis, eczema and skin infections. Alternatively, a solution of antimicrobial metals with atomic disorder can be applied as a rinse or bath or wash to treat a wound or a surgical site.
Or a solution of antimicrobial metals with atomic disorder can be applied to mouth tissue (e.g., the gums) as an oral rinse. Or a solution of antimicrobial metals with atomic disorder can be applied to throat tissue as a gargle.
Or a solution of antimicrobial metals with atomic disorder can be applied to nasal passages and the sinus, e.g., to treat sinusitis and allergic rhinitis. Or a solution of antimicrobial metals with atomic disorder can be applied to the eyes as eyedrops.
Or a solution of antimicrobial metals with atomic disorder can be applied to the ears as ear drops. It is also possible to apply a solution of antimicrobial metals with atomic disorder, in liquid form, to internal anatomy using a small-needle and/or needle-less drug delivery systems, including catheter- based drug delivery systems. Thus, for example, a solution of antimicrobial metals with atomic disorder may be introduced by catheter into the bladder to treat a bladder infection; or injected into the middle ear to treat middle ear infections; or injected or instilled or otherwise introduced into the abdomen to treat a post-surgical abdominal abscess or to treat an infection from peritoneal dialysis; or injected or instilled or otherwise introduced into other internal anatomical structures, including body cavities, so as to treat conditions such as, but not limited to, endocardititis, pericarditis, prostatitis, sinusitis, osteomyelitis and onychomycosis; or injected into skin tissue to treat acne, psoriasis, eczema and/or or other skin conditions; etc.
Use Of Antimicrobial Metals With Atomic Disorder In Solution Form - Aerosol Application
A solution of antimicrobial metals with atomic disorder may also be applied, in aerosol form, to a wide range of different tissues in therapeutically effective amounts so as to therapeutically treat a wide range of different medical disorders.
By way of example, a solution of antimicrobial metals with atomic disorder may be applied in aerosol form to surface tissues as a spray. Thus, a solution of antimicrobial metals with atomic disorder can be applied as a spray to treat a dermal condition such as, but not limited to, acne, psoriasis, eczema and skin infections. Alternatively, a solution of antimicrobial metals with atomic disorder can be applied as a spray to treat or clean a wound or a surgical site. By way of further example, a solution of antimicrobial metals with atomic disorder, in aerosol form, may be inhaled by a patient for deployment to the throat, the nasal and sinus passages and/or the lungs.
The aerosol of antimicrobial metals with atomic disorder may be created by passing a liquid solution of antimicrobial metals with atomic disorder through a mechanical mister (e.g., a simple spray bottle or nebulizer) and may be applied directly (e.g., via a hand inhaler) or through some other delivery system (e.g., an oxygen tent, etc.).
With respect to an aerosol of antimicrobial metals with atomic disorder, it should be appreciated that the droplet size of the aerosol can be important, for at least two reasons. First, the droplet size of the aerosol can affect the dosage of antimicrobial metals with atomic disorder being applied to the tissue, i.e., a larger droplet size results in delivery of more antimicrobial metals with atomic disorder to the tissue. Second, the droplet size of the aerosol can also affect delivery of the antimicrobial metals with atomic disorder to the target tissue, e.g., where the aerosol is inhaled through the mouth, big droplets tend to stay in the throat whereas small droplets (e.g., approximately 10 microns or so) tend to travel to the lungs . Thus, depending on the dosage required and the target tissue, it may be important to regulate the droplet size of the aerosol.
In this respect, it has been found that droplet size can be regulated, to at least some extent, by the device (e.g., the mechanical mister) which is used to produce the aerosol.
In addition, it has also been discovered that the aerosol's droplet size can be adjusted, to at least some extent, by modifying the surface tension of the solution. More particularly, the solution of antimicrobial metals with atomic disorder has water as its solvent, and water has a relatively high surface tension, so it is relatively straightforward to create an aerosol having a relatively small droplet size. In accordance with the present invention, it has also been discovered that surfactants can be added to the solution so as to reduce the surface tension of the solution, whereby to create an aerosol having a relatively large droplet size. By way of example, such surfactants may comprise phospholipids, e.g., lecithin, sphingomyelin, etc. Suspensions Of Antimicrobial Metals With Atomic Disorder
It is also possible to provide antimicrobial metals with atomic disorder in suspension form. The suspension form of antimicrobial metals with atomic disorder can be advantageous in many applications, since it has a relatively long storage life and, perhaps even more importantly, has a relatively long- lasting therapeutic life.
Antimicrobial metals with atomic disorder may be provided in suspension form in a variety of different embodiments. More particularly, a suspension of antimicrobial metals with atomic disorder can be created in free-standing form or as a dried gel applied to a medical device.
Thus, in one form of the invention, a suspension of antimicrobial metals with atomic disorder can comprise a free-standing form, i.e., it can comprise a liquid such as a lotion; or a semi-solid such as a gel (i.e. a water-based hydrocolloid) or an emulsion (i.e., an oil-in-water or water-in-oil suspension) such as a cream or ointment. Formulations can include carboxymethyl cellulose ("CMC"), polyvinyl alcohol, methyl parabin, proply parabin, and 0.1% antimicrobial metals with atomic disorder in powder form.
In another form of the invention, a suspension of antimicrobial metals with atomic disorder can comprise a dried gel applied to a medical device. In this embodiment, a hydrated form of the gel is created, applied to a medical device, and then dehydrated. During use, the gel becomes rehydrated, whereby the antimicrobial metals with atomic disorder are released to provide their therapeutic effect to tissue.
Regardless of whether the suspension is free-standing or a dried gel applied to a medical device, the suspension may also include biologically active agents such as cytoconductive agents, etc. By way of example, betaglucan, a complex carbohydrate which appears to have cytoconductive properties, may be added to the suspension.
Of course, when formulating the suspension, care must be taken to avoid generating a blend which might deactivate the therapeutic effect of the antimicrobial metals with atomic disorder. Thus, for example, glycerol can be deleterious to the therapeutic effect of the antimicrobial metals with atomic disorder, and should be avoided.
Use Of Antimicrobial Metals With Atomic Disorder In Suspension Form - Free-Standing Form
As noted above, a suspension of antimicrobial metals with atomic disorder can comprise a freestanding form, i.e., it can comprise a liquid such as a lotion; or a semi-solid such as a gel (i.e. a water- based hydrocolloid) or an emulsion (i.e., an oil-in- water or water-in-oil suspension) such as a cream or ointment. These free-standing forms of the suspension are intended to be applied topically to the tissue which is to be treated, in therapeutically effective amounts, and can be used to treat a dermal condition such as, but not limited to, acne, psoriasis, eczema and skin infections. Alternatively, the free-standing forms of the suspension can be applied topically to treat a wound or a surgical site, etc. Use Of Antimicrobial Metals With Atomic Disorder In Suspension Form - Dried Gel
It is also possible to provide a suspension of antimicrobial metals with atomic disorder in the form of a dried gel applied to medical devices. The hydrated form of the gel is created, applied to a medical device (e.g., during manufacture of the medical device), and then dehydrated. During use, the gel becomes rehydrated, whereby the antimicrobial metals with atomic disorder are released in therapeutically effective amounts so as to provide their therapeutic effect to tissue. Examples of medical devices which are prime candidates for a dried gel coating include catheters (e.g., urological catheters, in-dwelling catheters, drainage catheters, etc.), bone screws, total joints, vascular grafts, hernia meshes, surgical dressings, surgical packing materials, etc.
In this respect it should be appreciated that the dried gel can be quite stable and easy to handle when dehydrated, but very slippery when rehydrated. Thus, dried gels can be particularly advantageous with certain types of medical devices which might otherwise require lubrication during use, since the rehydrated gel automatically provides such lubrication. 5 Urological catheters are one example of a medical device which generally requires lubrication during use, and which would benefit from the natural lubrication provided by the rehydrated gel.
It is also possible to provide a dried gel which 10 is less slippery, or even non-slippery, when rehydrated.
Example 1
L5 6 milligrams of antimicrobial metals with atomic disorder, in free-standing powder form, are sprinkled lightly onto 6.5 cm2 of burned tissue, and thereafter wet with a light spray of water or wound exudate or TDWL (Trans Dermal Water Loss) or other bodily fluids,
!0 so as to provide an antimicrobial treatment to the burned tissue. The treatment is repeated every 24 hours until the therapeutic effects are no longer needed. Example 2
0.5 milligrams of antimicrobial metals with atomic disorder, in free-standing powder form, are injected, using a small-needle drug delivery system or a needle- less drug delivery system, into gum tissue so as to treat gingivitis. The treatment is repeated every 3 days until the therapeutic effects are no longer needed.
Example 3
A solution of antimicrobial metals with atomic disorder is prepared by dissolving 6 milligrams of antimicrobial metals with atomic disorder in 1 gram of water. The solution of antimicrobial metals with atomic disorder is applied as a rinse or bath or wash to a wound site so as to provide an antimicrobial treatment to the wound site. The treatment is repeated every 24 hours until the therapeutic effects are no longer needed. Example 4
A solution of antimicrobial metals with atomic disorder is prepared by dissolving 6 milligrams of antimicrobial metals with atomic disorder in 1 gram of water. The solution of antimicrobial metals with atomic disorder is applied to the interior of the bladder via a catheter so as to provide antimicrobial treatment to the bladder. The treatment is repeated every 8 hours until the therapeutic effects are no longer needed.
Example 5
A solution of antimicrobial metals with atomic disorder is prepared by dissolving 6 milligrams of antimicrobial metals with atomic disorder in 1 gram of water. The solution of antimicrobial metals with atomic disorder is injected (using a small-needle or needle-less injection system) under the toenails or into the nail bed and/or the surrounding tissue of a person suffering from onychomycosis so as to provide an antimicrobial treatment to the tissue. The treatment is repeated 2 times a day until the therapeutic effects are no longer needed.
Example 6
Summary Solutions of nanocrystalline noble metals were prepared by immersing Acticoat® burn dressings (distributed by Smith & Nephew) in reverse osmosis water that had been pretreated with C02 in order to reduce the pH. Two different concentrations of antimicrobial metals with atomic disorder solutions were prepared by this method, the concentrations being 85 μg/mL and 318 μg/mL. Solutions of silver nitrate were also prepared to use as comparisons in the experiments. The concentrations of the silver nitrate were 103 ppm of silver and 295 ppm of silver as determined by Atomic Absorption Spectroscopy.
The solutions were in turn placed in an ultrasonic nebulizer that created small droplets containing dissolved and suspended parts of the solution of nanocrystalline noble metals. The output from the nebulizer was directed into a chamber made from a stainless steel frame and base. Petri dishes containing Mueller Hinton agar streaked with 4 h old cultures of Pseudomonas aerugi ona and Staphyl ococcus aureus were exposed to nanocrystalline noble metal aerosols and the silver nitrate aerosols.
The results of the tests show that nanocrystalline noble metal aerosols transmit the antimicrobial activity of the dressings to remote sites, and nanocrystalline noble metal aerosols are more effective than comparable concentrations of silver nitrate.
Introduction In many instances the delivery of antimicrobial materials may most expeditiously be accomplished by using aerosols (e.g., in the treatment of pneumonia). The drawback of aerosols is the requirement for a high concentration of the active ingredient to ensure that a sufficient amount is delivered to achieve the biological effect desired without causing problems with the carrier solvent (e.g., water). The essential requirement of the equipment for producing an aerosol that contains dissolved and suspended components of antimicrobial metals with atomic disorder is that it must form droplets of aerosol directly from the liquid form, and the aerosol droplets must be small enough to reach the lungs. This means that the droplets should be preferably less than approximately 10 μm. To meet these requirements, the aerosol cannot be created by first evaporating the liquid and then condensing it to form droplets, since this would remove the desired antimicrobial metals with atomic disorder from the aerosol. There are two methods that can be used to relatively easily form the droplets directly: (1) mechanical disruption of the liquid; and (2) air, under pressure, passing through some form of orifice that combines the air and the liquid in a way that creates droplets instead of evaporating the liquid.
Several experiments were carried out with antimicrobial metals with atomic disorder and silver nitrate solutions to determine if the antimicrobial activity of the dressing could be transferred through a direct droplet aerosol to a Petri dish. Equipment The method used to create an aerosol for these tests was the mechanical method in the form of an ultrasonic nebulizer. For convenience, an ultrasonic humidifier was used. The liquid containing the dissolved and suspended antimicrobial metals with atomic disorder was placed in the water reservoir of the humidifier. When power was applied to the humidifier, aerosol droplets of dissolved and suspended antimicrobial metals with atomic disorder were generated and flowed from the output nozzle.
A test chamber was constructed using a stainless steel frame with a transparent plastic covering. The frame was placed on a stainless steel plate. The output nozzle from the humidifier was modified so that the aerosol could be directed into the chamber at a height of approximately 30 cm from the base. The plates and other test samples were placed on the stainless steel plate and exposed to the aerosol for a prescribed length of time. Solution 1 A solution of antimicrobial metals with atomic disorder was prepared by immersing 518 sq. inches of Acticoat® burn dressing in IL of reverse osmosis water, which was treated with C02 to maintain a pH of 6.5. After 20 minutes the concentration of silver in the water was 85 μg/mL.
Solution 2 A solution containing 370 μg/mL of silver from a
Acticoat® dressing was prepared as follows: 1 L of reverse osmosis water was purged with commercial grade carbon dioxide until the pH was 4.3. Sufficient Acticoat® dressing was added to bring the pH up to 6.5. At that time, the silver concentration was 370 μg/mL.
Solution 3 Ag as AgNo3 was prepared by dissolving 0.157 g of AgNo3 into 1 L of reverse osmosis water and mixed until dissolved. The solution was analyzed by Atomic
Absorption Spectroscopy and found to be 102.9 ppm of silver. Solution 4 Ag as AgN03 was prepared by dissolving 0.427 of AgN03 into 1 L of reverse osmosis water and mixed until dissolved. The solution was analyzed by Atomic
Absorption Spectroscopy and found to be 295 ppm of silver.
Aerosolization Petri dishes, containing Mueller Hinton agar, were streaked with 4 h old cultures of Pseudomonas aeruginosa or Staphyl ococcus a ureus . The plates were then weighed and their exposed outer surfaces were coated with Parafilm to prevent condensation from occurring on these surfaces. These plates were placed in the aerosol chamber uncovered. The ultrasonic nebulizer was then started and run for 53 minutes. The plates were then removed from the chamber, the plastic was removed and the dishes re-weighed so that the amount of moisture loss/gain could be determined. The plates were then placed in a 35° C incubator for 16 h. After incubation the pattern and amount of growth was assessed on the plates for both organisms.
Viability Assessment
Three of the six plates made for each organism were tested to determine if the antimicrobial effect was cidal or static in nature. This was accomplished by rinsing or placing a piece of the clear section of agar in the Petri dish plates into Tryptic soy broth in a test tube and incubating for 4 h or 16 h. If the medium turned turbid in 4 h it would indicate that the antimicrobial affect was bacteriostatic in nature. If the organism took more than 16 h to grow, as indicated by turbidity, it was considered an indication that both static and cidal effects occurred. If no growth occurred, the effect was bactericidal.
Results The results for Solutions 1 and 2 are summarized in Tables 1 and 2, respectively. Table 1. Solutions 1 and 3 Results
Figure imgf000050_0001
Table 2. Solutions 2 and 4 Results
Figure imgf000050_0002
Discussion At the low concentration of silver in solution, the Acticoat® dressing generated silver was effective at controlling the growth of both organisms while the silver nitrate only prevented the growth of
Ps . aeruginosa . Viability tests showed that at the low concentration, neither form of silver was completely bactericidal although the poor growth on the plates treated with antimicrobial metals with atomic disorder compared to the silver nitrate treated plates suggests that a significant log reduction occurred in the plates treated with the aerosol of antimicrobial metals with atomic disorder.
At a higher concentration of silver, both antimicrobial metals with atomic disorder (370 μg/mL)
and AgNo3 (300 μg/mL) were effective at controlling P. aerugi nosa . Since no re-growth occurred, it is assumed that the agent at this concentration was bactericidal. Antimicrobial silver with atomic disorder was more effective than AgN03 at controlling S. aureus. No re- growth occurred on any plates or in the broth indicating a total kill of the organism while, in the AgN03 treatment, a large number of organisms grew at 16h.
Based on weight gain during aerosol treatments, a dose per unit area can be calculated. In each case for Solution 1, the dose was 8.5 μg/sq. inch, while for
Solution 2, the dose was 38 μg/sq. inch. These doses, on a per lung basis, would be less than 10 mg of silver per hour of treatment. Each hour of treatment with antimicrobial silver with atomic disorder aerosols appears to provide at least 48 h of protection. Therefore, the dose per day, from the high concentration treatment, would be about 5 mg or a little less than the silver released by 2 sq. inches of SSD per day. The most significant advantage of using antimicrobial silver with atomic disorder may be the lack of a toxic action such as N03 or sulfadiazine.
Conclusions (1) Aerosols of antimicrobial metals with atomic disorder transmit the antimicrobial activity of the dressings to remote sites. (2) Aerosols of antimicrobial metals with atomic disorder are more effective than comparable concentrations of silver nitrate.
(3) The dose delivered is acceptable and would not appear to be excessive.
(4) No toxic cations (N03 or sulfadiazine) are introduced to the patient.
Example 7
Gels of Antimicrobial Metals With Atomic Disorder
Gel products of antimicrobial metals with atomic disorder encompass both "wet" and "dry" materials.
A "wet" gel product of antimicrobial metals with atomic disorder is a product that provides moisture to a dry skin condition (psoriasis, eczema, acne, wound, etc.) and facilitates autolytic debridement of necrotic tissue. It also delivers the antimicrobial and anti-inflammatory properties of the suspended antimicrobial metals with atomic disorder powders.
In many instances it is also beneficial to supply biologically active molecules to elicit a specific response such as cell migration, etc. Since these biologically active molecules are susceptible to microbial degradation if not protected, it is beneficial to include them in gels of antimicrobial metals with atomic disorder that will provide the necessary protection.
"Dry" gel products of antimicrobial metals with atomic disorder are physically stabilized (dry or cross-linked) materials that provide lubricious, antimicrobial, antithrombogenic, and anti-inflammatory properties to a variety of implantable, trancutaneous or topically applied devices. The coatings may also provide other benefits such as accelerating or otherwise facilitating tissue integration by creating a favorable environment for cell proliferation. This favorable environment may be created by including cytoconductive agents or anti-adhesion agents such as bone morphogenetic proteins, B-glucan hyaluronic acids in the gel. The gel may be stabilized by cross-linking the gel components (collagen, gelatin, etc.) or by drying the coated materials.
Examples of the primary gelling agents are listed in Table 3. Biologically active ingredients that may be used, in any combination with the primary gelling agents, are given in Table 4 . Materials that should not be used with gels of antimicrobial silver with atomic disorder are given in Table 5.
Table 3
Figure imgf000055_0001
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Table 4
Figure imgf000056_0001
Table 5
Figure imgf000056_0002
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Example 8
Examples of Gels with Antimicrobial Metals With Atomic Disorder
No. 1 A commercial carboxymethyl cellulose/pectin gel (Duoderm Convatec) was combined with antimicrobial metals with atomic disorder powder to produce a gel with 0.1% silver. A logarithmic reduction test was performed as follows in the gel using Pseudomonas aeruginosa .
The inoculum was prepared by placing 1 bacteriologic loopful of the organism in 5 mL of trypticase soy broth and incubating it for 3-4 h. The inoculum (0.1 mL) was then added to 0.1 mL of gel and vortexed (triplicate samples) . The mixture was incubated for one-half hour. Then 1.8 L of sodium thioglycollate-saline (STS) solution was added to the test tube and vortexed. Serial dilutions were prepared on 10"1 to 10"7. A 0.1 mL aliquot of each dilution was plated in duplicate into Petri plates containing Mueller-Hinton agar. The plates were incubated for 48 h and then colonies were counted. Surviving members of organisms were determined and the logarithmic reduction compared to the initial inoculum was calculated.
The logarithmic reduction for this mixture was 6.2, indicating a significant bactericidal effect.
No. 2 Carboxymethyl cellulose (CMC) fibers were coated directly to produce a defective nanocrystalline antimicrobial coating. The CMC was then gelled in water by adding 2.9 g to 100 mL volume. This material was tested using the method of No. 1. The material generated a 5.2 logarithmic reduction of Pseudomonas aeruginosa, demonstrating that the gel had a significant bactericidal effect.
No. 3 An alginate fibrous substrate was directly coated with a defective nanocrystalline antimicrobial coating. The alginate (5.7 g) was added to 100 mL volume of water to create a gel. This material was tested using the method of No. 1. The material generated a 5.2 logarithmic reduction of Pseudomonas aeruginosa , demonstrating that the gel had a significant bactericidal effect.
No. 4 A commercial gel containing CMC and alginate (Purilin gel Coloplast) was mixed with a defective nanocrystalline silver powder to give a product with 0.1% silver. This was tested as above with both Pseudomonas aeruginosa and Staphylococcus a ureus . Zone of inhibition data was also generated for this gel as follows. An inoculum ( Pseudomonas aerugi nosa and Staphyl ococcus a ureus) was prepared as in No. 1 and 0.1 mL of this was spread onto the surface of Mueller-Hinton agar in a Petri dish. A six mm hole was then cut into the agar at the center of the Petri dish and removed. The well was filled with either 0.1 mL of the silver containing gel, a mupirocin containing cream or a mupirocin containing ointment. The Petri plates were then incubated for 24 h and the diameter of the zone of inhibition was measured and recorded.
The silver containing gel produced 9 mm zones against both Pseudomonas aerugi nosa and Staphyl ococcus a ureus, while the mupirocin cream and ointment produced 42 and 48 mm zones against Staphylococcus a ureus and 0 mm zones against Pseudomonas aerugi nosa .
The silver containing gel reduced the Pseudomonas aeruginosa and Staphylococcus a ureus properties 4.4 and 0.6 logs, respectively, showing good bactericidal activity. The mupirocin cream and ointment generated 0.4 and 0.8, and 0.8 and 1.6, log reductions against Staphyl ococcus a ureus and Pseudomonas aeruginosa , respectively. The silver gel had both a greater bactericidal effect and spectrum of activity than the mupirocin containing products.
Nos. 5-10 The formula for Nos. 5-10 are summarized in
Table 6. Zones of inhibitions were determined in No. 4 and log reductions were determined in No. 1. All formulae provided a broader spectrum of activity and a greater bactericidal effect than did mupirocin in a cream or ointment form. The mupirocin cream produced zones of inhibition of 42 and 0, and log reduction of 0.4 and 0.8, against Staphyl ococcus a ureus and Pseudomonas aerugi nosa , respectively.
Table 6
Figure imgf000061_0001
No. 11 A commercially available gel (glyceryl polymethacrylate) was blended with antimicrobial metals with atomic disorder powder to produce a gel with a silver content of 0.1%. This gel was tested as in Nos. 5-10 and was found to produce zones of 15 mm against both Staphyl ococcus a ureus and Pseudomonas aerugi nosa . Log reductions of 1.7 and >5 were produced against Staphyl ococcus a ureus and Pseudomonas aerugi nosa . This gel product had a greeted spectrum of activity than did mupirocin cream or ointment.
No. 12 A gel coat for a urinary catheter was prepared using the formula in No. 6. The coating was applied to the catheter using a dipping method. The coating was air dried overnight.
The dried gel coat was smooth and easy to handle. It was not tacky to touch and had excellent abrasion and adhesion properties. Upon rewetting, the surface became extremely slippery indicating excellent lubricious properties.
A zone of inhibition test was performed against Pseudomonas aerugi nosa using an inoculum as prepared in No. 1. The inoculum (0.1 mL) was spread over the surface of Mueller-Hinton agar in a Petri plate. The catheter was cut into 1" segments which were laid on their side into the middle of the Petri plate. Petri plates were incubated for 24 h and then the zone of inhibitions was measured.
In all cases, zones of inhibition were generated that ranged from 7-10 mm. This indicates that getting drying and rehydrating had no negative effect on the antimicrobial activity of the gel coat.

Claims

What Is Claimed Is:
1. A method for treating tissue, comprising: forming a free-standing powder comprising at least one antimicrobial metal with atomic disorder; and injecting the free-standing powder in therapeutically effective amounts to the tissue which is to be treated.
2. A method according to claim 1 wherein the at least one antimicrobial metal is in nanocrystalline form.
3. A method according to claim 2 wherein the at least one antimicrobial metal is nanocrystalline silver.
4, A method according to claim 1 wherein injection is effected by the use of a needle.
5. A method according to claim 1 wherein injection is needle-less injection.
6. A method according to claim 1 wherein the tissue is to be treated for one of the group consisting of acne, psoriasis, eczema and skin infections.
5 7. A method according to claim 1 wherein the tissue is to be treated for one of the group consisting of endocarditis, pericarditis, prostatitis, sinusitis, osteomyelitis and onychomycosis .
10 8. A method according to claim 1 wherein the tissue is to be treated for one of the group consisting of mouth, gum and throat afflictions.
9. A method according to claim 1 wherein the 15 tissue is to be treated for arthritis.
10. A method according to claim 1 wherein the tissue to be treated is a tumor.
Ϊ0 11. A method according to claim 1 wherein the f ee-standing powder is applied by injection into a body cavity so as to contact the tissue which is to be treated.
12. The use of a free-standing powder to treat tissue, wherein the free-standing powder comprises at least one antimicrobial metal with atomic disorder, and wherein the free-standing powder is injected in therapeutically effective amounts to the tissue which is to be treated.
13. The use according to claim 12 wherein the at least one antimicrobial metal is in nanocrystalline form.
14. The use according to claim 13 wherein the at least one antimicrobial metal is nanocrystalline silver.
15. The use according to claim 12 wherein injection is effected by the use of a needle.
16. The use according to claim 12 wherein injection is needle-less injection.
17. The use according to claim 12 wherein the tissue is to be treated for one of the group consisting of acne, psoriasis, eczema and skin infections.
18. The use according to claim 12 wherein the tissue is to be treated for one of the group consisting of endocarditis, pericarditis, prostatitis, sinusitis, osteomyelitis and onychomycosis.
19. The use according to claim 12 wherein the tissue is to be treated for one of the group consisting of mouth, gum and throat afflictions.
20. The use according to claim 12 wherein the tissue is to be treated for arthritis.
21. The use according to claim 12 wherein the tissue to be treated is a tumor.
22. The use according to claim 12 wherein the free-standing powder is applied by injection into a body cavity so as to contact the tissue which is to be treated.
23. A method for treating tissue, comprising: forming a free-standing powder comprising at least one antimicrobial metal with atomic disorder; and applying the free-standing powder in therapeutically-effective amounts to the tissue which is to be treated, wherein the tissue comprises at least one tissue selected from the group consisting of endocardium tissue, pericardium tissue, bone tissue, and joint tissue.
24. A method according to claim 23 wherein the at least one antimicrobial metal is in nanocrystalline form.
25. A method according to claim 23 wherein the at least one antimicrobial metal is nanocrystalline silver .
26. A method according to claim 23 wherein the free-standing powder is applied by sprinkling it onto the tissue which is to be treated.
27. A method according to claim 23 wherein the free-standing powder is applied by injection into the tissue which is to be treated.
5
28. A method according to claim 27 wherein injection is effected by the use of a needle.
29. A method according to claim 27 wherein 10 injection is needle-less injection.
30. A method according to claim 23 wherein the free-standing powder is applied by injection into a body cavity so as to contact the tissue which is to be
L5 treated.
31. A method for treating tissue, comprising: forming a solution at a site remote from the tissue which is to be treated by dissolving in water at !0 least one antimicrobial metal with atomic disorder; and applying the solution in therapeutically effective amounts to the tissue which is to be treated, wherein the tissue comprises at least one tissue selected from the group consisting of endocardium tissue, pericardium tissue, bone tissue, and joint tissue.
32. A method according to claim 31 wherein the at least one antimicrobial metal is in nanocrystalline form.
33. A method according to claim 32 wherein the at least one antimicrobial metal is nanocrystalline silver.
34. A method according to claim 31 wherein the solution is applied by passing it through a catheter to the tissue which is to be treated.
35. A method according to claim 31 wherein the solution is applied by injection into the tissue which is to be treated.
36. A method according to claim 35 wherein injection is effected by the use of a needle.
VILil-l
37. A method according to claim 35 wherein injection is needle-less injection.
38. A method according to claim 31 wherein the solution is applied by injection into a body cavity so as to contact the tissue which is to be treated.
39. The use of a solution to treat tissue, wherein the solution is formed at a site remote from the tissue which is to be treated by dissolving in water at least one antimicrobial metal with atomic disorder, and wherein the solution is applied in therapeutically effective amounts to the tissue to be treated, and further wherein the tissue comprises at least one tissue selected from the group consisting of endocardium tissue, pericardium tissue, bone tissue, and joint tissue.
40. The use according to claim 39 wherein the at least one antimicrobial metal is in nanocrystalline form.
41. The use according to claim 40 wherein the at least one antimicrobial metal is nanocrystalline silver.
42. The use according to claim 39 wherein the solution is applied by passing it through a catheter to the tissue which is to be treated.
43. The use according to claim 39 wherein the solution is applied by injection into the tissue which is to be treated.
44. The use according to claim 43 wherein injection is effected by the use of a needle.
45. The use according to claim 43 wherein injection is needle-less injection.
46. The use according to claim 39 wherein the solution is applied by injection into a body cavity so as to contact the tissue which is to be treated.
PCT/US2002/012690 2001-04-23 2002-04-23 Therapeutic treatments using the direct application of antimicrobial metal compositions WO2002085299A2 (en)

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PCT/CA2002/000547 WO2002085385A2 (en) 2001-04-23 2002-04-23 Medicament containing a metal such as silver, gold, platinum or palladium as an antimicrobial agent and their use in the treatment of diseases of the mucosa
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074949A1 (en) * 2004-02-02 2005-08-18 Nucryst Pharmaceuticals Corp. Treatment of ungual and subungual diseases with antimicrobial metal compositions
EP1567101A2 (en) * 2002-10-22 2005-08-31 Nucfryst Pharmaceuticals Corp. Prophylactic treatment methods
WO2010143075A2 (en) * 2009-06-10 2010-12-16 Willoughby Andrew J M Dental uses of silver hydrosol
US20130210925A1 (en) * 2002-09-27 2013-08-15 Jay E. Birnbaum Concepts Llc Subunguicide, and method for treating onychomycosis
US8865227B2 (en) 2007-12-20 2014-10-21 Smith & Nephew (Overseas) Limited Metal carbonate particles and methods of making thereof
US10456568B2 (en) 2013-03-14 2019-10-29 Hallux, Inc. Method of treating infections, diseases or disorders of nail unit

Families Citing this family (305)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9119705B2 (en) 1998-06-08 2015-09-01 Thermotek, Inc. Method and system for thermal and compression therapy relative to the prevention of deep vein thrombosis
WO2005000324A2 (en) * 2003-06-03 2005-01-06 American Biotech Labs Colloidal silver composition having antimicrobial properties
US7135195B2 (en) * 1999-06-01 2006-11-14 American Silver, Llc Treatment of humans with colloidal silver composition
US7179849B2 (en) 1999-12-15 2007-02-20 C. R. Bard, Inc. Antimicrobial compositions containing colloids of oligodynamic metals
US9522217B2 (en) 2000-03-15 2016-12-20 Orbusneich Medical, Inc. Medical device with coating for capturing genetically-altered cells and methods for using same
US8088060B2 (en) 2000-03-15 2012-01-03 Orbusneich Medical, Inc. Progenitor endothelial cell capturing with a drug eluting implantable medical device
US20030185901A1 (en) * 2000-07-27 2003-10-02 Burrell Robert E. Methods of treating conditions with a metal-containing material
US20060115541A1 (en) * 2000-07-27 2006-06-01 Gillis Scott H Treatment of bladder conditions
US7008647B2 (en) * 2001-04-23 2006-03-07 Nucryst Pharmaceuticals Corp. Treatment of acne
US7427416B2 (en) * 2000-07-27 2008-09-23 Nucryst Pharmaceuticals Corp. Methods of treating conditions using metal-containing materials
DE10043151A1 (en) * 2000-08-31 2002-03-28 Peter Steinruecke Bone cement with antimicrobial effectiveness
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
EP1383521A2 (en) * 2001-04-23 2004-01-28 Nucryst Pharmaceuticals Corp. Medicament containing a metal such as silver, gold, platinum or palladium as an antimicrobial agent and their use to induce apoptosis in cancerous tissue
US20040092890A1 (en) * 2001-05-10 2004-05-13 Ash Stephen R. Catheter lock solution including a photo-oxidant
US7727221B2 (en) 2001-06-27 2010-06-01 Cardiac Pacemakers Inc. Method and device for electrochemical formation of therapeutic species in vivo
US20030059375A1 (en) * 2001-08-20 2003-03-27 Transave, Inc. Method for treating lung cancers
DE10146050B4 (en) * 2001-09-18 2007-11-29 Bio-Gate Ag Process for the preparation of an antimicrobial adhesive and coating material
JP3795364B2 (en) * 2001-09-27 2006-07-12 シャープ株式会社 Integrated circuit and receiver
CN1612804A (en) 2001-12-03 2005-05-04 C·R·巴德公司 Microbe-resistant medical device, microbe-resistant polymeric coating and methods for producing same
TWI255224B (en) * 2002-01-09 2006-05-21 Novartis Ag Polymeric articles having a lubricious coating and method for making the same
US8118789B2 (en) * 2002-02-20 2012-02-21 Abbott Research Group, Inc. Deodorizer devices and systems for controlling perspiration-related body odor
US7270653B2 (en) * 2002-02-20 2007-09-18 Abbott Research Group Methods of treating abnormal biological conditions using metal oxides
US6589216B1 (en) 2002-02-20 2003-07-08 Abbott Research Group, Inc. Vaginal douches, vaginal douche applicators and methods of vaginal douching
WO2004002202A1 (en) * 2002-06-21 2003-12-31 Continental Teves Ag & Co. Ohg Printed board for electronic devices controlling a motor vehicle
US6865810B2 (en) * 2002-06-27 2005-03-15 Scimed Life Systems, Inc. Methods of making medical devices
US9186322B2 (en) * 2002-08-02 2015-11-17 Insmed Incorporated Platinum aggregates and process for producing the same
AU2003302314A1 (en) * 2002-08-02 2004-07-09 Transave, Inc. Platinum aggregates and process for producing the same
US7485259B2 (en) * 2002-10-08 2009-02-03 Eldred Bradley J Organic compound and metal ion synergistic disinfection and purification system and method of manufacture
AU2003303306A1 (en) * 2002-10-09 2004-09-06 California Institute Of Technology Sensor web
WO2004037187A2 (en) * 2002-10-22 2004-05-06 Nucryst Pharmaceuticals Corp. Metal-containing materials, compositions and methods
US8066854B2 (en) * 2002-12-18 2011-11-29 Metascape Llc Antimicrobial coating methods
US20050008676A1 (en) 2002-12-19 2005-01-13 Yongxing Qiu Medical devices having antimicrobial coatings thereon
US8409618B2 (en) * 2002-12-20 2013-04-02 Kimberly-Clark Worldwide, Inc. Odor-reducing quinone compounds
US7666410B2 (en) 2002-12-20 2010-02-23 Kimberly-Clark Worldwide, Inc. Delivery system for functional compounds
ATE354380T1 (en) * 2003-02-03 2007-03-15 Polaschegg Hans-Dietrich Dr Te COMPOSITION FOR THE PREVENTION OF INFECTIONS THROUGH SUBCUTANEOUS PROSTHESIS
US20040151716A1 (en) * 2003-02-03 2004-08-05 Hamer Richard A. Material and method for treating microbial mediated dermatological conditions
US20040156874A1 (en) * 2003-02-11 2004-08-12 Bradley Pharmaceuticals, Inc. Urea- a topical anti-inflammatory
JPWO2004075920A1 (en) * 2003-02-26 2006-06-01 大塚製薬株式会社 Sustained release pharmaceutical composition for pulmonary administration
US20040180093A1 (en) * 2003-03-12 2004-09-16 3M Innovative Properties Company Polymer compositions with bioactive agent, medical articles, and methods
WO2004084973A2 (en) * 2003-03-24 2004-10-07 Becton, Dickinson And Company Invisible antimicrobial glove and hand antiseptic
US20040236290A1 (en) * 2003-04-23 2004-11-25 Zimmermann Stephan A. Minimally invasive vascular apparatus modified to minimize scarring at introduction site
US6874165B2 (en) * 2003-05-19 2005-04-05 Mao-Sheng Lee Modified NBR gloves
WO2004108091A2 (en) * 2003-06-06 2004-12-16 Board Of Regents, The University Of Texas System Antimicrobial flush solutions
DE10328261B4 (en) 2003-06-23 2007-10-25 Beiersdorf Ag Disinfecting coating with silver coating and its use
WO2004112852A1 (en) * 2003-06-23 2004-12-29 Beiersdorf Ag Antimicrobial wounddressing
US7480530B2 (en) * 2003-06-30 2009-01-20 Johnson & Johnson Consumer Companies, Inc. Device for treatment of barrier membranes
US8734421B2 (en) * 2003-06-30 2014-05-27 Johnson & Johnson Consumer Companies, Inc. Methods of treating pores on the skin with electricity
US20050025817A1 (en) * 2003-07-03 2005-02-03 Bhatia Kuljit S. Delivery system for topical medications
US8574278B2 (en) * 2006-05-09 2013-11-05 Thermotek, Inc. Wound care method and system with one or both of vacuum-light therapy and thermally augmented oxygenation
US8128672B2 (en) 2006-05-09 2012-03-06 Thermotek, Inc. Wound care method and system with one or both of vacuum-light therapy and thermally augmented oxygenation
DK200301128A (en) * 2003-08-05 2005-02-06 Thomsen Joern Oddershede Grant Preparation
US20050028563A1 (en) * 2003-08-08 2005-02-10 Milliken & Company Garment for use with sensitive skin, and method and fabric for us in making same
DE10340277B4 (en) * 2003-08-29 2006-11-23 Bio-Gate Bioinnovative Materials Gmbh Personal care products containing silver agglomerates
US8519146B2 (en) * 2004-09-07 2013-08-27 The University Of Akron Metal complexes of N-heterocyclic carbenes as antibiotics
US20050054774A1 (en) * 2003-09-09 2005-03-10 Scimed Life Systems, Inc. Lubricious coating
US7794737B2 (en) 2003-10-16 2010-09-14 Kimberly-Clark Worldwide, Inc. Odor absorbing extrudates
US7879350B2 (en) 2003-10-16 2011-02-01 Kimberly-Clark Worldwide, Inc. Method for reducing odor using colloidal nanoparticles
US7678367B2 (en) 2003-10-16 2010-03-16 Kimberly-Clark Worldwide, Inc. Method for reducing odor using metal-modified particles
US7745509B2 (en) * 2003-12-05 2010-06-29 3M Innovative Properties Company Polymer compositions with bioactive agent, medical articles, and methods
US20050123621A1 (en) * 2003-12-05 2005-06-09 3M Innovative Properties Company Silver coatings and methods of manufacture
US20050123590A1 (en) * 2003-12-05 2005-06-09 3M Innovative Properties Company Wound dressings and methods
US20050152955A1 (en) * 2003-12-16 2005-07-14 Akhave Jay R. Electrostatically self-assembled antimicrobial coating for medical applications
DE10359338B4 (en) * 2003-12-17 2007-07-19 Heraeus Kulzer Gmbh Antimicrobial nanosilver additive for polymerizable dental materials
GB0401821D0 (en) * 2004-01-28 2004-03-03 Qinetiq Nanomaterials Ltd Method of manufacture of polymer composites
US20050256553A1 (en) * 2004-02-09 2005-11-17 John Strisower Method and apparatus for the treatment of respiratory and other infections using ultraviolet germicidal irradiation
US7457667B2 (en) * 2004-02-19 2008-11-25 Silverleaf Medical Products, Inc. Current producing surface for a wound dressing
US7662176B2 (en) * 2004-02-19 2010-02-16 Vomaris Innovations, Inc. Footwear apparatus and methods of manufacture and use
US20050196463A1 (en) * 2004-03-03 2005-09-08 Stiles James Alexander R. NO-containing complexes
US20070065522A1 (en) * 2004-03-18 2007-03-22 Transave, Inc. Administration of high potency platinum compound formulations by inhalation
WO2005089448A2 (en) * 2004-03-18 2005-09-29 Transave, Inc. Administration of cisplatin by inhalation
US20050271746A1 (en) * 2004-05-18 2005-12-08 Abbott Chun L Topical treatments for abnormal biological conditions and method of topically treating such conditions
US7758892B1 (en) * 2004-05-20 2010-07-20 Boston Scientific Scimed, Inc. Medical devices having multiple layers
CA2566174A1 (en) * 2004-05-21 2005-12-01 Transave, Inc. Treatment of lung diseases and pre-lung disease conditions
DE102004031955A1 (en) * 2004-06-24 2006-01-12 Paul Hartmann Ag wound dressing
US20060002967A1 (en) * 2004-07-01 2006-01-05 Smestad Thomas L Resorbable implant with lubricious coating
US10016583B2 (en) 2013-03-11 2018-07-10 Thermotek, Inc. Wound care and infusion method and system utilizing a thermally-treated therapeutic agent
US10765785B2 (en) 2004-07-19 2020-09-08 Thermotek, Inc. Wound care and infusion method and system utilizing a therapeutic agent
US20060034899A1 (en) * 2004-08-12 2006-02-16 Ylitalo Caroline M Biologically-active adhesive articles and methods of manufacture
US20060035039A1 (en) * 2004-08-12 2006-02-16 3M Innovative Properties Company Silver-releasing articles and methods of manufacture
CN2734238Y (en) * 2004-08-25 2005-10-19 任晓艳 Nano silver coated suture line
US20060068024A1 (en) * 2004-09-27 2006-03-30 Schroeder Kurt M Antimicrobial silver halide composition
AU2005306802A1 (en) * 2004-11-08 2006-05-26 Transave, Inc. Methods of treating cancer with lipid-based platinum compound formulations administered intraperitoneally
AP2007004039A0 (en) * 2004-11-23 2007-06-30 Internat Biotherapeutic Res In Method of delivery of therapeutic metal ions, alloys and salts
JP2008523063A (en) * 2004-12-06 2008-07-03 ノヴァセントリックス コープ Antiviral usage of metal nanomaterial composition
US20090155316A1 (en) * 2004-12-13 2009-06-18 Apt Co., Ltd. Oral Wash
US7749529B2 (en) * 2005-02-08 2010-07-06 Ash Access Technology, Inc. Catheter lock solution comprising citrate and a paraben
US20080202967A1 (en) * 2005-02-23 2008-08-28 Kerryne Krause-Neufeldt Cosmetic Product
DE102005063438A1 (en) * 2005-02-24 2007-12-27 Lohmann & Rauscher Gmbh & Co. Kg Process for the preparation of porous sponges from purified marine collagen
US8864730B2 (en) 2005-04-12 2014-10-21 Rochester Medical Corporation Silicone rubber male external catheter with absorbent and adhesive
US8399027B2 (en) * 2005-04-14 2013-03-19 3M Innovative Properties Company Silver coatings and methods of manufacture
JP4741656B2 (en) * 2005-05-02 2011-08-03 コロプラスト アクティーゼルスカブ Method for sterilizing medical devices having a hydrophilic coating
US20060275223A1 (en) * 2005-06-02 2006-12-07 Burr James B Erythritol compositions for teeth and gums
JP2009513182A (en) * 2005-07-21 2009-04-02 エフエムシー バイオポリマー エイエス Medical parts coated with a biocompatible coating that dissolves rapidly
WO2007013100A1 (en) * 2005-07-26 2007-02-01 Virchow Biotech Private Limited Gel formulation comprising platelet derived growth factor
DE102005041005B4 (en) * 2005-08-29 2022-10-20 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Biocidal composition containing nanoparticulate silver, the use of this composition and a method for the production of biocidal products using this composition
US20070185432A1 (en) * 2005-09-19 2007-08-09 Transport Pharmaceuticals, Inc. Electrokinetic system and method for delivering methotrexate
US20090311298A1 (en) * 2005-10-18 2009-12-17 Oranogenesis, In.C Antimicrobial Collagenous Constructs
US20070190182A1 (en) * 2005-11-08 2007-08-16 Pilkiewicz Frank G Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
US20070190180A1 (en) * 2005-11-08 2007-08-16 Pilkiewicz Frank G Methods of treating cancer with high potency lipid-based platinum compound formulations administered intravenously
US20070190181A1 (en) * 2005-11-08 2007-08-16 Pilkiewicz Frank G Methods of treating cancer with lipid-based platinum compound forumulations administered intravenously
US9107824B2 (en) 2005-11-08 2015-08-18 Insmed Incorporated Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
US20070122350A1 (en) * 2005-11-30 2007-05-31 Transave, Inc. Safe and effective methods of administering therapeutic agents
US20070128247A1 (en) * 2005-12-01 2007-06-07 Kato Yasushi P Method for Ionically Cross-Linking Polysaccharide Material for Thin Film Applications and Products Produced Therefrom
US8840660B2 (en) 2006-01-05 2014-09-23 Boston Scientific Scimed, Inc. Bioerodible endoprostheses and methods of making the same
US20070166399A1 (en) * 2006-01-13 2007-07-19 3M Innovative Properties Company Silver-containing antimicrobial articles and methods of manufacture
US20070166344A1 (en) * 2006-01-18 2007-07-19 Xin Qu Non-leaching surface-active film compositions for microbial adhesion prevention
US8089029B2 (en) 2006-02-01 2012-01-03 Boston Scientific Scimed, Inc. Bioabsorbable metal medical device and method of manufacture
US8053030B2 (en) * 2006-02-01 2011-11-08 Hollister Incorporated Methods of applying a hydrophilic coating to a substrate, and substrates having a hydrophilic coating
US7897800B2 (en) * 2006-02-03 2011-03-01 Jr Chem, Llc Chemical compositions and methods of making them
US7927614B2 (en) 2006-02-03 2011-04-19 Jr Chem, Llc Anti-aging treatment using copper and zinc compositions
US7687650B2 (en) 2006-02-03 2010-03-30 Jr Chem, Llc Chemical compositions and methods of making them
GB0603487D0 (en) * 2006-02-22 2006-04-05 Agt Sciences Ltd Delivery means
US20070212425A1 (en) * 2006-03-09 2007-09-13 Barna Ivan J Cidal formulations and methods of use
US20070224244A1 (en) * 2006-03-22 2007-09-27 Jan Weber Corrosion resistant coatings for biodegradable metallic implants
US20070224288A1 (en) * 2006-03-22 2007-09-27 Kiss Nail Products, Inc. Antibacterial gel coating and pedicure spa with antibacterial function
US20100048451A1 (en) * 2006-04-06 2010-02-25 Taro Pharmaceuticals North America, Inc. Novel spill-resistant formulations comprising hydrocolloidal polymers
JP5049268B2 (en) * 2006-04-07 2012-10-17 久光製薬株式会社 Microneedle device and transdermal drug administration device with microneedle
US8048150B2 (en) * 2006-04-12 2011-11-01 Boston Scientific Scimed, Inc. Endoprosthesis having a fiber meshwork disposed thereon
US8273381B1 (en) 2006-04-14 2012-09-25 Auburn University Compositions for and methods of controlling olfactory responses to odorants
WO2007122651A1 (en) 2006-04-24 2007-11-01 Nm Tech Ltd. Nanomaterials And Microdevices Technology Functional nanomaterials with antibacterial and antiviral activity
DE602006015539D1 (en) 2006-06-14 2010-08-26 Nm Tech Ltd Nanomaterials And NANOMATERIAL COATS FOR OSTEO INTEGRATED BIOMEDICAL PROSTHESES
US20070292397A1 (en) * 2006-06-19 2007-12-20 Mcnulty Amy K Method for the detection and neutralization of bacteria
US20110135742A1 (en) * 2006-06-20 2011-06-09 The Regents Of The University Of California Controlled release encapsulated anti-bacterial and anti-inflammatory nanoparticles
US20080044491A1 (en) * 2006-06-30 2008-02-21 Nucryst Pharmaceuticals Metal-containing formulations and methods of use
US20080027410A1 (en) * 2006-07-28 2008-01-31 Becton, Dickinson And Company Vascular access device non-adhering membranes
US8512294B2 (en) * 2006-07-28 2013-08-20 Becton, Dickinson And Company Vascular access device antimicrobial materials and solutions
US8197452B2 (en) * 2006-07-28 2012-06-12 Becton, Dickinson And Company Vascular access device non-adhering surfaces
CA2659761A1 (en) 2006-08-02 2008-02-07 Boston Scientific Scimed, Inc. Endoprosthesis with three-dimensional disintegration control
ES2368125T3 (en) * 2006-09-15 2011-11-14 Boston Scientific Scimed, Inc. BIOEROSIONABLE ENDOPROOTHESIS WITH BIOESTABLE INORGANIC LAYERS.
CA2663271A1 (en) 2006-09-15 2008-03-20 Boston Scientific Limited Bioerodible endoprostheses and methods of making the same
CA2663303A1 (en) * 2006-09-15 2008-03-20 Boston Scientific Limited Endoprosthesis with adjustable surface features
EP2959925B1 (en) 2006-09-15 2018-08-29 Boston Scientific Limited Medical devices and methods of making the same
US20080071353A1 (en) * 2006-09-15 2008-03-20 Boston Scientific Scimed, Inc. Endoprosthesis containing magnetic induction particles
WO2008034007A2 (en) * 2006-09-15 2008-03-20 Boston Scientific Limited Medical devices
US8808726B2 (en) * 2006-09-15 2014-08-19 Boston Scientific Scimed. Inc. Bioerodible endoprostheses and methods of making the same
JP2010503486A (en) * 2006-09-18 2010-02-04 ボストン サイエンティフィック リミテッド Endoprosthesis
WO2008036548A2 (en) 2006-09-18 2008-03-27 Boston Scientific Limited Endoprostheses
CA2663717A1 (en) * 2006-09-18 2008-03-27 Boston Scientific Limited Controlling biodegradation of a medical instrument
US7867522B2 (en) 2006-09-28 2011-01-11 Jr Chem, Llc Method of wound/burn healing using copper-zinc compositions
PL2079302T3 (en) * 2006-10-12 2014-08-29 Nm Tech Nanomaterials Microdevice Tech Ltd Use of a composition having anti-microbial properties
US20100098949A1 (en) * 2006-10-18 2010-04-22 Burton Scott A Antimicrobial articles and method of manufacture
US20080097577A1 (en) * 2006-10-20 2008-04-24 Boston Scientific Scimed, Inc. Medical device hydrogen surface treatment by electrochemical reduction
US20080103459A1 (en) * 2006-10-30 2008-05-01 Anthony Di Salvo Enzyme inhibition using nanoparticles
US20080122582A1 (en) * 2006-11-29 2008-05-29 Texas Instruments Incorporated Location Based Portable Device Feature Disabler
US20080132991A1 (en) * 2006-11-30 2008-06-05 Leonard Pinchuk Method for Ionically Cross-Linking Gellan Gum for Thin Film Applications and Medical Devices Produced Therefrom
US20080147734A1 (en) * 2006-12-18 2008-06-19 Cuticeuticals, Inc Method of topical steroidal organization
EP2277563B1 (en) 2006-12-28 2014-06-25 Boston Scientific Limited Bioerodible endoprostheses and method of making the same
CA2677640A1 (en) * 2007-02-09 2008-08-14 Poniard Pharmaceuticals, Inc. Stabilized picoplatin oral dosage form
US20080221533A1 (en) * 2007-03-09 2008-09-11 Anthem Orthopaedics Llc Implantable device with bioabsorbable layer, kit and method for use therewith, and apparatus for preparing same
US20080226701A1 (en) * 2007-03-15 2008-09-18 John Deignan Medicated patches
EP2155324A1 (en) * 2007-04-20 2010-02-24 Nitric Biotherapeutics, Inc. A single use applicator cartridge for an electrokinetic delivery system and method for self administration of medicaments
US8309222B2 (en) * 2007-04-25 2012-11-13 Covidien Lp Coated filaments
US20100069957A1 (en) * 2007-04-25 2010-03-18 Ferass Abuzaina Coated Filaments
KR20080070482A (en) * 2007-05-31 2008-07-30 (주)디딤바이오텍 A lubricating composition comprising agents which induce the mucosal immunity and a preparation method thereof
WO2008157485A1 (en) * 2007-06-15 2008-12-24 Transport Pharmaceuticals, Inc. Current concentration system and method for electrokinetic delivery of medicaments
US8133553B2 (en) 2007-06-18 2012-03-13 Zimmer, Inc. Process for forming a ceramic layer
US20080319371A1 (en) * 2007-06-19 2008-12-25 Transport Pharmaceuticals, Inc. Method and system for treating of onychomycosis with an applicator having a gel medicament layer
US8309521B2 (en) 2007-06-19 2012-11-13 Zimmer, Inc. Spacer with a coating thereon for use with an implant device
JP5159183B2 (en) * 2007-06-22 2013-03-06 アイノベックス株式会社 Composition for improvement or treatment of infertility
DE102007031650A1 (en) 2007-07-06 2009-01-08 Stada Arzneimittel Ag Dermatology for the treatment and / or care of the skin in atopic dermatitis
US8052745B2 (en) 2007-09-13 2011-11-08 Boston Scientific Scimed, Inc. Endoprosthesis
EP2200619B1 (en) * 2007-09-28 2015-08-12 Johnson & Johnson Consumer Companies, Inc. Electricity-generating particulates and the use thereof
BRPI0817416A2 (en) * 2007-10-03 2014-10-07 3M Innovantive Properties Company MULTIPLICATION LIMITING PROCESS OF MICROORGANISMS
ES2319064B1 (en) * 2007-10-05 2010-02-15 Universidad De Santiago De Compostela USE OF ATOMIC QUANTIC CLUSTERS (AQCS) AS ANTIMICROBIALS AND BIOCIDES.
US20110230973A1 (en) * 2007-10-10 2011-09-22 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate
US8608049B2 (en) * 2007-10-10 2013-12-17 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate
US20090143855A1 (en) * 2007-11-29 2009-06-04 Boston Scientific Scimed, Inc. Medical Device Including Drug-Loaded Fibers
US20100008970A1 (en) * 2007-12-14 2010-01-14 Boston Scientific Scimed, Inc. Drug-Eluting Endoprosthesis
US20090163887A1 (en) * 2007-12-20 2009-06-25 Arehart Kelly D Odor control cellulose granules with quinone compounds
US8273791B2 (en) 2008-01-04 2012-09-25 Jr Chem, Llc Compositions, kits and regimens for the treatment of skin, especially décolletage
US20090187256A1 (en) * 2008-01-21 2009-07-23 Zimmer, Inc. Method for forming an integral porous region in a cast implant
US20090198286A1 (en) * 2008-02-05 2009-08-06 Zimmer, Inc. Bone fracture fixation system
WO2009108147A1 (en) * 2008-02-27 2009-09-03 Qlt Usa, Inc. Dapsone to treat rosascea
WO2009126967A1 (en) * 2008-04-11 2009-10-15 Pediadermics, Llc Systems and methods for treatment kits
JP5738753B2 (en) * 2008-04-24 2015-06-24 メドトロニック,インコーポレイテッド Rehydratable polysaccharide particles and sponges
WO2009132228A1 (en) 2008-04-24 2009-10-29 Medtronic, Inc. Chitosan-containing protective composition
ES2610881T3 (en) 2008-04-24 2017-05-03 Medtronic, Inc Protective gel based on chitosan and oxidized polysaccharide
JP2011518837A (en) 2008-04-24 2011-06-30 メドトロニック,インコーポレイテッド Rehydratable thiolated polysaccharide particles and sponges
ES2530723T3 (en) * 2008-05-07 2015-03-04 Univ California Therapeutic replacement and enrichment of ocular surface lubrication
US8506944B2 (en) 2008-05-07 2013-08-13 The Regents Of The University Of California Replenishment and enrichment of ocular surface lubrication
US7998192B2 (en) 2008-05-09 2011-08-16 Boston Scientific Scimed, Inc. Endoprostheses
US8389583B2 (en) 2008-05-23 2013-03-05 Zurex Pharma, Inc. Antimicrobial compositions and methods of use
US8236046B2 (en) * 2008-06-10 2012-08-07 Boston Scientific Scimed, Inc. Bioerodible endoprosthesis
US20100004733A1 (en) * 2008-07-02 2010-01-07 Boston Scientific Scimed, Inc. Implants Including Fractal Structures
IT1391669B1 (en) * 2008-07-23 2012-01-17 Universita' Degli Studi Di Trieste NANOCOMPOSITE MATERIALS FORMED FROM A POLYSACCHARIDIC MATRIX AND METALLIC NANOPARTICLES, THEIR PREPARATION AND USE
US7985252B2 (en) 2008-07-30 2011-07-26 Boston Scientific Scimed, Inc. Bioerodible endoprosthesis
US20100030170A1 (en) * 2008-08-01 2010-02-04 Keith Alan Keller Absorptive Pad
US8150525B2 (en) * 2008-08-27 2012-04-03 Johnson & Johnson Consumer Companies, Inc. Treatment of hyperhydrosis
US20100082088A1 (en) * 2008-08-27 2010-04-01 Ali Fassih Treatment of sweating and hyperhydrosis
WO2010027189A2 (en) * 2008-09-02 2010-03-11 가톨릭대학교 산학협력단 A new use for homoisoflavanone or a salt thereof
US8382824B2 (en) 2008-10-03 2013-02-26 Boston Scientific Scimed, Inc. Medical implant having NANO-crystal grains with barrier layers of metal nitrides or fluorides
EP2218447B1 (en) * 2008-11-04 2017-04-19 PharmaSol GmbH Compositions containing lipid micro- or nanoparticles for the enhancement of the dermal action of solid particles
US20100124568A1 (en) * 2008-11-20 2010-05-20 Med-Eez, Inc Pharmaceutical articles coated with lubricious coatings
US8551517B2 (en) * 2008-12-16 2013-10-08 Kimberly-Clark Worldwide, Inc. Substrates providing multiple releases of active agents
WO2010085753A1 (en) 2009-01-23 2010-07-29 Jr Chem, Llc Rosacea treatments and kits for performing them
US8267992B2 (en) 2009-03-02 2012-09-18 Boston Scientific Scimed, Inc. Self-buffering medical implants
US20100229282A1 (en) * 2009-03-11 2010-09-16 Ansell Limited Powder-Free Anti-Blocking Coated Glove
US9149567B2 (en) * 2009-03-11 2015-10-06 Ansell Limited Powder-free antimicrobial coated glove
US20100234925A1 (en) * 2009-03-16 2010-09-16 PinPoint U.S.A., Inc. Treatment of microbiological pathogens in a toe nail with antimicrobial light
US20120089232A1 (en) 2009-03-27 2012-04-12 Jennifer Hagyoung Kang Choi Medical devices with galvanic particulates
CA2763221C (en) 2009-05-26 2019-01-08 The General Hospital Corporation Method and apparatus for dermal delivery of a substance
US8906883B2 (en) 2009-06-10 2014-12-09 Exthera Ab Treatment of oral mucositis by administering an ionic complex of chitosan and a negatively charged polysaccharide selected from heparin, heparan sulfate and dextran sulfate
US8821455B2 (en) * 2009-07-09 2014-09-02 Becton, Dickinson And Company Antimicrobial coating for dermally invasive devices
US20110008271A1 (en) * 2009-07-13 2011-01-13 Jr Chem, Llc Rosacea treatments using polymetal complexes
US20110022158A1 (en) * 2009-07-22 2011-01-27 Boston Scientific Scimed, Inc. Bioerodible Medical Implants
US8814922B2 (en) * 2009-07-22 2014-08-26 New Star Lasers, Inc. Method for treatment of fingernail and toenail microbial infections using infrared laser heating and low pressure
US20110065798A1 (en) * 2009-09-17 2011-03-17 Becton, Dickinson And Company Anti-infective lubricant for medical devices and methods for preparing the same
US20110091571A1 (en) * 2009-10-16 2011-04-21 Moore Michael F Method of controlling the propagation of mrsa, staph and other infections that colonize in the nose
EP2498763A4 (en) 2009-11-09 2015-10-07 Spotlight Technology Partners Llc Polysaccharide based hydrogels
AU2010314994B2 (en) 2009-11-09 2016-10-06 Spotlight Technology Partners Llc Fragmented hydrogels
KR20120091335A (en) * 2009-11-13 2012-08-17 존슨 앤드 존슨 컨수머 캄파니즈, 인코포레이티드 Galvanic skin treatment device
US8701671B2 (en) 2011-02-04 2014-04-22 Joseph E. Kovarik Non-surgical method and system for reducing snoring
US9549842B2 (en) 2011-02-04 2017-01-24 Joseph E. Kovarik Buccal bioadhesive strip and method of treating snoring and sleep apnea
JP2011135009A (en) * 2009-12-25 2011-07-07 Tokyo Electron Ltd Method and apparatus for drying substrate
KR20110091461A (en) * 2010-02-05 2011-08-11 존슨 앤드 존슨 컨수머 캄파니즈, 인코포레이티드 Lip compositions comprising galvanic particulates
CN102781406B (en) * 2010-03-01 2015-07-08 强生消费者公司 Skin care composition having desirable bulk color
US8668732B2 (en) 2010-03-23 2014-03-11 Boston Scientific Scimed, Inc. Surface treated bioerodible metal endoprostheses
US20110236491A1 (en) * 2010-03-25 2011-09-29 Jeannette Chantalat Topical anti-inflammatory composition
US9999702B2 (en) 2010-04-09 2018-06-19 Kci Licensing Inc. Apparatuses, methods, and compositions for the treatment and prophylaxis of chronic wounds
US20110301553A1 (en) * 2010-06-04 2011-12-08 Smiths Medical Asd, Inc. Antimicrobial lubricant
RU2452498C2 (en) * 2010-07-20 2012-06-10 Общество с ограниченной ответственностью "Научно-производственное объединение "Ликом" Method for preparing anti-tuberculosis drug
DK3210591T3 (en) 2010-08-27 2019-04-15 Sienna Biopharmaceuticals Inc COMPOSITIONS AND METHODS OF TARGETED THERMO MODULATION
US9572880B2 (en) 2010-08-27 2017-02-21 Sienna Biopharmaceuticals, Inc. Ultrasound delivery of nanoparticles
JP5646277B2 (en) * 2010-10-25 2014-12-24 クラシエホームプロダクツ株式会社 Disinfectant and acne treatment / prevention agent
US9572329B2 (en) * 2010-11-18 2017-02-21 Samuel P Hopkins Antimicrobial containing fish hook and method of using and manufacturing same
US8952057B2 (en) 2011-01-11 2015-02-10 Jr Chem, Llc Compositions for anorectal use and methods for treating anorectal disorders
US9987224B2 (en) 2011-02-04 2018-06-05 Joseph E. Kovarik Method and system for preventing migraine headaches, cluster headaches and dizziness
US10512661B2 (en) 2011-02-04 2019-12-24 Joseph E. Kovarik Method and system for reducing the likelihood of developing liver cancer in an individual diagnosed with non-alcoholic fatty liver disease
US10548761B2 (en) 2011-02-04 2020-02-04 Joseph E. Kovarik Method and system for reducing the likelihood of colorectal cancer in a human being
US10687975B2 (en) 2011-02-04 2020-06-23 Joseph E. Kovarik Method and system to facilitate the growth of desired bacteria in a human's mouth
US11357722B2 (en) 2011-02-04 2022-06-14 Seed Health, Inc. Method and system for preventing sore throat in humans
US11273187B2 (en) 2015-11-30 2022-03-15 Joseph E. Kovarik Method and system for reducing the likelihood of developing depression in an individual
US11844720B2 (en) 2011-02-04 2023-12-19 Seed Health, Inc. Method and system to reduce the likelihood of dental caries and halitosis
US10842834B2 (en) 2016-01-06 2020-11-24 Joseph E. Kovarik Method and system for reducing the likelihood of developing liver cancer in an individual diagnosed with non-alcoholic fatty liver disease
US11523934B2 (en) 2011-02-04 2022-12-13 Seed Health, Inc. Method and system to facilitate the growth of desired bacteria in a human's mouth
US10245288B2 (en) 2011-02-04 2019-04-02 Joseph E. Kovarik Method and system for reducing the likelihood of developing NASH in an individual diagnosed with non-alcoholic fatty liver disease
US10086018B2 (en) 2011-02-04 2018-10-02 Joseph E. Kovarik Method and system for reducing the likelihood of colorectal cancer in a human being
US11419903B2 (en) 2015-11-30 2022-08-23 Seed Health, Inc. Method and system for reducing the likelihood of osteoporosis
CN106214110B (en) 2011-02-16 2018-03-20 通用医疗公司 photo-coupler for endoscope
US9707375B2 (en) 2011-03-14 2017-07-18 Rochester Medical Corporation, a subsidiary of C. R. Bard, Inc. Catheter grip and method
US8597264B2 (en) 2011-03-24 2013-12-03 Kci Licensing, Inc. Apparatuses, methods, and compositions for the treatment and prophylaxis of chronic wounds
WO2012131931A1 (en) * 2011-03-30 2012-10-04 ダイワボウホールディングス株式会社 Wound-covering material
CA2829095C (en) * 2011-03-30 2019-08-27 Gr Intellectual Reserve, Llc Novel gold-platinum based bi-metallic nanocrystal suspensions, electrochemical manufacturing processes therefor and uses for the same
GB2497115A (en) * 2011-12-01 2013-06-05 Lrc Products Coated condom
JP6017883B2 (en) * 2012-08-08 2016-11-02 バイオエポック株式会社 Manufacturing method of toothpaste
WO2014039533A2 (en) 2012-09-04 2014-03-13 Eleison Pharmaceuticals, Llc Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin
CN102872159A (en) * 2012-09-29 2013-01-16 广东同德药业有限公司 Nano-silver chitosan gel foam preparation for treating vaginal bacterial inflammation, and preparation method thereof
RU2646809C2 (en) 2012-10-11 2018-03-07 Нанокомпозикс, Инк. Silver nanoplates compositions and methods
CN102872160A (en) * 2012-10-26 2013-01-16 广东同德药业有限公司 Nano-silver foaming agent used for sterilizing wounds of scalds and burns and ulcer wounds
AU2013334061A1 (en) * 2012-10-26 2015-05-14 Sienna Labs, Inc. Metastable silver nanoparticle composites
US9872969B2 (en) 2012-11-20 2018-01-23 Rochester Medical Corporation, a subsidiary of C.R. Bard, Inc. Catheter in bag without additional packaging
US10092728B2 (en) 2012-11-20 2018-10-09 Rochester Medical Corporation, a subsidiary of C.R. Bard, Inc. Sheath for securing urinary catheter
US20140377318A1 (en) * 2012-12-06 2014-12-25 S. Douglas Cornell Antimicrobial sanitizer systems and methods of killing or inhibiting pathogens
EP2764876A1 (en) * 2013-02-11 2014-08-13 Lacerta Technologies Inc. Bone substitute material with biologically active coating
US9750928B2 (en) 2013-02-13 2017-09-05 Becton, Dickinson And Company Blood control IV catheter with stationary septum activator
US9695323B2 (en) 2013-02-13 2017-07-04 Becton, Dickinson And Company UV curable solventless antimicrobial compositions
GB2511528A (en) 2013-03-06 2014-09-10 Speciality Fibres And Materials Ltd Absorbent materials
US9750927B2 (en) 2013-03-11 2017-09-05 Becton, Dickinson And Company Blood control catheter with antimicrobial needle lube
US9327095B2 (en) 2013-03-11 2016-05-03 Becton, Dickinson And Company Blood control catheter with antimicrobial needle lube
US20140271919A1 (en) * 2013-03-15 2014-09-18 Chun Lim Abbott Topical Copper Ion Treatments and Methods of Treatment Using Topical Copper Ion Treatments in the Genital-Rectal Areas of the Body
US10398733B2 (en) 2013-03-15 2019-09-03 Cda Research Group, Inc. Topical copper ion treatments and methods of treatment using topical copper ion treatments in the dermatological areas of the body
US10792337B2 (en) 2013-03-15 2020-10-06 Kci Licensing, Inc. Wound healing compositions
US11000545B2 (en) 2013-03-15 2021-05-11 Cda Research Group, Inc. Copper ion compositions and methods of treatment for conditions caused by coronavirus and influenza
US11007143B2 (en) * 2013-03-15 2021-05-18 Cda Research Group, Inc. Topical copper ion treatments and methods of treatment using topical copper ion treatments in the oral-respiratory-otic areas of the body
US11318089B2 (en) 2013-03-15 2022-05-03 Cda Research Group, Inc. Topical copper ion treatments and methods of making topical copper ion treatments for use in various anatomical areas of the body
US11083750B2 (en) 2013-03-15 2021-08-10 Cda Research Group, Inc. Methods of treatment using topical copper ion formulations
US9095566B1 (en) * 2013-06-28 2015-08-04 Edward Quicksilver Yavitz Eyelash and eyelid margin infections
US11833177B2 (en) 2013-12-20 2023-12-05 Seed Health, Inc. Probiotic to enhance an individual's skin microbiome
US11826388B2 (en) 2013-12-20 2023-11-28 Seed Health, Inc. Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation
US11839632B2 (en) 2013-12-20 2023-12-12 Seed Health, Inc. Topical application of CRISPR-modified bacteria to treat acne vulgaris
US20150182673A1 (en) 2013-12-30 2015-07-02 Boston Scientific Scimed, Inc. Functionalized lubricious medical device coatings
CN104814831A (en) * 2014-01-30 2015-08-05 柯惠有限合伙公司 Preparation of occlusive dressings
US10376686B2 (en) 2014-04-23 2019-08-13 Becton, Dickinson And Company Antimicrobial caps for medical connectors
US9789279B2 (en) 2014-04-23 2017-10-17 Becton, Dickinson And Company Antimicrobial obturator for use with vascular access devices
US9675793B2 (en) 2014-04-23 2017-06-13 Becton, Dickinson And Company Catheter tubing with extraluminal antimicrobial coating
US10232088B2 (en) 2014-07-08 2019-03-19 Becton, Dickinson And Company Antimicrobial coating forming kink resistant feature on a vascular access device
CN106659820A (en) 2014-08-26 2017-05-10 C·R·巴德股份有限公司 Urinary catheter
US9459442B2 (en) 2014-09-23 2016-10-04 Scott Miller Optical coupler for optical imaging visualization device
CN104577135B (en) * 2015-01-04 2017-01-18 哈尔滨工业大学 Preparation method of three-dimensional silver mesh
US10548467B2 (en) 2015-06-02 2020-02-04 GI Scientific, LLC Conductive optical element
US10856724B2 (en) 2015-07-21 2020-12-08 GI Scientific, LLC Endoscope accessory with angularly adjustable exit portal
RU2611999C2 (en) * 2015-08-05 2017-03-01 Федеральное государственное бюджетное учреждение науки Иркутский институт химии им. А.Е. Фаворского Сибирского отделения Российской академии наук Silver nanocomposite based on arabinogalactan conjugate and flavonoids with antimicrobial and antitumor action and preparation method thereof
US10040957B2 (en) * 2015-09-17 2018-08-07 Eastman Kodak Company Ink jettable, UV-curable compositions
DE102015115878B4 (en) * 2015-09-21 2018-03-29 Aap Implantate Ag A method of treating a metallic surface and bodies having a treated metallic surface
US10493244B2 (en) 2015-10-28 2019-12-03 Becton, Dickinson And Company Extension tubing strain relief
CN108601930B (en) * 2016-02-08 2021-12-14 祥丰医疗私人有限公司 Drug eluting balloon
US10792477B2 (en) 2016-02-08 2020-10-06 Orbusneich Medical Pte. Ltd. Drug eluting balloon
BR102016016340A2 (en) * 2016-07-14 2018-02-06 Francisco Pianowski Luiz ANTIMICROBIAN MUCOSAL FORMULATION AND USE OF ANTIMICROBIAN MUCOSAL FORMULATION
US11330931B2 (en) 2016-09-29 2022-05-17 Levo Oil Infusion Apparatus and method for infusing and dispensing oils, and drying and heating infusing materials
US10537658B2 (en) 2017-03-28 2020-01-21 DePuy Synthes Products, Inc. Orthopedic implant having a crystalline gallium-containing hydroxyapatite coating and methods for making the same
US10537661B2 (en) 2017-03-28 2020-01-21 DePuy Synthes Products, Inc. Orthopedic implant having a crystalline calcium phosphate coating and methods for making the same
AU2018337731C1 (en) 2017-09-19 2024-02-01 C.R. Bard, Inc. Urinary catheter bridging device, systems and methods thereof
US10912739B2 (en) 2017-10-16 2021-02-09 Peace Out Inc. Hydrocolloid-based skin treatment
RU2659580C1 (en) * 2017-10-16 2018-07-05 Федеральное государственное бюджетное образовательное учреждение высшего образования "Кировский государственный медицинский университет" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Кировский ГМУ Минздрава России) Method for obtaining agent for topical treatment of skin lesions based on nanoscale silver particles, ointment base and solid additives
JP7365409B2 (en) 2018-06-28 2023-10-19 エイアールエックス エルエルシー Dispensing method for producing soluble unit dose membrane constructs
CN108853557A (en) * 2018-07-23 2018-11-23 衢州玛济克医疗科技有限公司 A kind of wet erythema medical dressing of infant and its production method
CN109646456A (en) * 2018-12-31 2019-04-19 四川金凯医疗器械有限公司 It is a kind of for treating the new type gel of periodontitis
CN109731103B (en) * 2019-01-20 2022-03-22 桂林理工大学 Preparation method of P-type molecular sieve-chitosan-sodium alginate-potassium diformate sustained-release antibacterial agent
US11193184B2 (en) 2019-02-22 2021-12-07 Cda Research Group, Inc. System for use in producing a metal ion suspension and process of using same
RU2730480C1 (en) * 2019-07-30 2020-08-24 Общество с ограниченной ответственностью "БиоМед" Method of administering a pharmaceutical substance into a polymer substrate of a dressing
DE102021205475A1 (en) 2021-05-28 2022-12-01 FNT-GmbH Antimicrobial composition, method of making an antimicrobial composition and use of an antimicrobial composition
CN113479975A (en) * 2021-07-01 2021-10-08 辽宁锦海医药科技有限公司 Preparation method and application of oxidation potential acidic water
KR20230081979A (en) * 2021-11-30 2023-06-08 경희대학교 산학협력단 Composition for anti-inflammation comprising gold nanoparticle-peanut sprout extract as an active ingredient
US11684586B1 (en) 2022-02-28 2023-06-27 Peace Out, Llc Anhydrous hydrocolloid matrix comprising homogeneously distributed encapsulated therapeutic agents

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5837275A (en) * 1992-05-19 1998-11-17 Westaim Technologies, Inc. Anti-microbial materials

Family Cites Families (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB420052A (en) 1932-10-17 1934-11-23 Consortium Elektrochem Ind Manufacture of shaped articles from polyvinyl alcohols
FR732895A (en) 1932-10-18 1932-09-25 Consortium Elektrochem Ind Articles spun in polyvinyl alcohol
FR882M (en) 1961-01-18 1961-10-06
GB1270410A (en) 1969-09-25 1972-04-12 Allor Corp Colloidal composition and method of preparing the same
US3757786A (en) 1970-11-06 1973-09-11 D Smith Synthetic surgical sutures
US3800792A (en) 1972-04-17 1974-04-02 Johnson & Johnson Laminated collagen film dressing
US3988434A (en) * 1972-08-07 1976-10-26 Schole Murray L Dental preparation
US3918446A (en) 1974-05-03 1975-11-11 E Med Corp Securement device for intravenous catheter and its tubing
US4059105A (en) * 1976-03-24 1977-11-22 Omnimed, Inc. Cannula securing device
DE2748882A1 (en) 1977-11-02 1979-05-03 Arnis Dr Med Rava Plaster protecting wound against infection - esp. during application of intravenous catheter, permitting continuous use for ten days
DE2929706C2 (en) 1979-07-21 1982-09-30 Drägerwerk AG, 2400 Lübeck Breathing air humidifiers and warmers for ventilation systems
US4324237A (en) * 1980-02-26 1982-04-13 E-Med Corporation Intravenous catheter and tubing securement and dressing device with a window over the puncture or wound site
GB2073024B (en) 1980-03-27 1984-06-27 Nat Res Dev Antimicrobial surgical implants
US4476590A (en) 1980-03-27 1984-10-16 National Research Development Corporation Antimicrobial surgical implants
DE3176658D1 (en) 1981-12-10 1988-03-31 Revlon Process for making metallic leafing pigments
JPS58126910A (en) 1982-01-21 1983-07-28 Nippon Steel Corp Dephosphorizing method of molten metal
GB2140684B (en) 1983-04-25 1986-07-30 Stavros Christodoulou Mineral oil composition for use in the treatment of eczema
JPS6021912A (en) 1983-07-14 1985-02-04 Mitsubishi Rayon Co Ltd Manufacture of metallized synthetic fiber staple
US4828832A (en) 1983-09-07 1989-05-09 Laboratorios Biochemie De Mexico Method of manufacturing a composition for treating skin lesions
EP0136768A3 (en) 1983-09-07 1986-07-30 Laboratorios Biochemie De Mexico S.A. DE C.V. Composition and method for treatingskin lesions
US4581028A (en) 1984-04-30 1986-04-08 The Trustees Of Columbia University In The City Of New York Infection-resistant materials and method of making same through use of sulfonamides
GB8421706D0 (en) * 1984-08-28 1984-10-03 Pharmaceutical Holdings Ltd Pharmaceutical preparations
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US4633863A (en) 1985-09-27 1987-01-06 Filips Chester P Arterial anchor bandage
US4960413A (en) 1985-11-09 1990-10-02 The Shirley Institute Wound dressing
US5122418A (en) 1985-12-09 1992-06-16 Shiseido Company Ltd. Composite powder and production process
US4847049A (en) * 1985-12-18 1989-07-11 Vitaphore Corporation Method of forming chelated collagen having bactericidal properties
JPS62185807A (en) 1986-02-08 1987-08-14 Mitsubishi Shindo Kk Production of metallic flat powder
GB8607159D0 (en) * 1986-03-22 1986-04-30 Smith & Nephew Ass Pharmaceutical composition
GB8612598D0 (en) 1986-05-23 1986-07-02 Tarnpure Ltd Liquid/gas interface apparatus
US5236421A (en) 1986-05-28 1993-08-17 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Fixing system for fastening catheters, cannulas or the like to the skin surface and process for the sterile fastening thereof
EP0254413A3 (en) 1986-06-13 1989-11-08 Yoshiaki Matsuo Silver-ionic water and its uses
US4952411A (en) 1987-02-25 1990-08-28 Trustees Of Columbia University In The City Of New York Method of inhibiting the transmission of AIDS virus
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US5143717A (en) 1987-12-30 1992-09-01 Code Blue Medical Corporation Burn foam and delivery system
US5019096A (en) 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
DE3807944A1 (en) 1988-03-10 1989-09-21 Braun Melsungen Ag Device for fastening a catheter or a cannula on the skin surface
NZ228367A (en) * 1988-03-23 1992-02-25 Smithkline Beecham Corp Topical composition containing a gold compound for treating inflammatory conditions
AU4045489A (en) 1988-08-18 1990-03-23 Konrad Minninger Silver sulfadiazine containing pharmaceutical product for the local external therapy
US4956350A (en) 1988-08-18 1990-09-11 Minnesota Mining And Manufacturing Company Wound filling compositions
US4908355A (en) 1989-01-09 1990-03-13 Dow Corning Corporation Skin treatment method
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5270358A (en) * 1989-12-28 1993-12-14 Minnesota Mining And Manufacturing Company Composite of a disperesed gel in an adhesive matrix
JP3169621B2 (en) 1991-01-29 2001-05-28 株式会社タカミツ Antimicrobial external preparation
EP0570452A1 (en) 1991-02-06 1993-11-24 Minnesota Mining And Manufacturing Company Improved surgical hardware with bacteriostatic silver coating, and method of using same
US5484886A (en) * 1991-04-25 1996-01-16 Merck & Co., Inc. Human neurokinin-1 receptor
US5348799A (en) 1991-09-03 1994-09-20 Minnesota Mining And Manufacturing Company Antistatic coatings comprising chitosan acid salt and metal oxide particles
US5681575A (en) 1992-05-19 1997-10-28 Westaim Technologies Inc. Anti-microbial coating for medical devices
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
USD349958S (en) 1992-07-24 1994-08-23 Bioject Inc. Needleless injector
CN1034090C (en) 1992-08-06 1997-02-19 蒋建华 Long-acting broad-spectrum antiseptic fabric and its producing method
IT1256111B (en) 1992-11-23 1995-11-28 Lifegroup Spa SALTS OF TRAUMATIC ACID WITH CICATRIZING AND ANTIBACTERIAL ACTIVITY
JP2981528B2 (en) 1992-12-25 1999-11-22 三菱電機株式会社 Cathode ray tube and method of manufacturing the same
JP3513199B2 (en) * 1993-01-01 2004-03-31 キヤノン株式会社 Liquid ejecting head, liquid ejecting head cartridge and recording apparatus using the same, and method of manufacturing liquid ejecting head
US5631066A (en) * 1993-01-25 1997-05-20 Chronopol, Inc. Process for making metalized films and films produced therefrom
US5534288A (en) 1993-03-23 1996-07-09 United States Surgical Corporation Infection-resistant surgical devices and methods of making them
US5848995A (en) 1993-04-09 1998-12-15 Walder; Anthony J. Anti-infective medical article and method for its preparation
US5454889A (en) * 1993-08-19 1995-10-03 Ici Canada Inc. Prill coating
WO1995012602A1 (en) 1993-11-05 1995-05-11 Meiji Milk Products Co., Ltd. Antibacterial, antifungal and antiviral agent
CA2136455C (en) * 1993-11-18 1999-06-29 Robert Edward Burrell Process for producing anti-microbial effect with complex silver ions
US5454886A (en) 1993-11-18 1995-10-03 Westaim Technologies Inc. Process of activating anti-microbial materials
US5372589A (en) 1993-11-24 1994-12-13 Davis; W. Gordon Fenestrated transparent catheter securing device and method
WO1995014484A1 (en) 1993-11-26 1995-06-01 Kimurakogyo Co., Ltd. In vivo free-radical generator
US5817325A (en) 1996-10-28 1998-10-06 Biopolymerix, Inc. Contact-killing antimicrobial devices
JPH07220702A (en) * 1994-02-02 1995-08-18 Nec Corp Battery pack
EP0788305B1 (en) * 1994-03-28 2004-11-03 The Trustees of Columbia University in the City of New York Composition for inactivating irritants in fluids
US5899880A (en) 1994-04-08 1999-05-04 Powderject Research Limited Needleless syringe using supersonic gas flow for particle delivery
US5563132A (en) 1994-06-21 1996-10-08 Bodaness; Richard S. Two-step cancer treatment method
US6544357B1 (en) * 1994-08-01 2003-04-08 Franz Hehmann Selected processing for non-equilibrium light alloys and products
US5578073A (en) 1994-09-16 1996-11-26 Ramot Of Tel Aviv University Thromboresistant surface treatment for biomaterials
US5569207A (en) 1994-10-13 1996-10-29 Quinton Instrument Company Hydrocolloid dressing
GB9424562D0 (en) 1994-12-06 1995-01-25 Giltech Ltd Product
US5589177A (en) 1994-12-06 1996-12-31 Helene Curtis, Inc. Rinse-off water-in-oil-in-water compositions
GB9502879D0 (en) 1995-02-14 1995-04-05 Oxford Biosciences Ltd Particle delivery
CA2224164C (en) 1995-06-07 2007-12-11 Robert S. Neuwirth Intrauterine chemical necrosing method and composition
CA2225808C (en) 1995-06-30 2002-12-17 Christopher C. Capelli Silver-based pharmaceutical compositions
US6013050A (en) 1995-10-20 2000-01-11 Powderject Research Limited Particle delivery
DE19541735A1 (en) 1995-11-09 1997-05-15 Iris Roller Use of hydrothermal rock deposits e.g. calcite precursors
US5686096A (en) 1995-12-22 1997-11-11 Becton Dickinson And Company Medical device for the protection of a catheter penetration site
US6201164B1 (en) 1996-07-11 2001-03-13 Coloplast A/S Hydrocolloid wound gel
US5895419A (en) * 1996-09-30 1999-04-20 St. Jude Medical, Inc. Coated prosthetic cardiac device
DE19640365A1 (en) 1996-09-30 1998-04-02 Basf Ag Polymer-hydrogen peroxide complexes
EP0834319A1 (en) * 1996-10-07 1998-04-08 Kartar Dr. Lalvani Mineral and vitamin combinations in arthritic pain
GB9623962D0 (en) * 1996-11-15 1997-01-08 Tillotts Pharma Ag Pharmaceutical composition
US7625420B1 (en) 1997-02-24 2009-12-01 Cabot Corporation Copper powders methods for producing powders and devices fabricated from same
US6333093B1 (en) 1997-03-17 2001-12-25 Westaim Biomedical Corp. Anti-microbial coatings having indicator properties and wound dressings
GB2324732B (en) 1997-05-02 2001-09-26 Johnson & Johnson Medical Absorbent wound dressings
WO1998051273A1 (en) 1997-05-12 1998-11-19 Sage Pharmaceuticals, Inc. Topical spray for burn treatment and anti-infection
US6071543A (en) 1997-06-02 2000-06-06 Cellegy Pharmaceuticals, Inc. Pyridine-thiols reverse mucocutaneous aging
KR20010013377A (en) 1997-06-04 2001-02-26 데이비드 엠 모이어 Mild, leave-on antimicrobial compositions
EP0991702B2 (en) 1997-06-20 2017-07-19 Coloplast A/S A hydrophilic coating
DE19728489A1 (en) 1997-07-03 1999-01-07 Huels Chemische Werke Ag Medical device for improving the skin fixation of indwelling catheters and other transcutaneous implants with a reduced risk of infection
US6165440A (en) 1997-07-09 2000-12-26 Board Of Regents, The University Of Texas System Radiation and nanoparticles for enhancement of drug delivery in solid tumors
US6153210A (en) * 1997-08-14 2000-11-28 Periodontix, Inc. Use of locally delivered metal ions for treatment of periodontal disease
JP3411195B2 (en) 1997-08-18 2003-05-26 栄一 築地 Active oxygen remover
JPH11116488A (en) 1997-10-08 1999-04-27 Toagosei Co Ltd Carcinostatic agent
JP4039719B2 (en) * 1997-10-17 2008-01-30 富士フイルム株式会社 Antitumor agent
US6312643B1 (en) * 1997-10-24 2001-11-06 The United States Of America As Represented By The Secretary Of The Air Force Synthesis of nanoscale aluminum alloy powders and devices therefrom
HU221676B1 (en) * 1998-02-20 2002-12-28 István Budai Pharmaceutical composition, containing ethanol or water-ethanol solution having iodine and silver nitrate and process for producing it
FR2775696B1 (en) * 1998-03-05 2000-04-14 Saint Gobain Vitrage SUBSTRATE WITH PHOTOCATALYTIC COATING
US20020014406A1 (en) * 1998-05-21 2002-02-07 Hiroshi Takashima Aluminum target material for sputtering and method for producing same
US6123925A (en) 1998-07-27 2000-09-26 Healthshield Technologies L.L.C. Antibiotic toothpaste
US6071541A (en) 1998-07-31 2000-06-06 Murad; Howard Pharmaceutical compositions and methods for managing skin conditions
US6398999B1 (en) * 1998-10-23 2002-06-04 Avery Dennison Corporation Process for making high aspect ratio reflective metal flakes
US6238986B1 (en) * 1998-11-06 2001-05-29 Advanced Micro Devices, Inc. Formation of junctions by diffusion from a doped film at silicidation
EP1128824A1 (en) 1998-11-09 2001-09-05 Ira Jay Newman Ionic silver complex
US6096002A (en) * 1998-11-18 2000-08-01 Bioject, Inc. NGAS powered self-resetting needle-less hypodermic jet injection apparatus and method
US6436422B1 (en) 1998-11-23 2002-08-20 Agion Technologies L.L.C. Antibiotic hydrophilic polymer coating
US6365130B1 (en) 1998-11-23 2002-04-02 Agion Technologies L.L.C. Antimicrobial chewing gum
US6224579B1 (en) * 1999-03-31 2001-05-01 The Trustees Of Columbia University In The City Of New York Triclosan and silver compound containing medical devices
US6258385B1 (en) 1999-04-22 2001-07-10 Marantech Holding, Llc Tetrasilver tetroxide treatment for skin conditions
JP4454062B2 (en) 1999-05-17 2010-04-21 敬 三宅 Ultrafine particle silver milky body and method for producing the same
EP1066825A1 (en) * 1999-06-17 2001-01-10 The Procter & Gamble Company An anti-microbial body care product
CN1161511C (en) 1999-07-27 2004-08-11 蒋建华 Long-acting wide-spectrum antiseptic nanometer silver fabric and its making method
JP2001151681A (en) 1999-11-24 2001-06-05 Lintec Corp Prophylactic and/or therapeutic agent for systema digestorium disease
CN1108786C (en) 1999-12-28 2003-05-21 天津市化妆品科学技术研究所 Silver foil cosmetics
JP2003519188A (en) * 2000-01-06 2003-06-17 マランテック ホールディング リミテッド ライアビリティ カンパニー Compositions and methods for promoting skin growth and treating skin conditions
US7137968B1 (en) 2000-03-13 2006-11-21 Nucryst Pharmaceuticals Corp. Transcutaneous medical device dressings and method of use
US6224898B1 (en) 2000-03-23 2001-05-01 The United States Of America As Represented By The Secretary Of The Army Antimicrobial dendrimer nanocomposites and a method of treating wounds
US6719987B2 (en) * 2000-04-17 2004-04-13 Nucryst Pharmaceuticals Corp. Antimicrobial bioabsorbable materials
SE516537C2 (en) * 2000-05-19 2002-01-29 Alfa Laval Ab Flat pack and plate heat exchanger
US6592888B1 (en) 2000-05-31 2003-07-15 Jentec, Inc. Composition for wound dressings safely using metallic compounds to produce anti-microbial properties
PT1395289E (en) * 2000-06-08 2011-03-16 Sang Dr Christine Treatment of neuropathic pain with a n-methyl-d-aspartate (nmda) receptor antagonists
ES2231528T3 (en) 2000-07-27 2005-05-16 Nucryst Pharmaceuticals Corp. USE OF NOBLE METALS FOR THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE TREATMENT OF HYPERPROLIFERATIVE SKIN DISORDERS AND DISEASES.
US7008647B2 (en) 2001-04-23 2006-03-07 Nucryst Pharmaceuticals Corp. Treatment of acne
US20030170314A1 (en) * 2000-07-27 2003-09-11 Burrell Robert E. Compositions of metal-containing compounds
DE10037353A1 (en) 2000-07-29 2002-02-07 Hans E Sachse Catheter with bioabsorbable coating to prevent rising infections
CN1279222A (en) 2000-07-31 2001-01-10 金华尖峰陶瓷有限责任公司 Antibacterial inorganic ceramics and its production technology
CN1291667A (en) 2000-08-14 2001-04-18 骏安科技投资有限公司 Nanometer silver anti-bacteria cloth and its industrial production technology
CN1147640C (en) 2000-09-19 2004-04-28 南京希科集团有限公司 Antibacterial fabric containing nm-class silver powder and its making method
CN1159488C (en) 2001-01-20 2004-07-28 南京希科集团有限公司 Antibacterial flexible material containing nm silver and its preparing process and application
CN1179646C (en) 2001-04-20 2004-12-15 朱红军 Aggregation-preventing nanometer wide-spectrum antibacterial silve powder and its inductrial production process
EP1383521A2 (en) * 2001-04-23 2004-01-28 Nucryst Pharmaceuticals Corp. Medicament containing a metal such as silver, gold, platinum or palladium as an antimicrobial agent and their use to induce apoptosis in cancerous tissue
CN1183285C (en) 2001-04-25 2005-01-05 朱红军 Aggregation-preventing wide-spectrum nanometer antibiotic silver yarn and its industrial production process

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5837275A (en) * 1992-05-19 1998-11-17 Westaim Technologies, Inc. Anti-microbial materials

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1390013A2 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130210925A1 (en) * 2002-09-27 2013-08-15 Jay E. Birnbaum Concepts Llc Subunguicide, and method for treating onychomycosis
EP1567101A2 (en) * 2002-10-22 2005-08-31 Nucfryst Pharmaceuticals Corp. Prophylactic treatment methods
EP1567101A4 (en) * 2002-10-22 2009-06-03 Nucryst Pharm Corp Prophylactic treatment methods
WO2005074949A1 (en) * 2004-02-02 2005-08-18 Nucryst Pharmaceuticals Corp. Treatment of ungual and subungual diseases with antimicrobial metal compositions
US8865227B2 (en) 2007-12-20 2014-10-21 Smith & Nephew (Overseas) Limited Metal carbonate particles and methods of making thereof
WO2010143075A2 (en) * 2009-06-10 2010-12-16 Willoughby Andrew J M Dental uses of silver hydrosol
WO2010143075A3 (en) * 2009-06-10 2011-04-21 Willoughby Andrew J M Silver hydrosol, dental applications and other uses thereof
US9192626B2 (en) 2009-06-10 2015-11-24 American Silver, Llc Dental uses of silver hydrosol
US10456568B2 (en) 2013-03-14 2019-10-29 Hallux, Inc. Method of treating infections, diseases or disorders of nail unit

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