BRPI0706861A2 - method for making a packaged microbicidal article, packaged microbicidal articles and method for bleaching at least a portion of a microbicidal article - Google Patents

Abstract

METHOD FOR MANUFACTURING A PACKED MICROBICIDE ARTICLE, PACKED MICROBICIDE ARTICLES AND METHOD FOR WHITENING AT LEAST ONE PORTION OF A MICROBICIDE ARTICLE The present invention relates to a silver composition comprising silver sulfate, methods of preparing microbicidal articles, particularly packaged microbicidal articles, methods for bleaching microbicidal articles and packaged microbicidal articles.

Description

"METHOD FOR THE MANUFACTURE OF A PACKED MICROBICIDE ARTICLE, PACKED MICROBICIDE ARTICLES AND A PARABILITY METHOD FOR AT LEAST A PORTION OF AN ARTICLE

MICROBICIDE "

Background of the Invention

Although wound healing is more effective in moist environments, the risk of bacterial infection is higher. The use of antibiotics to treat bacterial infections can create bacterial resistance. Silver compounds are known to impart microbicidal effects to a surface with minimal risk of developing bacterial resistance. Silver is applied to the surface by the sustained release of silver ions from the surface when in contact with wet environments, such as a wound bed.

Silver compositions, such as silver nitrate and depradiated sulfadiazine, are effective microbicides used in a variety of applications. However, they are typically not stable to light, leave a stain on them with which they come in contact, and in this case. of silver nitrate can be rapidly depleted in an aqueous environment. The use of microbicidal silver salts has included the use of stabilizing agents to increase light stability, such as those described in US Patent No. 2791,518 (Stokes etal.) (Using a first solution of ammonia, silver nitrate and barium nitrate; and a second solution of sodium chloride and sodium sulfate); and in Patent No. 6,669,981 (Parsons et al.) (a silver salt in water / organic solvent followed by one or more stabilizing agents (e.g., ammonium salts, thiosulfates, chlorides and / or peroxides)).

Brief Description of the Invention

The present invention is directed to methods of preparing microbicidal articles, particularly packaged microbicidal articles, bleaching methods of microbicidal articles and packaged microbicidal articles.

In one embodiment, the present invention provides a method for making a packaged microbicidal article. The method includes: preparing a composition comprising silver sulfate; coating the silver desulfate composition on a substrate; drying the coated substrate to form a microbicidal article; place the microbicidal article in packaging material which has a volatile organic content of at most 100mg per square meter; and sealing the packaging material with the microbicidal article therein.

In another embodiment, the present invention provides a method for bleaching at least a portion of a microbicidal article. The method includes: providing a packaged microbicidal article having at least one non-white colored portion, the article comprising a substrate coated with a silver salt composition comprising at least a portion of silver in the brave zero state, and the microbicidal article is sealed within the packaging material which has a volatile organic content of at most 100 milligrams per square meter (100 mg / m2); and irradiating the packed microbicidal article to whiten at least a portion of the microbicidal article.

In other embodiments, the present invention provides packaged microbicidal articles. In one embodiment, a packaged microbicidal article includes: a microbicidal article including a substrate coated with a silver sulfate composition; and packaging having the microbicidal article in it; wherein the package comprises material having a volatile organic content of at most 100 mg / m2.

In certain preferred embodiments of the present invention, microbicidal articles exhibit color stability, particularly during and / or after irradiation. In this context, "color stability" means that the color of the dry silver sulfate composition applied as a coating on a substrate does not exhibit a significant change in color and / or homogeneity to the human eye over time (preferably at least 4 hours, more preferably at least 8 hours, more preferably at least 48 hours, and even more preferably at least 1 week) compared to the same substrate coated composition that has not been exposed to light (e.g. fluorescent, natural, UV) . Preferably, "color stability" means that the color of the dry silver sulfate composition applied as a coating on a substrate exhibits no noticeable change in color and / or homogeneity for the human eye over time (preferably at least 4 hours, more preferably at least 8 hours, even more preferably at least 48 hours, and even more preferably at least 1 week) as compared to the same composition coated on a substrate that has not been exposed to light (e.g. fluorescent, natural, UV) .

Color change can be assessed in many ways using a number of grading scales. For example, the decor change can be assessed by visual classification under fluorescent lighting. Samples are compared to color patterns and determined at an index based on visual comparison. On this rating scale, 0, 1 and 2 are classified as "whitish" including white to cream, 3 to 5 are classified as "yellowish" including light yellow to golden yellow and 6 to 10 are classified as rust to dark brown. The color change is the difference in the index obtained by subtracting the initial index from the index after treatment. Positive indices represent a darkening appearance and negative indices represent a darkening appearance. A color change on this scale of 1 or less is acceptable as long as the color is substantially homogeneous. If the color is inhomogeneous, even a color change of 0.5 is considered a "significant" and unacceptable change. The color change can also be measured using a colorimeter as a Minolta (CR-300, produced by Konica Minolta Photo ImagingU.SA, Inc., Mahwah, NJ1 USA) using trimerim values. A color change on this scale to the "Y" value of 15% or less is acceptable as long as the color is homogeneous. If the color is inhomogeneous, even a 5% color change in the "Y" value is considered a "significant" and unacceptable change.

Color change can also be measured using a colorimeter in accordance with ASTM D2244. The resulting CIELAB color difference (DE *) between the sample after exposure for the indicated time period and the unexposed sample can be determined. For reference purposes only, a DE *, or color change of about 2 units is simply detectable to the naked eye, while a DE * of 20 or more represents a substantial or "significant" color change and is not acceptable.

In certain preferred embodiments of the present invention, the microbicidal articles are maintained in an environment of no more than 50% relative humidity (i.e. a water activity of 0.5) at room temperature. In certain preferred embodiments of the present invention, the microbicidal articles are kept in an environment of no more than 30% relative humidity at ambient temperature. In this context "ambient temperature" means an average ambient temperature, typically 23 ° C +/- 2 ° C. "Relative humidity" is the ratio of the amount of water vapor present in the atmosphere to the amount that would saturate the atmosphere at a given temperature.

For use in the present invention, "one", "one", "o", "a", "at least one", "at least one", "one or more" and "one or more" are used interchangeably. For use in the present invention, integer range recitations include all numbers included within this range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

The terms "comprise" and variations thereof do not have a limiting meaning, and these terms appear in the description and claims

The words "preferred" and "preferably" refer to embodiments of the invention that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Moreover, the recitation of one or more preferred embodiments does not imply the disuse of other embodiments and is not intended to exclude other embodiments from the scope of the invention.

The foregoing summary of the present invention is not intended to address each of the embodiments set forth or all implementations of the present invention. The following description further exemplifies the illustrative embodiments.

Detailed Description of the Invention

The present invention is directed to methods for preparing microbicidal articles, particularly packaged microbicidal articles, bleaching methods for microbicidal articles and packaged microbicidal articles.

In certain embodiments, the microbicidal articles are prepared using a composition including silver sulfate (e.g., an aqueous based composition), coating the silver sulfate composition on a substrate, and drying the coated substrate to form an artigomicrobicide. The microbicidal article is placed in the packaging material and the packaging material sealed with the microbicidal article therein. Accordingly, the present invention provides a packed microbicidal article including a microbicidal article including a coated substrate with a silver sulfate composition, and packaging having the same material. artigomicrobicide sealed in it. In certain embodiments, the sealed microbicidal article in the packaging material is irradiated.

In certain embodiments, the package includes material having a volatile organic content of up to 100 microns per square meter (mg / m2). In other embodiments, the volatile organic content is a maximum of 50 mg per square meter. In this context, the "volatile organic content" is defined by the equation: (mass of packaging material prior to oven exposure - mass of packaging material after oven exposure) / surface area. This can be determined using ASTM D 2369-03 as described in the Examples Section.

Packaging materials useful for the present invention may be porous or non-porous while maintaining sterility of the product after sterilization. Useful packages may include one or more layers of materials. There may be one or more packages surrounding the substrate. For example, there may be one or more inner containment bags within an outer containment bag. In such a situation, the innermost containment bag (ie, which is in direct contact with the microbicidal article) is preferably porous. Sufficient porosity may allow the transfer of released gases during irradiation of the packaged microbicidal article.

Typically, in such a situation where the innermost holding bag is porous, the outermost holding bag of the packaging material is non-porous or of very low porosity, particularly with respect to oxygen permeability and wet vapor permeability.

In certain embodiments, the package includes material having an oxygen permeability of less than 0.01 cubic centimeter per 645 square centimeters for 24 hours. In this context, "oxygen permeability" is defined as the volume of oxygen gas that spreads through 645 square centimeters (100 square inches) of wrapping film for 24 hours. This can be determined using ASTM D3985.

In certain embodiments, the package includes material having a moisture vapor transmission rate (MVTR) of less than 0.01 g per 645 square centimeters for 24 hours. In this context, MVTR is the mass of water that spreads through 645 square centimeters (100 square inches) of wrapping film for 24 hours. This can be determined using ASTM F1249.

Packaging materials having such properties include constructions on TPC-0765B / TPC-0760B (Tolas Health Care; Feasterville, PA, USA) and Techni-Pouch packaging (Technipaq, Inc., Crystal Lake, IL1 USA) with a construction of PET (polyester) material / Aluminum foil / LDPE (low density linear polyethylene).

In certain embodiments, the package includes a porosoque material having a Gurley Hill porosity of less than 100 seconds per 100 cubic centimeters of air (100 s / 100 cc air). In certain embodiments, aporosity is at least 5 seconds per 100 cubic centimeters of air. Porous packaging materials having this property include those commercially available under the trade name of TYVEK as TYVEK1073B / TPF-0501A (a film construction / YVEK) available from TolasHealth Care Packaging1 Feasterville, PA, USA; and packaging constructiontype paper or film as available under the trade name CONVERTERS Sterilization Pouches (for example, 7.5 cmχ 20 cm (3 inch χ 8 inch); Catalog 90308) distributed by CardinalHealth of McGaw Park, IL1 USA.

In certain embodiments, the packaging material includes an inner containment bag and an outer containment bag, the containment shaker having a Gurley Hill porosity of less than 100 s / 100 cc of air (preferably 5 s to 100 s / 100 cc of air), and the outer containment bag has an oxygen permeability of less than 0.01 cubic centimeter per 645 square centimeters for 24 hours and / or a moisture vapor transmission rate of less than 0.01 g per 645 square centimeters for 24 hours.

In certain embodiments, a microbicidal article is produced by dissolving silver sulfate in an aqueous-based composition, coating the composition on a substrate, and drying the coated substrate. In certain embodiments, the silver sulfate coated substrate remains stable to light (e.g. visible, UV) and heated without the addition of traditional stabilizing agents such as ammonia, ammonium salts (eg, ammonium acetate, ammonium sulfate and carbonate). ammonium salts), thiosulfates, water-insoluble salts of metals (eg halides with chlorides), peroxides, magnesium trisilicate and / or polymers. Preferably, any component that would function as a stabilizing agent is present in amounts of less than 100 parts per million (ppm), more preferably less than 50 ppm, most preferably less than 20 ppm, based on the total weight of the silver sulfate composition. Alternatively, any component that would function as a stabilizing agent is present in amounts of less than 1000 ppm, more preferably less than 500 ppm, most preferably less than 100 ppm, based on the total weight of the microbicidal article comprising a dry silver sulfate composition. applied as a coating on a substrate.

The resulting solution containing the silver sulfate solution may be applied as a coating on a substrate, preferably an absorbent substrate, although non-absorbent substrates may also be used. The coated substrate is dried to expel volatile components such as water and organic solvents (eg methanol, ethanol, isopropanol, acetone or other organic solvents that are miscible in water). Drying may be performed at room temperature or by heating the coated substrate. The heat will accelerate the drying process. In a preferred embodiment, the coated substrate is dried to temperatures below 190 ° C, more preferably below 170 ° C, more preferably below 140 ° C, to minimize reduction of silver compounds and also to prevent oxidation of a cellulosic material when used as a substrate.

In addition, the tensile strength of an oxidizable substrate (such as cotton) is maximized when the silver sulphate composition on the substrate is dried at low temperature, preferably less than 140 ° C, more preferably less than 100 ° C and with most preferably, less than 70 ° C.

Once dried, the substrate remains coated with silver sulfate. The coated composition typically contains the highest amount of silver sulfate. Low levels of silver metal (i.e., brave zero silver) may be present in amounts, preferably less than 20% by weight, and more preferably less than 10% by weight, based on the total weight of the silver components. in the composition. In some embodiments, choice of starting materials and drying temperatures results in a residue-free coating, essentially only the depratate sulfate remains on the substrate, and all other components of the depratate solution are removed from the substrate upon drying.

When applied, silver sulfate solution penetrates and impregnates the interior of the substrate. For example, when using gauze, the silver solution permeates between the gauze fibers.

The silver sulfate concentration on the substrate is a function of the amount of silver sulfate in the solution, the total amount of solution applied over a unit area of the substrate and the drying temperature. The silver sulfate concentration on the substrate is typically less than 30 mg / cm2 and, in certain embodiments, less than 5 mg / cm2. In a preferred embodiment, the concentration of silver sulphate over the substrate is in the range of 0.001 mg / cm2 to 5 mg / cm2 and, in certain embodiments, from 0.001 mg / cm2 to 1 mg / cm2.

The substrate may be a fabric or a non-woven material (e.g., a gauze) made of synthetic or natural compounds. The substrate may be a porous or non-porous film. It may be a knitted fabric, a foam or a hydrocolloid, for example.

In certain embodiments, the substrate is an oxidizable silver denitrate substrate. In certain embodiments, the substrate includes a cellulosic material. Examples of cellulosic materials include modified polysaccharides or polysaccharides, regenerated cellulose (such as rayon), paper, cotton, these materials are available under the tradename TENCEL, carboxy methyl cellulose and the like.

Other materials may be used, including for example, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl ether, polyacrylate, polyacrylamide, collagen and gelatin. Non-absorbent substrates may also be used including, but not limited to, nylon, polyester, polyethylene and polypropylene.

Other suitable substrate materials include polycrylonitrile, polyvinylidene difluoride, polytetrafluoro ethylene, polyoxymethylene, polyvinyl chloride, polycarbonate, styrene-butylene styrene elastomer, styrene-butylene styrene elastomer and styrene-isoprene-elastomer combination same. Other desubstrate materials are described later in this document. Various material combinations may be included within the substrate. In certain embodiments, the substrate includes a material selected from the group consisting of cellulosic material, nylon, polyester fiber and combinations thereof. In certain embodiments, the substrate includes a cellulosic material. In certain embodiments, the cellulosic substrate includes cotton.

The method provides a silver sulfate solution to coat a substrate without the use of acid. The presence of acid may hydrolyze cellulosic material. This aspect of the process allows the coating to be applied without weakening the cellulosic substrate. Preferably the coating solution has a pH of at least 4, more preferably at least 5. Preferably the coating solution has a pH of at most 9.

High temperatures may also accelerate the oxidation of cellulose by a silver salt, resulting in effects such as decreased tensile strength and color change of the silver sulfate composition on the substrate. The color change in a cellulosic material such as cotton sedates, probably due to the reduction of silver salt to common silver metal following the oxidation of the cellulose substrate. The cotton has lower tensile strength.

If silver sulfate is coated on a cellulosic substrate or another easily oxidizable substrate (for example, an oxidizable silver denitrate substrate), the article will have its color changed in proportion to the drying temperature and time in the drying device as a generally no change in color is observed when the substrate coated with the silver sulfate composition is dried below approximately 100 ° C for 15 minutes. For example, when the moistened cotton is dried in an oven with a temperature greater than about 100 ° C, the cotton substrate darkens in proportion to the oven temperature and turns yellow, then brown and then dark brown.

If a synthetic substrate such as polyester, which is not easily oxidized, is coated with the dried silver sulfate coating solution, the polyester remains white even when dried at a temperature above 100 ° C. Similarly, when polyester or other desubstrate material such as polyester, nylon, polyethylene, polypropylene, polyvinylidene difluoride, polytetrafluoro ethylene, polyoxymethylene, polyvinyl chloride, polycarbonate, styrene-ethylene-butylene styrene elastomer, styrene-styrene butylene elastomer or styrene-isoprene-styrene elastomer, irradiated after being coated with the deprata sulfate coating solution and dried, the material typically does not change its color.

The silver compositions, once coated, are preferably color stable (i.e., light stable as defined herein). In addition, preferably the compositions are also stable to at least one of the following: heat and / or humidity. Regarding the choice of substrate, the silver sulfate composition preferably has color stability. The initial development of the silver sulphate solution after drying at a specific temperature will remain unchanged over time (e.g. preferably at least 4 hours, more preferably at least 8 hours, most preferably at least 48 hours). and even more preferably at least 1 week) even with or without light exposure.

In certain situations, however, the coated silver sulfate will change its color. For example, in certain situations, irradiation of an artigomicrobicide after the article is placed in the package and the packaging material is sealed will cause color change. This often occurs when the substrate of the microbicidal article includes a cellulosic material. Radiation typically includes gamma radiation and / or electron beam radiation. Such radiation is typically used to sterilize microbicidal articles. Thus, typical radiation levels include those necessary to ensure a level of sterility assurance of 10-6, based on the AAMI sterility assurance method.

It has been found that this color change upon irradiation may occur in certain situations in the standard packaging with a relatively high volatile organic content (i.e., a volatile organic content (VOC) greater than 100 mg / m2). Examples of such standard packages include those available from Phoenix HealthcareProducts, LLC, Milwaukee1 W1 USA and VP Group, Feuchtwangen, Germany. Use of packaging material having a volatile organic content of at most 100 mg / m2 as described in the present invention, however, in certain situations will reduce, and often eliminate, such radiation-induced color change.

Low VOC packaging can be particularly useful when the color of the article is changed from its initial color (eg whitish) to a yellowish color or some colors other than another whitish color. The heat may cause color change to a state that is more stable to radiation than the initial color. For example, a silver sulfate composition that is dried to an off-white state will become dark when irradiated in the package with respect to volatile organic content; however, when it is heated to a temperature that causes the color change to yellowish, this state is generally more stable to irradiation and typically will not change color when irradiated in a package under VOC (ie, as in 100 g / m2 VOC), particularly when low humidity conditions are used to package the article, although it is in a high VOC package (unless large quantities of substrate material are used in relation to the amount of packaging material). For certain embodiments, the present invention provides a method for manufacturing a packaged microbicidal article that includes drying the coated substrate at a temperature, which causes the development of a yellowish color of the silver sulfate composition (typically due to the formation of silver in the valence state). zero during drying), which exhibits color stability during and / or after irradiation (typically, after irradiation, and preferably during and after irradiation).

This is particularly true for yellowish articles in a low VOC package (ie no larger than 100 g / m2 VOC) during and after electron beam irradiation, or for yellowish articles in a low VOC package after gamma irradiation (although color change occurs during gamma irradiation), or for yellowish articles in a low VOC package during or after gamma irradiation when low package moisture conditions are used (eg 30% relative or lower unit).

Off-white articles do not necessarily have color stability as yellowish articles under similar conditions, however, off-white articles may have color stability in low VOC packages with activated charcoal in the package, particularly after electron beam or gamma irradiation. Accordingly, the present invention provides a method for making a packaged artigomicrobicide which includes: preparing a composition comprising silver sulfate; coating the silver sulfate composition on a substrate; drying the coated substrate at a temperature which induces the deprata sulfate composition to develop an off-white color; place the microbicidal article in packaging material that has a volatile organic content of up to 100 mg per square meter; and sealing the packaging material with the artigomicrobicide therein; Activated charcoal is present in the packaging, and the microbicidal article has color stability during or after irradiation.

However, the low VOC package is not necessarily required with a yellowish article when the amount of artigofor substrate is greater than 2 mg per square centimeter within the packaging material. Accordingly, the present invention provides a packaged microbicidal article having color stability (and a manufacturing method) which includes: a microbicidal article including a substrate coated with a silver sulfate composition; and packaging having the microbicidal article in it; wherein the package includes a material having a volatile organic content of at most 100 mg per square meter, and the ratio of the microbicidal article substrate to the packaging material is greater than 2 mg substrate per square centimeter within the packaging material. Dry coated substrate includes zero-valence silver, has a yellowish tint and preferably exhibits color stability after irradiation.

The color stability of the silver coated sulphate composition provides several advantages. Color stability provides an indication to the end user that the product has a highly consistent quality. Therefore, the color stability indicates that the depressed shape on the substrate has not changed considerably, indicating that its performance (ie silver release microbicidal activity) is essentially constant over time in the package (eg preferably at least 1 month, more preferably at least 2 months, more preferably at least 6 months, and more preferably at least 1 year). Thus, the use of packaging as described in the present invention is desirable when the microbicidal articles of the present invention are irradiated and such color stability is desirable.

Such compositions are useful in medical articles, particularly wound bandages and wound covering materials, although a wide variety of other products may be coated with silver sulfate compositions. The stability of the silver sulfate coated substrate is prolonged and / or enhanced. when the relative humidity (RH) at ambient temperature (particularly during the packaging process) is maintained at 50% or less; more preferably at 30% or less; and most preferably at 20% or less. Relative humidity may be reduced to 30% and preferably to 20% or less for the silver sulfate coated substrate by a number of methods including: 1) placing the coated substrate in an environment that has a humidity 30% or less, and preferably 20% or less, and then pack the product in the same environment; 2) dry the net in an oven, then immediately pack the net, and 3) add a desiccant into the package. Preferably, to maintain a low relative humidity in the dry silver sulfate composition, the article should be packaged in a package with a low moisture vapor transmission rate (MVTR), such as a Techni-Pouch package (Technipaq, Inc., Crystal Lake). , IL1 USA) with a material / PET / LLDPE construction. The low relative humidity increases the thermal stability of silver sulfate treated cotton.

In certain situations, it may be desirable to take advantage of color change by irradiation (e.g., gamma radiation and / or electron beam radiation) which may occur in packaging with a volatile organic content greater than 100 mg / m 2. Thus, the present invention also provides a method for bleaching at least a portion of a microbicidal article. For example, if a microbicidal article has at least one colored portion beyond the off-white portion, and the article includes a substrate coated with a silver salt composition that includes at least one portion of the silver in the zero valence state, the irradiation may whiten the colored portion.

Silver compounds, including silver sulfate, provide sustained release of silver ions over time based in part on their equilibrium conditions of limited solubility and inherent dissociation. The silver sulphate composition may have other salt salts, including those without color stability, in varying amounts, provided that the composition, when coated on the substrate, remains color stable. In addition to silver sulfate, other silver compounds that may be applied as a coating on a substrate other than silver sulfate include oxide deprata, silver acetate, silver nitrate, silver citrate, silver chloride, silver lactate, silver phosphate. , silver stearate, silver thiocyanate, silver carbonate, silver saccharate, silver anthranilate, silver benzoate and combinations thereof. Silver metal may also be present on the substrate. Preferably, the amount of silver compounds other than silver sulfate is less than 20 wt%, more preferably less than 10 wt%, based on the total weight percent (wt%) of the silver components. in the silver sulfate composition coated on the substrate.

The silver sulfate coated substrate remains stable when it contains silver sulfate in combination with other silver salts with limited color stability. Preferably, the amount of deprata sulfate is at least 60 wt%, more preferably at least 75 wt%, and most preferably at least 90 wt% based on the total weight percent ( % by weight) of the silver components in the silver sulfate coated composition on the substrate.

Articles may be prepared by using the foil solution described herein according to a variety of coating methods. When a porous substrate is coated, the process typically used allows threads, filaments or films, such as perforated or microporous films, to be coated, although they leave most openings unobstructed by the composition. Depending on the structure of the support used, the amount of solution employed will vary over a wide range.

The silver sulphate coating solution may be prepared by mixing silver sulphate and distilled water. The silver sulphate coating solution may have a concentration range of up to about 0.6% water solubility at room temperature. Higher concentrations of silver sulfate are obtained by dissolving the silver sulfate in hot water. Optionally, sulfate may be added in other forms, such as sodium sulfate.

The process can be performed as a continuous process, or it can be performed in one step or with a single solution for the coating. The coating application process does not require high temperatures, and can be applied at temperatures below 70 ° C. The coating solution may be maintained at a pH below 9, and preferably less than 7, to minimize adverse effects to the substrate. The coating solution can be kept at a pH above 4.

In one embodiment of this process, a substrate may be passed through a silver composition bath. The substrate coated by the silver sulfate composition is then dried, for example, in an oven at a temperature sufficient to evaporate the solution constituents. The temperature is preferably below 190 ° C, more preferably below 170 ° C and most preferably below 140 ° C.

The silver sulfate solution may also be coated onto a carrier mesh or reinforcement (described below) using a coating technique such as gravure coating, curtain coating, matrix coating, knife coating, cylinder coating or coating. by sprinkling. A preferred coating method is gravure coating.

Medical Articles The silver compositions of the present invention may be used in a wide variety of products, although they are preferably used in medical articles. These medical articles may be in the form of wound bandages, wound covering materials or other materials that are directly applied to a wound. Other potential products include clothing, bedding, masks, dust cloths, shoe inserts, hospital diapers, such as blankets, dressings and surgical gowns.

Silver compositions may be coated on various reinforcements (i.e. a support substrate). The support reinforcement or substrate may be porous or non-porous. The composition of the present invention may be coated on or impregnated with the support substrate, for example.

Suitable materials are preferably flexible, and may be woven, nonwoven or woven polymeric webs, polymer films, hydrocolloids, foams, foils, paper and / or combinations thereof. More specifically, cotton gauzes are useful in the silver compositions of the present invention. For certain embodiments, it is desirable to use a permeable substrate (e.g., relative to moisture vapor) and with openings (i.e. a scrim). For certain embodiments, the substrate may be a hydrocolloid, such as a hydrophilic polymer or hydrophobic depolymer matrix containing hydrophilic particles, as described in U.S. Patent Application Nos .2004 / 0180093 and 2005/0124724.

The substrates (ie reinforcements) are preferably porous to allow the passage of wound fluids, moisture vapor and air. In certain embodiments, the substrates are substantially impermeable to liquids, especially to wound exudates. In certain embodiments, the substrates are capable of absorbing liquids, especially differing exudates. In certain embodiments, the substrate is a liquid permeable apertured substrate.

Suitable porous substrates include meshes, fabrics (e.g. cotton wool and gauze), nonwovens (including non-woven continuous-blanking and BMF (blown microfibers), extruded porous leaves and perforated leaves. The apertures (i.e. holes) in the porous substrates are of sufficient size and number to facilitate high air permeability.For certain embodiments, porous substrates have at least 1 square centimeter aperture.For certain embodiments, porous substrates have no more than 225 apertures per square centimeter. an average aperture size (i.e. the largest aperture dimension) of at least 0.1 millimeter (mm). For certain embodiments, the apertures have an average aperture size (i.e. the largest aperture dimension) not greater than 0, 5 centimeter (cm).

For certain embodiments, porous substrates have a basis weight of at least 5 grams / meter2. For certain embodiments, porous substrates have a weight of no greater than 1000 grams / meter2, and in some embodiments no larger than 200 grams / meter2.

The porous substrates (i.e. reinforcements) are preferably flexible and tear resistant. For certain embodiments, the thickness of the porous substrates is at least 0.0125 millimeter (mm). For certain embodiments, the thickness of porous substrates is not greater than 15 mm, and for other embodiments not greater than 3 mm.

Reinforcement or support substrate materials include a wide variety of materials including paper, natural or synthetic fibers, filaments and yarns made from materials such as cotton, rayon, wool, hemp, jute, nylon, polyesters, polyacetates, polyacrylic, alginates. , ethylene propylene diene rubbers, natural rubber, polyesters, polyisobutylenes, polyolefins (for example, polypropylene polyethylene, ethylene propylene, and ethylene butylene copolymers), polyurethanes (including polyurethane foams), vinyls including polyvinyl chloride eacetate ethylene vinyl, polyamides, polystyrenes, glass fibers, ceramic fibers and / or combinations thereof.

The reinforcement may also be provided with extension release properties. The term release by extension refers to the property of an adhesive article characterized by the fact that when the article is pulled from a surface, it detaches from the surface without leaving significant residues visible. For example, a film reinforcement may be formed from a highly extensible and highly elastic composition which includes ABA elastomeric and thermoplastic block polymers having a low rubber modulus, a longitudinal elongation of at least 200% up to and a 50% modulus. of rubber not exceeding 13.8 megapascals (MPa) (2,000 pounds / square inch). Such reinforcements are described in U.S. Patent No. 4,024,312 (Korpman). Alternatively, the reinforcement may be highly extensible and substantially non-recoverable, as described in U.S. Patent No. 5,516,581 (Kreckel etal).

In certain embodiments, the coated substrates of the present invention are non-adherent, although it should be understood that a adhesive (e.g., a pressure sensitive adhesive) could be added to an article coated with the solution. For use in the present invention, the silver compositions of the present invention when applied with coating on a substrate do not significantly adhere to a wound tissue such that they do not cause pain and / or destruction of the wound tissue upon removal and exhibit a peel resistance. 180 ° less than 1 N / cm of steel as described in US Patent Application No. 2005/0123590.

In certain embodiments, silver-coated substrates may be coated on one or both sides by a non-adherent permeable outer layer to reduce adhesion and attachment to the wound. The non-adherent layer may be attached to the substrate, such as coating or lamination. Alternatively, the coated substrate may be enclosed within a non-stick layer such as a glove. Nonstick fabrics may be produced from woven or non-woven materials such as nylon coatings or perfluorinated materials on cotton gauze. The non-stick layer avoids the attachment of materials to the enclosed silver-coated substrate. At the same time, the non-adherent layer adversely affects the sustained release of silver from the coated substrate.

In another embodiment, the reinforcement or support substrate may be comprised of non-adherent materials. For example, a non-stick hydrophilic polymer may be used as the reinforcement or support material, or applied as a coating on a permeable porous substrate as described in U.S. Patent Nos. 2004 / 0180093,2005 / 0123590 and 2005/0124724.

If desired, the coated substrate may be covered by two protective films (e.g., thin polyester films). Such films may optionally include nonstick treatment and may function to facilitate extraction from a package and handling of the article. If desired, the coated substrate may be cut into individual pads of suitable size, packaged in sealed, sterile sachets.

Pressure sensitive adhesives used in medical articles may be used in the articles of the present invention. That is, a pressure sensitive adhesive material could be applied to the article of this invention, for example, around the periphery for the purpose of adhering the article to the skin.

Examples

The objects and advantages of this invention are further illustrated by the following examples, but the particular materials and quantities reported in these examples, as well as other conditions and details, should not be construed to unnecessarily limit this invention. Except where otherwise noted, all parts and percentages are on a weight basis, all water is distilled water, and all weight average molecular weight are.

Test ProtocolsVolatile Organic ContentVolatile organic content (VOC) can be determined using an ASTM D 2369-03. Three containment bags were placed in a room with constant temperature and humidity (CTH) (50% relative humidity at 23 ° C) for 48 hours. Six samples were extracted with a 8.9 cm by 8.9 cm puncture matrix for each containment bag material. Each sample was weighed on a Mettler scale. The samples were placed with the polyethylene facing up on aluminum trays and placed in an oven with forced air circulation at 110 ± 5 ° C for 60 minutes (min). The samples were rebalanced in the room with constant temperature and humidity for 48 hours and then re-weighed.

Color Change

Color change was assessed by visual classification under fluorescent lighting (Philips, F32T8 / TL735, Universal / Hi-Vision, E4). Samples were compared to color patterns and determined on an index based on visual comparison. The color change was the difference in index obtained by subtracting the initial index from the index after treatment. Positive indices represent a darkening appearance and negative indices represent a darkening appearance.

Samples with color ratings (1 to 10) of silver-coated cotton samples were also measured using a 5 Minolta Chroma Meter (CR-300, produced by Konica Minolta Photo Imaging, Inc., Mahwah1 NJ1 USA) and presented the following results.

Table 1. Classifications of measured color core

<table> table see original document page 25 </column> </row> <table>

Silver Measurements

Total Silver

Silver content in the bandage was measured using the EPA1 EPA 601OB procedure with ICP-AES detection.

Bandage Silver Ion Release

The release of silver ions from the bandage after 30 minutes of immersion in distilled water was determined using an ion-selective Ag electrode (Orion, available from VWR International, Batavia1 IL1 USA). Two 3,175 cm diameter disks were cut from the blanket, weighed and placed in 98 milliliters (mL) of distilled water and 2 mL of 5M NaNO3 added to the amber bottle. The bottle was capped with a TEFLON screw cap and placed on a container cylinder. After 30 minutes, an ion selective electrode and a double junction reference electrode were placed in the solution. The temperature was 21.2 ° C. The voltage across the electrode was measured. A standard curve was determined by graphically representing the Iog (silver ion concentration) versus standard millivolts (mV), 1 microgram (pg) Ag + AnL and 10 pg Ag + / mL and using this curve to determine the sample ion release. of silver converting semV into concentration of silver ions.

Substrate Anion Content

The anion content of the substrates was determined using the following procedure.

Extraction: Samples were weighed into 50 mL polypropylene centrifuge tubes with 25 mL of 18 pip pipetted water. Samples were extracted for 24 hours at room temperature, during which time the cotton was removed. The sample was analyzed in triplicate with triplicate controls using ion chromatography (IC).

IC: Solutions were transferred to 0.7 mL self-sampling vials. Then, a 30 µl aliquot was injected from each autosampler vial into a DIONEXDX500 ion chromatograph using an AS3500 autosampler. The DIONEX chromatograph used a GP40 gradient pump and EG40 eluent generator to establish an eluent flow (10 to 54 mM water gradient with 18MQ) of 1 mL per minute. A conductivity detector (ED40), a self-regenerating suppressor and columns AS18 (analytical) and AG18 (guard) were used. The concentration of extractable anions in units of parts per million (ppm, pg / g) was determined by using standard solutions to calibrate the system for fluoride, acetate, formate, chloride, sulfate, bromide nitrate and phosphate.

Several substrates were evaluated for anion content before being coated with silver salts. The anion content was determined through the use of ion chromatography by the procedure described above which provided the results in table 2.

<table> table see original document page 27 </column> </row> <table>

<table> table see original document page 27 </column> </row> <table> <table> table see original document page 28 </column> </row> <table>

Example 1

Silver Sulfate Coated Upper Anion Containing Cotton Substrate

A silver sulfate coating solution was produced by mixing silver sulfate (Colonial Metals Inc., Elkton, MD1 USA) and water to produce a solution of 0.133 g AgSO4 per 100 g water. The 100% hydroentangled cotton blanket (50 g / m2; 30.48 cm wide, produced by Spuntech Industries, Upper Tiberius, Israel) was lined with a slit die. The pump speed was 316 mL / min. The mantle coat was dried at 180 ° C (356 ° F). The length of the oven was 15.24 meters (m). The speed of the blanket was 3.048 m / min. The dry blanket was golden yellow. The blanket was wrapped and placed in a thermoselable foil containment bag. 4.7 mg total silver was obtained per gram of stamping (method: EPA 601OB using ICP-AES). The release of deprata ions was determined at 4.2 mg Ag + / g bandage by the defined method.

The bandages were cut by matrix and placed in various materials for packing at a water activity = 0.5 and the packing was sealed. The packaged silver bandages were either beam irradiated at 30 kGy or gamma ray 38 kGy. The samples were stored at room temperature for 1 to 8 weeks before the color change was assessed. Table 4 presents the results of these evaluations.

Table 4. Example 1 Color Change.

<table> table see original document page 29 </column> </row> <table>

indicates that the banding after irradiation was not homogeneous in color due to stripe or edge bleaching; pre-irradiation color = 4Example 2

Silver Sulfate Coated Lower Anion Containing Cotton Substrate

The bandage of example 2 was produced according to example 1 except that the 100% hydroentangled cotton blanket was produced by Unitika Ltd., Osaka, Japan; under the tradename COTTOASE, 280 mm (mm) wide; 50 grams per square meter (g / m2). This resulted in a 5.5 mg bandage of total silver per gram bandage (method: EPA 601OB using ICP-AES) and a silver ion release of 3.6 mg Ag + / g of the bandage was measured by the method on Test. The dry bandage was yellow in color.

The bandages were cut by matrix and placed in various materials for packing at a water activity = 0.5 and the packing was sealed. The packaged silver bandages were either beam irradiated at 30 kGy or gamma ray 38 kGy. The samples were stored at room temperature for 1 to 8 weeks before the color change was assessed. Table 5 presents the results of these evaluations.

Table 5. Example 2 Color Change.

<table> table see original document page 30 </column> </row> <table>

* indicates that the bandage after irradiation was not homogeneous in cordevivo to bleaching on stripes or edges; pre-irradiation color = 3Example 3

Silver Sulphate Coated Lower Anion Containing Cotton Substrate The bandage of Example 3 was prepared according to Example 2 except that the drying temperature was 79 ° C (175 ° F). The dry silver sulfate-coated cotton was white. 5.3 mg total silver per gram of bandage was obtained (method: EPA B using ICP-AES) and the release of silver ions in the bandage was 3.5 mg Ag + / g of bandage by the method defined in the protocol. test. The bandages were die cut and placed into the various packaging materials at a water activity = 0.5 and an inserted activated carbon pipe (ACC) was then added and the thermoseal packing, comband packing and no insert elements were also prepared. The packaged silver bandages were either irradiated by a 30 kGy electron beam or 38 kGy gamma irradiated. The samples were stored at room temperature for 1 to 8 weeks before the color change was assessed. The table shows the effect that present activated carbon on packaging has on the white bandage material of example 3 in various packaging materials.

<table> table see original document page 31 </column> </row> <table> <table> table see original document page 32 </column> </row> <table>

indicates that the bandage after irradiation was not homogeneous in cordevivo to bleaching on stripes or edges; pre-irradiation color = 0

Example 4

Silver Sulfate Coated Multiple Component Nonwoven

Silver sulfate coated on the substrate was prepared as in Example 1 except that the mat was a multicomponent composite Tencel Iiocel fiber / CELBOND type 254 bicomponent fiber (PET / Copolyester, 2.0 denier): 95/5 A Tencel's Iiocel fiber was produced by Lenenzing AG. CELBOND Type 254 bicomponent fiber was produced by Trevira1 Spartanburg, SC. 4.7 mg total silver was obtained per gram of stamping (method: EPA 601OB using ICP-AES). Deprate ion release was measured as 2.5 mg Ag + / g bandage by the test procedure described in the Test Protocol section.

The bandages of example 4 did not show stability for 8 weeks in the P-1 package after electron beam irradiation or gamma irradiation at a water activity of 0.5 or near water activity 1.

The wraps in example 4 did not exhibit stability at 50% relative humidity or 100% relative humidity in the To-1 package after the electron beam.

A silver sulfate coating solution was prepared by placing 0.289 g silver sulfate and 200 g distilled water in a glass bottle, capping and stirring at room temperature overnight. The resulting silver sulfate solution (approximately 1000 pg Ag / g) was coated on a 100% cotton hydroentangled nonwoven web (COTTOASE containing less than 20 ppm chloride) by pipetting the solution to saturate the net. which was contained in a polystyrene plate. Each piece of non-woven mesh (50 grams per square meter (gsm)) was treated with approximately 5.5 g of solution in a 11.11 cm x 11.11 cm (4.375 inch by 4.375 inch) mesh piece. Approximately one gram of coating solution was drained from the mesh before the mesh was suspended in the oven for drying. Some additional solution drained from the mesh in the oven (estimated at 1 g). The redcoat was dried in a forced-air oven (Memmert Universal University, available from the Wisconsin Oven Company, East Troy, WI, USA) by heating at 170 ° C for 12 minutes. The color of the samples after drying was golden yellow. The samples were placed in a foil-containing bag (Tolas Health Care Packaging, construction TPC-0765B / TPC-0760B) after drying and kept at a relative humidity within the containment bag of less than 25%. The samples were also sealed in the foil holding bag after drying and then exposed to gamma irradiation (32.9 to 33.5 kGy). Samples were removed from the containment bags for color measurement at 2 and 29 days after irradiation. The CIE trimestimetric color values of the samples were measured using a Minolta chromometer (CR-300, produced by Konica Minolta Photo Imaging U.S.A., Inc., Mahwah, NJ, USA). The results are shown in Table 7.Table 7. Color of Example 5.

<table> table see original document page 34 </column> </row> <table>

Example 6

The samples were prepared in the same manner as shown in

Example 5, except that the substrate was 100% cotton nonwoven 5 available from Suntec Union, Japan (Nissinbo, AN20601050, 60 gsm). The sample strings were a uniform golden yellow. Results are shown in Table 8.

Table 8. Example 6 color.

<table> table see original document page 34 </column> </row> <table>

Example 7

The samples were prepared in the same manner as examples 5 and 6 and were then measured for silver release into a distilled water and sodium nitrate solution using an ion-selective silver electrode (Orion, available from VWR International, Batavia1 IL, USA). Sodium nitrate is used as an ionic strength adapter. Release was measured as described in the test protocol section. The results of these measurements are in Table 9.

Table 9. silver ion release. _

<table> table see original document page 35 </column> </row> <table>

Example 8

A 40 g / m2 100% hydroentangled cotton nonwoven substrate was continuously immersed coated in an approximately saturated silver sulfate solution, stirred to remove the solution for overcoating, and then dried at approximately 175 ° C. The resulting coated substrate contained a total of 6 mg silver per gram of substrate and had a golden yellow color. Samples of 10 cm x 20 cm (four inches by 8 inches) were cut from the coated substrate, and then folded into two 10-layer samples x 10 cm (4 inches x 4 inches). These two-layer samples were then placed in porous packages of 14.6 cm χ 24.8 cm (5.75 "χ 9.75") unprinted Chevron non-sticking containment bags; uncoated construction TYVEK 1073B / TPF-0501A; Fools Health CarePackaging1 Feasterville1 PA, USA containing a VOC content of less than 50 mg / m2), and the package has been heat sealed. Some of these packed samples were then irradiated by electron beams at 21.5 to 28.9 kGypor Steris Isomedix in Libertyville, IL, USA, and some of these packed samples were not irradiated.

Three packed samples (irradiated by electron beams or not) were then placed in a second non-porous package (custom-made by Technipaq Inc. Crystal Lake, IL USA; unprinted bottom interlining zipper bag; DO 31.8 cm χ26.7 cm x, 6.4 cm (12.5 inches χ 10.5 inches χ 2.5 inches) Nylon Biax 60 ga / A / 0.00035 sheet metal / A / 0.009 cm (3.5 mil) low density linear polyethylene construction) along with a 3.0 g activated carbon / silica gel (50/50) sorbent sachet (MultisorbTechnologies, Inc., Buffalo, NY, USA). After addition of the packaged samples and absorbent sachet, the second non-porous package was thermosealed, and then aged at room temperature.

Samples were removed from both containment bags for color measurement at specific aging times as described in table 10. The CIE sample color trimmers values were measured using a Minolta chrometer (CR-300, produced by Konica Minolta Photo Imaging USA, Inc., Mahwah, NJ, USA). The results are shown in Table 10.

Table 10. Color of Example 8.

<table> table see original document page 36 </column> </row> <table> <table> table see original document page 37 </column> </row> <table>

The full patent descriptions, patent documents and cited publications of the present invention are incorporated herein by reference in their entirety as if each were individually incorporated. Various modifications and changes to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It is to be understood that this invention is not intended to be unduly limited by the embodiments and illustrative examples set forth herein, and that such examples and embodiments are given by way of example only, and the scope of the invention is intended to be limited only by the claims set forth herein as follows. form.

Claims (10)

Method for the manufacture of a packed ARTIGOMICROBICIDE, characterized in that it comprises: preparing a composition comprising silver sulfate, coating the silver sulfate composition with a substrate, drying the coated substrate to form a microbicidal article, placing the article microbicide in packaging material having a volatile organic content of at most 100 mg / m2; and seal the packaging material with the microbicidal article therein. Method according to claim 1, characterized in that the substrate is an oxidizable silver nitrate substrate. Method according to claim 2, characterized in that the drying of the coated substrate occurs at a temperature which causes the development of a yellowish color of the silver desulfate composition, due to the formation of silver in the zero-valence state and also , wherein the microbicidal article exhibits color stability after irradiation. Method according to claim 1, characterized in that the microbicidal article is maintained in an environment of no more than 50% relative humidity at ambient temperature. Method according to claim 1, characterized in that the packaging material has an oxygen permeability of less than 0.01 cm3 / 645 cm2 / 24 hours and / or a moisture vapor transmission rate of less than 0.01 g / 645 cm 2/24 hours. Method according to claim 1, characterized in that the packaging material comprises an inner containment bag and an outer containment bag, the inner containment bag having a Gurley Hill porosity of less than 100 s / 100 cm3 less. , and the outer containment bag has an oxygen permeability of less than 0.01 cm3 / 645 cm2 / 24 hours and / or a vapor transmission rate of less than 0.01 g / 645 cm2 / 24 hours. Method according to claim 1, characterized in that the silver sulfate composition further comprises silver compounds other than silver sulfate. PACKED MICROBICIDE ARTICLE, characterized in that it is produced by the method as described in claim 1. 9. PACKED MICROBICIDE ARTICLE, characterized in that it comprises: a microbicidal article comprising a substrate coated with a silver sulfate composition; and the package having the microbicidal article sealed therein, the package comprising material having a volatile organic content of at most 100 mg / m 2. 10. Method for whitening at least a portion of a microbicidal article, comprising: colored portion other than white, the article comprising a substrate coated with a silver salt composition comprising at least one silver portion in the valence state, and the artigomicrobicide being sealed within the package comprising material having a volatile organic content greater than 100 mg / m2; radiate the packaged microbicidal article to whiten at least a portion of the microbicidal article. provide a packaged microbicidal article having at least one