Patent 6,923,990

The present invention relates to new silver-ion super-complex compositions. More particularly, the present invention describes silver-ion super-complex compositions comprising a silver-thiosulfate ion complex further complex with a primary, secondary or tertiary amine. These silver-ion super-complex compositions are stable in a saline environment and have improved solvent miscibility.

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to silver ion compositions and processes for making such compositions effective as antibacterial, antiviral and/or antifungal agents. In one embodiment, the invention relates to a method of producing silver thiosulfate ion compositions, coating medical devices comprising such compositions. In a preferred embodiment, the present invention relates to carrier-free aqueous silver thiosulfate complexes stabilized by amines.

The present invention also relates to amine stabilized silver thiosulfate ion complexes that have improved water stability (i.e., maintaining antimicrobial activity in an aqueous environment). More particularly, the present invention describes amine stabilized silver thiosulfate ion complexes comprising a silver thiosulfate ion complex and an amine stabilizing agent, wherein said stabilized silver-ion complex composition is carrier-free and has increased stability when dissolved in an aqueous solution. Still further, the present invention describes amine stabilized silver thiosulfate ion complexes comprising a silver thiosulfate ion complex and an amine stabilizing agent and a preservative for said amine stabilizing agent. These compositions are useful to produce medicinals that have antibacterial, antiviral and/or antifungal activity. In one embodiment, amine stabilized silver thiosulfate ion complexes can be used to produce medical devices, such as, but not limited to, a wound dressing, an ostomy appliance, an incontinence device, and the like.

The antiseptic activity of silver compounds is a known property. Although it is not necessary to understand the mechanism of an invention, it is believed that the bacteriostatic and fungistatic effect of the silver thiosulfate complexes contemplated by the present invention is caused by the silver ion. For example, one compound known in the art that has been clinically useful is silver nitrate. Aqueous silver nitrate solutions of 0.5%-1% show disinfectant properties and are used for preventing infections in burns or for prophylaxis of neonatal conjunctivitis. Another silver compound, silver sulfadiazine, has an pronounced antibacterial effect. It is known in the art that the inherent antibacterial property of sulfadiazine ion is enhanced by complexation with a silver ion. In contrast to silver nitrate, the solubility of silver sulfadiazine is low, and hence, both the silver ion and sulfadiazine ion are present in low concentrations but may be present over a longer period of time. Silver sulfadiazine is extensively used in the treatment of wounds, in particular burns, under the trademarks Silvadene® and Flamazine®. Silver-protein combinations are yet other antiseptic formulations which have been used in low concentrations as eye drops.

Bacteriostatic silver ion compositions are marketed in various medical devices. One example is a wound dressing having an activated charcoal cloth dressing (Actisorb®, Johnson & Johnson). Another example is a wound dressing of modified pigskin impregnated with a soluble silver compound intended for treatment of burns (EZ-Derm®, Genetic Laboratories).

A specific advantage in using the silver ion as bacteriostatic agent is the general lack of formation of bacterial tolerance or resistance to the compound. This is in contrast to many types of antibiotics (i.e., development of "antibiotic resistance"). A major drawback of using ionic silver for bacteriostatic purposes is the marked degradation (i.e., appearance of a dark stain) of the silver ion complex. It is believed that this marked degradation is mediated by a chemical reduction of the silver ion to free silver. Such staining has been reported to give potentially permanent pigmentation of the skin, the so-called argyria. It is commonly recognized that silver containing compounds will also discolor under the influence of light and or heat. Additionally, radiation sterilization protocols may lead to silver ion composition color changes, irrespective of its use as a solution, cream, gel or on a medical device. These phenomena result in the avoidance of silver ion complexes by those skilled in the art when contemplating medical device sterilization. Furthermore, such medical or cosmetic products often comprise antibacterial compositions wherein discoloration is highly undesirable or unacceptable to the user.

Recently, the principles of antimicrobial photostable metal-based compositions have been disclosed. Capelli, U.S. Pat. No. 5,326,567, Oka, U.S. Pat. No. 5,429,819; and Nishino, U.S. Pat. No. 5,510,109 (all incorporated herein by reference). Specifically, the '567 patent discloses a unique "host-guest" relationship between silver ions and acyclic polyethers accomplished through the use of excess of halide ions. Additionally, the '819 patent describes a porous particulate carrier requirement for photostable compositions comprising a complexation of silver ion with a thiosulfate salt. More recently, a photostable composition comprising a complex of silver ion with a thiosulfate salt has been disclosed that does not require a porous particulate carrier. Capelli, U.S. Pat. No. 6,093,414 (hereby incorporated by reference). The silver compositions of the '414 patent are unusually stable in the presence of both heat and light. However, in the presence of water, or any aqueous solution containing bases or polymers, even a silver thiosulfate ion complex undergoes marked degradation. Although it is not necessary to understand the mechanisms involved for successful use of the invention, it is believed that this silver thiosulfate ion complex degradation occurs because the thiosulfate ligand component of the silver thiosulfate ion complex experiences a chemical breakdown. The effect of this chemical process results in an overall destabilization and degradation of the silver thiosulfate ion complexes with concomitant loss of medicinal activity.

Amine Stabilization of Silver Ions

The improvement of silver ion composition stability in an aqueous environment is known by the formation of a complex with a primary, secondary or tertiary amine. Pedersen, U.S. Pat. No. 6,468,521 (herein incorporated by reference). Although the '521 patent discloses that the production of these amine stabilized silver complexes utilize " . . . readily soluble salts like the nitrate, lactate, or acetate or more heavily soluble salts like the halogenides such as the chloride or bromide.", there is no teaching regarding the stability of the amine stabilized silver complexes in an aqueous environment particularly wherein the aqueous environment contains a significant amount of sodium chloride. In fact, the silver ion complexes, as taught by the '521 patent, are unstable in the presence of sodium chloride ions (e.g., ions derived from dissolved sodium chloride). That is to say, in aqueous solutions containing chloride ions, the silver in the silver ion complex immediately precipitates as silver chloride. Silver chloride retains a minimal amount of antimicrobial activity due to the low dissociation rate of silver ions from silver chloride. However, the antimicrobial activity of silver chloride is poor relative to soluble silver salts or silver ion complexes.

The stability of silver ion complexes in an environment containing sodium chloride is relevant because of the importance of silver ion complexes in clinical medicine. Bodily fluids found in a typical wound environment contain a substantial amount of chloride ions. As a result, the silver ion complex compositions contemplated by the '521 patent will precipitate in the form of silver chloride when used in a wound environment. As a result, this type of silver composition has minimal in situ antimicrobial activity.

In one embodiment, the present invention contemplates a stabilized silver ion composition having antibacterial, antiviral and/or antifungal activity comprising an amine stabilized silver thiosulfate ion complex wherein said stabilizing amine is selected from the group consisting of a primary amine, a secondary amine and a tertiary amine. Preferably, stabilizing amines contemplated by various embodiments of the present invention are lower alkyl amines or amino alcohols having a free lone pair of electrons. In one embodiment, a lower alkyl stabilizing amine is selected from the group comprising mono-, di- or trimethyl, ethyl, propyl or butyl amines or mixtures thereof. In another embodiment, a lower alkyl stabilizing amino alcohol is selected from the group comprising mono-, di- or trimethyl ethyl or propyl aminoalcohols or mixtures thereof. In one embodiment, a stabilizing amine is trihydroxymethyl-aminomethane (THAM).

Amine Stabilization of Silver Thiosulfate Complexes

Specifically, silver thiosulfate ion complexes contemplated by this invention are obtained by adding a silver halide, e.g., silver chloride, to an aqueous solution and then adding a thiosulfate salt (e.g., for example, sodium thiosulfate) to the solution. Preferably, a silver thiosulfate ion complex of the present invention is derived from the complexation of a silver cation from a silver halide (e.g., for example, silver chloride) with an anion from a sodium thiosulfate salt; the molar ratio of thiosulfate anions to silver cations is preferably at least 1:1 and more preferably at least 3:1. It is desirable that silver thiosulfate ion complexes are solid and essentially pure (i.e., they do not contain significant amounts of waste salts or other substances that interfere with their antimicrobial activity) and, in addition, they do not require carrier particles (i.e., carrier-free). Though the benefit provided by the complexes of the present invention is not limited by an understanding of the precise nature of the complexes, the chemical formula of a silver thiosulfate ion complex formed when a large excess of thiosulfate salt is used is believed represented by [Ag(S₂O₃)₃]^5-;. By comparison, the chemical formula of a silver thiosulfate ion complex formed when only a small excess of thiosulfate salt is used is believed represented by [Ag₂(S₂O₃)₃]^4-;. In one embodiment, the present invention contemplates a silver thiosulfate ion complex represented by [Ag₂(S₂O₃)₃]^4-;. Preferably, any silver thiosulfate ion complex contemplated by the present invention is a relatively pure solid form, stable, highly water soluble and antimicrobially active.

In one embodiment, the present invention contemplates an amine stabilization of aqueous carrier-free silver thiosulfate complexes, wherein amines are in molar excess of the silver thiosulfate ion complex. Preferably, amines are in 1 to 10 molar excess of the silver thiosulfate ion complex; more preferably, amines are in 2 to 5 molar excess of the silver thiosulfate ion complex.

Without restricting the invention to any specific theory, it is believed that the stabilization of a silver thiosulfate ion complex is to be ascribed to by an ionic relationship between a silver thiosulfate ion and an amine. Furthermore, it is believed that amines provide a free lone pair of electrons to establish this ionic relationship.

One of the surprising and unexpected findings of the present invention is that amine stabilized silver thiosulfate ion complexes not only have good stability in the presence of chloride ions, but such compositions have improved resistance to degradation in an aqueous environment relative to non-stabilized silver thiosulfate ion complexes as disclosed in the '414 patent. Despite the known fact that silver thiosulfate-ion compositions of '414 patent are stable against heat and light, they degrade over time in an aqueous environment. This degradation of silver thiosulfate occurs when a thiosulfate ion component of the silver thiosulfate ion complexes undergoes a chemical breakdown. The effect of this chemical process is a breakdown of silver thiosulfate ion complexes and a concomitant loss in antimicrobial activity.

While an understanding of the mechanisms involved in the successful use of the invention is not necessary, it is believed that a thiosulfate ion within a silver thiosulfate ion complex is formed by adding a sulfur atom to a sulfite ion in a complex reaction that can be summarized by the following chemical equation: S+SO₃^2-;=S₂O₃^2-;. The sulfur atom that is added to the sulfite ion to give S₂O₃^2-; is somewhat labile; thus, S₂O₃^2-; is more appropriately represented as S-SO₃^2-;. Therefore, in aqueous solutions, thiosulfate decomposes over time. At moderately low pH levels the sulfur atom readily splits off, nominally yielding sulfur and sulfuric acid as follows: S-SO₃^2-;+H⁺=S+HSO₃^1-;.

As a result of this inherent instability of thiosulfate ion, aqueous silver thiosulfate ion complex solutions chemically decompose over time. Although it is not necessary to understand the mechanisms of an invention, it is believed that when thiosulfate ions of the silver thiosulfate ion complex chemically break down, silver ions are released which react with simultaneously released sulfur ions to form silver sulfide. Silver sulfide is a black material having a molecular formula of Ag₂S. Due to silver sulfide's high dissociation constant (pK=49.1), a silver sulfide is essentially devoid of any antimicrobial activity. That is to say, silver ion is bound so tightly to the sulfur ion that minimal ionization of a silver sulfide occurs. As a result, silver sulfide provides little, if any, ionized silver to provide antimicrobial activity.

Likewise, non-stabilized silver thiosulfate ion complexes (i.e., for example, those disclosed by the '414 patent), when added to either an ointment base which contains a small proportion of water or a water-containing cream base, will decompose over a relatively short period of time with a concomitant loss of antimicrobial activity. During this degradation, the silver thiosulfate composition turns black as silver thiosulfate ion complexes decompose to silver sulfide.

In one embodiment, the present invention contemplates an improvement of the characteristic insolubility of non-stabilized silver thiosulfate complexes in non-aqueous solvents. Preferably, amine stabilized silver thiosulfate complexes are added to products such as alcohol-based mouthwashes or alcohol-based skin cleaners/washes.

In another embodiment, the compositions of the present invention are added to medical devices comprising ionic and/or polar hydrophilic polymers. Such combinations create medical devices that are effectively antimicrobial in nature, and very desirable from a practical standpoint. Preferably, hydrophilic polymers suitable for the present invention are selected from synthetic hydrophilic polymers and derivatives of animal or vegetable hydrophilic polymers. In one embodiment, a hydrophilic polymer is selected from compounds such as, but not limited to, polysaccharides (i.e., for example, cellulose derivatives such as, but not limited to, sodium carboxymethylcellulose and hydroxyethylcellulose), alginates (i.e., for example, sodium alginate), collagen (i.e., for example, porcine collagen), etc. Other preferred polymers include, but are not limited to, polylactic acid, polyhydroxybutyrates or similar polyesters, polyvinyl alcohol, polyvinylpropylene, polyacrylates, hydrophilic polyurethanes, polymaleic acid and polymers of natural origin like glucosaminoglycans, collagen and fibrin or the like, as well as copolymers or derivatives thereof. The hydrophilic polymers listed above may be crosslinked, partially crosslinked or non-crosslinked.

One aspect of the present invention contemplates compositions comprising a wound dressing and an amine stabilized silver thiosulfate ion complex. In one embodiment, a wound dressing includes, but is not limited to, gauzes and compresses, hydrocolloid dressings, xerogel dressings and foam dressings. Preferably, wound dressings comprise silver thiosulfate ion complexes according to the present invention that are readily incorporated by dissolution in water and is impregnated into said dressings or they may be introduced as an independent component of a dressing, (e.g., for example, as an adhesive composition), by any manner that is well known in the art. In one embodiment, the present invention contemplates a method for incorporating an amine stabilized silver thiosulfate ion complex into alginate fiber dressings or other similar dressings. In one embodiment, an amine stabilized silver thiosulfate ion complex is added to a solution comprising alginate prior to production of the dressing. In another embodiment, an amine stabilized silver thiosulfate ion complex is added to a solution in the form of a powder obtained by grinding a lyophilized or spray-dried silver ion composition material. In another embodiment, an amine stabilized silver thiosulfate ion complex is added to a wound dressing, wherein said stabilized complex is impregnated into an adhesive for fixing the dressing to the wound site, or into another part of the dressing, for instance onto a foam pad.

The amine stabilized silver thiosulfate ion complexes of the present invention and formulations thereof are useful for their antibacterial, antiviral and/or antifungal activity in either human or veterinary medicine. One aspect of the present invention contemplates impregnating medical devices with amine stabilized silver thiosulfate ion complexes, wherein said medical devices include, but are not limited to, medical implants, wound care devices, body cavity and personal protection devices, and the like. By way of illustration only, with no intention to limit the invention, an amine stabilized silver thiosulfate ion complex may be mixed with an anhydrous polymer matrix for coating a urinary catheter in order to prevent an infection. In another embodiment, an amine stabilized silver thiosulfate ion complex may be used in cosmetics and personal care products to provide microbial resistance. Preferably, such cosmetics may include, but are not limited to, lipsticks and glosses, lip pencils, mascaras, eye liners, eye shadows, moisturizers, liquid and powder makeup foundations, powder and cream blushes, perfumes, colognes, various creams and toners, etc., and assorted applicators like combs, brushes, sponges, 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, moisturizers, tampons, sanitary napkins, panty shields, diapers, baby wipes, facial tissues, toilet tissues, etc.

In one embodiment, amine stabilized silver thiosulfate ion complexes are incorporated into a foam pad or related insert for uses including, but not limited to, continence care, condoms, male external urine catheters, skin adhesives etc. In another embodiment, amine stabilized silver thiosulfate ion complexes are incorporated into powders for removal of odor in incontinence pads or for incorporation into ostomy pouches. Preferably, said powders are impregnated into a medical device and are not in direct contact with the body.

One aspect of the present invention contemplates amine stabilized silver thiosulfate ion complexes impregnated into implants, sutures or other similar materials that contact body surfaces for an extended period of time; for example, during or after surgery where the risk of infection is always latent. In one embodiment, an amine stabilized silver thiosulfate ion complex is combined with a systemic prophylactic antibiotic treatment and a skin antiseptic treatment. In another embodiment, an amine stabilized silver thiosulfate ion complex is combined with antiseptics and/or antibiotics that are impregnated into a medical device intended for implantation or use within a surgical opening. Specific advantages of the present invention over previously disclosed silver ion compositions are broad spectrum antiseptic properties and long-term stability.

One aspect of the present invention contemplates impregnating or coating a medical device with a composition comprising an amine stabilized silver thiosulfate ion complex wherein said amine may be primary, secondary or tertiary and said complex is associated with one or more hydrophilic polymers. In one embodiment, the present invention contemplates a method for producing compositions having antibacterial, antiviral and/or antifungal activity wherein a silver thiosulfate ion complex is dissolved in water, an amine is added in molar excess, and the resulting solution is incubated for a period of from approximately 1 to 100 hours, preferable from approximately 12-24 hours. Optionally, after adjusting the pH using an acid to approximately 6.5-9.0, the resulting mixture is added to a hydrophilic polymer (i.e., such as, carboxymethylcellulose, hydroxyethylcellulose and alginate) and optionally dried and micronised. In another embodiment, the present invention contemplates an amine stabilized silver ion complex comprising a silver thiosulfate ion that is further associated with a primary, secondary or tertiary amine. Preferably, this amine stabilized silver thiosulfate ion complex is associated with one or more hydrophilic polymers, wherein said composition has antibacterial, antiviral and/or antifungal activity. In one embodiment, the amine stabilized silver thiosulfate complex is impregnated into a medical device including, but not limited to, a wound dressing, an ostomy appliance, an incontinence device, and other medical devices or hydrophilic coatings.

Claim 1 of 26 Claims

1. A composition, comprising a silver thiosulfate ion complex in association with an amine, wherein said amine comprises tri-hydroxymethyl aminomethane.

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