CA2263473C

CA2263473C - Silver-based antimicrobial compositions

Info

Publication number: CA2263473C
Application number: CA002263473A
Authority: CA
Inventors: Christopher C. Capelli
Original assignee: Individual
Current assignee: Individual
Priority date: 1996-08-16
Filing date: 1997-08-15
Publication date: 2003-04-22
Anticipated expiration: 2017-08-15
Also published as: AU735373B2; WO1998006260A1; EP0920252A1; CA2263473A1; AU4079797A; EP0920252A4

Abstract

The present invention relates generally to silver-based antimicrobial compositions and processes for making such compositions. More particularly, the present invention describes stable, purified silver-based antimicrobial compositions, and processes for making such compositions, comprising carrier - free silver thiosulfate ion complexes either suspended in a base or incorporated into a matrix. These silver thiosulfate ion complex antimicrobi al compositions are useful in the treatment and prevention of infections and diseases.

Description

SILVER-BASED ANTIMICROBIAL COMPOSITIONS
FIELD OF THE INVENTION
' 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.
BACKGROUND OF THE INVENTION
1. Antimicrobial Agents Antimicrobial a<,ents are chemical compounds that either destroy microbes, prevent their pathogenic action, or prevent their growth. Antimicrobial agents. often referred to as anti-infective absents, are frequently applied topically to the skin and mucous membranes in the form of a solution. cream. or ointment: appropriate formulations may be applied to wounds and body cavities, and to the eyes, nose, and mouth.
I s In general. topical antimicrobial a<~ents are directed at bacteria.
viruses. and fungi.
They have been used successfully in the prevention and treatment of a number of infections.
includin!, impetigo. candidiasis. tinea pedis (athletes foot), acne vulearis, and infections resulting from burns and suretical wounds.
Most agents have a limited spectrum of activity For example. some are specific for '_'0 particular !gram (+) organisms, while others are specific for particular ~~ram (-) organisms.
Moreover. bactericidal absents typically are not tun~Ticidal. while fun~licidal a'_ents typically are not bactericidal.
In addition, due to the widespread use and frequent over-prescribin!~ of antimicrobial a«ents. there is an increasin~~ incidence of microbes acquiring_ dru~_-resistance. fn other words, ?S a microbe that was once susceptible (I.e., inhibited or killed) to a particular antimicrobial a~_ent is no longer susceptible. This is especially important with regard to bacteria.
Acquired dru~~ resistance is usually caused by a mutation within the genome of the microbe or by the acquisition of a plasmid. For example. one of the major mechanisms of resistance to the (3-lactam antibiotics. including,.: penicillins. is the production of ~i-lactamases.
;0 Moreover, resistance to one member of a class of agents le.;~., the aminopeniciilin ampicillin) can result in complete cross-resistance to other members of that class (e.~,~., the aminopenicillin amoxicillin).
SUBSTITUTE SHEET (RULE 26) II. Topical Silver-Containing Agents A. Currently Used Therapeutic Agents Two formulations co~Ztaining silver have been utilized for therapeutic purposes, silver nitrate and silver sulfadiazine. As ser_ forth hereafter, each is associated with potentially se-aere adverse effects and other limitations.
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 salver nitrate solution does not readily penetrate into tissue. Unfortunately, the silver salts stain t=issue 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 routinely used as an adjunct in the prevention and treatment of infection in burn victims. [See U.S. Patent. No. 3,761,590 to Fox] Silver sulfadiazine, produced by the reaction of silver nitrate with sulfadiazine, rnas been associated with necrosis of the skin. In addition, :~ulfadiazine may accumulate in patients with impaired hepatic or renal function, requiring in severe cases examination of the patients urine for sulfonamide crystals. Moreover, patients allergic to sulfa agents may exhibit cross-hypersensitivity with silver sulfadiazine.
[See generally; AHF~~ Drug Information. Gerald K. McKevoy, ed., pp. 1704-05 and 2215-16 (1993)].
B. Newer Antimicrobial Silver-Containing Compositions One of the reasons why there are few commercially available 2a silver-containing therapeutic formulations is the difficulty of making such formulations photostable. That is, such formulations turn a dark color and frequently lose antimicrobial efficacy upon short-term (e. g., 3-4 days) exposure to ambient light.
There have been several recent efforts to produce a silver-containing formulation that exhibits high antimicrobial efficacy and photost~abil:ity. For_ example, LJ.S. Patent No.
5,326,567 to Capelli, describes an antimicrobial composition comprising a stabilizing acyclic polyether polymer, silver ion, and a stabilizing h<~lide. T:he composition may be used in several manners, including topical application to a subject <~nd incorpo:ration into a medical device.
In addition, a new c:l.ass of silver-containing agents, the silver thiosulfate Lion complexes, has recently been disclosed in U.S. Patent No 5,429,819 to Oka et al.
(hereafter "the Oka Patent"). [See also Tomioka et al., "Synthes:is of .~ntimicrobial Agent Composed of Silver-Thiosulfate Complex Ion." Nippon Ka«aku Kaishi 10:848-50 ( 1995)). The Oka Patent describes an antiviral composition that contains l) a thiosulfate salt and ii) at least one thiosulfate complex salt of a metal and iii) a porous particulate carrier; the metal is either silver, copper or zinc. and the salts are carried on the porous particulate carrier. According to the Oka Patents teachings, the thiosulfate complex salt and thiosulfate metal complex salt are first prepared as a solution.
Thereafter, a porous carrier such as silica gel is impre~.:nated with the solution. Finally, the thiosuifate 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 antimicrobial compositions taught in the Oka Patent are associated with several notable shortcomings. First. the silver thiosulfate ion complex compositions contain a relatively larvae concentration of waste salts. resultin<, from the complexation oY a thiosulfate salt, sulfite salt, and a silver salt, and are thus relatively impure. For example, producing I
1 S part of a silver thiosulfate ion complex using l part of silver nitrate (or silver acetate) to 2 parts sodium thiosulfate and/or 2 parts sodium sulfite will result in I part waste sodium nitrate (or sodium acetate); the inclusion of these salts results in a lower concentration of silver.
Similarly, as indicated above. the silver thiosulfate ion complex requires the use of porous carrier particles; the necessity of these carrier particles limits the concentration of thiosulfate ~0 complex snit and thiosulfate metal complex salt. Thus, the amount of porous carrier particles needed to provide silver at antimicrobial concentrations is hush. and. as a result. a topical antimicrobial composition would feel !~rittv and would be irritating= to the skin or wound. In addition, if the concentration of thiosulfate complex salt and thiosulfate metal complex salt carried on the porous carrier is too high, the composition may discolor.
'_'S Finally, the compositions tau';ht by the Oka Patent cannot be easily incorporated into a polymer matrix at hi~,~h concentrations. As stated above. 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 (c.,y., a hydrocolloid matrix that is stiff and less absorptive). In addition. such incorporation can be s0 unwieldy. For example, in an alrinate matrix containing_ water-insoluble fibers, the silver-containing porous carrier cannot be incorporated into the al~~inate fibers; as a result, the porous carrier must be mixed loosely within the alginate fibers.
Unfortunately, the porous carrier can fall out when the al~linate matrix is handled.

SUBSTITUTE SHEET (RULE 26) WO 9$/06260 PCT/US97/14697 From the above. it should be clear that the commercially-available silver-based antimicrobiai agents have limited applications and can be associated with severe adverse effects. Moreover, many recent efforts to develop a topical silver-containing formulation are connected with drawbacks. as exemplified by the prior art requirement of a carrier. What is needed is a stable silver-containinv~ antimicrobial composition which is suitable for use in the treatment and prevention of a broad range of infections and that is not associated with the adverse effects and limitations of the agents that have previously been described.
SUMMARY OF THE INVENTION
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. In particular. the present invention relates to stable silver-based antimicrobial compositions, and processes for makin<~ such compositions. comprising carrier-free, suspended silver thiosulfate ion complexes in a base. Preferably, the silver thiosulfate ion complexes are I ~ homo~=eneously suspended in an anhydrous base. .alternatively, 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 by combining the silver thiosulfate ion complexes with medicinal agents, including but not limited to antimicrobial a~,ents, steroids, and anesthetics.
~'0 One advantage of providin'= silver thiosulfate ion complexes in a carrier-free form is the ability to produce antimicrobial compositions containin« high concentrations of silver thiosulfate ion complexes so as to provide potent antimicrobial activity :~
further advanta~_e of the carrier-free compositions is the elimination of irritation that may result from the carrier upon topical administration. Thus. the invention contemplates a method of treating, or preventin~, infections in comprising applying topically to the site (or potential site) of infection an etfective amount of the foregoing composition.
.-~s alluded to above, the invention also contemplates methods of making the stable silver-based antimicrobial compositions. It is preferred that the silver complexes of the present invention are derived from the complexation of silver cations from silver halides s0 (preferably silver chloride) with anions from the sodium thiosulfate salts;
the molar ratio of the thiosulfate anions to the silver canons is preferably at least 1:l and more preferably at least I.s:l. It is desirable that the silver thiosulfate ion complexes are solid and essentially SUBSTITUTE SHEET (RULE 26) pure. i.e.. they do not contain si~mificant amounts of waste salts or other substances that interfere with their antimicrobial activity; in addition, they do not require carrier particles.
The 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 (c~.~=., topical) agents (e.~~., Bactroban"
[mupirocin], SmithKline Beecham). Such combination may serve to avoid antimicrobial resistance, increase the spectrum of activity, and have a synergistic effect.
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. By way of illustration. purified silver thiosulfate ion complexes may be incorporated with an anhydrous polymer matrix that is used to coat a urinary catheter in order to prevent infection. Similarly, the silver thiosulfate ion complexes may be used in cosmetics and personal care products to make them resistant to antimicrobial contammauon. Examples of cosmetics include lipsticks and ~,losses. lip pencils, mascaras, eye liners, eve shadows, moisturizers. liquid and powder makeup foundations, powder and cream blushes, perfumes, colognes, various creams and toners, etc.. and assorted applicators like combs, brushes. sponv~es, and cotton swabs and balls. and examples of personal care products include deodorants. razors, shaving creams, shampoos, conditioners, various hair treatments like mousses and sprays, toothpastes, mouthwashes. dental flosses and tapes, sunscreens.
'_'0 moisturizers. tampons. sanitary napkins. panty shields, diapers, baby wipes, facial tissues.
toilet tissues, etc.
The present invention contemplates a composition. comprisin~~ carrier-tree suspended silver thiosultate ion complexes suspended in a base. In one embodiment, the base is anhydrous. It is contemplated that the concentration of silver thiosulfate ion complexes within the base is sufficient to provide a therapeutic benefit. Speciticallv, the present invention contemplates concentrations of silver thiosulfate ion complexes within the base from 0.01% to s0% (wiw) and from 0.1°i° to _s.0°'° (w/w) The preferred concentration of silver thiosultate ion complexes within the base is from 0.2% to 1.5°i° (wiw). In one embodiment, the base is selected from the <croup consisting of polyethylene glycol. .-~quaphor". and white petrolatum.
s0 The present invention also contemplates a method of treating or preventing a topical microbial infection. comprisinv= the steps of a) providin~~ i j a subject infected with a topical microbial infection and ii) an effective amount of carrier-free suspended silver thiosuifate ion complexes in a base: and b) administering topically the effective amount of the carrier-tree SUBSTITUTE SHEET (RULE 26) suspended silver thiosuifate ion complexes in a base to the subject. thereby treating or preventing the topical microbial infection. In one embodiment, the base is anhydrous.
It is contemplated that the concentration of silver thiosulfate ion complexes within the base is sufficient to provide a therapeutic benefit. For example, the present invention specifically contemplates concentrations of silver thiosulfate ion complexes within the base from 0.01% to 30% (w/w) and from 0.1% to 3.0% (wiv,~). The preferred concentration of silver thiosulfate ion complexes within the base is from 0.?°% to I.5%
(w/w). In one embodiment, the base is selected from the ~_roup consisting, of polyethylene ~~lycol.
Aquaphor~, and white petrolatum.
The present invention further contemplates a method of imparting antimicrobial protection to an object, comprisin~~ the steps of: a) providinv; i) an object and ii) an effective amount of carrier-free suspended silver thiosulfate ion complexes; and b) applyin~l the effective amount of the carrier-free suspended silver thiosulfate ion complexes in a base to the object, thereby imparting antimicrobial protection to the object. It is preferred that the object I S is solid and chemically inert.
In one embodiment, the concentration of silver thiosulfate ion complexes is sufficient to provide a therapeutic benefit. Specifically, the present invention contemplates concentrations of silver thiosulfate ion complexes from 0.01°% to 30%
(w/w) and from 0.1%
to 3.0°~ (w/w) The preferred concentration of silver thiosulfate ion complexes is from 0.2%
?0 to I 5°% (w/w).
In still further embodiments, the object is a medical device. In particular embodiments. the medical device comprises a matrix. In some embodiments the matrix is a holvmer. while it is anhydrous in still Further embodiments The present invention also contemplates a process for producing, essentially anhydrous silver thiosulfate ion complexes. comprising_: a) makings an aqueous solution of silver thiosulfate ion complexes; b) addin~s a solvent to the solution to create a biphasic separation wherein the silver thiosulfate ion complexes separate into one phase: c) collectin~~ the phase containing the silver thiosulfate ion complexes; and d) removin~T water from the collected phase such that the silver thiosulfate ion complexes are essentially anhydrous. In particular s0 embodiments. the ratio of thiosulfate ions to silver ions is ~sreater than or equal to 2:1 and preferably less than 3:1.
In some embodiments. the aqueous solution of silver thiosuifate ion complexes is formed by reacting a silver halide and sodium thiosulfate. In other embodiments, the molar -b-SUBSTITUTE SHEET (RULE 26) ratio of silver cations from the silver halide to thiosulfate anions from the sodium thiosulfate is preferably at least 1:1 and more preferably at least 1.3:1. In still further embodiments, the silver halide is silver chloride.
In other embodiments. the solvent is water-miscible. The solvent is selected from the group consisting of ethyl alcohol, isopropyl ai,cohol, methyl alcohol, acetone, and tetrahvdrofuran in certain embodiments.
Additionally. the present invention contemplates a process for producing essentially anhydrous silver thiosulfate ion complexes, comprising: a) makings an aqueous solution of silver thiosulfate ion complexes; b) adding a solvent to the solution to precipitate the silver thiosulfate ion complexes; c) collectinv; 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. In particular embodiments. the ratio of thiosulfate ions to silver ions is less than 2:1 and preferably ~_reater than I: I
In some embodiments, the aqueous solution of silver thiosulfate ion complexes is I s formed by reacting a silver halide and sodium thiosulfate. In other embodiments, the molar ratio of silver cations from the silver halide to thiosulfate anions from the sodium thiosulfate is preferably at least I : I and more preferably at least I. 3:1 In still further embodiments, the silver halide is silver chloride.
In other embodiments, the solvent is water-miscible. The solvent is selected from the '_'0 ''roup consistin~~ of ethyl alcohol, isopropyl alcohol, methyl alcohol, acetone, and tetrahvdrofuran in certain embodiments.
The present invention also contemplates a pharmaceutical mixture. comprisin~~:
a) a medicinal av~ent; and b) silver thiosulfate ion complexes. In preferred embodiments, the silver thiosulfate inn complexes are carrier-free. In particular embodiments. the pharmaceutical ~s mixture further comprises an anhydrous base; in some embodiments, the base is selected from the group consisting, of polyethylene glycol. Aquaphor", and white petrolatum.
In some embodiments of the present invention. the concentration of the silver thiosulfate ion complexes in the pharmaceutical mixture is from 0.01% to 30°/> (weight to wei'~itt). In further embodiments, the concentration of silver thiosulfate ion complexes is s0 from 0 1% to 3.0% (weight to wei~,ht), while in still further embodiments the concentration is from 0.2°i° to f .5°% (weight to wei~.:ht).
In particular embodiments. the medicinal absent of the pharmaceutical mixture is an antimicrobial agent. In some embodiments. the antimicrobial a~.:ent is selected from the ~.:roup _7_ SUBSTITUTE SHEET (RULE 26) consisting of acyclovir. chloramphenicol, chlorhexidine. chlortetracycline.
itraconazole, mafenide. metronidazole. mupirocin, nitrofurazone, oxvtetracycline, penicillin. and tetracycline. When the medicinal agent is an antimicrobial absent, in some embodiments the pharmaceutical mixture has a broader spectrum of antimicrobial protection than the silver thiosulfate ion complexes.
Furthermore, the medicinal went of the pharmaceutical mixture is a steroid in certain embodiments. In particular embodiments. the steroid is selected from the group consisting of betamethasone benzoate, betamethasone valerate, desonide, fiuocinolone acetonide, halcinonide, hydrocortisone. and metandienone.
Finally, the medicinal went of the pharmaceutical mixture is an anesthetic in still other embodiments. In certain embodiments. the anesthetic is selected from the group consistinv~ of benzocaine. dibucaine. lidocaine. pramoxine hydrochloride and tetracacine.
DEFINITIONS
I s To facilitate understanding, of the invention set forth in the disclosure that follows, a number of terms are defined below.
The term "carrier" refers to a substance. like an inor~fanic oxide, in which a material can be impregnated and then, if necessary, immobilized throu~_h drviny;. For example, the Oka Patent describes the impre~~nation of a porous particulate carrier (c.~.~,1., silica ~,;el) with a ?0 solution containing thiosulfate complex salt and thiosulfate metal complex salt. In contrast, the term "carrier" does not refer to the mere suspension of materials like silver thiosulfate ion complexes in a base. The term "carrier-free" refers to bein<_ without such thing's as carrier particles. porous particulate carriers. and the like used as carriers for other materials. For example, the compositions of the present invention are "carrier-free" in that they comprise silver thiosulfate ion complexes that do not require such a carrier.
The term "base" refers to any substance useful for the suspension of the silver thiosulfate ion complexes of the present invention. In a preferred embodiment.
the base iv "anhydrous" (e.~,r., an ointment) and can be used to suspend a medicinal absent for topical administration. Useful anhydrous bases include. but are not limited to. white petrolatum.
s0 .~quaphor' ointment base, and polvethvEene glycol (PEG) polymers with molecular weights ';reater than 600. 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 hydrolyze the thiosulfate ligand. It should be noted that some water is tolerable in _ g _ SUBSTITUTE SHEET (RULE 26) the final product but that, yenerallv speaking. the presence of water will reduce the shelf-life of the composition. For example. an anhydrous base which contains no water and few, if any, hydroxy or acid groups should have a shelf life of many years, while a base containing small amounts of water (e.~J., less than ~%) would have a shorter shelf-life (e.y., less than (l months). If a PEG ointment base has a verv small amount of water (c~.~., much less than I%), the silver thiosulfate ion complexes should be stable enough to provide the product with an acceptable shelf-life (~.~_., greater than one vear). In one embodiment.
the base is semisolid.
The term "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 specificallv, the silver thiosulfate ion complexes are obtained by addin!_= a silver halide, c~.~., silver chloride. to an aqueous solution and then addin<_J a thiosuifate salt. c.,~=., sodium thiosulfate, to the solution. Thou_=h the benetit provided by the complexes of the present invention is not limited by an understanding_ of the precise nature of I S the complexes. 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,O,),]'-. By comparison, the chemical formula of the primary silver thiosulfate ion complexes formed when only a small excess of thiosulfate salt is used is represented by [Ayu;(S,O~),]'- The preferred silver thiosulfate ion complexes are those represented by [A~=(S,O,),]~~. The ?0 resultin'; silver thiosulfate ion complexes are in a relatively pure solid form, and are stable, i~i~~hlv water soluble and antimicrobialiv active.
The term "essentially anhydrous silver thiosulfate ion complexes" refers t~
silver thiosulfate ion complexes that may be essentially free of all remnant water.
i.~~.. they may contain a small amount of water ( ~~enerallv less than s°% of the original amount of water present, preferably less than I°,~o, and most preferably less than 0 I°%), provided that the water does not interfere with the antimicrobial function of the complexes.
The term "suspended" revers broadly to the dispersion (i.c~., not dissolution) of material (e.,L~., silver thiosulfate ion complexes) in the base. The material is preferably finely divided and preferably dispersed homo~ eneously throughout the base.
s0 The term "aqueous solution" refers to a liquid mixture containin~~, among, other thing's, water.
_g_ SUBSTITUTE SHEET (RULE 26) The term "solvent" refers to a liquid that is capable of dissolving a substance. The term "water-miscible solvent" refers to a solvent that is capable of beiny~
mixed with water and remaining so after completion of the mixing process.
The term "phase" refers to a physically distinct and separable portion of a heterogeneous system. The term "biphasic separation" refers to the creation of two phases:
';eneral(v speakin~~, a "biphasic separation" allows a material (~.,~~., silver thiosulfate ion complexes) to be partitioned into one of the resulting phases, thereby facilitatin~,~ isolation of that material. As described in further detail below, the addition of an appropriate solvent (e.~~., ethyl alcohol) to an aqueous solution of silver thiosulfate ion complexes results in a biphasic separation. 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.
The terms "collectin~l." "collect" and the like refer to the !general processes of isolatin~~, partitioning, etc. one material from another. For example. a desired material may partition I ~ into one phase of a biphasic system: the phase containin~~ that material (c.~,~., the silver thiosulfate ion complexes of the present invention) can be removed from the biphasic system using well known means (e.,~~., pipet and separatory funnel).
The term "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 (i.c., the ~0 collected phase). The present invention is not limited to any particular method: rather.
~~enerallv known methods ot~ removal (e. ~., freeze drvin~~. oven drvin~~.
evaporation. and solvent extraction) may be used in conjunction with the present invention.
The term "effective amount" refers to that amount of essentially anhydrous silver thiosulfate ion complexes that is required to provide some "therapeutic benefit". The present invention is not limited by the nature or scope of the therapeutic benefit provided. The de'_ree of benefit may depend on a number of factors, r.,~~., the severity of a .f. crnrmr.,~
infection and the immune status of the individual.
The term "therapeutic composition" refers to a composition that includes essentially anhydrous silver thiosulfate ion complexes in a pharmaceutically acceptable form. The s0 characteristics of the form will depend on a number of factors, including the site of topical administration and the method by which the form will be used. For example. 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 SUBSTITUTE SHEET (RULE 26) characteristics of the personal care product itself. The therapeutic composition may contain diluents. adjuvants and excipients. among other things.
The terms "subject" and "host" refer to humans and animals.
The term "approximately" refers to the actual value being within a ran~,~e of the indicated value. In general, the actual value will be between 5% (plus or minus) of the indicated value.
The terms "topical," "topically." and the tike include, but are not limited to, the surface of the skin and mucosal tissue, in wounds. in the eves, nose. mouth, anus and vagina.
The term "wound" includes a burn, cut sore, blister. rash or any other lesion or area of disturbed skin. The term "wound dressing" includes foam dressin'=s, thin film dressings, burn dressin~~s, surgical dressin<~s, absorptive dressings, gauze, sheets or other types of medical device used to treat wounds.
The terms "microbe. "microbial." and the like include bacteria, fungi. and viruses. The terms "antimicrobial" and "antimicrobial activity" refer to the ability to kill or inhibit the I S ~~rowth of microbes.
The term "photostable" means that an object or material is resistant to discoloration when exposed to ambient li~~ht for a period of at least 7~ hours.
The terms "matrix," "matrices" and the like refer broadly to materials in which the silver thiosulfate ion complexes of the present invention can be embedded in.
attached to, or '_'0 otherwise associated with. ~ "polymer matrix" is one type of matrix comprisinv.: one or more natural or synthetic compounds. usually of hi'Th molecular wei~~ht. in the form of repeated linked units. The term "anhydrous polymer nlatfi\" refers to ilflV soled material that may be tree of water or that may contain a small amount of water f ~~enerallv less than ~°,'° by wei~.~.ht), provided that the water does not interfere with the antimicrobial function of the complexes carried by the matrix. The preferred anhydrous polymer matrix materials are materials compatible with the silver thiosulfate ion complexes of the present invention.
The most preferred polymer matrix materials are those bein<~ compatible with the silver thiosulfate ion complexes and havin<~ some capacity to absorb and/or swell in the presence of water.
Examples of anhydrous polymer matrix materials, include. but are not limited to. adhesives such as acrylic-based pressure sensitive adhesives; biopolvmers such as silk;
hydrocolloid materials such as sodium carboxvmethvlcellulose. either alone or when bound in a polymer;
and polymers such as polyurethane in the form of coatin~~s, films. foams. etc.
SUBSTITUTE SHEET (RULE 26) The term "medical device" refers broadly medical implants, wound care devices, body cavity and personal protection devices, and the like. )Vledical implants include, but are not limited to, urinary and intravascular catheters, dialysis shunts. wound drain tubes, skin sutures, vascular grafts and implantable meshes, intraocular devices, and heart valves.
Wound care devices include, but are not limited to, general wound dressings, non-adherent dressings, burn dressings, biological ~,~ratt materials, tape closures and dressings, and surgical drapes. Finally, body cavity and personal protection devices include, but are not limited to, tampons, sponges, surgical and examination gloves, toothbrushes. intrauterine devices, diaphra~~ms, and condoms.
The silver thiosulfate ion complexes of the present invention can be use to impart antimicrobial protection to objects includin~~, but not limited to. medical devices.
The term "puritied" means that the material has been subjected to a process (c.~~., extraction) to remove impurities. Followin~T the process. the material may be free from contamination of extraneous matter or, more commonly, only contain impurities at levels that do not interfere with the intended function. For example, it is advantageous to produce silver I s thiosulfate ion complexes that do not contain significant amounts of waste salts (c.,s,~., sodium nitrate or sodium acetate); if such waste salts are incorporated into compositions or medical devices. they may be irritating to the skin or other tissue. tn addition. they may reduce the concentration of antimicrobiallv active silver. For example, if the silver thiosulfate ion complexes are made using, silver iodide silver salt and sodium thiosulfate salt, the resultinrr '_'0 waste salt would be sodium iodide. The iodide ion would a'~gressivelv compete for the dissociated ("free") silver ion. resulting in reduced concentration of antimicrobiallv active silver DET.-AILED DESCRIPTION OF THE INVENTION
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. In particular. 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 s0 incorporated into an anhydrous polymer matri~c and used with a medical device.
The description of the invention is divided into the following parts: I) Processes To Obtain Silver Thiosulfate Ion Complexes In A Solid Form; II) Compositions Containin<=
Silver Thiosulfate Ion Complexes: III) Therapeutic Use Of Compositions Containing Silver SUBSTITUTE SHEET (RULE 26) 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.
I. PROCESSES TO OBTAIN SILVER THIOSULFATE ION COMPLElCES
MATERIAL iN A SOLID FORM
As previously indicated. the compositions of the Oka Patent contain a thiosulfate salt, at least one thiosulfate salt of a metal, and a porous particulate 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, l1. 45-46). In contrast to the Oka IO Patent. the present invention is directed at a process for obtaining carrier-free silver thiosulfate ion complexes. Based on the prior arts acknowledged difficulty in obtaining silver thiosulfate ion complexes in a carrier-tree solid state. the discovery of the process disclosed I~ereatter was both surprisin<~ and unexpected. Mtoreover. the process of the present invention also results in carrier-free silver thiosulfate ion complexes in hi~~h yields.
another surprisinu I S and unexpected result.
The present invention contemplates the production of carrier-free silver thiosulfate ion completes wherein the ratio of thiosulfate ion to silver ion is preferably at least 1.3 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.,~~., subjected to methods to '_'0 remove contaminants such as waste salts in an amount that adversely interferes with the silver concentration obtainable).
The present invention provides nvo processes of producin~~ purified silver thiosulfate ion complexes from thiosulfate ions and silver ions. The first process is preferred when the ratio of thiosulfate ions to silver ions is greater than or equal to ?-to-I.
and the second process is preferred when the ratio is less than 2-to-1.
A. Process For Producing Silver Thiosulfate Ion Complexes When The Ratio Of Thiosulf~te Ions To Silver Ions Is Greater Thin Or Equal To 2-to-1 s0 The process for producing.: essentially anhydrous silver thiosulfate ion complexes when the ratio of thiosulfate ions to silver ions is greater than 2-to-I involves four major steps. The first step consists of makin<~ an aqueous solution of silver thiosulfate ion complexes. The aqueous solution of the silver thiosulfate ion complexes is obtained by first adding, a silver SUBSTITUTE SHEET (RULE 26) halide. such as silver chloride. silver bromide. etc.. to an aqueous solution.
Thereafter. a thiosuifate salt. such as sodium thiosuifate or potassium thiosulfate, is added to the aqueous solution.
The use of a silver halide instead of another silver-containing molecule is preferred because the silver thiosulfate ion complexes produced are associated with increased short-term stability. This is especially important when the concentration of the silver thiosulfate ion complexes is high and/or the ratio of thiosulfate ions to silver ions is low.
Likewise, the use of a silver halide promotes stability when making a solution of the silver thiosulfate ion complexes when the concentration of silver thiosulfate ion complexes in the resulting aqueous solution is hi~~h. As indicated above. when making silver thiosulfate ion complexes where the primary silver ion complexes formed is represented by the formula [~g(S,O,),]'', the preferred proportions of thiosulfate salt to silver salt are equal to or ~~reater than ?
moles of thiosulfate salt for I mole of silver salt. The most preferred proportions of thiosulfate salt to silver salt are equal to or greater than 3-to-1.
I ~ In making the aqueous solution of the silver thiosulfate ion complexes, the preferred silver halide is silver chloride. It should be noted that the silver chloride, as well as other silver halides, can be made in .~~inr in the aqueous solution In this way. a mater-soluble silver salt such as silver nitrate or silver acetate is first dissolved in the aqueous solution. .fin equivalent or greater molar amount of a halide salt containin~~ the chloride ion, such as ?0 sodium chloride, potassium chloride, and the like, is then added, resuitin~
in the precipitation of the silver chloride salt.
~dditionallv. in makin<~ the aqueous solution of the silver thiosuifate ion complexes. it is preferred that the concentration of the initial silver halide in the aqueous solution be less than ?S°~ 1-Ii~,her concentrations of the silver halide can lead t0 Illstabtlitv of the resultin~~
silver thiosulfate solution; that is to say, the silver thiosulfate ion complexes within the aolution will "break down" or decompose. leadin~l 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 resultin'_ from the first step to create a biphasic separation: in this way, the silver thiosulfate ~0 ion complexes separate into one phase. The preferred solvents are those which are water miscible. Solvents such as ethyl alcohol, isopropyl alcohol. methyl alcohol.
acetone.
tetrahvdrofuran. and the like, are examples of solvents which are useful in causin~~ phase separation. The solvent is added to the silver thiosulfate ion complexes solution in an amount _ 1 ~t _ SUBSTITUTE SHEET (RULE 26) such that the solution separates into two phases. Durin~~ the formation of two distinct phases, the silver thiosulfate ion complexes separate into one phase. Tvpicallv, the volume of the phase containing the silver thiosulfate ion complexes is onlv a fraction (e.~,r., less than 20%) of the total volume of liquid; this denser liquid phase resembles a liquid mixture containing a heavy oil and an aqueous solution where the heavy oil accumulates at the bottom of the vessel containinvu the liquid mixture.
The phase containing the silver thiosulfate ion complexes is thought to consist of a hi~,;h concentration (i.~.. 50 - 70% of the total volume) of relatively pure silver thiosuifate 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.
In the third step, the separated phase containing the silver thiosulfate ion complexes can be collected using! well known means. For example. the phase can be drawn up using, a pipet and removed from the solution. Likewise, a separatorv funnel can be used to separate the phase from the solution.
After the liquid phase containing the silver thiosulfate ion complexes has been collected, the fourth step involves treatment of the collected phase to create essentially anhydrous silver thiosulfate complexes. The silver thiosulfate complexes are purified, containin~~ insignificant amounts of waste salts (~.,~~., sodium nitrate or sodium acetate) and other extraneous materials. Treatments which are useful include. but are not limited to, '_'0 evaporation, oven drying, freeze drvin!;, solvent extraction. and the like. Atter the treatment.
the essentially anhydrous silver thiosulfate complexes are ~_round into a fine powder.
Q. Process For 1'rodncing Silver Thiosnlfate Ion Complexes When The Ratio Of Thiosulfate Ions To Silver Ions Is Lcss Than 2-to-I
The process for producing.: essentially anhydrous silver thiosulfate ion complexes when the ratio of thiosuifate ions to silver ions is less than 2-to-I involves four major steps. Tlje first step, making_ an aqueous solution of silver thiosulfate ion complexes.
is analogous to the SUBSTITUTE SHEET (RULE 26) WO 98/06260 PCTlUS97/14697 first step of the process where the ratio is ~~reater than 2-to-I. The mayor difference of this process from that where the ratio is y_reater than 2-to-1 is that the second step of this process involves precipitation of the silver thiosulfate ion complexes from the aqueous solution (described below).
In the second step, a solvent is added to the aqueous solution of silver thiosulfate ion complexes to precipitate the silver thiosulfate ion complexes. The preferred solvents are those solvents which are water miscible. Solvents such as ethyl alcohol. isopropyl alcohol, methyl alcohol. acetone, tetrahydrofuran. etc., are examples of solvents which are useful in causing, precipitation. The solvent is added to the silver thiosulfate ion complexes solution in an amount such that the complexes precipitate.
In the third step, the silver thiosulfate ion complexes precipitate can be separated from the solution using any standard. well-known technique. Filtration represents one preferred separation technique. Tire silver thiosulfate ion complexes are relatively pure. containing insi'~niticant amounts of waste salts (o.,~~., sodium nitrate or sodium acetate) and other extraneous materials like excess thiosulfate salts that are thou~~ht to remain in solution (i.e., they do not form a solid precipitate).
Following,_ separation. the fourth and final step of removing essentially all remnant water from the complexes from the collected phase creates essentially anhydrous silver thiosulfate ion complexes. Methods which are useful include, but are not limited to, ~0 evaporation, oven drying, freeze drying, and the like. ~t~ter the treatment. the essentially anhydrous silver thiosulfate ion complexes are aground into a tine powder.
C. The iVatnre Of The Silver Thiosult'ate Ion (~ompiexes While the benefit provided by the complexes of the present invention is not limited by an understandins: of the precise nature of the complexes, the solid material produced by the two processes described above is thought to consist of a salt where the silver thiosulfate ion complexes are represented by the formulas [A';(S,O,),]'-, [.agr(S,O,),]'-.
[A~,;,(S,O,),J'-, [Ay~,(S=O,);]' ~, and similar complexes. Unexpectedly, it was found that the form of the silver thiosultate ion complexes produced is very dependent on the ratio of thiosulfate ion to silver ;0 ion.
If the ratio of the thiosulfate ion to silver ion is low (i.c~., less than 2:1 ), silver thiosulfate ion complexes represented by the formulas [A';=(S,O,),]'~, [.a~~,,(S,O,),]'- and the SUBSTITUTE SHEET (RUtE 26) like can be produced. The preferred silver thiosulfate ion complexes are those represented by [Ay~,(S,O.,),]~-, which can be produced in accordance with the following chemical equation:
3 Na,S,O, + 2 AgCI --~ NaaA~,(S,O,), + ~ NaCI
Conversely, if the ratio of the thiosulfate ion to silver ion is high (i.e., greater than 2:l), relatively pure silver thiosulfate ion complexes represented by the formulas [Ag(S,O,)~]'-, [Ag(S,O,),]'' and the like can be produced.
The preferred sliver 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 carrier-free, photostable, highly water soluble, non-staining and antimicrobiallv active. This combination of features is not present in anv commercialfv available or previously described silver-containin~, composition.
i1. COMPOSITIONS CONTAINING SILVER THIOSUL~ATE lON
1 ~ COMPLEYES
Topical antimicrobial agents include therapeutic heavy metal compounds such as silver-containing compounds. Silver, in its ionic state (A~_ ), possesses a broad spectrum of antibacterial, antifungal, and antiviral properties and is reiativelv safe.
Early studies showed that the silver ion is oligodynamic. i.r., active at verv low concentrations.
[.fc~c~ ,~~crrcr-crllo, ~'0 Russell e~ crl.. Antimicrobial Activity and Action of Silver," Progress in Medicinal Chemistry 31:351-70 ( 1994)) The present invention is directed at. amon~~ other thin<,s, carrier-free silver thiosuifate ion complexes compositions. Tl~e provision of carrier-tree silver thiosulfate ion complexes is advanta~_eous for at least two reasons. First. it provides the ability to make antimicrobial ailver thiosuffate ion complexes compositions without the need for potentially irritatin~~ porous carrier particles. Second, it provides the ability to produce antimicrobial silver thiosulfate ion complexes compositions which can contain hi~_h concentrations of silver.
resultin~T in compositions with potent antimicrobial activity.
As set forth above, the carrier-tree silver thiosulfate ion complexes are stable.
~0 However. the complexes are not stable in all pharmaceutically-acceptable compositions.
Indeed. it was found that the silver thiosulfate ion complexes decompose when incorporated into certain base compositions (,fe~c~ Experimental Section. irrJior). The decomposition of the silver thiosulfate ion complexes results in the silver-based composition both chan~,~iny; to a _ 17 _ SUBSTITUTE SHEET (RULE 26~

black color and losing_ antimicrobial activity. Given the instability of silver thiosulfate ion complexes when incorporated in certain base compositions. it was surprising and unexpected to discover silver thiosulfate ion complexes compositions which were, in fact, stable.
The stable silver thiosulfate ion complexes compositions of the present invention comprise carrier-free suspended silver thiosulfate ion complexes in a base.
The preferred base is anhydrous. and in one embodiment the base is semisolid. The stable silver-based compositions maintain their antimicrobial activity. Moreover, the amount of silver in the compositions can be varied over a large ranue of concentrations to provide compositions with different levels of antimicrobial potency.
f 0 During the first step of the previously-described process for producing essentially anhydrous silver thiosulfate ion complexes, 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 or cream composition;
in other words. a composition can be made after completing only the first of the four steps. However, 1 ~ the resulting antimicrobial ointment or cream composition suffers from two major drawbacks.
First, the resulting_ silver thiosulfate ion complexes compositions will contain large quantities of excess thiosulfate salts as well as waste salts (e~.,~f., sodium nitrate, potassium nitrate, and potassium acetate). When applied topically. the antimicrobial composition containin~~ these impurities may be irritatin«. The second major problem is that ointment or cream ~0 compositions made with silver thiosulfate ion complexes from such an aqueous solution are not stable for lone periods of time That is to say, over a period of time the resultin~l silver-based antimicrobial compositions will turn black and lose antimicrobial efficacy.
This destabilization occurs whether or not the silver-based compositions are stored in an opaque container or a clear container Therefore. the destabilization is not a photo-reduction of the silver. Rather. what occurs is that the thiosulfate ion component of the silver thiosuifate ion complexes experiences a chemical breakdown The effect of this chemical process is the breakdown of the silver thiosulfate ion complexes.
.-~~_ain. while an understanding of the mechanisms involved is not necessary.
it is believed that the thiosulfate ion which makes up the silver thiosulfate ion complexes is s0 formed by adding a sulfur atom to a sulfite ion in a complex reaction that can be summarized by the following chemical equation: S + SO,=- --~ S,O,='. The sulfur atom that is added to the sulfite ion to ~_ive S,O,-- is somewhat labile; thus, S,O,w may appropriately be represented as S-SO,~ -. In aqueous solutions. thiosulfate decomposes over time. .fit SUBSTITUTE SHEET (RULE 26) moderately low pH levels the sulfur atom readily splits oft. nominally yielding sulfur as follows:
S-SO,' - + H- -~ S + HSO,' -While the acid decomposition of the thiosulfate ion nominally yields sulfur, it should be s mentioned that very finely divided particles of sulfur in an acidic aqueous solution have the character of polysultide ions. [Levenson: Complementary Processes (Ch. 14), in The 7%~c~~u-v y/nhc l'hrno~~-crphic l'rr~ce.ss, Fourth Ed. MacMillan Publishing Co.. Inc., New York ( 1977)].
As a result of the instability of the thiosulfate ion. when dissolved in water silver thiosuffate 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 sulfide is a black material havin_~ the molecular formula of A~ ,S. Due to silver sulfide's high dissociation constant (pK = -l~). I ), silver sulfide is essentially non-antimicrobial. That is to say, the silver ion is bound tightly to the sulfur ion so that it can only ionize very slowly I ~ from the silver sulfide salt. As a result, little, if any, ionized silver is available to provide antimicrobial activity.
Likewise, silver thiosulfate ion complexes. when added to either an ointment base which contains a small proportion of water or a water-containin~~ cream base in order to form an antimicrobial composition, will decompose over a r-elativelv short period of time. The ?0 resulting antimicrobial composition will turn black as the silver thiosulfate ion complexes in the composition decompose to silver sulfide. :~dditionallv. the composition will lose its antimicrobial efficacy with decomposition of the silver thiosultate ion complexes.
In contrast, the previously described four-step process for producing_=
essentially anhydrous silver thiosulfate ion complexes allows the production of compositions that are ~'S stable over long periods of time. The stable silver thiosulfate ion complexes compositions of this invention comprise carrier-tree suspended silver thiosultate ion complexes in a base. The bases v.vhich are most useful for the present invention entail any compound or mixture which is capable of suspending the complexes. Preferably, the base is essentially anhydrous and can be used topically to deliver a medicinal a~~ent. I3y way of illustration.
bases that are useful ,0 include white petrolatum. .Aquaphor~ ointment base, polaxomers. and polyethylene glycol (PEG) polymers with molecular wei~,hts ~=renter than 600 The preferred base is a PEG
ointment composition containiny~ a combination of PEG polymers with molecular wei~~hts greater than 1.000 and polaxomers.

SUBSTITUTE SHEET (RULE 26) The methods for suspendin<~ the purified silver thiosulfate ion complexes, in the form of a tine 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 homo~_eneous suspension.
The concentration of the silver thiosulfate ion complexes within the base is such as to provide antimicrobial activity. The preferred concentration of the silver thiosulfate ion complexes is 0.1% to 3.0°,%. However, 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%. Generalfv speaking, the effective concentration is that concentration which is higher than the minimum inhibitory concentration for a particular microbe. :~s would be expected. certain microbes are more sensitive to silver than other microbes. ~.,~1., gram (-) microbes are generally more sensitive than ,Tram (+) I s microbes ~s a result, a concentration less than 0 !% could be effective depending on the microbe and the intended use of the final product.
The resulting silver thiosulfate ion complexes compositions of the present invention are antimicrobially active and stable when compared to compositions that use bases which ar-e not anhydrous. Additionally, the silver-based antimicrobial compositions of this invention '_'0 show no photo-discoloration when exposed to ambient room light over a 72 hour period.
Though the compositions must be in an anhydrous base in order to maintain their atabilim. it is not intended that the compositions of the present invention be limited by the particular nature of the therapeutic preparation for example. the present invention contemplates compositions that include phvsiolo~,icallv tolerable diluents, adjuvants and excipients. such as pharmaceutical grades of mannitol. lactose. starch.
magnesium stearate.
sodium saccharin, cellulose. ma!_nesium carbonate, and the like. These compositions typically contain I°o-95% of active ingredient. preferably ?°0-70°~~. In addition. if desired the compositions may contain minor amounts of auxiiiarv substances such as stabilizin~~ or pH
bufferin~~ a~=ents or preservatives.
;0 SUBSTITUTE SHEET (RULE 26) III. THERAPEUTIC IISE OF COMPOSITIONS CONTAINING SILVER
THIOSULFATE ION COMPLEXES
The silver thiosulfate ion complexes 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. As alluded to above, the compositions are effective against bacteria, viruses, and fungi. For example. 1:. cw/i and many species of Kleh.sicllcr, !'ro~eu.s, l'.,~enclunnour.s, .ftcrphvlncnccvr.s. and ('crndidcr may be inhibited or killed by the compositions of the present invention. In general, 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 particularized requirements of individual hosts.
The therapeutic preparations can be administered for clinical use in humans and for veterinary use. such as with domestic animals. in manners known in the art and similar to either therapeutic a~_ents. Thou~Th not limited to any particular means of application, the antimicrobial compositions can be applied using gloved hands or by an applicator. Likewise.
I 5 the antimicrobiai compositions can be applied to the surface of a dressinv~, which can then be applied topically. Ophthalmic infections can be treated using standard procedures in the art, such as by pulling, down the lower eyelid to form a pocket and applying the composition thereto. 'By way of further illustration, infections of the mouth can be treated by applying,.: the composition with a sponge applicator or a toothbrush.
'_'0 Bacterial resistance to silver is known to occur in certain situations;
more specifically, 1~:.~c~l~cric~hicr c.wli and .fcrlrrrnrrrlkr rylrinnrnirrr7r are known to develop plasmid-encoded resistance to silver. [Russell e~ cr/.. Pro~_ress in Medicinal Chemistry , I
:351-70 ( 1994)]. Two related methods are commonly used to prevent and combat dm~_ resistance.
The first method entails the combination of two or more therapeutic a<_ents into a final composition. For example. the ~i-lactamase inhibitor clavulanate potassium has been added to amoxicillin. resulting in a combination preparation (Au~,~mentinT"':
SmithKline Beecham) with expanded antimicrobial activity While clavuianic acid has only weak antibacterial activity when used alone. its combination with amoxicillin results in a svner~~istic effect.
The second method entails the concomitant administration of two or more distinct s0 antimicrobial a~,ents. This method is based on the principle that a microbe that is resistant to une a~=ent may be susceptible to another. This is especially important. r.;;., in tuberculosis, which is caused by A~It~cmhacmrium nrhorcnrlo.si.,~. Particular ~l./
mhcrcvrln.~~i.~~ bacteria that cause tuberculosis are known to display resistant to each of the primary therapeutic absents. As a SUBSTITUTE SHEET (RULE 26) result. treatment of tuberculosis often requires combinations of three or more druta for periods exceeding one year. [Se.~e Dooly e~ al. "~lultidru~J-resistant tuberculosis," Ann. Int.
Med. I I 7:257-59 ( 1992); Nadler "Wultidru'_ resistant tuberculosis," N. Eng.
J. Med.
327:1 I 72-75 ( 1992)].
The present invention contemplates combinin~~ a topical silver-containing preparation with another medicinal a.=ent to form a pharmaceutical composition. Indeed.
the present invention contemplates the use of many diverse medicinal a~_ents, including antimicrobial agents. topically active drugs, and systemicalfv active drugs. The preferred medicinal agents contemplated for use in the pharmaceutical compositions of the present invention are those that can be used as antimicrobial agents in the treatment and prevention of infection and disease. Suitable antimicrobial a<_ents include, but are not limited to.
penicillin, tetracycline, oxytetracycline. chlortetracycline. chloramphenicol. chlorhexidine. mupirocin.
metronidazole.
miconazole. acvclovir. itraconazole and sulfonamides. :additional antimicrobial absents include antimicrobial peptides such as ma~~ainins, cecropins. prote~=rins, bacteriocins and defensins.
I ~ The pharmaceutical 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 may aid in preventing=
the formation of drug-resistant microbes. ~1oreover, since silver ions are oli~,odvnamic and ~0 are not immediately exhausted (i.c.. they have a lon~,-Iastin~T or "residual" effect), the presence of silver ions in the pharmaceutical compositions results in compositions which are Ion<~er iastin~_ than those containin~~ a sin~sle antimicrobial absent i~1edicinal ay_ents besides antimicrobial a'=ents are also contemplated for use in the pharmaceutical compositions of the present invention, includin!= topically active drugs for the treatment of diseases. Suitable topically active drugs include, but are not limited to. acne preparations such as isotretinoin. benzovl peroxide. salicylic acid and tetracycline; anesthetics for topical administration such as dibucaine. lidocaine, benzocaine.
tetracacine, deperodon and pramoxine hydrochloride; anti-inflammatory agents such as betamethasone benzoate.
betamethasone valerate. desonide. Iluocinolone acetonide. halcinonide.
hydrocortisone;
_~0 antiperspirants and medications used in the treatment of hvperhidrosis such as '~lutaraldehvde.
methenamine, glycopyrrolate, scopolamine hvdrobromide; antipruritic and external analgesic agents such as camphor. menthol. salicylic acid. methvlsalicviate; cleansin~T
a~_ents such as soaps and shampoos: keratolvtic. cvtotoxic, and destructive a!rents such as anthralin.

SUBSTITUTE SHEET (RULE 26) cantharidin. tluorouracil, podophyllotoxin. resorcinol: and pigmenting and'~i'dpi~Ffienti7ig agents. sunscreens such as hvdroquinone. monobenzone, trioxsalen and p-aminobenzoic acid;
anabolic steroids for building up tissues under wound healing such as methandienone;
proteolvtic a<.:ents for the decomposition of fibrin such as trypsin;
vasodilating substances for improving the flow of blow during wound healing such as tolazoline; thrombosis-hampering substances such as heparin; certain biologically active substances which affect tissue formation and tissue stabilization such as ascorbic acid and EGF (epidermal <,rowth factor), EGF-URo (EGF-uro~;astron). somatostatin. somatotropin asellacrine. and TGF; and mucolvtic and antiviral medicaments which are globulins such as lysozvme.
A pharmaceutical composition with a broad spectrum of antimicrobial protection is produced by combining one or more topicaliv active drugs in a stable fashion with a pharmaceutical composition containing= silver thiosulfate ion complexes. In situations where the topically active drugs are used to treat a disease which has an abundance of dead tissue (c.,y., a fun~~atinv; tumor or a decubitus ulcer), the addition ot~
antimicrobial silver ions will aid I s in the prevention of a secondary infection at the diseased site.
Furthermore, the presence of ionized silver in the pharmaceutical composition can aid in the prevention of malodor caused by anaerobic and aerobic microbes at the diseased site. Finally. combining= a topically active drus: with the silver thiosulfate ion complexes minimizes the need to apply additional topical antimicrobial compositions which may be incompatible with the medicinal a~=ent. resulting in ~0 both time and cost savings.
In addition to medicinal a~_ents which are antimicrobial a~,ents or topically active absents. the present invention also contemplates the use of systemically active dm~~s in the pharmaceutical compositions of the present invention. The systemically active drur;s are absorbed by the body surface when applied topically, either neat or with the aid of a solvent.
Suitable systemically active dnrgs include, but are not limited to. sedatives and hvpnotics such as pentobarbital sodium. Phenobarbital, secobarbital sodium, carbromal. and sodium Phenobarbital; psychic energizers such as 3-(?-I-aminopropyl)-indole acetate and 3-(2-aminobutvl)-indole acetate; tranquilizers such as reserpine. chlorpromazine hydrochloride, and thiopropazate hydrochloride; hormones such as adrenocorticosteroids. for example. 6-a.-s0 methvlprednisolone. cortisone, cortisol, and triamcinolone: andro~~enic steroids, for example, methyl-testosterone, and tluoxvmesterone: estrogenic steroids. for example, estrone, 17p-estradiol and ethinyl estradiol; Pro~;estational steroids, for example 17-cc-hydroxyprogesterone acetate. medroxvprogesterone acetate. 19-norpro~~esterone, and SUBSTITUTE SHEET (RULE 26) norethindrone; and thyroxine; antipyretics such as aspirin. salicylamide. and sodium salicvlate:
antispasmodics such as atropine. methscopolamine bromide. and methscopolamine bromide with Phenobarbital: antimalarials such as the 4-aminoquinolines. 8-aminoguinolines, and pyrimethamine; and nutritional agents such as vitamins. essential amino acids.
and essential fats.
:~ pharmaceutical composition with a broad spectrum of antimicrobial protection is produced by combining one or more systemically active drugs in a stable fashion with silver thiosulfate ion complexes. The addition of silver thiosulfate ion complexes with one or more systemically active drugs to produce a pharmaceutical composition assists in the preservation of the pharmaceutical composition by protecting it from microbial proliferation and over~~rowth, which could otherwise lead to spoilage of the medicinal composition containing the systemically active drug's.
f=inally, the antimicrobial compositions may be useful in making_ infection-resistant cosmetics and personal care products.
IS
IV. INCORPORATION OF SILVER THiOSULFATE ION COMPLEXES
INTO MATRICES AND THE USE OF SUCH MATRICES
This section describes the incorporation of silver thiosulfate ion complexes into matrices. most preferably anhydrous polymeric matrices. In turn, the matrices products can '_'0 be used in conjunction with medical devices for the treatment and prevention of infections and diseases. In ~_eneral. the silver thiosulfate ion complexes can be incorporated into the polymer matrix either (i) durin~~ the production of the polymer matrix or (ii) after the polymer matrix has been produced. It is most preferred that the complexes are homo~_eneouslv dispersed in the matrix A. The Nature of Silver Thiosulfate lon-Containing Anhydrous Polymeric iYlatrices Similar to the situation described above re~,ardin~s compositions. aqueous solutions of aiiver thiosulfate ion complexes which have not been purified can be incorporated into ~0 polymer matrices to render the matrices compositions antim~icrobial.
However. the resultin~;
matrices compositions will contain large quantities of excess thiosulfate salts as well as waste salts such as sodium nitrate, potassium nitrate. potassium acetate. etc. .~s set forth above, these impurities may be irritatin~~ when the matrices compositions are applied topically.

SUBSTITUTE SHEET (RULE 26) Furthermore. the presence of the waste salts may have a negative impact on the physical characteristics (c~.~,~, feel. strength, and stiffness) of the final matrices compositions.
The purifred carrier-free silver thiosulfate ion complexes of this invention can be incorporated into an anhydrous polymer 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 si~~nificant amount of water may be used as an anhydrous polymer matrix. The preferred anhydrous polymer matrix material is any material that is compatible (i.e., does not contain reactive components which could lead to the destruction of the thiosulfate ligand, thereby destabilizing the silver thiosulfate ion complexes) with the silver thiosulfate ion complexes of this invention. The most preferred polymer 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 of water; the ability of the polymer matrix to absorb andior swell in the presence of water assists in the dissolution and diffusion of the silver thiosulfate ion complexes from the polymer I ~ matrix.
It should be noted that the silver thiosulfate ion complexes of the present invention can be used with anhydrous polymer matrices which do have reactive components as lon~~ as the media is such that the reactive chemical component of the polymer matrices cannot react with the silver thiosulfate ion complexes. For example. when incorporated into a solution of ~O aly~inate material (which contains a number of chemical reactive ~Troups such as carboxylic acid). the silver thiosulfate inn complexes of the resultin!~ composition are unstable over lone periods: the water in the solution acts as a media in which the reactive groups of the alginate materials can destabilize the silver thiosulfate ion complexes However. when the al~~inate material is dry. the silver thiosulfate ion complexes remain stable anhydrous polymer matrix materials useful in this invention include. but are not limited to, the followings: adhesives such as acrylic-based. pressure-sensitive adhesives;
biopolvmers such as silk. al:.linate materials, etc.: hvdrocolloid materials such as sodium carboxvmethvlcellulose. either alone or when bound in a polymer; polymers such as polyurethane, silicone. etc. in the form of coatin~.a, films or foams. and the like. These s0 anhydrous polymer matrix compositions can be used alone or as a component of another material, such as a medical device.
The concentration of the silver thiosulfate ion complexes within the anhydrous polymeric matrix should be such as to provide antimicrobial activity. The preferred SUBSTITUTE SHEET (RULE 26) concentration of the silver thiosulfate ion complexes in the final polymeric matrix is 0.1% to 3.0%. However. 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 I
.5°'°. The resulting silver thiosulfate ion complexes-containin~~ matrices compositions of this invention are antimicrobiallv active and stable. Additionally, the compositions of this invention show no photo-discoloration when exposed to ambient room li~~ht over a 72-hour period It should be noted that the silver thiosuifate 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.
>Vloreover, as previously alluded to, the matrices compositions can be used to make medical devices such as dressin~~s, tamponades, etc. which can be used in the treatment and prevention of infection.
B. Incorporation During Production Of Polymer Matrix The method of incorporatin~~ the silver thiosulfate ion complexes durin~~ the production of the polymer matrix itself will be dependent on the production process for that polymer matrix. The methods of incorporation for several polymer matrices follows. Of course, deviations from these methods as well as the use of different matrices than those specifically mentioned are within the scope of the present invention.
~0 The first method of incorporation is useful if the polymer matrix is produced from a aolvent solution of polymer matrix material. In this situation. the silver thiosulfate ion complexes in a solid powder form can be added to that solution and mixed thorou~Thlv l:pon elimination of the solvent throu~~h standard means in the art. the remaining_ polymer matrix material will have the silver thiosulfate ion complexes dispersed: preferably the complexes are ~'s dispersed homo'_eneouslv. For example. in an adhesive material dissolved in a solvent, the silver thiosulfate ion complexes in a powder form are thorouuhlv mixed in. The mixture is then coated on a liner and dried. The resultin~, adhesive film has the silver thiosuitate ion complexes incorporated as a dispersion.
Another method of incorporation is useful if the production process for the polymer ,0 matrix involves the use of water as a solvent. (i.r.. latex polymer systems. solvent extraction systems) or as a reactant (i.e., polyurethane foam production. al<~inate fiber production. etc.l.
With this method. the silver thiosulfate ion complexes can be dissolved in the water prior to the production process. To illustrate, if a polymer film is bein_~ produced by coatinu with a SUBSTITUTE SHEET (RULE 26) polymer latex solution. the silver thiosulfate ion complexes can be added directly to the latex solution. Once added. the silver thiosulfate ion complexes will dissolve.
otter coating and drvin~" the resulting polymer elm will have the silver thiosulfate ion complexes homo~,eneousiy dispersed in the film.
Likewise, in producing a polyurethane foam matrix by reacting the polyurethane prepotymer with water. the silver thiosulfate ion complexes can be dissolved in the water prior to reacting it with the prepolvmer. after the polyurethane foam has reacted and been dried, the silver thiosulfate ion complexes will be dispersed throu~_hout the foam matrix.
additionally, in producing: a water insoluble al<~inate material by reacting an alginate solution with an aqueous calcium chloride bath, the silver thiosulfate ion complexes can be dissolved in either the water makings up the al~~inate solution or the calcium chloride bath.
The al~~inate solution. when extruded into the calcium chloride bath. will result in crossiinked al~_inate fibers which incorporate the silver thiosulfate ion complexes. Upon drying of these tibers, the silver thiosulfate ion complexes will be dispersed throu'_hout the alv~inate matrix.
I ~ Another method of incorporation can be used in conjunction with the production of polymer matrices such as a hvdrocolloid matrix made up of a hvdrocolloid material (c~.~,~., carboxymethvlcellulose) in a polymer binder. In this situation. the silver thiosulfate ion complexes. in a solid form. can be mixed directly with the Itvdrocolloid material prior to the production process. Likewise. the silver thiosulfate ion complexes can be dissolved in water ?0 which is then used to treat the hvdrocolloid material so that the solution is absorbed by the I~vdrocolloid material and then dried. Thereafter. the treated hydrocolloid material is processed using standard procedures to produce the hydrocolloid polymer matrix which contains the silver thiosulfate ion complexes dispersed in the hvdrocolloid component of the matnx.
C. Incorporation after Production Of Polymer Matrix In addition to incorporation prior to or durin~~ the production of the polymer matrix, silver thiosulfate ion complexes can be incorporated after the polymer matrix has been produced. One approach is to form an aqueous solution of the silver thiosulfate ion complexes and then apply this solution to the tinished polymer matrix. This silver thiosuftate ,0 ion complexes solution can be applied to the polymer matrix by spravin~=, dipping, paintin« or other suitable means.
By way of illustration. an aliquot of the silver thiosulfate ion complexes can be applied onto and absorbed into a tinished foam dressing_=. After drvin~_, the silver-based foam SUBSTITUTE SHEET (RULE 26) 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.
D. Precautions During Incorporation Regardless of the method of incorporating the silver thiosulfate ion complexes with the polymeric matrix, certain precautions need to be considered. First. if incorporation of the silver thiosulfate ion complexes into the polymeric matrix involves the use of water, it is verv important that the water be removed from the polymeric matrix. If the water is not removed, the silver thiosulfate ion complexes will become destabilized within the polymeric matrix over time.
Second. thou~lh the water can be removed using inv standard method. if the water is removed by drying the polymeric matrix in an oven. care should be taken to use only moderate temperatures: temperatures of 20°C to 70°C IllaV be used. while temperatures of I S 30°C to 50°C are preferred. If the temperature becomes too hot, rapid destabilization of the silver thiosulfate ion complexes can occur.
Finally. when the silver thiosulfate ion complexes are in solution_ contact with metal surfaces should be avoided. The silver thiosulfate ion complexes solution can be destabilized upon contact with metal surfaces such as aluminum and copper. An effort should be made to ?0 ensure that the solution comes into contact with materials such as ~~lass or plastic. which appear to be less destabiliziny~.
E\PERIMEIY'1'AL
In the disclosure which follows, the foilowin'; abbreviations apply: L
(liters); ml (milliliters); yi (microliters); g (;=rams); m~; (milliL~rams); ~tv~
(micro~~rams); mol (moles);
mmol (millimoles); tunol (micromoles); cm (centimeters l: mm (millimeters); nm (nanometers); °C (de<~rees Centi'==ride); MW and M1.W. (molecular weight); N (normal); w/w (wei!~ht-to-weight); wiv (wei~lfn-to-volume); min. (minutes): No. (number);
ICP (inductively coupled plasma); CFU (colony forming, units); PEG (polyethylene <glycol); MHM
(Mueller s0 Hinton Medium); ZOI (zone of inhibition); .-~TCC (American Tvpe Culture Collection.
Rocf:ville. MD); USP (United States Pharmacopeia); NCCLS (National Committee for Clinical Laboratory Standards); NIOSH (National Institute of Safety ind Health); Avitar (.Avitir. Inc.. Canton. MA); Aldrich ()Vlilwaukee. WI); Avery Dennison. lnc.
(Mill Hall, PA);
_ 28 _ SUBSTITUTE SHEET (RULE 26) BASF (BASF Corp., Chemical Division; Parsippany, NJ); Belersdorf Inc. (BDF
Plaza Nor-walk. CT); Columbus (Columbus Chemical Industries: Columbus. WI); Cook Composites and Polymers (Kansas Citv, MO); Difco (Difco Laboratories, Detroit, MI);
Hampshire (Hampshire Chemical Co.. Lexington, MA); Johnson & Johnson Medical, Inc.
{Arlington, Tx); Owen Laboratories (San Antonio, TX); Protan (Drammen, Norway); Roundy (Roundy's Inc., Milwaukee, WI); Si~~ma (Sigma Chemical Company, St. Louis, MO);
SmithKline Beecham (Philadelphia. PA); Steriseal (Steriseal Ltd, En~~land); Whatman (Whatman International Ltd., England); WOHL (Wisconsin Occupational Health Laboratory, Madison, wI).
The followiny~ examples serve to illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. The experimental disclosure which follows is divided into: t) Processes To Obtain Silver Thiosuifate Eon Complexes: I1) Compositions Containin<~ Silver Thiosulfate ton Complexes;
fII) Antimicrobial Activity Of Compositions Containing Silver Thiosulfate Ion Complexes:
I S IV) Use Of Silver Thiosulfate Ion Complexes in Medical Devices, and V) Use Of Silver Thiosulfate Ion Complexes in Combination With Other Medicinal A~~ents.
I. PROCESSES TO OBTAIN SILVER TI-IIOSULC'ATE ION COMPLEXES
'0 EXAMPLE 1 Process For Makin~~ Silver Thiosulfate Ion Complexes Usin~~ Silver Chloride When The Ratio Of Thiosulfate Ions To Silver- Ions is Cheater Than ?-to-I
This example illustrates the process for producing silver thiosulfate ion complexes when the ratio of thiosulfate ions to silver ions. is greater than 2-to-I.
That is. a biphasic separation is employed in this example.
The silver thiosulfate ion complexes were produced by tirst making a silver chloride precipitate in an aqueous solution (hereafter. "silver chloride precipitate/aqueous solution").
The silver chloride precipitate/aqueous solution was made by mixin!= 20 ml of a silver nitrate s0 (Aldrich: deionized water as the diluent) solution ( 1 mmol/m~l) with 2? ml of a sodium chloride solution ( 1 mmol/ml) (Aldrich; deionized water as the diluent) in a X00 ml separatorv funnel. To the resulting silver chloride precipitate/aqueous solution was added 60 mi of a sodium thiosulfate (Columbus; deionized water as the diluent) solution ( I
mmol/ml). The SUBSTITUTE SHEET (RULE 26) WO 98!06260 PCT/US97/14697 resuitin~~ mixture was agitated by shaking the separatorv funnel until all of the silver chloride precipitate was dissolved.
The silver thiosulfate ion complexes produced were separated by adding 200 ml of ethyl alcohol to the container. C.!pon addition of the ethyl alcohol, the solution became cloudy and separated into two separate phases. The two phases were separated using the separatory funnel. The wei~~ht of the material in the phase containinSr the silver thiosulfate ion complexes was approximately 17 <'. 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 sittiny~ 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 tine white powder using a mortar and pestle. The wei~~ht of the dried silver thiosulfate ion complexes was 10.03 ~~
The silver thiosulfate ion complexes were analyzed for silver. sodium and sulfur using, I ~ Inductively Coupled Plasma Argon Emission Spectrometry. The analysis, performed by Wisconsin Occupational Health Laboratory (WOHL), included measurement of the amount of silver using a method based on NIOSH 5182. Briefly, a representative portion of the silver thiosulfate ion complexes was wei<shed and diluted (/1000 in a dilute nitric acid solution.
Thereafter, an aliquot of the sample was analyzed (Jarrel .-ASH ICP: Franklin, MA); the '_'0 analysis ~~ave the following results !expressed as percenta~_es of the air dried samples):
Silver-Sodium 17%
Sulfur ;?%
The results of the analysis suu'~est that the silver thiosultate ion complexes were relatively pure and corresponded to the formula: Va,H[A~_(S~Ot),] (Silver:
?0.1 I°,o (w/w), Sodium: 17.13% (wiw), Sulfur: ;; 75~% (wiw)).
The calculated yield of silver thiosuftate ion complexes usiny~ the process of this example is 9 3.7%.
;0 SUBSTITUTE SHEET (RULE 26) Process For Making Silver Thiosulfate Ion Complexes Using Silver Chloride When The Ratio Of Thiosulfate Ions To Silver Ions Is Equal To 2-to-1 This example illustrates the process for producing silver thiosulfate ion complexes when the ratio of thiosultate ions to silver ions is equal to ?-to-I. The silver thiosulfate ion complexes were isolated throu~~h the use of a biphasic separation.
In this example, silver thiosulfate ion complexes were produced by first making a silver chloride precipitate in an aqueous solution by mixing_ 10 ml of a silver nitrate (Aldrich;
deionized water as the diluent) solution ( I mmol/ml) with 10 ml of a sodium chloride (Aldrich; deionized water as the diluent) solution ( I mmol/ml) in a 100 ml specimen container. To this silver chloride precipitateiaqueous solution was added 20 rnl of a sodium thiosulfate (Columbus: deionized water as the diluent) solution ( i mmol/ml).
The resulting_ mixture was agitated by shakings the container until all of the silver chloride precipitate was I s dissolved.
Thereafter. the silver thiosulfate ion complexes were separated by addin'= s0 ml of acetone to the container. Upon addition of the acetone. the solution became cloudy and separated into two separate phases. The nvo phases were separated into individual containers using a pipet. The phase containin!, the silver thiosulfate ion complexes was treated by ''0 uddin~_ >0 ml of acetone to make tire silver thiosulfate ion complexes essentially anhydrous.
.-otter sittings overniy~ht, the silver thiosultate ion complexes were in the t'orm of a pure white solid material. Thereafter. the solvent was decanted and the white Solid was dried in an oven ((>?°C) and aground to a tine white powder tisin~; a mortar and pestle. The wei~,ht of the dried silver thiosulfate ion complexes was 3.07 <drams.
The resultin~~ silver thiosulfate ion complexes material was analyzed for silver, sodium and sulfur usin~~ an Inductively Coupled Plasma (ICP; described above). The analysis ~~ave the tollowin~T results:
S i lver 25%
Sodium 17%
_;c) Sulfur 30%

SUBSTITUTE SHEET (RULE 26) The results of the analysis indicate that the silver thiosulfate ion complexes were relatively pure corresponding with the following theoretical formula:
Na,[Ag(S,O,)~]~2H.,0.
(Silver: ?4.7% (w/w), Sodium: 15.78% (w/w), Sulfur: X9.3% (w/w)).
The calculated yield of makin<~ silver thiosulfate ion complexes using the process of this invention is 90.8%.
EXAIViPLE 3 Process For Making Silver Thiosulfate ton Complexes Usin;> Silver Chloride When The Ratio Of Thiosulfate Ions To Silver tons is Less Than 2-to-1 This example further illustrates the process for producin~, silver thiosulfate ion complexes when the ratio of thiosulfate ions to silver ions is less than 2-to-I. .-~s in the preceding_ example, the silver thiosulfate ion complexes were isolated through the formation of a precipitate rather than a biphasic separation.
I 5 In this example, silver thiosulfate ion complexes were made by tirst making a silver chloride precipitate in an aqueous solution by mixing 10 ml of a silver nitrate (Aldrich;
deionized water as the diluentl solution ( I mmol/ml) with ''0 ml of a sodium chloride (Aldrich; deionized water as the diluent) solution ( 1 mmol/ml) in a 100 ml specimen container. To this silver chloride precipitate/aqueous solution was added I 5 ml of a sodium ~0 thiosulfate (Columbus; deionized water as the diluent) solution ( I
mmol/ml). The resultin!s mixture was a<~itated by shakin~l the container until all of the silver chloride precipitate was dissolved.
Thereafter, the silver thiosulfate ion complexes were precipitated from the solution by oddin~_ ~0 ml of acetone to the container. The precipitated silver thiosuifate ion completes were in the form of a pure white solid material. The solvent was decanted and the white solid was dried in an oven (62°C) and ~,~round to a tine white powder using a mortar and pestle.
The silver thiosulfate ion complexes were analyzed for silver. sodium and sulfur usin~~
an Inductively Coupled Plasma ( ICP: described above) The analysis ~,ave the following=
.,0 results:

SUBSTITUTE SHEET (RULE 26) Silver Sodium 14%
Sulfur 29%
The results of the analysis indicate that the silver thiosulfate ion complexes were relatively pure corresponding with the following theoretical formula Na,[Ag,(S~O,),,J~H_,O.
(Silver: 32.6% (w/w) , Sodium: 13.9% (w/w), Sulfur: 29.0% (w/w}).

Process For Making Silver Thiosulfate Ion Complexes Usin~~ Silver Bromide In makinz the aqueous solution of silver thiosulfate ion complexes. the preferred silver halide is silver chloride (Examples I-3): this example illustrates that other silver halides may be used.
t > In this example, the silver thiosulfate ion complexes were produced by first making a silver bromide precipitate in an aqueous solution (hereafter. "silver bromide precipitate/aqueous solution") by miring, 2 ml of a silver nitrate (Aldrich:
deionized water as the diluent) solution ( 1 mmol/ml) with 2.? ml of a sodium bromide (Aldrich;
deionized water as the diluent) solution ( I mmol/ml) in a ~0 ml beaker. To this silver bromide ?0 precipitate/aqueous solution was added 6.0 ml of a sodium thiosulfate (Columbus; deionized water as the diluent> solution ( 1 mmol/ml). Tl~e resultin~_ mixture was a~sitated (v stirrin!, until all of the sodium bromide precipitate was dissolved.
The silver thiosulfate ion complexes were separated by addin~~ X0.0 ml of acetone to the container. Upon addition of the acetone, the solution separated into two phases. The '_'S phase containin<, the silver thiosulfate ion complexes was collected and treated by addin~= 7.0 ml ethyl alcohol and ~.0 ml of acetone to make the silver thiosulfate ion complexes anhydrous. after sitting overnight. the silver thiosulfate ion complexes were in the tone of a white solid material at the bottom of the container. The solvent was decanted and the w ~f~ite solid was dried in an oven (62°C) and v~round to a tine white powder using a mortar and s0 pestle. The resultin'~ weight of the dried silver thiosulfate ion complexes was 0.88 V;.

SUBSTITUTE SHEET (RULE 26) EXANtPLE 5 Process For Making Silver Thiosulfate Ion Complexes Devoid Of A Phase Separation Procedure To illustrate the importance of makin<~ silver thiosulfate ion complexes using the processes of this invention, 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 'heater than 2-to- I .
This comparison process was performed by first making a silver chloride precipitate in IO an aqueous solution (hereafter, "silver chloride precipitateiaqueous solution") by mixing 2 ml of a silver nitrate (Aldrich; deionized water as the diluent) solution ( f mmol/ml) with 2.2 ml of a sodium chloride (Aldrich: deionized water as the diluent) solution ( l mmol/ml) in a ~0 ml beaker. To this silver chloride precipitate/aqueous solution was added 6.0 mi of a sodium thiosulfate (Columbus; deionized water as the diluent) solution ( I mmol/ml).
The resulting I s mixture was agitated by stirrings until all of the sodium chloride precipitate was dissolved.
The resulting silver thiosulfate ion complexes solution was placed in a convection oven at ~2 °C overni~~ht 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.
'0 II. COMPOSITIONS CONT;~INING SILVER TIiIOSIJLfATE ION
(_'OMPLE\ES
EXAI\~tPLE 6 =' Stable Antimicrobial Composition - PEG Base The previous examples were directed at processes for makin« silver thiosulfate ion complexes. This example, as well as Examples 7-9 that follow. compare various antimicrobial compositions containin~~ tire silver thiosulfate ion complexes.
In this example. a s0 silver-based antimicrobial composition was produced in a PEG base.
Speciticallv. ~0 ~~ of a poivethvlene y~lycol (PEG) base (PEG 600:PEG 1000 = 0 3:0.7: Aldrich) was melted. While cooling, 0.47 '; of the silver thiosulfate ion complexes of Example I were stirred into the melted PEG base. The stirrings vsas continued until the silver thiosulfate ion complexes were SUBSTITUTE SHEET (RULE 26) homo~~eneously suspended. While stirrin<" the melted PEG/silver thiosulfate ion complexes composition was cooled to produce a semisolid base. The amount of silver in this silver-based antimicrobial composition was equivalent to 0.5°,o silver nitrate.

Stable Antimicrobial Composition - Aquaphor"
To further illustrate a silver-based antimicrobial composition of this invention, 40 g of Aquaphor~ Cholesterolized Absorbent Eurcerite Ointment Base was melted.
AquaphorN is a I (7 stable, neutral. odorless, anhydrous ointment base (Belersdorf Inc).
While cooling, I .?6 ~ of the silver thiosulfate ion complexes of Example I were stirred into the melted Aquaphor"
base. The stirring_ was continued until the silver thiosulfate ion complexes were homo''eneouslv suspended. While stirrin<_, the melted Aquaphor"/silver thiosulfate ion complexes composition was cooled to a semisolid base. The amount of silver in this silver-I S based antimicrobial composition was equivalent to I .0°,r silver nitrate.

Stable Antimicrobial Composition - White Petrolatum USP
?0 To illustrate an alternative silver-based antimicrobial composition of the present invention. 40 ~~ of white petrolatum USP (Roundv~s Pure Petroleum Jelly. White Petrolatum ElSP) was melted. \Vhile coolin~~, '.5? '~ ot~ the silver thiosulfate ion complexes ot~ Example 1 were stirred into the melted wf~ite petrolatum base. The stirrin<, was continued until the silver thiosultate ion complexes were homo'~eneouslv suspended. lVhile stirring, the melted white petrolatumisilver thiosulfate ion complexes composition was cooled to a semisolid base. The amount of silver in this silver-based antimicrobial composition was equivalent to 2.0°,'o silver nitrate.

Stability Of Anhydrous rind Hydrated Antimicrobial Compositions This example illustrates the instability of hydrated silver-based antimicrobial compositions comprisin~1 silver thiosulfate ion complexes. The experiments of this example SUBSTITUTE SHEET (RULE 26) WO 98/0b260 PCT/US97/14b97 utilize the compositions produced in Examples C-8. as well as a composition containing a different base. Velvachol ~ Cream.

PEG Base Plus Water r~ hydrated silver-based antimicrobial composition was made where the composition base was PEG. The composition was made by mixin~~ 9 « of the silver-based antimicrobial composition of Example 6 with I ml of water. This silver-based antimicrobial composition contained approximately 10% water by weight.

-~quaphor" Plus Water ,A hydrated silver-based antimicrobial composition was made where the composition base was Aquaphor" The composition was made by mixing- 9.5 ~= of the silver-based antimicrobial composition of Example 7 with 0.5 ml of water. This silver-based antimicrobial composition contained approximately s°'° water.

White Petrolatum Plus Water -\ hydrated silver-based antimicrobial composition was made where the composition base was white petrolatum. The composition was made bwnixing 9.s <, of the silver-based '_'S antimicrobial composition of Example 8 with Q.s ml of water. This silver-based antimicrobial composition contained approximately ~°% water.

SUBSTITUTE SHEET (RULE 26) Velvachol Cream A silver-based antimicrobial composition containing 0.47 ~ of the silver thiosulfate ion complexes of Example 1 were stirred into 20 g of Velvachol "' (Owen Laboratories).
Velvachol~ is a neutral. hydrophilic 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 G, 7, 8,and 9A-D
was evaluated over time. The stability of the compositions was determined by measuring the change of color, if any. when the compositions were stored in transparent containers in ambient li~lht. Chan<~e of color indicates decomposition of the silver thiosulfate ion complexes. Table I below indicates the initial color of each composition and the change in color on days 7 and 14 and after I month.
I S .As depicted by the results of this study, the silver-based compositions described in Examples 6, 7 and 8 demonstrated no chan~~e in color. In contrast, the hydrated silver-based compositions, Examples 9A-D, demonstrated major chancres in color. some after only 7 days (Examples 9B and 9D): all of these compositions, i.c.~., Examples 9A-D.
changed from their initial color to a brown or black color. Thus, the results of this study indicate that the anhydrous compositions of this invention were stable. while the analo~~ous hydrated samples were not.
-_s7-SUBSTITUTE SHEET (RULE 26) Stability Of Silver-Based Comnnsi~innc S APpear:~nce l Of Ointment amp e Dxv Day 7 Day 14 Month Month Month Eaantplc (~: PEG GrayishNo No No No No Composition White Change Change Change Change Change Ex:1t11pIC 7: Slight No NO NO No No Aquaphor"

Composition Yellow Change Change Chance Change Change Eaamplc H: White Slight No No No No No Petrolatum CotnpositionYellow Change Change Change Change Change Eaample'lA: HydratedGrayishNo Slight Brown Brown Black Tan PEG Composition White Chance Eaantplc'JB: HydratedSlight Slight Brown Dark Black Black Aquaphor"' CompositionYcllon Tnn Brown Exantplc'JC': Sliglu No T:m Black Black Black Hydrated \Vltitc I'ctrolatumY'cllowC'hanr;c Composition Exantple'JD: Velvachol~White Tan Brown Black Black Black Crc:tm ?0 III. .-~NTIMICROI31AL ACTIVITY OF COMPOSITIONS CONTAINING
SILVER TH10SULFATE ION COMPLE\ES
EXAMPLE l0 Antimicrobial ,Activity Of Silver Tltiosulfate Ion Complexes ,;
The iir t~iwn antimicrobial activity was evaluated by tindin~_ the minimum inhibitory concentration for the powder of silver thiosulfate ion complexes from Example _s. This powder was tested in serial two-told dilutions ranging_ from I.~)5 to 250 tt~/ml. Broth microdilution was performed in serial dilution of the silver thiosulfate powder in tryptic soy s0 broth (Ditto). Each dilution was inoculated with 0.005 ml of a 24-hour ~,rowth of a microbe f 10' to 10' CFU/ml). After the dilutions were incubated at ,7°C
overnit-rht, the lowest dilution of the silver thiosulfate ion complexes that was without evidence of ~~rowth (i.c~.. was not cloudy) was the minimum inhibitory concentration (>\11C) reported in terms of l.t~.:/ml.
The results shown in Table ? demonstrate that the silver thiosulfate ion complexes s5 powder has antimicrobial activity a~,ainst both ~~ram (+) and ~~ram (-) microbes (Difco).

SUBSTITUTE SHEET (RULE 26) Isolate ATCC Accession Silver Thiosolt:lte Ion Complexes No. (~c~,/ml) .5'. nlrreu.v ?i9~3 ' 1.95 .~~. C'l7lC~C'1'llllll(.1'I~2?5 ! I.r)j l.. call Z~~)22 < 1.95 l'. nerr~t'inn.vn2753 < I.')s EXAMPLE l t t 0 Antimicrobial Activity Of Silver-Based Compositions The antimicrobial activity of the silver-based compositions of Eramples ~. 7.
and 8 were evaluated usin<~ a zone of inhibition (ZOI) protocol In this ZOI
protocol. I cm-diameter discs (Whatman Filter Paper, Quantitative l ) were coated with a thin layer of the I ~ compositions from Examples 6. 7. and 8. These coated discs were placed on )V1ueller Hinton fvledium (MHIVI; Difco) with lawns of,f. ur~rm.~~ (ATCC '_'923; ?4 hours ~~rowth from MHM
plate). :otter incubation at 3G °C for 18 hours. the size of the zone of ~Trowth inhibition was measured' (in mm j from the ed_'e of the disc to the point of microbial urowth. Table 3 shows the ZOI results for each composition on Day I and at one month.

~ntimicrobi:vl Activim Of Silver-Based C'onlnositions Zone of Inhibition S Imml 1.5'. urtrcusl l amp e Day I 1 Month Exanlplc c,: PEG CompositionI s.~ mnl I-t.lt mm Exanlplc 7 .~quapilor"

C OIIlpOS1110I1 I (1,11 111111 I .s.1) Illlll Exaulplc 1: White Pctroiallnn COIIIpOS1l1011 111.1) 111111 Il).~ 111111 .-~s can be seen by the results of this study, the silver-based compositions of this .,0 invention (E~camples 6. 7 and 8) demonstrated wood antimicrobial activity that was stable for the duration of the study period. That is to say. the size of the zone of growth inhibition was essentially unchan~~ed over the one month period.

SUBSTITUTE SHEET (RULE 26) IV. USE OF SILVER THIOSULFATE ION COMPLEXES IN MEDICAL
DEVICES

Foam Dressin~_=s Containing, Silver Thiosulfate Ion Complexes ,as previously indicated. 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. In this example, the complexes were incorporated into the matrix durin'_ the manufacturing of the polymer matrix.
-~ foam dressin~~ was produced by first dissolvin~~ 0.~4 ~_= of silver thiosulfate ion completes powder in 150 ml of a 0 5°o Platonic L-62 (l3r~SF) ac)ueous solution. This solution was the mixed with 140 ~, of a polyurethane prepolvmer (Hypo) 2002, Hampshire) in I S a I-liter disposable plastic beaker The resultin'1 mixture instantly be<,an to react to form a foam. :otter 10 minutes the foam was removed from its container and sliced to produce individual foam dressinss (approximately 7.5 cm in diameter The slices of foam dressings were dried at 50°C in a dark convection oven.
These foam dressin<,s were light stable and antimicrobially active. In this example and '_'0 Examples 13-18 that follow, the terms "li';ht stable." "photostable," and the like mean that the samples did not discolor after 7'_' hours of exposure to ambient room li~sht.
In this example and Examples I ,-13 that follow. the term "antimicrobiallv active" means that a small piece 1 nominally I cm x 1 cm or I cm strands in the case of al«inate fibers I
produced zones of inhibition when placed on both a lawn of.f. mrrc-rr.~~ (r~TCC '_'S9?;) and a lawn of l:. c.wli (.~TCC 2593?). The lawns were produced by plating ?4-(tour growth microbes on MHM
plates: after incubation For ?4 hours. each sample was examined to determine whether a zone of inhibition was present This foam dressing,_= can be used for a larvae variety of medical applications, includin~s as an antimicrobial absorptive foam dressings.
s0 SUBSTITUTE SHEET (RULE 26) Foam Dressing Containing Silver Thiosulfate Ion Complexes This example further illustrates the use of silver thiosulfate ion complexes to prepare a medical device made up of a foam polymer matrix. In contrast to the previous example, the silver thiosulfate ion complexes were incorporated into polymer matrix following the matrix' manufacture.
In this example, a foam dressing (Hvdrasorb ~ Sponge Foam Dressing ( 10 cm x cm); Avitar) was submerged in an aqueous solution containing silver thiosulfate ion complexes powder from Example 3 (0. 1 ~ per liter). The foam dressing samples were removed and dried at SO°C in a convection oven. These silver thiosulfate ion compiexes-containin<s foam dressin<~s were li<sht stable and antimicrobiallv active. As indicated in the previous example. these foam dressin~~s can be used for a lar~_e variety of medical applications. including as an antimicrobiai absorptive foam dressin'as.
IS
EXAV1PLE t4 Hydrocolloid Dressing Containin~_ Silver Thiosulfate Ion Complexes This example illustrates the use of the silver thiosulfate ion complexes to prepare a ?0 medical device which is made up of a hvdrocolloid absorbent polymer matrix.
In this example. the complexes were incorporated into the matrix Burin<s the manufacturing= of the polymer matrix.
-~ hydrocolioid dressin~_ containin~T silver thiosulfate ion complexes was produced by first thorou~_hly mixing 0. 157 ~; of silver thiosulfate ion complexes powder (mesh l00) from ?5 Example I with l0.0 '; of sodium carboxvmethvl cellulose (Aldrich).
Thereafter. ~! <, of this treated carboxvmethyl cellulose was mixed thorou~ahfy with ~ '; of a polyurethane prepolvmer (Aquapol 035-0031. Cook Composites and Polymers). This mixture was then pressed between a polyurethane film and a silicone-treated hvdrocoiloid matrix and was allowed to cure for 2=1 hours.
s0 The resulting silver thiosulfate ion complexes-containin~~ hvdrocolloid dressing was photostable and antimicrobially active. This type of dressing is useful on exudating, malodorous wounds.
SUBSTITUTE SHEET (RULE 26) Hydrocolloid Dressing Containing: Silver Thiosuifate Ion Complexes This example further illustrates the use of silver thiosuifate ion complexes of this invention to prepare a medical device which is made up of an hydrocolloid absorbent polymer matrix. However. in this example the 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 0.157 ~1 of a silver thiosulfate ion complexes powder (mesh >100) from Example i in 10.0 ml of water. To this solution was added 100 g of sodium carboxymethyl cellulose (Aldrich, Milwaukee, W1) which absorbed the solution The treated sodium carboxymethvl cellulose was allowed to dry at room temperature. Thereatter. -1 ~_ of the dried treated carboxvmethvl cellulose was mixed thorou~~hly with 4 V1 of a polyurethane prepolvmer (Aquapol 035-0031. Cook Composites and Polymers). This mixture was then pressed between a polyurethane tilm and a silicone treated 1 ~ liner and was allowed to cure for 2=1 hours.
As with the silver thiosulfate ion complexes-containin~~ hvdrocolloid dressin~~ produced in the precediny~ example. the hvdrocolloid dressing is photostabie and antimicrobialiv active and is useful on exudating, malodorous wounds.
-'0 EXAMPLE IG
-adhesive Films Containing Silver Thiosulfate Ion Complexes This example illustrates the use of silver thiosulfate ion complexes to produce adhesive films. Specifically, a pressure sensitive adhesive (PSA) containing silver thiosulfate ion complexes was produced in this example. Adhesive films are. among other things, especially useful in covering painful abrasive-type skin wounds and partial skin graft sites.
The silver thiosulfate ion complexes-containing PSA was made by mixing 0.25 ~~
of the silver thiosulfate ion complexes powder from Example I in An adhesive solution consisting of 45 '_ of a proprietary medical <,rade acrylic based latex (s8%
solids) (Avery ~0 Dennison. Inc.) and > g polyethylene ~.:lycol (M.W. 600) (.aldrich) was first prepared. Then.
0.?5 '; of the silver thiosulfate ion complexes powder from Example I was mixed with the adhesive solution. forming an adhesive mixture. This adhesive mixture. when coated and dried, produces a tacky. adhesive film.

SUBSTITUTE SHEET (RULE 26) WO 98!06260 PCT/US97/14697 The adhesive film is photostable and antimicrobiallv active. This adhesive film can be laminated to dressing backing materials to produce dressin~Ts which are antimicrobiallv active.
Dressings with the silver thiosulfate ion complexes-containin~1 PSA are especially useful in covering painful abrasive-type skin wounds and partial skin graft sites.

Alginate Materials Containins_~ Silver Thiosulfate Ion Complexes This example illustrates the use of silver thiosulfate ion complexes to produce a medical device which is made up of non-adherent alginate material.
Specifically, the method of this example involves the use of a calcium chloride bath which results in crosslinked al~~inate fibers that incorporate the silver thiosulfate ion complexes.
First. water-swellable aluinate fibers were produced containin'1 silver thiosulfate ion complexes. The alginate fibers were made by using a svrin'~e to inject a s°,'° sodium alginate I S solution (Pronova LV ~1 Sodium al~_inate. Protan) into a bath consisting, of a 10% calcium chloride solution (Aldrich. deionized water as diiuent) containing 0.1 ~;iliter 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).
'_'0 The resulting fibers are photostable and antimicrobiallv active. These fibers can be used to make antimicrobial al<sinate dressing=s and tamponades. -~l~_inate materials containin~~
silver thiosulfate ion complexes are especially useful in coverin<_ painful abrasive-type ,kin wounds and wound ulcers as well as for tilliny~ in deep wounds and cavities.

Alginate Materials Containin<~ Silver Thiosulfate !on Complexes To further illustrate the use of the silver thiosulfate ion complexes of this invention to produce a medical device which is made up on non-adherent al<.:inate material.
this example s0 utilizes a method that does not include a calcium chloride bath.
First. an aqueous solution containing, 0. I y'/liter of a silver thiosulfate ion complexes from Example 3 was prepared. The resulting aqueous solution was then applied to a 9.5 cm O.S cm al~_inate dressing (Steriseal Sorbsan Sur~~ical Dressin~~. Steriseal) by spravinv~ the _ .13 _ SUBSTITUTE SHEET (RULE 26) solution onto the dressings. ~Iternative(y, the silver thiosulfate ion complexes solution can be applied by dipping the alginate dressin'; into the solution. The al~~inate Ebers of the dressing absorbed the applied solution; thereafter, the treated alginate dressin~l was allowed to dry (room temperature).
The alginate dressing was light stable and was antimicrobially active, and, as noted in the preceding example. it is especially useful for malodorous wounds as well as for coverin~~
painful abrasive-type skin wounds and wound ulcers.
V. USE OF SILVER THIOSULFATE ION COMPLEXES IN COMBINATION
WITH OTHER MEDICINAL AGENTS
EXAMPLE l9 Pharmaceutical Composition (~ombinin~~ Vlupirocin With Silver Thiosulfate Ion Complexes To illustrate an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more absents, 0.02 ~; of the silver thiosulfate ion complexes from Example ? were blended into ?.0 g of a mupirocin ointment (Bactroban' ['_'°o mupirocin acid in a PEG base], SmithKline Beecham).
'_'0 The mupirocin ointment is a topical antimicrobial with excellent gram (+) antimicrobial properties. The silver thiosulfate inn comple~ces were blended into the mupirocin ointment by first meltin« the mupirocin ointment and then stirrings the silver thiosulfate ion complexes into the melted ointment. The ointment mas stirred continually until it cooled and resolidified.

Pharmaceutical Composition Combining Mafenide With Silver Thiosulfate Ion Complexes To further illustrate an antimicrobial pharmaceutical composition consisting of a s0 combination of the silver thiosulfate ion complexes of this invention with one or more a~,ents.
0.25 ~_ of mafenide (Si';ma) (y-aminomethvlbenzesulfonamide) and 0.?5 v~ of the silver thiosulfate ion complexes of Example 3 were blended into ?-I.50 g of a PEG
composition ("PEG Composition"); the PEG Composition was produced by melting to~~ether a blend of SUBSTITUTE SHEET (RULE 26) 40% PEG (M.W. 3450) and 60% PEG (M.W. 600). The pharmaceutical composition was produced by first melting the PEC Composition and then stirrin~l in the silver thiosulfate ion complexes and mafenide. The resulting pharmaceutical composition was stirred continually until cooled and resolidified. The resulting pharmaceutical composition has use as a broad spectrum topical antimicrobial.

Pharmaceutical Composition Combining Metronidazole With Silver Thiosulfate Ion Complexes To further illustrate an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more absents. 0.?5 ~1 of metronidazoie (Siv~mal and 0.25 yz of the silver thiosulfate ion complexes of Example _> were blended into 24.50 g of a PEG composition ("PEG Composition");
the PEG
I 5 Composition was produced by melting together a blend of 40% PEG (M.W.
3450) and 60%
PEG (M.W 600). The pharmaceutical composition was produced by first meltin~~
the PEG
Composition and then stirrin~,~ in the silver thiosulfate ion complexes and metronidazole. The resulting pharmaceutical composition was stirred continually until it cooled and resolidified.
This pharmaceutical composition has use as a broad spectrum topical antimicrobial and is ?0 especially useful in the treatment of malodorous wounds.
CXAh~IPLE 22 Pharmaceutical Composition Combinin~, Chlorhexidine With Silver Thiosulfate lon Complexes ,;
To further illustrate an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more a<.~.ents. 0.25 ~ of chlorhexidine diacetate hydrate (Aldrich) and 0.35 ~1 of the silver thiosulfate ion complexes of Example 3 were blended into 24.5 y~ of Aquaphor" (a cholesterolized ,0 absorbent Eucerite" ointment base produced by Belersdorf Inc.). The pharmaceutical composition was produced by first meltiny~ the Aquaphor" ointment and then stirrin<' in the silver thiosulfate ion complexes and chlorhexidine. The resulting=
pharmaceutical composition SUBSTITUTE SHEET (RULE 26) was stirred continually until it cooled and resolidified. This pharmaceutical composition has use as a broad spectrum topical antimicrobial.

Pharmaceutical Composition Combinin~_ Triciosan With Silver Thiosulfate Ion Complexes To further illustrate an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more f 0 medicinal agents, 0.50 ~ of triclosan (Irgasan DP 300, Ciba-Geigy, Greensboro, NC) and 0.50 ~; of the silver thiosulfate ion complex of Example 3 were blended into 24.00 ~ of Aquaphor"
(a cholesterolized absorbent Eucerite" ointment base produced by Belersdorf inc.). The pharmaceutical composition was produced by tirst meltin~~. the Acluaphor"
ointment and then stirring in the silver thiosulfate ion complexes and triclosan. The resulting pharmaceutical I S composition was stirred continually until it cooled and resolidified. This pharmaceutical composition has use as a broad spectrum topical antimicrobial.
EXAMPLE 2~t Pharmaceutical Composition Combining Hydrocortisone '-0 With Silver Thiosulfate Ion Complexes To further illustrate an antimicrobiai pharmaceutical composition consistin~, of a combination of the silver thiosulfate ion complexes of the present invention with one or more ay.:ents. 0.50 ~ of Hydrocortisone ? I-Acetate (Sigma) and 0.50 '~ of the silver thiosulfate ion '_'s complexes of Example 3 were blended into 2.00 '; of Aduaphor" (a cholesterolized absorbent Eucerite~ ointment base produced by Belersdorf Inc.). The pharmaceutical composition was produced by tirst meltin~~ the Ac~uaphor' ointment and then stirrin_1 in the silver thiosulfate ion complexes and hydrocortisone. The resulting pharmaceutical composition was stirred continually until it cooled and resoliditied. This pharmaceutical composition has use topically 30 as an anti-inflammatory and an anti-itch treatment which also has antimicrobial properties to prevent a secondary infection when applied topically to blistered wounds caused by dermatitis.
insect bites. poison ivy, etc.

SUBSTITUTE SHEET (RULE 26) Pharmaceutical Composition Combinin~_ Lidocaine With Silver thiosulfate Ion Complexes To further illustrate an antimicrobial pharmaceutical composition consisting of a combination of the silver thiosulfate ion complexes of the present invention with one or more av.:ents. 0.50 ~ of lidocaine (Sigma) and 0.50 ~ of the silver thiosulfate 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 (MI.W.). The pharmaceutical composition was produced by first melting the PEG
Composition and then stirrinv~ 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 secondary infection when applied to exposed tissues or wounds.
t~

Pharmaceutical Composition Combining Pramoxine With Silver Thiosulfate ion Complexes .0 To further illustrate an antimicrobial pharmaceutical composition consisting, of a combination of the silver thiosulfate ion complexes of the present invention with one or more absents. 1.00 ~, of pramoxine hydrochloride (Si«ma) and 0 ~0 ~~ of the silver thiosulfate ion complexes of Example _i were blended into ?3.5U ~.; of PEG composition ("PEG
CVO IIIpUSILIOn"); the PEG Composition was produced by meltin« touether a blend of 40°..o PEG
(M.W. 3450) and 60% PEG (N1.W O00). The pharmaceutical composition was produced by first meltin'T the PEG Composition and then stirrin~~ in the silver 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 properties to prevent a secondary infection when applied to ~0 exposed tissues or wounds.
From the above, it should be evident that the present invention provides for silver-based antimicrobial compositions and processes for makin~l such compositions that are SUBSTITUTE SHEET (RULE 26) 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 fore~roiny~ 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 departins: from the spirit or scope thereof. .

SUBSTITUTE SHEET (RULE 26)

Claims

CLAIMS:

1. An antimicrobial composition comprising carrier-free silver thiosulfate ion complexes in a base.

2. The composition of claim 1, wherein said silver thiosulfate ion complexes are homogeneously suspended in said base.

3. The composition of claim 1 or 2, wherein said base is anhydrous.

4. The composition of claim 1, 2 or 3, wherein the concentration of said silver thiosulfate ion complexes within said base is from 0.01% to 30% (w/w).

5. The composition of claim 1, 2 or 3, wherein the concentration of said silver thiosulfate ion complexes within said base is from 0.1% to 3.0% (w/w)

6. The composition of claim 1, 2 or 3, wherein the concentration of said silver thiosulfate ion complexes within said base is from 0.2% to 1.5% (w/w).

7. The composition of any one of Claims 1 to 6, wherein said base is selected from the group consisting of polyethylene glycol, Aquaphor®, and white petrolatum.

8. The composition of any one of claims 1 to 7, wherein said silver thiosulfate ion complexes are derived from the complexation of a silver cation from silver halides with anions .

9. The composition of claim 8, wherein said silver halide comprises silver chloride and said anions comprise sodium thiosulfate salts.

10. The composition of claim 9, wherein the molar ratio of the thiosulfate anions too silver cations is at least 1:1.

11. The composition of claim 9, wherein the molar ratio of thiosulfate anions to silver cations is at least 1.3:1.

12. A pharmaceutical mixture, comprising:
a) a medicinal agent: and b) carrier-free silver thiosulfate ion complexes.

13. The pharmaceutical mixture of claim 12, further comprising an anhydrous base.

14. The pharmaceutical mixture of claim 13, wherein said base is selected from the group consisting, of polyethylene glycol, Aquaphor®, and white petrolatum.

15. The pharmaceutical mixture of claim 12, 13 or 14, wherein the concentration of said silver thiosulfate ion complexes in said pharmaceutical mixture is from 0.01% to 30% (w/w) .

16. The pharmaceutical mixture of claim 12, 13 or 14, wherein the concentration of said silver thiosulfate ion complexes in said pharmaceutical mixture is from 0.1% to 3.0% (w/w) .

17. The pharmaceutical mixture of claim 12, 13 or 14, wherein the concentration of said silver thiosulfate ion complexes in said mixture is from 0.2% to 1.5% (w/w).

18. The pharmaceutical mixture of any one of claims 12 to 17, wherein said medicinal agent of said pharmaceutical mixture is an antimicrobial agent.

19. The pharmaceutical mixture of claim 18, wherein said antimicrobial agent is selected from the group consisting of acyclovir, chloramphenicol, chlorhexidine, chlortetracycline, itraconazole, mafenide, metronidazole, mupirocin, nitrofurazone, oxytetracycline, penicillin, and tetracycline .

20. The pharmaceutical mixture of any one of claims 12 to 17, wherein said medicinal agent of said pharmaceutical mixture is a steroid.

21. The pharmaceutical mixture of claim 20, wherein said steroid is selected from the group consisting of betamethasone benzoate, betamethasone valerate, desonide, fluocinolone acetonide, halcinonide, hydrocortisone, and metandienone .

22. The pharmaceutical mixture of any one of claims 12 to 17, wherein said medicinal agent of said pharmaceutical mixture is an anesthetic.

23. The pharmaceutical mixture of Claim 22, wherein said anesthetic is selected from the group consisting of benzocaine, dibucaine, lidocaine, pramoxine hydrochloride and tetracacine.

24. A method of imparting antimicrobial protection, comprising a) providing:
i) a product, and ii) 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 product.

25. The method of claim 24, wherein said product is solid.

26. The method of claim 24 or 25, wherein said product is a medical device.

27. The method of claim 26, wherein said medical device comprises a matrix.

28. The method of claim 27, wherein said matrix is a polymer.

29. The method of claim 28, wherein said polymer is anhydrous.

30. The method of claim 24, wherein said product is a personal care product.

31. The method of claim 30, wherein said personal care product is selected from the group consisting of lipsticks, lipgloss, 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.

32. The method of claim 30, wherein said personal care product is selected from the group consisting of combs, brushes, sponges, cotton swabs, cotton balls, razors, dental flosses, dental tapes, sunscreens, moisturizers, tampons, sanitary napkins, panty shields, diapers, baby wipes, facial tissues and toilet tissues.

33. A device, comprising a medical device coated with an antimicrobial composition comprising carrier-free silver thiosulfate ion complexes, wherein said medical device is selected from the group consisting of medical implants, wound care devices, urinary catheters, body cavity devices and personal protection devices.

34. The device of claim 33, wherein said silver thiosulfate ion complexes comprise an anhydrous polymer matrix.

35. A method of treating or preventing a microbial infection, comprising:
a) providing:
i) a subject, said subject either infected or at risk of infection by a topical microbial infection, and ii) an effective amount of carrier-free suspended silver thiosulfate ion complexes in a base to form a pharmaceutical mixture; and b) administering the effective amount of the carrier-free suspended silver thiosulfate ion complexes in a base to the subject.

36. The method of claim 35, wherein said base is anhydrous.

37. The method of claim 35 or 36, wherein said base is selected from the group consisting of polyethylene glycol, Aquaphor®, and white petrolatum.

38. The method of any one of claims 35 to 37, wherein the concentration of said silver thiosulfate ion complexes in said pharmaceutical mixture is from 0.01% to 30% (w/w).

39. The method of any one of claims 35 to 37, wherein the concentration of said silver thiosulfate ion complexes in said pharmaceutical mixture is from 0.1% to 3.0% (w/w).

40. The method of any one of claims 35 to 37, wherein the concentration of said silver thiosulfate ion complexes in said mixture is from 0.2% to 1.5% (w/w).

41. The method of any one of claims 35 to 40, wherein said pharmaceutical mixture further comprises a medicinal agent.

42. The method of claim 41, wherein said medicinal agent is an antimicrobial agent.

43. The method of claim 42, wherein said antimicrobial agent is selected from the group consisting of acyclovir, chloramphenicol, chlorhexidine, chlortetracycline, itraconazole, mafenide, metronidazole, mupirocin, nitrofurazone, oxytetracycline, penicillin, and tetracycline.

44. The method of claim 41, wherein said medicinal agent of said pharmaceutical mixture is a steroid.

45. The method of claim 44, wherein said steroid is selected from the group consisting of betamethasone benzoate, betamethasone valerate, desonide, fluocinolone acetonide, halcinonide, hydrocortisone, and metandienone.

46. The method of claim 41, wherein said medicinal agent of said pharmaceutical mixture is an anesthetic.

47. The method of claim 46, wherein said anesthetic is selected from the group consisting of benzocaine, dibucaine, lidocaine, pramoxine hydrochloride and tetracacine.

48. Use of the antimicrobial composition of any one of claims 1 to 11, for treating or preventing a microbial infection in a subject, said subject either infected or at risk of infection by a topical microbial infection.

49. Use of the pharmaceutical mixture of any one of claims 12 to 23, for treating or preventing a microbial infection in a subject, said subject either infected or at risk of infection by a topical microbial infection.