An antimicrobial composition is formed from about 5 to about 25 wt % of an antimicrobial formulation and about 75 to about 95 wt % of a silicone resin. The antimicrobial formulation is formed from about 60 to about 95 wt % of an antimicrobial material, about 1 to about 30 wt % calcium chelator, about 0.001 to about 0.25 wt % pigment, and about 0.5 to about 3.5 wt % lubricant. The silicone resin may be a dispersion of about 40 to about 60 w/v % of an RTV silicone resin in a solvent, a liquid silicone resin, or a solid silicone resin. An antimicrobial coating may be formed on the surface of an article by applying an antimicrobial composition to the article and permitting the solvent to evaporate. It may also be formed by making a mixture of about 5 to about 12 wt % of an antimicrobial formulation and about 88 to about 95 wt % of a liquid or solid silicone resin and molding, overmolding, or extruding the article from the compounded mixture.

Description of the Invention

SUMMARY OF THE INVENTION

Silicone surfaces are difficult to coat with other polymers, but in this invention this problem has been overcome. A coating on the surface of an article is achieved either by coating the article with a composition containing a room temperature vulcanizing (RTV) silicone resin or by compounding an antimicrobial formulation with a liquid or solid silicone resin, which is molded, overmolded, or extruded into the article. The coating becomes integrated with the surface of the article and does not delaminate, swell, or separate. Due to the slow release of the antimicrobial material, such surfaces show a consistent and continuous antimicrobial activity when challenged with microorganisms.

The principal object of the present invention is to produce an antimicrobial composition that is useful for coating medical articles, or can be incorporated into medical articles, to prevent the formation of biofilms and encrusting deposits thereon.

Another object of the present invention is to provide a coatable composition that includes an RTV silicone resin dissolved in a solvent.

It is yet another object of this invention to provide coatable compositions for urinary catheters, urological devices, feed tubes, gastric buttons, and other types of catheters that are made of silicone, and enhance the lubricity of the surface of a medical article by releasing a lubricious, non-toxic compound from a coating of the composition.

Yet another object of this invention is to provide antimicrobial silicone coatings for silica particles, surface modified silica based ceramics, textile finishes, filament wound water filters, cartridges, storage tanks, sealing caps, glove linings, gloves, and fabric coatings such as water repellent finishes.

Another object of this invention is to provide a chemical formulation for direct blending with liquid silicone materials for direct extrusion or overmolding onto an article.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The Antimicrobial Composition

The antimicrobial composition of this invention has two parts, an antimicrobial formula with four components and a silicone resin, which may be an RTV, a liquid silicone, or a solid silicone resin.

Part I (Antimicrobial Formulation)

(1) antimicrobial material;

(2) calcium chelator;

(3) pigment; and

(4) lubricant.

Part II (Silicone Resin)

The purpose of the antimicrobial material is to kill bacteria, yeasts, and molds. Examples of suitable antimicrobial materials include nanosize particles of metallic silver or an alloy of silver containing about 2.5 wt % copper (hereinafter referred to as "silver-copper"), salts such as silver citrate, silver acetate, silver benzoate, bismuth pyrithione, zinc pyrithione, zinc percarbonates, zinc perborates, bismuth salts, various food preservatives such as methyl, ethyl, propyl, butyl, and octyl benzoic acid esters (generally referred to as parabens), citric acid, and sodium percarbonate. The preferred antimicrobial materials are silver, partially water soluble compounds of silver, silver pyrithione, zinc pyrithione, bismuth pyrithione, parabenzoic acid esters, and mixtures thereof. Silver particles having a particle size of about 1 to about 100 nm are believed to slowly release silver ions, Ag+, which are antimicrobial. Silver and silver salts, such as silver citrate, are especially preferred, because they are very effective and safe bactericides due to their rapid release of silver ions. Butyl paraben and octyl paraben are the preferred antimicrobial materials for yeasts and molds due to their low solubility in water. About 65 to about 95 wt % of the antimicrobial formulation may be the antimicrobial material; less is ineffective. Preferably, about 40 to about 65 wt % of the antimicrobial material is used in the formulation of which about 15 to about 25 wt % is silver, silver-copper, a partially water soluble silver salt, or a mixture thereof and about 25 to about 40 wt % is parabenzoic acid esters. The antimicrobial material slowly leaches from the formulation, keeping the coated surface free of live bacteria, yeasts, and molds.

The calcium chelator prevents deposits of calcium and/or magnesium from forming, which may impede the flow of urine. Examples of suitable chelators include EDTA (acid form), citric acid, hydroxyethylidene phosphonic acid, polyvinylphosphoric acid, polyvinylsulfonate, acrylic acid, and aminophosphonic acid. The preferred chelators are citric acid and EDTA (acid form) because of their ability to solubilize silver and form complexes with calcium ions. About 1 to about 55 wt % (based on the weight of the antimicrobial formulation) may be chelator. More is undesirable because of its acidity and less is undesirable because the efficacy of the long term release may be reduced. Preferably, the chelator is about 20 to about 25 wt % citric acid and about 20 to about 25 wt % EDTA (acid form).

The purpose of the pigment is for coloring, as the silver imparts a dark grayish color. The addition of the pigment imparts a bluish gray shade. Copper phthalocyanine (pigment blue) is the preferred pigment because it is believed to also have a bacteriostatic effect and is used in surgical sutures. FDA approved coloring pigments commonly used by the medical industry may also be used. About 0.001 to about 0.25 wt % (based on the weight of the antimicrobial formulation) may be pigment. More is undesirable because of the high intensity in color and the blocking effect of the large pigment molecules, and less is undesirable because the benefit of the color is lost (i.e., the color is visually not pleasing). Preferably, about 0.1 to about 0.25 wt % of the pigment is used.

The purpose of the lubricant is to make the surface lubricious, which is advantageous because it helps to prevent bacteria from adhering to the filter. Examples of suitable lubricants include polyethylene oxide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl alcohol, and derivatives thereof. The preferred lubricant is polyethylene oxide because it discourages cell adhesion and can be incorporated into the antimicrobial formulation. About 3 to about 5 wt % (based on silicone solids in the formulation) is lubricant. More is undesirable because of it may make processing more difficult and less is undesirable because the surface may not be sufficiently lubricious. Preferably, about 4 to about 5 wt % lubricant is used.

The silicone resin helps a coating of the formulation to adhere to various surfaces. The silicone resin used in the composition of this invention may be a liquid silicone resin or a solid silicone resin, but it is preferably an RTV silicone resin. RTV silicone resins are available in one part (RTV-1) and two-part (RTV-2) systems. One part systems consist of polydialkylsiloxane with terminal hydroxyl groups, which are reacted with organosilicon cross-linking agents. The reaction is performed in a moisture-free environment and results in the formation of a tetrafunctional structure. Curing takes place when the materials are exposed to moisture. Atmospheric moisture is sufficient to trigger the reaction. The thickness of the coating should be limited if only one side of the it is exposed to a source of moisture. Curing is relatively slow, as it relies on moisture migrating into the polymer. The examples that follow use the one part system.

Two part systems can be divided into two categories, condensation cross-linked materials and addition cross-linked polymers. Condensation systems involve the reaction of silanol-terminated polydimethylsiloxanes with organosilicon cross-linking agents such as Si(RO).sub.4. Storage life depends on the catalyst employed and ambient conditions. Addition-cured materials must be processed under clean conditions as curing can be affected by contaminants such as solvents and catalysts used in condensation RTVs. Addition-cured materials are suitable for use with polyurethane casting materials. Of the two types of RTV silicone resins, the one part systems are preferred because they are easier to process.

The term "RTV silicone resin" is intended to include any silicone resin that can be dispersed in a solvent that can leave behind a solid resin. The preferred RTV silicone is made by General Electric Corp. and is sold as "GE-118." It is believed to have a composition of 1 to 5 wt % di-t-butoxydiacetoxysilane, 1 to 5 wt % methyltriacetoxysilane, 1 to 5 wt % octamethylcyclotetrasiloxane, 60 to 80 wt % dimethyl polysiloxane silanol/st, 5 to 10 wt % silanol/stpd siloxane with methyl silsesquioxanes, and 10 to 30 wt % amorphous silica. Other RTV silicone resins or silicone dispersions are that may be used are commercially available and may be purchased from General Electric, Bayer, Dow, and other companies. The mixture of the RTV silicone and the solvent should contain about 40 to about 60 w/v % RTV silicone and the remainder solvent (i.e., about 40 to about 60 gm of RTV silicone is dispersed in 100 mL of solvent) as less RTV silicone results in a low viscosity dispersion, causing the antimicrobial composition to settle faster, and the higher amount of solvent may pose a risk of chemical attack on the coated article. More than about 60 wt/v % RTV silicone makes dip coating difficult due to the higher viscosity. The preferred amount of RTV silicone in the mixture is about 48 to about 52 w/v %. The preferred amount helps to maintain a uniform suspension of the antimicrobial composition due to its higher viscosity, which keeps the particles suspended.

Any non-toxic organic solvent that will evaporate from a coating in a few hours at about 60.degree. C. may be used as the solvent. Examples include hexanes (a mixture of hexane isomers), methyl ethyl ketone, xylenes (a mixture of xylene isomers), and similar solvents. The preferred solvent is hexane because it is less toxic than some of the other solvents and can be evaporated in a few hours at a temperature below about 60.degree. C. The addition of the RTV silicone resin to the solvent may be performed with stirring at a temperature of about 15 to about 18.degree. C.

In addition to RTV silicone resins, liquid and solid silicone resins may also be used to make articles that have antimicrobial coatings on their surfaces by incorporating the antimicrobial formulation into a resin that can be extruded or molded into an article, as hereinafter described. Resins suitable for extruding or molding into articles include silicone resins are commercially available. Silicone resins are preferred because of the ability to blend the antimicrobial formulation with a gum-like silicone resin. However, higher cure temperatures are required for extrusion than for conventional silicone resins.

Liquid silicone is similar in properties to normal silicone but varies in its processing characteristics. It is purchased as a two part raw material with a viscosity similar to Vaseline. It is supplied deaerated, ready for use, often in premetered equipment. The two materials are pumped from a drum through a mixing head and injected into the cavities. Very low pressures are involved and the cure time is very fast (typically 20 to 45 seconds) at temperatures of about 200.degree. C. and post-curing is usually not required. The resin cures after mixing the two separate portions, by processes such as hydrosilylation. A full range of hardnesses can be achieved as well as colour matching in a very clean process. The fast cycles and low material usage offers a significant cost advantages on long runs

Solid silicone rubbers that may be used with the antimicrobial formulation are usually cured using peroxides such as benzoyl peroxide, 2,4-dichlorobenzoyl peroxide, t-butyl perbenzoate, and dicumyl peroxide. Alkyl hydroperoxides and dialkyl peroxides have also been used successfully with vinyl containing silicones. Hydrosilylation and hydrosilation are alternative curing methods for vinyl contiaining silicones and utilize hydrosilane materials and platinum-containing compounds for catalysts. Curing does not produce volatiles and heat cured conventional silicones with high tear strengths can be cured this way. Dow Chemical Corp. and General Electric Corp. are major commercial producers of such resins. These resins may be cured at temperatures close to about 150.degree. C. for short time or at room temperature for a longer period. Solid silicone resins typically require a cure temperature of about 300 to about 400.degree. C.

Optional components may also be included in the antimicrobial formulation. For example, it is preferable to include about 0.5 to about 4 wt % of nanosize (20 to 40 nm) high surface area titanium dioxide as a support for loading of the antimicrobial formulation and also to lighten the color. Zinc pyrithione or bismuth pyrithione are optional antimicrobial materials that may be included at very small percentages such as about 0.1 to about 0.5 wt % (based on the silicone in the formulation).

A preferred antimicrobial formulation is about 10 to about 16 wt % silver citrate, about 5 to about 70 wt % nanosize (i.e., less than about 100 nanometers) silver powder, about 5 to about 15 wt % EDTA or a vinyl phosphonic acid or hydroxy ethyl phosphonic acid, about 20 to about 40 wt % butyl paraben, and about 10 to about 22 wt % citric acid.

The antimicrobial composition of this invention may be prepared by finely blending the above-described components; blending may be performed, for example, in an industrial blender.

Uniform Blends of the Antimicrobial Formulation with Silicones of Different Types:

If an RTV silicone resin is used, a dispersion of the RTV silicone resin is preferably blended in as a solvent based dispersion using a sonicator after stirring in the other components. An optional amount of isopropyl alcohol at a level of about 0.1 to about 0.2% increases the pot-life of the coating formulation; however, the curing is considerably delayed.

For overmolding, or injection molding, the liquid silicone part 1 and part 2 are mixed while metering in the antimicrobial formulation, using static mixers. Commercial liquid silicone injection molding apparatus may be used. For conventional solid silicone resins, the antimicrobial formulation and other components may be directly mixed and compounded using a compounder, followed by extrusion.

Coating Surfaces

The antimicrobial coating composition of this invention may be used to coat the surfaces of articles to retard the growth of microbes thereon. Examples of articles that may be coated include silica particles, surface modified silica based ceramics, textile finishes, filament wound water filters, cartridges, storage tanks, sealing caps, glove linings, gloves, and fabric coatings such as water repellent finishes. While any surface may be coated with the composition, the composition is preferably used to coat the surfaces of medical devices such as catheters, stents, Foley catheters, gastrostomy tubes, feeding tubes, silicone coated latex type surfaces. silicone valves, balloons, septa, etc., that are prone to infection, silicone parts used in various medical pumps, tubings and earplugs, and as a textile finish for linings for hospital beds, window shades, and curtains. These articles may be made of various materials including plastics, metals, glass, and ceramics. Preferably, they are made of a polymeric material (a plastic), such as silicone, silicone coated plastics, and polyurethanes. The preferred material is silicone because the coating adheres better to silicone.

To coat a surface with the antimicrobial material, the surface is cleaned, if necessary, which may be done using, for example, a water-based detergent then drying thoroughly, or with an organic solvent such as ethanol, then drying and wiping the surface with hexane. The composition may be applied to the surface by any suitable technique. The following are examples of coating techniques that may be used, depending on the substrates: Dip/immersion coating Dip molding Kiss coating (lick roll) Knife coating (over air, roll or rubber sleeve) Rotogravure coating Spray coating Other methods such as bar coating or rotary screen printing The preferred methods are dip coating and dip molding using a mandrel in the same shape as the article.

The solution or dispersion may have to be applied several times to the surface in order to achieve the desired thickness for the coating. The thickness of the coating should be about 0.5 to about 2 mils as thinner coatings may be less effective and thicker coatings may not be necessary. A preferred thickness is about 1 to about 2 mils. After each layer of coating is applied, the surface is dried. This may be accomplished, for example, by air drying or by warming the surface in an oven. The composition is preferably dried at room temperature followed by drying at about 50 to about 60.degree. C. for about 3 to about 4 hours. Articles with balloons made of silicone, such as Foley silicone catheters, may be easily coated with the composition of this invention and were found to pass both the ASTM and the European standard test for balloon expansion in Foley catheters and the burst strength tests.

To form an article by dip molding, a mandrel in the shape of the article is heated, dipped into a tank holding an antimicrobial composition, and removed from the tank. Liquid or RTV silicone resins may be used in the antimicrobial composition, which is dissolved or dispersed in a solvent. The viscosity of the solution depends on its solids content, which can be increased by adding more solids or decreased by adding more solvent until the desired viscosity is attained. After dipping, the thin coating of the composition that remains on the surface of the mandrel is allowed to cure and/or cure, then is stripped off as a finished product. Multiple dipping steps may be used to increase the thickness of the coating and curing time, temperature, and speed of immersion may be adjusted to control the properties of the resulting article. Gloves, balloons, and other articles may be made by this process.

(B) Incorporation of the Formulation

The antimicrobial formulation of this invention may also be incorporated into an article, so that it will gradually leach to the surface of the article and form a coating on the surface that retards the growth of microbes thereon. When the formulation in this manner, a liquid or solid silicone resin is used instead of a RTV silicone resin and it is not necessary to form a dispersion of the silicone resin. Materials in which the formulation may be incorporated include silicone resins, liquid silicone, polyurethanes, polyvinyl chloride (PVC), and silicone-polyurethane blends. The preferred material is liquid silicone because of its ability to form conformal molded shapes and also conformal overmolded parts. This also avoids the need to use a solvent.

To incorporate the formulation into a material, the formulation is mixed with the material to produce a homogeneous mixture. The mixture may contain about 5 to about 12 wt % of the formulation; less formulation may not be sufficiently effective in retarding the growth of microbes and more formulation may adversely affect the properties of the material. Preferably, the formulation is about 5 to about 10 wt % of the mixture.

The mixture is then formed into a desired shape and is hardened. The article may be shaped by molding, overmolding, extrusion, or another process. Depending upon the resin used, hardening may occur as a result of exposure of the material to air, heat, moisture, or as the result of a chemical reaction that began when the resin was prepared.

The methods result in the formation of an excellent product that facilitates the slow release of antimicrobials to the surface. The silicone resin encapsulates the antimicrobial materials and releases them at a controlled rate. On exposure to aqueous fluids, such as various body fluids, the water soluble components of the antimicrobial formulation migrate to the surface, where an equilibrium between the silver, citric acid, and EDTA is established. This is important because silver ions are rendered insoluble due to the formation of silver chloride or phosphates in the presence of body fluids. The presence of EDTA, which complexes silver ions, forming soluble complexed species of silver, allows a continuous migration of these soluble species to the surface despite the presence of chloride ions. The presence of the other components of the formulation, such as parabens (para benzoic acid esters) and copper phthalocyanine, help to keep the surface of the coated article antimicrobial. The lubricant imparts a slippery feel when wetted with water; this property allows the insertion of the catheter without causing trauma to the patient. More importantly, the lubricant elutes continuously from the coating, keeping the surface hydrophilic and lubricious, thereby discouraging the adherence of bacteria.
 

Claim 1 of 22 Claims

1. An article having an antimicrobial coating made by (A) applying to an uncoated article an antimicrobial composition that comprises (1) about 5 to about 25 wt % of an antimicrobial formulation that comprises (a) about 40 to about 65 wt % of an antimicrobial material; (b) about 1 to about 55 wt % calcium chelator; (c) about 0.00 1 to about 0.25 wt % pigment; and (d) about 0.5 to about 5 wt % polyethylene oxide; and (2) about 75 to about 95 wt % of a silicone resin; and (3) an optional non-toxic organic solvent; and (B) permitting said coating to form on said uncoated article, whereby said antimicrobial material leaches from said antimicrobial formulation, keeping the surface of said coating free of live bacteria, yeasts, and molds.

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