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WO1998006260A1 - Compositions antimicrobiennes a base d'argent - Google Patents

Compositions antimicrobiennes a base d'argent Download PDF

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Publication number
WO1998006260A1
WO1998006260A1 PCT/US1997/014697 US9714697W WO9806260A1 WO 1998006260 A1 WO1998006260 A1 WO 1998006260A1 US 9714697 W US9714697 W US 9714697W WO 9806260 A1 WO9806260 A1 WO 9806260A1
Authority
WO
WIPO (PCT)
Prior art keywords
silver
ion complexes
thiosulfate ion
silver thiosulfate
thiosulfate
Prior art date
Application number
PCT/US1997/014697
Other languages
English (en)
Inventor
Christopher C. Capelli
Original Assignee
Capelli Christopher C
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/909,239 external-priority patent/US6093414A/en
Application filed by Capelli Christopher C filed Critical Capelli Christopher C
Priority to EP97938487A priority Critical patent/EP0920252A4/fr
Priority to CA002263473A priority patent/CA2263473C/fr
Priority to AU40797/97A priority patent/AU735373B2/en
Priority to CA002383742A priority patent/CA2383742C/fr
Publication of WO1998006260A1 publication Critical patent/WO1998006260A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B17/00—Sulfur; Compounds thereof
    • C01B17/64—Thiosulfates; Dithionites; Polythionates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A46—BRUSHWARE
    • A46D—MANUFACTURE OF BRUSHES
    • A46D1/00—Bristles; Selection of materials for bristles
    • A—HUMAN NECESSITIES
    • A46—BRUSHWARE
    • A46D—MANUFACTURE OF BRUSHES
    • A46D1/00—Bristles; Selection of materials for bristles
    • A46D1/006—Antimicrobial, disinfectant bristles, handle, bristle-carrier or packaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222—Steroids, e.g. corticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • the present invention relates to silver-based antimicrobial compositions and processes for making such compositions that are suitable for use in the treatment and prevention of infections
  • Antimicrobial agents are chemical compounds that either destrov microbes, prevent their pathogenic action, or prevent their growth
  • Antimicrobial agents often referred to as anti-infective agents, are frequently applied topicallv to the skin and mucous membranes in the form of a solution, cream, or ointment, appropriate formulations mav be applied to wounds and body cavities, and to the eyes, nose, and mouth
  • topical antimicrobial agents are directed at bacteria, viruses, and fungi
  • agents have a limited spectrum of activity For example, some are specific for particular gram (+) organisms, while others are specific for particular gram (-) organisms
  • bactericidal agents tvpicallv are not fungicidal w hile fungicidal agents tvpicallv are not bactericidal
  • Acquired drug resistance is usually caused bv a mutation within the genome of the microbe or bv the acquisition of a plasmid
  • or mechanisms of resistance to the ⁇ -lactam antibiotics, including penicillins is the production of ⁇ -lactamases
  • resistance to one member of a class of agents e g , the aminopenicilhn ampicilhn
  • ⁇ e.g., the aminopenicillin amoxicillin
  • a 1 % silver nitrate ophthalmic solution can be used in newborns for the prophylaxis of gonococcal ophthalmia (gonococcal ophthalmia neonatorum) Because the silver ion is precipitated by chloride, the silver nitrate solution does not readily penetrate into tissue. Unfortunately, the silver salts stain tissue black as a result of the deposition of reduced silver, some of the staining may persist indefinitely Thus, silver nitrate is not used topically for other indications (e.g. , impetigo)
  • Silver sulfadiazine 1 % topical cream is routineiv used as an adiunct in the prevention and treatment of infection in burn victims [See U S Patent No 3,761.590 to Fox. hereby incorporated by reference]
  • Silver sulfadiazine produced by the reaction of silver nitrate with sulfadiazine, has been associated with necrosis of the skin
  • sulfadiazine may accumulate in patients with impaired hepatic or renal function, requiring in severe cases examination of the patient ' s urine for sulfonamide crystals
  • patients allergic to sulfa agents may exhibit cross-hypersensitivity with silver sulfadiazine [See generally, AHFS Drug Information. Gerald K McKevoy, ed , pp 1704-05 and 2215- 16 ( 1993)]
  • the Oka Patent describes an antiviral composition that contains I) a thiosulfate salt and n) at least one thiosulfate complex salt of a metal and ⁇ i) a porous particulate carrier, the metal is either silver, copper or zinc, and the salts are carried on the porous paniculate carrier
  • the thiosulfate complex salt and thiosulfate metal complex salt are first prepared as a solution Thereafter, a porous carrier such as silica gel is impregnated with the solution Finally, the thiosulfate complex and thiosulfate metal complex salt are immobilized on the porous carrier through drying This metal-containing porous carrier is then formulated into the compositions described in the Oka Patent
  • the silver thiosulfate ion complex compositions contain a l elativelv large concentration of waste salts, resulting from the complexation of a thiosulfate salt, sulfite salt, and a silver salt, and are thus relativelv impure
  • a silver thiosulfate ion complex using 1 part of silver nitrate (or silver acetate) to 2 parts sodium thiosulfate and/or 2 parts sodium sulfite will result in 1 part waste sodium nitrate (or sodium acetate), the inclusion of these salts results in a lower concentration of silver
  • the silver thiosulfate ion complex requires the use of porous carrier particles, the necessity of these carrier particles limits the concentration of thiosulfate complex salt and thiosulfate metal complex salt
  • a topical antimicrobial composition would feel g ⁇ ttv and would be irritating to the skin oi wound
  • concentration of thiosulfate complex salt and thiosulfate metal complex salt carried on the porous carrier is too high, the composition av discolor
  • the compositions taught by the Oka Patent cannot be easily incorporated into a polymer matrix at high concentrations
  • incorporation of silver at antimicrobial concentrations requires concomitant incorporation of a large amount of porous carrier This can cause undesirable changes in the polymer matrix' physical properties (e.g.
  • the present invention relates generally to silver-based antimicrobial compositions and processes for making such compositions suitable for use in the treatment and prevention of infections
  • the present invention relates to stable silver-based antimicrobial compositions, and processes for making such compositions, comprising carrier-free, suspended silver thiosulfate ion complexes in a base
  • the silver thiosulfate ion complexes are homogeneously suspended in an anhydrous base
  • the silver thiosulfate ion complexes of the present invention can be incorporated into a matrix and used with a medical device
  • Pharmaceutical compositions can also be produced bv combining the silver thiosulfate ion complexes with medicinal agents, including but not limited to antimicrobial agents, steroids, and anesthetics
  • One advantage of providing silver thiosulfate ion complexes in a carrier-free form is the abilitv to produce antimicrobial compositions containing high concentrations of silver
  • the invention also contemplates methods of making the stable silver-based antimicrobial compositions
  • the silver complexes of the present invention are derived from the complexation of silver cations from silver ha des (preferably silver chloride) with anions from the sodium thiosulfate salts, the molar ratio of the thiosulfate anions to the silver cations is preferably at least I 1 and more preferably at least 1 3 1
  • the silver thiosulfate ion complexes are solid and essentially pure. / e . thev do not contain significant amounts of waste salts or other substances that interfere with their antimicrobial activity, in addition, they do not require carrier particles
  • compositions are able to contain high concentrations of silver thiosulfate ion complexes, thereby providing strong antimicrobial activity Moreover, the compositions may be used in combination with other pharmaceutical (e g , topical) agents ( g , Bactroban ⁇
  • the silver thiosulfate ion complexes of the present invention may be incorporated into medical devices, including medical implants, wound care devices, body cavity and personal protection devices, and the like
  • purified silver thiosulfate ion complexes may be incorporated with an anhydrous polymer matrix that is used to coat a u ⁇ narv catheter in order to prevent infection
  • the silver thiosulfate ion complexes mav be used in cosmetics and personal care products to make them resistant to antimicrobial contamination
  • cosmetics include lipsticks and glosses, l ip pencils, mascaras, eve l iners, eve shadows, moisturizers, liquid and powder makeup foundations, powder and cream blushes, perfumes, colognes, v arious creams and toners, etc .
  • combs, brushes, sponges, and cotton swabs and balls examples of personal care products include deodorants, razors, shaving creams, shampoos, conditioners, v arious hair treatments like mousses and spravs, toothpastes, mouthwashes. dental flosses and tapes, sunscreens, moisturizers tampons, sanitary napkins pantv shields, diapers, baby wipes, facial tissues, toi let tissues, etc
  • the present invention contemplates a composition comprising carrier-tree suspended si lver thiosulfate ion complexes suspended in a base
  • the base is anhydrous It is contemplated that the concentration of si lver thiosulfate ion complexes within the base is sufficient to provide a therapeutic benefit
  • the present invention contemplates concentrations of si lver thiosulfate ion complexes within the base from 0 0 1 % to 30% (w/w ) and from 0 1 % to 3 0% (w/w)
  • the preferred concentration of silver thiosulfate ion complexes within the base is from 0 2% to 1 5% (w/w)
  • the base is selected from the group consisting of polyethvlene glycol ⁇ quaphor' and white petrolatum
  • the present invention also contemplates a method of treating or preventing a topical microbial infection, comprising the steps of a) providing I ) a subject
  • the concentration of silver thiosulfate ion complexes within the base is sufficient to provide a therapeutic benefit
  • the present invention ⁇ specifically contemplates concentrations of silver thiosulfate ion complexes within the base trom 0 01 % to 30% (w/w) and from 0 1 % to 3 0% (w/ )
  • the preferred concentration of silver thiosulfate ion complexes within the base is from 0 2% to 1 5% (w/w)
  • the base is selected from the group consisting ot polvethvlene glycol, Aquaphor ⁇ , and white petrolatum
  • the present invention further contemplates a method of imparting antimicrobial protection to an ob
  • the concentration of silver thiosultate ion complexes is sufficient to provide a therapeutic benefit
  • the present invention contemplates concentrations of silver thiosulfate ion complexes trom 0 01 % to 30% (w/w) and from 0 1 % to 3 0% (w/w)
  • the preferred concentration of silver thiosultate ion complexes is from 0 2%
  • the present invention also contemplates a process tor producing essentially anhydrous
  • silver thiosulfate ion complexes comprising a) making an aqueous solution of silver thiosulfate ion complexes, b) adding a solvent to the solution to create a biphasic separation wherein the silver thiosultate ion complexes separate into one phase c ) collecting the phase containing the silver thiosulfate ion complexes and d) removing water from the collected phase such that the silver thiosulfate ion complexes are essentially anhvdrous
  • the ratio of thiosulfate ions to silver ions is greater than or equal to 2 1 and preferably less than 3 1
  • the aqueous solution ot si l er thiosulfate ion complexes is formed bv reacting a silver hahde and sodium thiosulfate
  • the molar ratio of silver cations from the silver ha de to thiosulfate anions from the sodium thiosulfate is preferably at least 1 1 and more preferably at least 1 3 1
  • the silver hahde is silver chloride
  • the solvent is water-miscible
  • the solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol, methvl alcohol, acetone, and tetrahvdrofuran in certain embodiments
  • the present invention contemplates a process for producing essentially anhydrous silver thiosulfate ion complexes, comprising a) making an aqueous solution of silver thiosulfate ion complexes, b) adding a solvent to the solution to precipitate the silver thiosulfate ion complexes, c) collecting the precipitated silver thiosulfate ion complexes, and d) removing water from the collected silver thiosulfate ion complexes such that the silver thiosulfate ion complexes are essentially anhydrous
  • the ratio of thiosulfate ions to silver ions is less than 2 1 and preferably greater than I I
  • the aqueous solution of silver thiosulfate ion complexes is formed by reacting a silver hahde and sodium thiosulfate
  • the molar ratio of silver cations from the silver hahde to thiosulfate anions from the sodium thiosulfate is preferably at least I 1 and more preferably at least 1 3 1
  • the silver hahde is silver chloride
  • the solvent is water-miscible
  • the solvent is selected from the group consisting of ethvl alcohol, isopropyl alcohol, methvl alcohol, acetone, and tetrahvdrofuran in certain embodiments
  • the present invention also contemplates a pharmaceutical mixture, comprising a) a medicinal agent, and b) silver thiosulfate ion complexes
  • the silver thiosulfate ion complexes are carrier-free
  • the pharmaceutical mixture further comprises an anhydrous base, in some embodiments, the base is selected from the group consisting of polyethylene glycol. Aquaphor * . and white petrolatum
  • the concentration of the si lver thiosulfate ion complexes in the pharmaceutical mixture is from 0 01 % to 30% (weight to weight)
  • the concentration of silver thiosulfate ion complexes is from 0 1 % to 3 0% (weight to weight)
  • the concentration is from 0 2% to I 5% (weight to weight)
  • the medicinal agent of the pharmaceutical mixture is an antimicrobial agent
  • the antimicrobial agent is selected from the group consisting of acyclovir, chloramphenicol, chlorhexidine chlortetracvchne. ltraconazole, mafenide. metronidazole. mupirocin, nitrofurazone, oxvtetracvchne, penicillin, and tetracvchne
  • the pharmaceutical mixture has a broader spectrum of antimicrobial protection than the silver thiosulfate ion complexes
  • the medicinal agent of the pharmaceutical mixture is a steroid in certain embodiments
  • the steroid is selected from the group consisting of betamethasone benzoate, betamethasone valerate, desonide. fluocinolone acetonide, halcinonide, hydrocortisone. and metandienone
  • the medicinal agent of the pharmaceutical mixture is an anesthetic in still other embodiments
  • the anesthetic is selected from the group consisting of benzocaine. dibucaine docaine pramoxine hvdrochlo ⁇ de and tetracacine
  • carrier refers to a substance, like an inorganic oxide, in which a material can be impregnated and then, if necessarv, immobilized through drying
  • a porous particulate carrier e ., silica gel
  • carrier-tree refers to being without such things as carrier particles porous paniculate carriers, and the like used as car ⁇ eis for other materials
  • compositions of the present invention are "carrier-free" in that thev comprise silver thiosulfate ion complexes that do not require such a carrier
  • base l efers to anv substance useful for the suspension of the silver thiosulfate ion complexes of the present invention
  • the base is "anhydrous" ( ., an ointment) and can be used to suspend a medicinal agent for topical administration
  • Useful anhydrous bases include, but are not limited to. white petrolatum.
  • the preferred anhydrous base is a PEG ointment composition, an ointment made up of PEGs can absorb and associate with a small amount of water so that the water is not free to hydrolvze the thiosulfate hgand It should be noted that some water is tolerable in the final product but that, generally speaking, the presence of water will reduce the shelf-life of the composition
  • an anhydrous base which contains no water and few, if anv, hydroxv or acid groups should have a shelf-life of many years, while a base containing small amounts of water (e g , less than 5%) would have a shorter shelf-life (e.g , less than 6 months) If a PEG ointment base has a verv small amount of water (e.g., much less than
  • the silver thiosulfate ion complexes should be stable enough to provide the product with an acceptable shelf-life ( , greater than one vear)
  • the base is semisohd
  • silver thiosulfate ion complexes refers to the silver-containing material produced by the process of the present invention and incorporated into the compositions of the present invention More specifically, the silver thiosulfate ion complexes are obtained by adding a silver hahde, g , silver chloride, to an aqueous solution and then adding a thiosulfate salt, e g , sodium thiosulfate.
  • the chemical formula of the primary silver thiosulfate ion complexes formed when a large excess of thiosulfate salt is used is represented by [Ag(S : 0,), "
  • the chemical formula of the p ⁇ marv silver thiosulfate ion complexes formed when onlv a small excess of thiosulfate salt is used is represented bv [Ag,(S : 0 1 ) 1 ] 4
  • the preferred silver thiosulfate ion complexes are those represented by [Ag : (S : 0 1 ) ⁇ ] 4'
  • the resulting silver thiosulfate ion complexes are in a relatively pure solid form, and are stable, highly water soluble and antimicrobial! v activ e
  • essentially anhvdrous silv er thiosulfate ion complexes l efers to silver thiosulfate ion complexes that mav be essentially free of all remnant water. / e they mav contain a small amount of water (generally less than 5% of the original amount of water present preferably less than 1 % and most preferably less than 0 1 %), provided that the water does not interfere with the antimicrobial function of the complexes
  • aqueous solution refers to a liquid mixture containing, among other things, water
  • solvent refers to a liquid that is capable of dissolving a substance
  • water-miscible solvent refers to a solvent that is capable of being mixed with water and remaining so after completion of the mixing process
  • phase refers to a physicallv distinct and separable portion of a ⁇ heterogeneous svstem
  • biphasic separation refers to the creation of two phases, generally speaking, a “biphasic separation” allows a material (e i ⁇ , silver thiosulfate ion complexes) to be partitioned into one of the resulting phases, therebv facilitating isolation of that material
  • an appropriate solvent e g , ethyl alcohol
  • a smaller, denser, liquid phase primarily contains the silver thiosulfate ion complexes associated with water, there is little, if any, solvent in this phase
  • a larger liquid phase primarily contains the waste salts and the solvent
  • ⁇ refers to the general processes ot isolating partitioning, etc one material from another
  • a desired material may partition 5 into one phase of a biphasic svstem.
  • the phase containing that material e , the silver thiosulfate ion complexes of the present invention
  • can be removed from the biphasic svstem using well known means e g , pipet and separatorv funnel
  • removing refers broadly to the use of methods for the complete or partial elimination of water from the phase containing the silver thiosulfate ion complexes (/ e the 0 collected phase)
  • the present invention is not limited to any particular method, rather general ly known methods of removal ( g , freeze drving oven drving evaporation and solvent extraction ) mav be used in coniunction with the present inv ention
  • the present ⁇ invention is not limited bv the nature or scope of the therapeutic benefit provided The degree of benefit mav depend on a number of factors, e , the seventy of a S aiireus infection and the immune status ot the individual
  • composition refers to a composition that includes essentially anhydrous silver thiosulfate ion complexes in a pharmaceutically acceptable form
  • the 0 charactenstics of the form will depend on a number of factors including the site of topical administration and the method bv which the form will be used
  • a composition for use in conjunction with personal care products must be formulated such that the composition retains its antimicrobial properties while not adversely affecting the characteristics of the personal care product itself
  • the therapeutic composition may contain diluents, adjuvants and excipients. among other things
  • subject and “host” refer to humans and animals
  • topical includes, but are not limited to, the surface of the skin and mucosal tissue, in wounds, in the eves, nose, mouth, anus and vagina
  • wound includes a burn, cut sore, blister, rash or any other lesion or area of disturbed skin
  • wound dressing includes foam dressings, thin film dressings, burn dressings, surgical dressings, absorptive dressings, gauze, sheets or other types of medical device used to treat wounds
  • microbe m icrobial
  • antimicrobial activity refers to the ability to kill or inhibit the growth of microbes
  • photostable means that an object or material is resistant to discoloration when exposed to ambient light for a period of at least 72 hours
  • matrix refers broadly to materials in which the si lver thiosulfate ion complexes of the present invention can be embedded in. attached to, or otherwise associated with
  • a "polymer matrix” is one tvpe of matrix comprising one or more natural or svnthetic compounds, usually of high molecular w eight, in the form of repeated l inked units
  • anhydrous polvmer matrix refers to anv sol id material that mav be free ot water or that mav contain a smal l amount of water (general lv less than 5% bv weight), prov ided that the water does not interfere with the antimicrobial function of the complexes carried bv the matrix
  • the preferred anhydrous polvmer matrix materials are materials compatible with the silver thiosulfate ion complexes of the present invention
  • the most preferred polvmer matrix materials are those being compatible with the silver thiosulfate i
  • Medical device refers broadlv medical implants, wound care devices, body cavity and personal protection devices, and the like Medical implants include, but are not limited to, urinary and intravascular catheters, dialysis shunts, wound drain tubes, skin sutures, vascular grafts and impiantable meshes, intraocular devices, and heart valves
  • Medical implants include, but are not limited to, general wound dressings, non-adherent dressings, burn dressings, biological graft materials, tape closures and dressings, and surgical drapes
  • body cavitv and personal protection devices include, but are not limited to, tampons, sponges, surgical and examination gloves, toothbrushes, intrauterine devices, diaphragms, and condoms
  • the silver thiosulfate ion complexes of the present invention can be use to impart
  • purified means that the material has been sub
  • I thiosulfate ion complexes that do not contain significant amounts of waste salts (e g , sodium nitrate or sodium acetate), if such waste salts are incorporated into compositions or medical devices, thev mav be irritating to the skin or other tissue In addition they mav reduce the concentration of antimicrobiallv active silver
  • waste salts e g , sodium nitrate or sodium acetate
  • the resulting 0 waste salt would be sodium iodide
  • the iodide ion would aggressively compete for the dissociated ("free" ) silver ion resulting in reduced concentration of antimicrobiallv active si lv ei
  • the present invention relates to silver-based antimicrobial compositions, and processes for making such compositions, that are suitable for use in the treatment and prevention of infections
  • the present invention relates to stable silver-based antimicrobial compositions, and processes for making such compositions, comprising carrier-free, suspended silver thiosulfate ion complexes in an a base, and silver thiosulfate ion complexes
  • the description of the invention is div ided into the following parts I) Processes To Obtain Silver Thiosulfate Ion Complexes In A Solid Form, II) Compositions Containing Silver Thiosulfate Ion Complexes III) Therapeutic Use Of Compositions Containing Silver Thiosulfate Ion Complexes and IV) Incorporation Of Silver Thiosulfate Ion Complexes Into Matrices For Use In Medical Devices Each of these parts will be discussed in turn
  • compositions of the Oka Patent contain a thiosulfate salt at least one thiosulfate salt of a metal, and a porous paniculate carrier
  • the carrier was required because the thiosulfate salt and the thiosulfate salt of a metal can "hardly be obtained as a simple substance in a solid state" [Oka Patent, col 2, 11 45-46]
  • the present invention is directed at a process for obtaining carrier-free silver thiosulfate ion complexes Based on the prior art s acknowledged difficulty in obtaining silver thiosulfate ion complexes in a carrier-tree solid state the discoverv of the process disclosed hereafter w as both surp ⁇ sinu and unexpected Moreover the process ot the present invention also results in carrier-free silver thiosulfate ion complexes in high yields, another surprising and unexpected l esult
  • the present invention contemplates the production ot carrier-free silver thiosulfate ion complexes wherein the ratio of thiosulfate ion to silver ion is preferably at least I 3 to I To optimize the antimicrobial effectiveness of the final products containing the silver thiosulfate ion complexes it is preferable that the complexes be purified (e i ⁇ , subjected to methods to l emove contaminants such as waste salts in an amount that adversely interferes with the silver concentration obtainable)
  • the present invention provides two processes ot producing purified silver thiosultate ion complexes trom thiosulfate ions and silver ions
  • the first process is preferred when the ratio of thiosulfate ions to silver ions is greater than oi equal to 2-to- l and the second process is preferred when the ratio is less than 2-to- l
  • the process for producing essentially anhydrous silver thiosulfate ion complexes when the ratio of thiosulfate ions to silv er ions is greater than 2-to- l involves four maior steps
  • the first step consists of making an aqueous solution of silver thiosulfate ion complexes
  • the aqueous solution of the silver thiosulfate ion complexes is obtained bv first adding a silver hahde such as silver chloride, silver bromide, etc , to an aqueous solution Thereafter, a thiosulfate salt, such as sodium thiosulfate or potassium thiosulfate, is added to the aqueous solution
  • a silver hahde instead of another silver-containing molecule is preferred because the silver thiosulfate ion complexes produced are associated with increased short-term stabihtv This is especially important when the concentration of the silver thiosulfate ion complexes is high and/or the ratio of thiosulfate ions to si lver ions is low Likewise, the use of a silver hahde promotes stabihtv when making a solution of the si lver thiosulfate ion complexes when the concentration of silver thiosulfate ion complexes in the resulting aqueous solution is high As indicated above when making silver thiosulfate ion complexes where the primary silver ion complexes formed is represented by the formula [Ag(S 2 0 1 ) ⁇ ] : ' , the preferred proportions of thiosulfate salt to si lver salt are equal to or greater than 2 moles
  • the concentration ot the initial si lv er hahde i n the aqueous solution be less than 25%
  • concentrations of the si lv er hahde can lead to i nstabi lity ot the resulting si lver thiosulfate solution, that is to say, the si lver thiosulfate ion complexes within the solution wil l "break down " or decompose, leading to discoloration of the solution and precipitation of silver sulfide
  • the second step in the process entails the addition of a solvent to the aqueous solution l esulting from the first step to create a biphasic separation in this wav, the silver thiosulfate ion complexes separate into one phase
  • the preferred solv ents are those which are water miscible Solvents such as ethvl alcohol, isopropvl alcohol methvl alcohol acetone tetrahvdrofuran, and the like, are examples of solvents which are useful in causing phase separation
  • the solvent is added to the silver thiosulfate ion complexes solution in an amount such that the solution separates into two phases During the formation of two distinct phases, the silver thiosulfate ion complexes separate into one phase Tv picallv, the volume of the phase containing the silver thiosulfate ion complexes is onlv a fraction (e.g. , less than 20%) of the total volume of liquid
  • the phase containing the silver thiosulfate ion complexes is thought to consist of a high concentration (/ e. , 50 - 70% of the total volume) of relatively pure silver thiosulfate ion complexes and water Excess thiosulfate salts, waste salts, solvent, and other contaminants are thought to remain in the other (larger) phase of the biphasic solution
  • the separated phase containing the silver thiosulfate ion complexes can be collected using well known means
  • the phase can be drawn up using a pipet and removed from the solution
  • a separatorv funnel can be used to separate the phase from the solution
  • the fourth step involves treatment of the collected phase to create essentially anhydrous silver thiosulfate complexes
  • the silver thiosulfate complexes are purified, containing insignificant amounts of waste salts (e , sodium nitrate or sodium acetate) and other extraneous materials Treatments which are useful include but are not limited to. evaporation, oven drving, freeze drving, solvent extraction and the like
  • the essentially anhydrous silver thiosulfate complexes are ground into a fine powder
  • the process for producing essentially anhydrous si lver thiosulfate ion complexes when the ratio of thiosulfate ions to silver ions is less than 2-to- l involves four major steps
  • the first step, making an aqueous solution of silver thiosulfate ion complexes, is analogous to the first step of the process where the ratio is greater than 2-to- l
  • the major difference of this process from that where the ratio is greater than 2-to- l is that the second step of this process involves precipitation of the silver thiosulfate ion complexes from the aqueous solution (described below) 5
  • a solvent is added to the aqueous solution of silver thiosulfate ion complexes to precipitate the si lver thiosulfate ion complexes
  • the preferred solvents are those solvents which are water miscible Solvents such as ethvl alcohol, isopropyl alcohol, methyl alcohol
  • the silver thiosulfate ion complexes precipitate can be separated from the solution using any standard well-known technique Tiltration represents one preferred separation technique
  • Tiltration represents one preferred separation technique
  • the si lv er thiosulfate ion complexes are relatively pure, containing insignificant amounts of waste salts ( g , sodium nitrate or sodium acetate) and other
  • the solid material produced bv the two processes described above is thought to consist of a salt where the silver thiosulfate ion complexes are represented bv the formulas [Ag(S : 0,)J 1 " , [ Ag(S : 0 1 ),] > " [Ag,(S : 0,),] 4 [Ag,( S : 0,) t ]” , and similar complexes
  • the form of the si lver thiosulfate ion complexes produced is v ery dependent on the ratio of thiosulfate ion to silvei
  • si lver thiosulfate ion complexes represented bv the formulas [Ag (S-,0 1 ),] 4" , [ A.g,(S 1 0,) ]" " and the like can be produced
  • the preferred silver thiosulfate ion complexes are those represented by [Ag : (S 2 0,),] 4 , which can be produced in accordance with the following chemical equation
  • the preferred silver thiosulfate ion complexes are those produced when the ratio of the thiosulfate ion to silver ion is low
  • the purified silver thiosulfate ion complexes are carner- free, photostable, highly water soluble, non-staining and antimicrobiallv active This combination of features is not present in any commercially available or previously described silver-containing composition
  • Topical antimicrobial agents include therapeutic heavy metal compounds such as silver-containing compounds Silver, in its ionic state ( Ag ), possesses a broad spectrum of antibacterial, antifungal, and antiviral properties and is relatively safe Early studies showed that the silver ion is ohgodynamic. / e , active at verv low concentrations [See genera/ , Russell el al . Antimicrobial Activity and Action of Silver.” Progress in Medicinal Chemistry
  • the present invention is directed at among other things, carrier-tree silver thiosulfate ion complexes compositions.
  • the piovision ot car ⁇ ei -tree si lver thiosulfate ion complexes is advantageous for at least two reasons First, it provides the ability to make antimicrobial silver thiosulfate ion complexes compositions without the need for potentially irritating porous carrier particles Second it provides the ability to produce antimicrobial silver thiosulfate ion complexes compositions which can contain high concentrations of silver resulting in compositions with potent antimicrobial activitv
  • the carrier-free silv er thiosulfate ion complexes are stable
  • the complexes are not stable in all pharmaceuticallv-acceptable compositions
  • the stable si lver thiosulfate ion complexes compositions of the present invention ⁇ comprise carrier-free suspended silver thiosulfate ion complexes in a base
  • the preferred base is anhvdrous. and in one embodiment the base is semisohd
  • the stable silver-based compositions maintain their antimicrobial activity Moreover, the amount of silver in the compositions can be varied over a large range of concentrations to provide compositions with different levels of antimicrobial potency
  • an aqueous solution of the complexes is made. It should be noted that aqueous solutions of silver thiosulfate ion complexes can be added to an ointment or cream base to make an antimicrobial ointment oi cream composition, in other words, a composition can be made after completing onlv the first of the four steps.
  • the resulting silver thiosulfate ion complexes compositions will contain large quantities of excess thiosulfate salts as wel l as waste salts ( g , sodium nitrate, potassium nitrate, and potassium acetate) When applied topical ly, the antimicrobial composition containing these impurities may be irritating
  • the second major problem is that ointment or cream 0 compositions made with si lver thiosulfate ion complexes from such an aqueous solution are not stable for long periods of time That is to sav. over a period of time the resulting silver- based antimicrobial compositions w i l l turn black and lose antim icrobial efficacy
  • silver thiosulfate ion complexes also chemically decompose over time It is believed that when the thiosulfate component of the silver thiosulfate ion complexes chemically breaks down, it releases silver ions which react with the released sulfur ions to form silver sulfide
  • silver thiosulfate ion complexes when added to either an ointment base which contains a small proportion of water or a water-containing cream base in order to form an antimicrobial composition, w i l l decompose over a i elativ ely short period of time
  • the l esuiting antimicrobial composition wi l l turn black as the si lver thiosulfate ion complexes in the composition decompose to silver sulfide ⁇ dd ⁇ t ⁇ onal lv the composition will lose its antimicrobial efficacy with decomposition ot the silver thiosulfate ion complexes
  • the stable si lver thiosulfate ion complexes compositions of this invention comprise carrier-free suspended silver thiosulfate ion complexes in a base
  • the bases which ai e most useful for the present invention entai l any compound or m ixture which is capable of suspending the complexes Preferablv, the base is essential ly anhvdrous and can be used topical ly to deliver a medicinal agent
  • bases that are useful include white petrolatum, Aquaphor" ointment base, polaxomers. and polvethvlene glycol
  • the preferred base is a PEG ointment composition containing a combination of PEG polymers with molecular weights greater than 1 000 and polaxomers
  • the methods for suspending the purified silver thiosulfate ion complexes, in the form of a fine powder, into a base to form a silver-based antimicrobial composition are well known in the art For example, one method involves heating the base until it has liquefied, then, while the base cools, adding the silver thiosulfate ion complexes and stirring until the base has resolidified This method produces a suspension of the silver thiosulfate ion complexes within the base, preferably a homogeneous suspension
  • the concentration of the silver thiosulfate ion complexes within the base is such as to provide antimicrobial activity
  • the preferred concentration of the si lver thiosulfate ion complexes is 0 1% to 3 0%
  • silver thiosulfate ion complexes concentrations can range up to 10% to 30% depending on the antimicrobial potency required
  • the most preferred concentration is between 0 2% and 1 5%
  • the effective concentration is that concentration w hich is higher than the minimum inhibitory concentration for a particular microbe Vs would be expected, certain m icrobes are more sensitive to silver than other microbes, g , gram (-) microbes are generally more sensitive than gram (+) microbes
  • a concentration less than 0 1 % could be effectiv e depending on the microbe and the intended use of the final product
  • the resulting silver thiosulfate ion complexes compositions of the present invention are antimicrobiallv active and stable when compared to compositions that use bases which ai e not anhvdrous Additionally, the silver-based antimicrobial compositions of this invention show no photo-discoloration when exposed to ambient room light over a 72 hour period
  • compositions must be in an anhvdrous base in order to maintain their stabihtv it is not intended that the compositions ot the present invention be l imited bv the particular nature of the therapeutic preparation
  • the present invention contemplates compositions that include physiological ly tolerable di luents, adjuvants and excipients. such as pharmaceutical grades of mannitol, lactose starch, magnesium stearate. sodium saccharin, cellulose, magnesium carbonate, and the like
  • These compositions typically contain l %-95% of active ingredient preferablv 2%-70%
  • the compositions may contain minor amounts of auxiliary substances such as stabilizing or pH buffering agents or preservatives III.
  • compositions of the present invention can be used topically, for example, on skin, in wounds, in the eyes, nose, and mouth, in the treatment and ⁇ prevention of infection
  • the compositions are effective against bacteria, viruses, and fungi
  • toll and manv species of Klehsiella, Proteus, Pseiidomonas, Slaphy/ococciis and Candida may be inhibited or killed by the compositions of the present invention
  • the dosage required for therapeutic efficacy will vary according to the microbe involved, the type of use and mode of administration, as well as the
  • the therapeutic preparations can be administered for clinical use in humans and for vete ⁇ narv use, such as with domestic animals in manners known in the art and similar to other therapeutic agents
  • the antimicrobial compositions can be applied using gloved hands or by an applicator Likewise.
  • the antimicrobial compositions can be applied to the surface of a dressing, which can then be applied topically Ophthalmic infections can be treated using standard procedures in the art, such as bv pulling down the lower evehd to form a pocket and applying the composition thereto
  • Ophthalmic infections can be treated using standard procedures in the art, such as bv pulling down the lower evehd to form a pocket and applying the composition thereto
  • infections of the mouth can be treated bv applying the composition with a sponge applicator or a toothbrush 0
  • Bacterial resistance to si lver is known to occur in certain situations, more specifically, schei ichia toll and Salmonella i ⁇ ph ⁇ m ⁇ t ⁇ mm are known to develop plasmid-encoded l esistance to silver [Russell el al Progress in Medicinal Chemistrv 3 1 35 1 -70 ( 1 994)] Two t elated methods are commonly used to prevent and combat drug resistance
  • the first method entails the combination of two or more therapeutic agents into a final ⁇ composition
  • a final ⁇ composition For example the ⁇ -lactamase inhibitor clav ulanate potassium has been added to amoxicilhn, resulting in a combination preparation (AugmentinTM SmithKhne Beecham) with expanded antimicrobial activity While clavulanic acid has only weak antibacterial activity when used alone its combination with amoxicilhn results in a svnergistic effect
  • the second method entails the concomitant administration of two or more distinct
  • compositions of the present invention possess an additional broad spectrum of antimicrobial protection by combining antimicrobial medicinal agents in a stable fashion with silver thiosulfate ion complexes Furthermore as previously indicated, the use of silver thiosulfate ion complexes with an antimicrobial medicinal agent mav aid in preventing the formation of drug-resistant microbes Moreover, since silver ions are oligodvnamic and are not immediately exhausted (/ e thev have a long-lasting or "residual" effect), the presence of silver ions in the pharmaceutical compositions results in compositions which are longer lasting than those containing a single antimiciobial agent
  • Medicinal agents besides antimicrobial agents are also contemplated for use in the pharmaceutical compositions of the present invention including topically active drugs for the treatment of diseases Suitable topically activ e drugs include but are not limited to. acne preparations such as isotretinoin benzovl peroxide, sahcvhc acid and tetracvchne, anesthetics for topical administration such as dibucaine. hdocaine, benzocaine. tetracacine, deperodon and pramoxine hvdrochlo ⁇ de, anti-inflammatorv agents such as betamethasone benzoate betamethasone valerate desomde fluocinolone acetonide halcinomde hvdrocortisone.
  • acne preparations such as isotretinoin benzovl peroxide, sahcvhc acid and tetracvchne
  • anesthetics for topical administration such as dibucaine. hdocaine, be
  • antiperspirants and medications used in the treatment ot hv perhidrosis such as glutaraldehvde, methenamine, glycopyrrolate. scopolamine hvdrobromide. antipru ⁇ tic and external analgesic agents such as camphor, menthol sahcvhc acid methvlsa cv late, cleansing agents such as soaps and shampoos, keratolvtic cv totoxic, and destructi e agents such as anthrahn, cantha ⁇ din. fiuorouracil, podophyllotoxin.
  • sunscreens such as hvdroquinone. monobenzone. t ⁇ oxsalen and /?-am ⁇ nobenzo ⁇ c acid, anabolic steroids for building up tissues under wound healing such as methandienone, proteolvtic agents for the decomposition of fibrin such as trvpsin, vasodilating substances for improving the flow of blow during wound healing such as tolazohne. thrombosis-hampering substances such as heparin.
  • compositions with a broad spectrum of antimicrobial protection is produced by combining one or more topically active drugs in a stable fashion with a pharmaceutical composition containing si lver thiosulfate ion complexes
  • the topical ly active drugs ai e used to treat a disease which has an abundance of dead tissue e g , a fungating tumor or a decubitus ulcer
  • the addition ot antimicrobial si lver ions wi l l aid in the prevention of a secondary infection at the diseased site
  • the presence of ionized si lver in the pharmaceutical composition can aid in the prevention of malodor
  • svstemical lv active drugs are absorbed bv the bodv surface when appl ied topical ly, either neat or w ith the aid of a solvent Suitable svstemical lv active drugs include, but are not lim ited to.
  • sedatives and hypnotics such as pentobarbital sodium, phenobarbital, secobarbital sodium, carbromal, and sodium phenobarbital, psychic energizers such as 3-(2- l -am ⁇ nopropvl )- ⁇ ndole acetate and 3-(2- ammobutvl )- ⁇ ndole acetate, tranquihzers such as reserpine. chlorpromazine hvdrochlonde, and thiopi opazate hvdrochlonde, hormones such as adrenocorticosteroids. for example, 6- - methvlprednisolone.
  • cortisone, cortisol, and t ⁇ amcinolone. androgenic steroids for example, methvl-testosterone. and fluoxvmesterone.
  • estrogenic steroids for example, estrone, l 7 ⁇ -estrad ⁇ oi and ethinyl estradiol
  • progestational steroids for example 1 7- ⁇ - hvdroxvprogesterone acetate, medroxvprogesterone acetate. 1 9-norprogesterone. and norethindrone. and thvroxine.
  • antipyretics such as aspirin, sahcylamide. and sodium sahcylate.
  • antispasmodics such as atropine.
  • methscopolamine bromide and methscopolamine bromide with phenobarbital.
  • antimala ⁇ als such as the 4-am ⁇ noqu ⁇ nohnes, 8-am ⁇ nogu ⁇ nohnes, and py ⁇ methamine
  • nutritional agents such as vitamins, essential amino acids, and essential 5 fats
  • a pharmaceutical composition with a broad spectrum of antimicrobial protection is produced by combining one or more svstemicallv active drugs in a stable fashion with silver thiosulfate ion complexes.
  • silver thiosulfate ion complexes with one or more svstemicallv active drugs to produce a pharmaceutical composition assists in the preservation 10 of the pharmaceutical composition bv protecting it from microbial proliferation and overgrowth, which could otherwise lead to spoilage of the medicinal composition containing the svstemicallv active drugs
  • antimicrobial compositions mav be useful in making infection-resistant cosmetics and personal care products I S
  • aqueous solutions of silver thiosulfate ion complexes which have not been purified can be incorporated into 30 polvmer matrices to render the matrices compositions antimicrobial
  • the resulting matrices compositions will contain large quantities of excess thiosulfate salts as well as waste salts such as sodium nitrate, potassium nitrate, potassium acetate, etc
  • waste salts such as sodium nitrate, potassium nitrate, potassium acetate, etc
  • these impurities mav be irritating when the matrices compositions are applied topically
  • the presence of the waste salts mav have a negative impact on the physical characteristics (e g, feel, strength, and stiffness) of the final matrices compositions
  • the purified carrier-free silver thiosulfate ion complexes of this invention can be incorporated into an anhvdrous polvmer matrix to produce photostable antimicrobial matrices ⁇ compositions, these compositions are useful in making medical devices
  • the present invention contemplates that anv solid material that does not contain a significant amount of water mav be used as an anhydrous polymer matrix
  • the preferred anhvdrous polymer matrix material is anv material that is compatible (/ e , does not contain reactive components which could lead to the destruction of the thiosulfate hgand, thereby destabilizing the silver 0 thiosulfate ion complexes) with the silver thiosulfate ion complexes of this invention
  • the most preferred polvmer matrix material is one that is compatible with the silver thiosulfate ion complexes of this invention and has some capacity to absorb and/or swell in the presence ot water the ability ot the pol
  • the silver thiosulfate ion complexes of the present invention can be used with anhvdrous polymer matrices which do have reactive components as long as the media is such that the reactive chemical component of the polymer matrices cannot react with the silver thiosulfate ion complexes
  • the silver thiosulfate ion complexes of the resulting composition are unstable ov er long periods the water in the solution acts as a media in which the reactiv e groups ot the alginate materials can destabilize the silver thiosulfate ion complexes
  • the alginate material is dry the silver thiosulfate ion complexes l emain stable ⁇
  • Anhvdrous polvmer matrix materials useful in this invention include, but are not limited to the following adhesi es
  • the concentration of the silv er thiosulfate ion complexes within the anhvdrous polymeric matrix should be such as to provide antimicrobial activity
  • the preferred concentration of the silver thiosulfate ion complexes in the final polvme ⁇ c matrix is 0 1% to 3 0%
  • silver thiosulfate ion complexes concentrations can range up to 10% to 30%, depending on the antimicrobial potency required and the permeability of the polymeric matrix
  • the most preferred concentration is between 0 2% and 1 5%
  • the resulting silver thiosulfate ion complexes-containing matrices compositions of this invention are antimicrobially active and stable Additionally, the compositions of this invention show no photo-discoloration when exposed to ambient room light over a 72-hour period
  • the silver thiosulfate ion complexes-containing matrices compositions of the present invention can be used alone in the treatment and prevention of infection in a manner analogous to the compositions described above Moreover, as previously alluded to, the matrices compositions can be used to make medical devices such as dressings, tamponades. etc which can be used in the treatment and prevention of infection
  • the first method of incorporation is useful if the polvmer matrix is produced from a solvent solution of polvmer matrix material
  • the si lv er thiosulf ate ion complexes in a solid powder form can be added to that solution and mixed thoroughl y I pon elimination of the solvent through standard means in the art the remaining polvmer matrix material w ill hav e the silver thiosulfate ion complexes dispersed, preferablv the complexes are dispersed homogeneously
  • the silver thiosulfate ion complexes in a powder form are thoroughly mixed in The mixture is then coated on a liner and dried
  • the resulting adhesive film has the silver thiosulfate ion complexes incorporated as a dispersion
  • Another method of incorporation is useful if the production process for the polymer matrix involves the use of water as a solvent. (/ e . latex polvmer systems, solvent extraction svstems) or as a reactant (/ e , polvurethane foam production, alginate fiber production, etc )
  • the silver thiosulfate ion complexes can be dissolved in the water prior to the production process.
  • the silver thiosulfate ion complexes can be added directlv to the latex solution Once added, the silver thiosulfate ion complexes will dissolve After coating and drving, the resulting polymer film will have the silver thiosulfate ion complexes homogeneously dispersed in the film
  • the silver thiosulfate ion complexes can be dissolved in the water prior to reacting it with the prepolvmer After the polvurethane foam has reacted and been dried, the silver thiosulfate ion complexes will be dispersed throughout the foam matrix
  • the silver thiosulfate ion complexes can be dissolved in either the water making up the alginate solution or the calcium chloride bath.
  • the alginate solution when extruded into the calcium chloride bath w ill result in crosshnked alginate fibers which incorporate the silver thiosulfate ion complexes Upon drving of these fibers, the silver thiosulfate ion complexes will be dispersed throughout the alginate matrix
  • Another method of incorporation can be used in conjunction w ith the production of polymer matrices such as a hvdrocolloid matrix made up ot a hvdrocolloid material (e.g , carboxvmethvlcellulose) in a polvmei binder
  • the silver thiosulfate ion complexes in a solid form, can be mixed directly with the hvdrocolloid material prior to the production process
  • the silver thiosulfate ion complexes can be dissolved in water which is then used to treat the hvdrocolloid material so that the solution is absorbed bv the hvdrocolloid material and then dried Thereafter, the treated hvdrocolloid material is processed using standard procedures to produce the hvdrocolloid polvmer matrix which contains the silver thiosulfate ion complexes dispersed in the hvdrocolloid component of the matrix
  • silver thiosulfate ion complexes can be incorporated after the polvmer matrix has been produced
  • One approach is to form an aqueous solution ot the silver thiosulfate ion complexes and then apply this solution to the finished polv mer matrix
  • This silver thiosulfate ion complexes solution can be applied to the polvmer matrix bv spraving, dipping, painting or other suitable means
  • an aliquot of the silver thiosulfate ion complexes can be applied onto and absorbed into a finished foam dressing After drv ing, the silver-based foam composition will be stable and antimicrobial Likewise, the silver thiosulfate ion complexes solution can be sprayed on the surface of a polymer or adhesive film which, after drying, will be stable and antimicrobial
  • the water can be removed using anv standard method, if the water is l emoved bv drving the polymeric matrix in an oven, care should be taken to use only moderate temperatures, temperatures of 20°C to 70°C mav be used, while temperatures of 30°C to 50°C are preferred If the temperature becomes too hot. rapid destabihzation of the silver thiosulfate ion complexes can occur
  • ICP inductively coupled plasma
  • CFU colony forming units
  • PEG polyethylene glycol
  • MHM Meleller Hmton Medium
  • ZOI zone of inhibition
  • ATCC American Tvpe Culture Collection.
  • compositions Containing Silver Thiosulfate Ion Complexes II) Compositions Containing Silver Thiosulfate Ion Complexes, III) Antimicrobial Activity Of Compositions Containing Silver Thiosulfate Ion Complexes, IV) Use Of Silver Thiosulfate Ion Complexes in Medical Devices, and V) Use Of Silver
  • This example il lustrates the process for producing silver thiosulfate ion complexes when the ratio of thiosulfate ions to silver ions is greater than 2-to- l That is. a biphasic separation is employed in this example
  • the silver thiosulfate ion complexes were produced bv first making a silver chloride precipitate in an aqueous solution (hereafter, "silver chloride precipitate/aqueous solution” )
  • the silver chloride precipitate/aqueous solution was made bv mixing 20 ml of a silver nitrate (Aldrich.
  • the silver thiosulfate ion complexes produced were separated by adding 200 ml of ethvl alcohol to the container Upon addition of the ethvl alcohol, the solution became cloudv and separated into two separate phases The two phases were separated using the separatorv funnel The weight of the material in the phase containing the silver thiosulfate ion complexes was approximately 1 7 g This phase was then treated by adding 70 ml ethyl alcohol and 40 ml of acetone to make the silver thiosulfate ion complexes essentially anhydrous After sitting overnight, the silver thiosulfate ion complexes were in the form of a pure, white solid material in the bottom of the container Thereafter, the solvent was decanted and the white solid was dried in an oven (62°C) and ground to a fine white powder using a mortar and pestle The weight of the dried silver thiosulfate ion complexes was 1 0 03 g
  • the silver thiosulfate ion complexes were analyzed for silver, sodium and sulfur using Inductively Coupled Plasma Argon Emission Spectrometrv The analysis, performed by
  • This example illustrates the process for producing silver thiosulfate ion complexes when the ratio of thiosulfate ions to silver ions is equal to 2-to- l
  • the silver thiosulfate ion complexes were isolated through the use of a biphasic separation
  • silver thiosulfate ion complexes were produced by first making a silver chloride precipitate in an aqueous solution bv mixing 10 ml of a silver nitrate (Aldrich, 0 deionized water as the diluent) solution ( 1 mmol/ml) with 10 mi of a sodium chloride
  • the silver thiosulfate ion complexes were separated bv adding 50 ml of acetone to the container Upon addition of the acetone, the solution became cloudv and separated into two separate phases The two phases were separated into individual containers using a pipet The phase containing the silver thiosulfate ion complexes was treated bv 0 adding 50 ml of acetone to make the silver thiosulfate ion complexes essentially anhvdrous
  • the si lver thiosulfate ion complexes were in the form of a pure w hite solid material Thereafter the solvent was decanted and the white solid w as dried in an cwen (62°C) and ground to a fine w hite powder using a mortar and pestle The weight of the dried silver thiosulfate ion complexes was 3 97 grams ⁇ The resulting silver thiosulfate ion complexes material was analyzed for silver, sodium and sulfur using an Inductively Coupled Plasma (ICP, described above) The analvsis gave the following results
  • the calculated yield of making silver thiosulfate ion complexes using the process of this invention is 90 8%
  • This example further illustrates the process for pioducing silver thiosulfate ion complexes when the ratio of thiosulfate ions to silver ions is less than 2-to- l
  • the silver thiosulfate ion complexes were isolated through the formation of a precipitate rather than a biphasic separation
  • silver thiosulfate ion complexes were made bv first making a silver chloride precipitate in an aqueous solution by mixing 1 0 ml of a silver nitrate (Aldrich, deionized water as the diluent) solution ( 1 mmol/ml) with 20 ml of a sodium chloride ( Aldrich, deionized water as the di luent) solution ( 1 mmol/m l ) in a 1 00 ml specimen container To this silver chloride precipitate/aqueous solution was added 1 5 ml of a sodium thios
  • si lver thiosulfate ion complexes were analyzed for silver, sodium and sulfur using an Inductively Coupled Plasma ( ICP, described above) The analysis gave the following r esults Silver 32%
  • the preferred silver hahde is silver chloride (Examples 1 -3 ) this example illustrates that other silver hahdes mav be used
  • the silver thiosulfate ion complexes were produced bv first making a silver bromide precipitate in an aqueous solution (hereafter "silver bromide precipitate/aqueous solution") bv mixing 2 ml of a silver nitrate (Aldrich.
  • the silver thiosulfate ion complexes were separated bv adding 20 0 ml of acetone to the container Upon addition of the acetone the solution separated into two phases The phase containing the silver thiosulfate ion complexes was collected and treated bv adding 7 0 ml ethvl alcohol and 4 0 ml of acetone to make the silver thiosulfate ion complexes anhvdrous After sitting overnight the silver thiosulfate ion complexes were in the form ot a white solid material at the bottom of the container The solvent was decanted and the white solid was dried in an oven (62°C) and ground to a fine w hite powder using a mortar and (nestle The resulting weight of the dried silver thiosulfate ion complexes was 0 88 g EXAMPLE 5
  • silver thiosulfate ion complexes were made by a process which did not use a phase separation procedure when the ratio of thiosulfate ions to silver ions is greater than 2-to- l
  • This comparison process was performed by first making a silver chloride precipitate in an aqueous solution (hereafter, "silver chloride precipitate/aqueous solution”) by mixing 2 ml of a silver nitrate (Aldrich, deionized water as the diluent) solution ( 1 mmol/ml) with 2 2 ml of a sodium chloride (Aldrich, deionized water as the diluent) solution ( 1 mmol/ml) in a 50 ml beaker To this silver chloride precipitate/aqueous solution was added 6 0 ml of a sodium thiosulfate (Columbus, deionized water as the diluent) solution ( 1 mmol/ml) The resulting mixture was agitated bv stirring until all of the sodium chloride precipitate was dissolved
  • the resulting silver thiosulfate ion complexes solution was placed in a convection oven at 62 °C overnight to evaporate the water
  • the solid material produced had a splotchy tan color with areas which had a deep brown color
  • the lack of a pure white solid indicates that this process leads to a breakdown or decomposition of silver thiosulfate ion complexes
  • a hydrated silver-based antimicrobial composition was made where the composition base was PEG The composition was made by mixing 9 g of the silver-based antimicrobial composition of Example 6 with 1 ml of water This silver-based antimicrobial composition contained approximately 10% water by weight
  • a hydrated silver-based antimicrobial composition was made where the composition base w as Aquaphor" The composition was made bv mixing 9 5 g of the silver-based antimicrobial composition of Example 7 with 0 5 ml of water This silver-based antimicrobial composition contained approximately 5% water
  • a hvdrated si lver-based antimicrobial composition was made where the composition base w as white petrolatum The composition was made bv mixing 9 5 g of the silver-based antimicrobial composition of Example 8 with 0 5 ml of water This silver-based antimicrobial composition contained approximately ⁇ % water EXAMPLE 9D
  • a silver-based antimicrobial composition containing 0 47 g of the silver thiosulfate ion complexes of Example 1 were stirred into 20 g of Velvachol " (Owen Laboratories)
  • VelvachoT is a neutral hvdrophihc cream which contains some water (amount unknown)
  • the amount of silver in this silver-based antimicrobial composition was equivalent to 1 0% silver nitrate
  • the stability of the silver-based compositions of Examples 6 7 8, and 9A-D was evaluated over time The stability of the compositions was determined by measuring the change ot color if anv when the compositions were stored in transparent containers in ambient light Change of color indicates decomposition ot the silver thiosulfate ion complexes Table 1 below indicates the initial color ot each composition and the change in color on days 7 and 14 and after 1 month As depicted bv the results of this study, the silver-based compositions described in
  • Examples 6 7 and 8 demonstrated no change in color
  • Examples 9 A-D demonstrated maior changes in color some after only 7 days (Examples 9B and 9D) all of these compositions / e
  • Examples 9A-D changed from their initial color to a brown or black color
  • the /// vino antimicrobial activity was ev sined bv finding the minimum inhibitory concentration tor the powder of silver thiosulfate ion complexes from Example ⁇ This powder was tested in serial two-fold dilutions ranging from I 95 to 250 ⁇ g/ml Broth microdilution was performed in serial dilution of the silver thiosulfate powder in tryptic sov ⁇ 0 broth (Difco) Each dilution was inoculated with 0 005 ml of a 24-hour growth of a microbe
  • ZOI zone of inhibition
  • 1 c - diametet discs (Whatman Filter Paper, Quantitative 1 ) were coated with a thin laver of the compositions from Examples 6 7 and 8 These coated discs were placed on Mueller Hinton Medium (MHM, Difco) with lawns of S auretis (ATCC 25923 , 24 hours growth from MFCvl plate) ⁇ fter incubation at 36 °C for 1 8 hours, the size of the zone of growth inhibition was measured (in mm ) from the edge of the disc to the point of microbial growth Table 3 shows the ZOI results for each composition on Dav 1 and at one month
  • the silv er-based compositions of this invention demonstrated good antimicrobial activity that was stable for the duration of the studv period That is to sav. the size of the zone of growth inhibition was essentially unchanged over the one month period IV.
  • the silver thiosulfate ion complexes of the present invention can be used in conjunction with medical devices
  • This example illustrates the use of silver thiosulfate ion complexes to prepare a medical device made up of a foam polymer matrix
  • the complexes were incorporated into the matrix during the manufacturing of the polymer matrix
  • a foam dressing was produced bv first dissolving 0 ⁇ 4 g of si lver thiosulfate ion complexes powder in 1 50 m l ot a 0 5 Pluromc L-62 (BASF) aqueous solution This solution was the mixed with 140 g of a polvurethane prepolvmer (Hypol 2002, Hampshire) in a 1 -I ⁇ ter disposable plastic beaker The resulting mixture instantly began to react to form a foam After 10 minutes the foam was removed from its container and sliced to produce individual foam dressings (approximately 7 5 cm in diametei The sl ices of foam dressings were dried at 50°C in a dark convection oven
  • foam dressings were light stable and antimicrobiallv active
  • the terms "l ight stable” “photostable " and the l ike mean that the samples did not discolor after 72 hours of exposure to ambient room l ight
  • the term "antimicrobiallv activ e” means that a small piece ( nominal ly 1 cm x I cm or I cm strands in the case of alginate fibers ) produced zones ot i nhibition when placed on both a lawn of S aiireus ( ATCC 25923 ) and a lawn ot /. toll ( ATCC 25922) The lawns were produced bv plating 24-hour growth microbes on MHM plates after incubation for 24 hours each sample was exam ined to determine whether a zone of inhibition was present
  • This foam dressing can be used for a large va ⁇ etv ot medical applications, including as an antimicrobial absorptive foam dressing EXAMPLE 13
  • This example further illustrates the use of silver thiosulfate ion complexes to prepare a medical device made up of a foam polymer matrix
  • the silver thiosulfate ion complexes were incorporated into polvmer matrix following the matrix ' manufacture
  • a foam dressing (Hvdrasorb " Sponge Foam Dressing ( 10 cm x 10 cm), Avitar) was submerged in an aqueous solution containing silver thiosulfate ion complexes powder from Example 3 (0 1 g per liter) The foam dressing samples were removed and dried at 50°C in a convection oven These silver thiosulfate ion complexes- containing foam dressings were light stable and antimicrobiallv active As indicated in the previous example, these foam dressings can be used for a large variety ot medical applications including as an antimicrobial absorptive foam dressings
  • This example illustrates the use of the silver thiosulfate ion complexes to prepare a medical device which is made up of a hvdrocolloid absorbent polymer matrix
  • the complexes were incorporated into the matrix during the manufacturing of the polvmer matrix
  • a hvdrocolloid dressing containing silv er thiosulfate ion complexes was produced bv first thoroughly mixing 0 1 57 g of silver thiosulfate ion complexes powder (mesh 100) from Example 1 with 10 O g of sodium carboxvmethyl cellulose ( Aldrich) Thereafter 4 g of this treated carboxvmethyl cellulose was mixed thoroughly with 4 g of a polyurethane prepolvmer
  • This example further illustrates the use of silver thiosulfate ion complexes of this 5 invention to prepare a medical device which is made up of an hvdrocolloid absorbent polymer matrix
  • silver thiosulfate ion complexes were incorporated into the polymer matrix by a different procedure than that presented in the preceding example
  • the hydrocolloid dressing was produced by first dissolving 0 1 57 g of a silver thiosulfate ion complexes powder (mesh 100) from Example 1 in 10 0 ml of water To this 10 solution was added 100 g of sodium carboxvmethyl cellulose (Aldrich, Milwaukee, WI) which absorbed the solution The treated sodium carboxymethvl cellulose was allowed to dry at room temperature Thereafter 4 g of the dried treated carboxvmethyl cellulose was mixed thoroughly with 4 g of a polyurethane prepolvmer ( Aquapol 035-003 1 Cook Composites and Polymers) This mixture was then pressed between a polyurethane film and a silicone treated I lmer and was allowed to cure for 24 hours
  • the hvdrocolloid dressing is photostable and antimicrobiallv active and is useful on exudating, malodorous wounds
  • Adhesive films are. among other things, especially useful in covering painful abrasive-tvpe skin wounds and partial skin graft sites
  • the silver thiosulfate ion complexes-containing PS A was made bv mixing 0 25 g of the si lver thiosulfate ion complexes powder from Example I in An adhesive solution consisting of 45 g of a proprietary medical grade acrylic based latex (58% solids) (Averv
  • This example illustrates the use of silver thiosulfate ion complexes to produce a medical device which is made up of non-adherent alginate material.
  • the method of this example involves the use of a calcium chloride bath which results in crosshnked alginate fibers that incorporate the silver thiosulfate ion complexes.
  • water-swellable alginate fibers were produced containing si lver thiosulfate ion complexes.
  • the alginate fibers were made by using a syringe to inject a 5% sodium alginate solution (Pronova LV M Sodium alginate. Protan) into a bath consisting of a 10% calcium chloride solution (Aldrich. deionized water as diluent) containing 0. 1 g/liter silver thiosulfate ion complexes powder from Example 3.
  • the alginate solution immediately formed water- insoluble alginate fibers upon contact with the calcium chloride/silver thiosulfate ion complexes bath.
  • the fibers were pulled from the bath and allowed to dry (50°C).
  • the resulting fibers are photostable and antimicrobiallv active.
  • These fibers can be used to make antimicrobial alginate dressings and tamponades.
  • Alginate materials containing si lver thiosulfate ion complexes are especially useful in covering painful abrasive-type skin wounds and wound ulcers as well as for filling in deep wounds and cavities.
  • this example utilizes a method that does not include a calcium chloride bath.
  • aqueous solution containing 0. 1 g/liter of a silver thiosulfate ion complexes from Example 3 was prepared.
  • the resulting aqueous solution was then applied to a 9.5 cm x 9.5 cm alginate dressing (Steriseal Sorbsan Surgical Dressing.
  • the silver thiosulfate ion complexes solution can be applied bv dipping the alginate dressing into the solution.
  • the alginate fibers of the dressing absorbed the applied solution, thereafter, the treated alginate dressing was allowed to dry (room temperature)
  • the alginate dressing was light stable and was antimicrobiallv active, and, as noted in the preceding example, it is especially useful for malodorous wounds as well as for covering painful abrasive-tvpe skin wounds and wound ulcers
  • an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more agents
  • 0 02 g of the silver thiosulfate ion complexes from Example 2 were blended into 2 0 g of a mupirocin ointment (Bactroban " [2% mupirocin acid in a PEG base], SmithKlme Beecham)
  • the mupirocin ointment is a topical antimicrobial with excellent gram (+) antimicrobial properties
  • the silver thiosulfate ion complexes were blended into the mupirocin ointment bv first melting the mupirocin ointment and then stirring the si lv er thiosultate ion complexes into the melted ointment The ointment was stirred continuallv until it cooled and resolidified
  • antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of this invention with one or more agents
  • an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more agents 0 25 g of metromdazole (Sigma) and 0 25 g ot the silver thiosulfate ion complexes of Example 3 were blended into 24 50 g of a PEG composition ("PEG Composition"), the PEG Composition was produced bv melting together a blend of 40% PEG (M W 3450) and 60%
  • an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more agents 0 25 g of chlorhexidme diacetate hydrate (Aldrich) and 0 25 g of the silver thiosulfate ion complexes of Example 3 were blended into 24 5 g ot Aquaphoi ⁇ (a cholesterolized absorbent Euce ⁇ te R ointment base produced bv Belersdorf Inc ) The pharmaceutical composition was produced by first melting the Aquaphor" ointment and then stirring in the silver thiosulfate ion complexes and chlorhexidme The resulting pharmaceutical composition was stirred continually until it cooled and resolidified This pharmaceutical composition has use as a broad spectrum topical antimicrobial
  • an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more medicinal agents
  • 0 50 g of tnclosan Irgasan DP 300 Ciba-Geigy, Greensboro, NC
  • 0 50 g of the silver thiosulfate ion complex of Example 3 were blended into 24 00 g of Aquaphor" (a cholesterolized absorbent Euce ⁇ te " ointment base produced bv Belersdorf Inc )
  • the pharmaceutical composition was produced bv first melting the Aquaphoi " ointment and then stirring in the silver thiosulfate ion complexes and tnclosan
  • the resulting pharmaceutical composition was stirred continually until it cooled and resolidified
  • This pharmaceutical composition has use as a broad spectrum topical antimicrobial
  • an antimicrobial pharmaceutical composition consisting ot a combination of the si lver thiosulfate ion complexes ot the present inv ention with one or more agents 0 50 g ot Hvdrocortisone 2 1 - Acetate ( Sigma) and 0 50 g of the si lver thiosulfate ion complexes of Example 3 were blended into 24 00 g ot Aquaphor" (a cholestei oi ized absorbent
  • an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more agents 0 50 g of lidocaine (Sigma) and 0 50 g of the silver thiosultate ion complexes of Example 3 were blended into 24 00 g of PEG composition ("PEG Composition"), the PEG Composition was produced by melting together a blend of 40% PEG (M W 3450) and 60% PEG (M W ) The pharmaceutical composition was produced bv first melting the PEG
  • composition Composition and then stirring in the silver thiosulfate ion complexes and lidocaine The resulting pharmaceutical composition was stirred continually until it cooled and resolidified
  • This pharmaceutical composition has use as a topical anesthetic which also has antimicrobial properties to prevent a secondarv infection when applied to exposed tissues or wounds
  • an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes ot the present invention with one or more agents I 00 g of pramoxine hvdrochlonde (Sigma) and 0 50 g ot the silver thiosulfate ion complexes of Example 3 were blended into 23 50 g of PEG composition ( "PEG Composition” ), the PEG Composition was produced bv melting together a blend of 40% PEG (M W 3450) and 60% PEG (M W 600) The pharmaceutical composition was produced by first melting the PEG Composition and then stirring in the si lver thiosulfate ion complexes and pramoxine The resulting pharmaceutical composition was stirred continually until it cooled and resolidified This pharmaceutical composition has use as a topical anesthetic which also has antimicrobial prope ⁇ ies to prevent a secondarv infection when applied to exposed tissues or wounds
  • the present invention provides for silver- based antimicrobial compositions and processes for making such compositions that are suitable for use in the treatment and prevention of infections It should be understood that the present invention is not limited to the specific compositions shown nor to the uses of the compositions described In light of the foregoing disclosure, it will be apparent to those skilled in the art that substitutions, alterations, and modifications are possible in the practice of this invention without departing from the spirit or scope thereof
  • An antimicrobial composition comprising silver thiosulfate ion complexes in a base
  • composition of Claim 1 vv' herein the concentration of said silver thiosulfate ion complexes within said base is from 0 01 % to 30% (w/w )
  • composition of Claim 1 wherein the concentration of said silver thiosulfate ion complexes within said base is from 0 1 % to 3 0% (w/w)
  • composition of Claim 1 wherein the concentration of said silver thiosulfate ion complexes within said base is from 0 2% to 1 5% (w/w)
  • composition of Claim 1 wherein said base is selected from the group consisting of polvethvlene glycol Aquaphor® and white petrolatum
  • composition of Claim I wherein said silver thiosulfate ion complexes are derived from the complexation of a silver cation from silver hahdes with anions
  • composition of Claim 8 wherein said silver hahde comprises silver chloride and said anions comprise sodium thiosulfate salts
  • composition of Claim 9 wherein the molar ratio of the thiosulfate anions to silver cations is at least 1 1 1 1
  • a pharmaceutical mixture comprising a) a medicinal agent, and b) silver thiosulfate ion complexes
  • a method of imparting antimicrobial protection comprising a) providing i ) a product, and n) an effective amount of carrier-free suspended silver thiosulfate ion complexes, and b) applying the effective amount of the carrier-free suspended silver thiosulfate ion complexes in a base to the ob)ect
  • said personal care product is selected from the group consisting of lipsticks, hpgloss, lip pencils, mascaras, eye liners, eye shadows, moisturizers, liquid makeup foundations, powder makeup foundations, powder blushes, cream blushes, perfumes, colognes, toners, deodorants, shaving creams, shampoos, conditioners, hair mousses, hairsprays, toothpastes, and mouthwashes,
  • a device comprising a medical device coated with an antimicrobial compositions comprising silver thiosulfate ion complexes
  • a method of treating or preventing a microbial infection comprising a) providing l) a subject, said sub
  • said antimicrobial agent is selected from the group consisting of acvclovir, chloramphemcol, chlorhexidme, chlortetracycline, itraconazole, mafenide metromdazole, mupirocin nitrofurazone. oxytetracvcline, penicillin, and tetracvchne
  • a method for producing essentially anhydrous silver thiosulfate ion complexes comprising a) providing an aqueous solution of silver thiosulfate ion complexes. b) adding a solvent to said solution to create a biphasic separation wherein said silver thiosulfate ion complexes separate into a single phase, c) collecting said single phase containing said silver thiosulfate ion complexes, and d) removing water from said single phase such that said silver thiosulfate ion complexes are essentially anhydrous
  • a method for producing essentially anhydrous silver thiosulfate ion complexes comprising a) providing an aqueous solution of silver thiosulfate ion complexes, b) adding a solvent to said aqueous solution to precipitate said silver thiosulfate ion complexes, c) collecting said precipitated silver thiosulfate ion complexes, and d) removing water from said collected silver thiosulfate ion complexes such that said silver thiosulfate ion complexes are essentially anhydrous
  • Group I claims 1-26 and 37-68 a composition and methods of use and production.
  • Group II claims 27-30 and 34-36 a medical device.
  • Group HI claims 31-33 personal care products

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Abstract

La présente invention concerne de manière générale des compositions antimicrobiennes à base d'argent et les procédés de fabrication desdites compositions. De manière particulière, la présente invention décrit des compositions antimicrobiennes stables et purifiées à base d'argent et des procédés de fabrication de telles compositions, comprenant des complexes ionisés de thiosulfate d'argent sans entraîneur soit en suspension dans une base, soit incorporées dans un support. Lesdites compositions antimicrobiennes de complexes ionisés de thiosulfate d'argent servent pour le traitement et la prévention de certaines maladies et infections.
PCT/US1997/014697 1996-08-16 1997-08-15 Compositions antimicrobiennes a base d'argent WO1998006260A1 (fr)

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EP97938487A EP0920252A4 (fr) 1996-08-16 1997-08-15 Compositions antimicrobiennes a base d'argent
CA002263473A CA2263473C (fr) 1996-08-16 1997-08-15 Compositions antimicrobiennes a base d'argent
AU40797/97A AU735373B2 (en) 1996-08-16 1997-08-15 Silver-based antimicrobial compositions
CA002383742A CA2383742C (fr) 1996-08-16 1997-08-15 Compositions antimicrobiennes a base d'argent

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US2410896P 1996-08-16 1996-08-16
US60/024,108 1996-08-16
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US08/909,239 US6093414A (en) 1997-08-11 1997-08-11 Silver-based antimicrobial compositions

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19956398A1 (de) * 1999-11-24 2001-06-13 Hahl Filaments Gmbh & Co Kg Monofile Kunstfaser
WO2001041774A1 (fr) * 1999-12-12 2001-06-14 Strathmore Ltd. Compositions bactericides hemostatiques
WO2003002089A1 (fr) * 2001-06-29 2003-01-09 Dow Global Technologies Inc. Polymeres superabsorbants a base de carboxyle presentant des proprietes desodorisantes et procede de fabrication associe
WO2003002164A3 (fr) * 2001-06-29 2003-04-17 Dow Global Technologies Inc Polymeres superabsorbants contenant un carboxyle et presentant des proprietes d'elimination des odeurs, et procede de preparation associe
RU2220982C2 (ru) * 2001-01-05 2004-01-10 Иркутский институт химии им. А.Е.Фаворского СО РАН Аргакрил - новое антисептическое и гемостатическое средство
EP1343510A4 (fr) * 2000-11-29 2004-10-13 Bristol Myers Squibb Co Substances anti-microbiennes stabilisees par rayonnement
US6908912B2 (en) 1999-06-25 2005-06-21 Arch Chemicals, Inc. Pyrithione biocides enhanced by zinc metal ions and organic amines
US7026308B1 (en) 1999-06-25 2006-04-11 The Procter & Gamble Company Topical anti-microbial compositions
EP1809264A4 (fr) * 2004-09-20 2008-11-19 Acrymed Inc Compositions antimicrobiennes amorphes
CN102274135A (zh) * 2011-08-25 2011-12-14 宁夏医科大学 防干裂唇膏
US8900624B2 (en) 2004-07-30 2014-12-02 Kimberly-Clark Worldwide, Inc. Antimicrobial silver compositions
US9259414B2 (en) 2013-02-28 2016-02-16 Dermira, Inc. Glycopyrrolate salts
US9381382B2 (en) 2002-06-04 2016-07-05 The Procter & Gamble Company Composition comprising a particulate zinc material, a pyrithione or a polyvalent metal salt of a pyrithione and a gel network
US9381148B2 (en) 2003-03-18 2016-07-05 The Procter & Gamble Company Composition comprising particulate zinc material with a high relative zinc lability
WO2016120332A1 (fr) * 2015-01-27 2016-08-04 Uniwersytet Medyczny W Lodzi Composé complexe d'argent, procédé de préparation du composé complexe et utilisation du composé complexe
US9610278B2 (en) 2013-02-28 2017-04-04 Dermira, Inc. Glycopyrrolate salts
US9687503B2 (en) 1999-12-30 2017-06-27 Avent, Inc. Devices for delivering oxygen to the wounds
US9970303B2 (en) 2014-05-13 2018-05-15 Entrotech, Inc. Erosion protection sleeve
WO2018185374A1 (fr) 2017-04-05 2018-10-11 Suominen Corporation Substrat à utilisation efficace pour l'assainissement et la désinfection
US10251392B2 (en) 2004-07-30 2019-04-09 Avent, Inc. Antimicrobial devices and compositions
US10493101B2 (en) 2005-12-14 2019-12-03 Convatec Technologies Inc. Antimicrobial composition
CN112897472A (zh) * 2021-02-03 2021-06-04 晋大纳米科技（厦门）有限公司 一种耐高温耐光照的络合银溶液的制备方法、络合银溶液及抗菌产品
US11135315B2 (en) 2010-11-30 2021-10-05 Convatec Technologies Inc. Composition for detecting biofilms on viable tissues

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7745686B2 (en) 2001-11-02 2010-06-29 Playtex Products, Inc. Catamenial device
EP2178990B1 (fr) 2007-08-02 2015-07-08 Covalon Technologies Ltd. Composition de revêtement antimicrobienne photostable
US20110301553A1 (en) * 2010-06-04 2011-12-08 Smiths Medical Asd, Inc. Antimicrobial lubricant

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US4677143A (en) * 1984-10-01 1987-06-30 Baxter Travenol Laboratories, Inc. Antimicrobial compositions
US5102401A (en) * 1990-08-22 1992-04-07 Becton, Dickinson And Company Expandable catheter having hydrophobic surface
US5510109A (en) * 1990-11-28 1996-04-23 Matsushita Electric Industrial Co., Ltd. Antibacterial and antifungal composition

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR882M (fr) * 1961-01-18 1961-10-06
US5429819A (en) * 1992-10-14 1995-07-04 Matsushita Electric Industrial Co., Ltd. Antiviral composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US4677143A (en) * 1984-10-01 1987-06-30 Baxter Travenol Laboratories, Inc. Antimicrobial compositions
US5102401A (en) * 1990-08-22 1992-04-07 Becton, Dickinson And Company Expandable catheter having hydrophobic surface
US5510109A (en) * 1990-11-28 1996-04-23 Matsushita Electric Industrial Co., Ltd. Antibacterial and antifungal composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0920252A4 *

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6908912B2 (en) 1999-06-25 2005-06-21 Arch Chemicals, Inc. Pyrithione biocides enhanced by zinc metal ions and organic amines
US7026308B1 (en) 1999-06-25 2006-04-11 The Procter & Gamble Company Topical anti-microbial compositions
DE19956398A1 (de) * 1999-11-24 2001-06-13 Hahl Filaments Gmbh & Co Kg Monofile Kunstfaser
WO2001041774A1 (fr) * 1999-12-12 2001-06-14 Strathmore Ltd. Compositions bactericides hemostatiques
US9687503B2 (en) 1999-12-30 2017-06-27 Avent, Inc. Devices for delivering oxygen to the wounds
US7267828B2 (en) 2000-11-29 2007-09-11 Bristol-Myers Squibb Company Light stabilized antimicrobial materials
EP1343510A4 (fr) * 2000-11-29 2004-10-13 Bristol Myers Squibb Co Substances anti-microbiennes stabilisees par rayonnement
NO337387B1 (no) * 2000-11-29 2016-04-04 Convatec Technologies Inc Lys-stabiliserte antimikrobielle materialer
RU2220982C2 (ru) * 2001-01-05 2004-01-10 Иркутский институт химии им. А.Е.Фаворского СО РАН Аргакрил - новое антисептическое и гемостатическое средство
RU2220982C9 (ru) * 2001-01-05 2016-04-20 Иркутский институт химии им. А.Е.Фаворского СО РАН, Государственное учреждение "Научный центр реконструктивной и восстановительной хирургии Восточно-Сибирского научного центра СО РАМН" Аргакрил - новое антисептическое и гемостатическое средство
WO2003002164A3 (fr) * 2001-06-29 2003-04-17 Dow Global Technologies Inc Polymeres superabsorbants contenant un carboxyle et presentant des proprietes d'elimination des odeurs, et procede de preparation associe
KR100870629B1 (ko) 2001-06-29 2008-11-26 에보닉 스톡하우젠 게엠베하 악취 방지 특성을 갖는 초흡수성 카복실 함유 중합체
KR100910546B1 (ko) * 2001-06-29 2009-08-03 에보닉 스톡하우젠 게엠베하 냄새 억제 특성을 갖는 고흡수성 카복실 함유 중합체, 이의 제조방법 및 당해 중합체를 포함하는 흡수성 구조물
WO2003002089A1 (fr) * 2001-06-29 2003-01-09 Dow Global Technologies Inc. Polymeres superabsorbants a base de carboxyle presentant des proprietes desodorisantes et procede de fabrication associe
US9381382B2 (en) 2002-06-04 2016-07-05 The Procter & Gamble Company Composition comprising a particulate zinc material, a pyrithione or a polyvalent metal salt of a pyrithione and a gel network
US9381148B2 (en) 2003-03-18 2016-07-05 The Procter & Gamble Company Composition comprising particulate zinc material with a high relative zinc lability
US10251392B2 (en) 2004-07-30 2019-04-09 Avent, Inc. Antimicrobial devices and compositions
US9888691B2 (en) 2004-07-30 2018-02-13 Avent, Inc. Antimicrobial silver compositions
US8900624B2 (en) 2004-07-30 2014-12-02 Kimberly-Clark Worldwide, Inc. Antimicrobial silver compositions
US9289378B2 (en) 2004-09-20 2016-03-22 Avent, Inc. Antimicrobial amorphous compositions
EP1809264A4 (fr) * 2004-09-20 2008-11-19 Acrymed Inc Compositions antimicrobiennes amorphes
US10493101B2 (en) 2005-12-14 2019-12-03 Convatec Technologies Inc. Antimicrobial composition
US11135315B2 (en) 2010-11-30 2021-10-05 Convatec Technologies Inc. Composition for detecting biofilms on viable tissues
CN102274135A (zh) * 2011-08-25 2011-12-14 宁夏医科大学 防干裂唇膏
US9259414B2 (en) 2013-02-28 2016-02-16 Dermira, Inc. Glycopyrrolate salts
US10004717B2 (en) 2013-02-28 2018-06-26 Dermira, Inc. Glycopyrrolate salts
US9610278B2 (en) 2013-02-28 2017-04-04 Dermira, Inc. Glycopyrrolate salts
US10543192B2 (en) 2013-02-28 2020-01-28 Dermira, Inc. Glycopyrrolate salts
US10548875B2 (en) 2013-02-28 2020-02-04 Dermira, Inc. Glycopyrrolate salts
US11291652B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
US11291651B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
US9970303B2 (en) 2014-05-13 2018-05-15 Entrotech, Inc. Erosion protection sleeve
WO2016120332A1 (fr) * 2015-01-27 2016-08-04 Uniwersytet Medyczny W Lodzi Composé complexe d'argent, procédé de préparation du composé complexe et utilisation du composé complexe
WO2018185374A1 (fr) 2017-04-05 2018-10-11 Suominen Corporation Substrat à utilisation efficace pour l'assainissement et la désinfection
US11944095B2 (en) 2017-04-05 2024-04-02 Suominen Corporation Substrate for efficient use in sanitizing and disinfecting
CN112897472A (zh) * 2021-02-03 2021-06-04 晋大纳米科技（厦门）有限公司 一种耐高温耐光照的络合银溶液的制备方法、络合银溶液及抗菌产品
CN112897472B (zh) * 2021-02-03 2022-09-06 晋大纳米科技（厦门）有限公司 一种耐高温耐光照的络合银溶液的制备方法、络合银溶液及抗菌产品

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AU735373B2 (en) 2001-07-05
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EP0920252A4 (fr) 2004-08-18
CA2263473C (fr) 2003-04-22
AU4079797A (en) 1998-03-06

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