Antimicrobial compositions and articles made therefrom

Abstract

An antimicrobial agent impregnated adhesive sheet includes an antimicrobial agent and a pressure sensitive adhesive. The sheet includes a first major surface and a second major surface. The sheet includes a plurality of surface recesses extending inwardly from the first major surface. An onset available fraction of the antimicrobial agent at the first major surface is at least 30% based on the total amount of antimicrobial agent in the antimicrobial-impregnated adhesive sheet. After accelerated aging, the sheet exhibits a retention of at least 50% of the starting available fraction of the antimicrobial agent at the first major surface.

Description

Background Art

[0001] Preservative impregnated adhesives are discussed, for example, in US Pat. Nos. 4,323,557, 9,713,659, and 9,764,059. DETAILED DESCRIPTION

[0002] Despite advances in infection control practices, surgical site infections (SSIs) remain a significant cause of morbidity, prolonged hospital stays, and mortality. In fact, SSIs are associated with a 3% mortality rate, and 75% of SSI-related deaths can be directly attributed to SSIs. Surgeons currently rely on surgical drapes with iodine-impregnated adhesives to reduce exposure to pathogenic microorganisms. Although povidone-iodine is a widely effective antiseptic, its use also has disadvantages. For example, povidone-iodine may cause skin irritation in some individuals, and its use on large wounds may lead to kidney problems, hypernatremia, and metabolic acidosis. In addition, povidone-iodine is not recommended for those who are less than 32 weeks pregnant, those who are prescribed lithium, or those who have thyroid problems. Chlorhexidine gluconate and octendine hydrochloride are viable alternatives that are not associated with the above backup drugs.

[0003] The development of antiseptic-impregnated adhesives (e.g., chlorhexidine gluconate and octenidine hydrochloride impregnated adhesives) would help reduce surgical site infection rates while potentially avoiding the side effects associated with povidone-iodine. Thus, pressure-sensitive adhesives capable of carrying and delivering chlorhexidine gluconate, octenidine hydrochloride, and the like are desirable.

[0004] Efforts to develop preservative-impregnated adhesives have encountered significant challenges. Chlorhexidine gluconate ("CHG") and octenidine hydrochloride ("octenidine"), each a highly polar compound, tend to precipitate from hydrophobic adhesive compositions. The lack of CHG solubility or octenidine solubility in the adhesive effectively immobilizes the CHG or octenidine, preventing it from adequately transferring to the surface. In addition, blending additives such as CHG and CHG solubilizing vehicles often compromise the strength of the adhesive, which results in premature adhesive failure. In the case of surgical drapes, this premature adhesive failure is referred to as "drape drift." When a surgical drape moves or "drifts," the patient is more exposed to microorganisms and becomes more susceptible to infection.

[0005] The present disclosure relates to compositions based on water-soluble antimicrobial agents (e.g., chlorhexidine gluconate-based or octenidine hydrochloride-based) for inclusion in pressure-sensitive adhesive (PSA) formulations, and medical articles made therefrom. Initially, it was believed that a hydrophilic (polar) vehicle was required to make chlorhexidine gluconate or octenidine hydrochloride compatible with adhesives. It was later discovered that hydrophobic (non-polar) vehicles with ortho (i.e., two atoms apart; adjacent) or otherwise proximal (i.e., three atoms apart) hydrogen bonding groups effectively dissolve chlorhexidine gluconate and octenidine hydrochloride, which in turn makes hydrophobic chlorhexidine gluconate solutions and hydrophobic octenidine solutions compatible with hydrophobic pressure-sensitive adhesives (see WO 2014 / 035981). It was later discovered that although chlorhexidine gluconate and octenidine are polar compounds, they are readily soluble in hydrophobic plasticizers having hydrogen bonding groups separated by more than three atoms, and that hydrophobic vehicles with vicinal hydrogen bonding groups may be detrimental to adhesive integrity compared to compositions without the hydrophobic vehicle.

[0006] However, it was subsequently discovered that compositions with such hydrophobic plasticizers, while initially providing adequate availability of chlorhexidine gluconate or octenidine at the working surface of the adhesive (i.e., the surface of the adhesive intended to be closest to the patient's skin) ("available surface concentration"), decreased significantly over time in storage. To address this deficiency, compositions and methods were discovered that included a PSA having certain HLB values ​​and an aqueous antimicrobial component having an increased water concentration to produce a preservative-impregnated PSA having very high initial available surface concentrations of chlorhexidine gluconate or octenidine at the working surface of the adhesive. However, while an improvement over existing compositions, these initially very high levels of preservative availability were found to decrease to undesirably low levels over time in storage in some cases.

[0007] Therefore, compositions and methods for minimizing the decrease in surface concentration of available preservatives over time remain desirable.

[0008] In this work, the following combinations of substances were surprisingly found:

[0009] (i) a PSA having a certain HLB value; and

[0010] (ii) an aqueous antimicrobial component (e.g., an aqueous chlorhexidine salt component) having (a) a content of water; and (b) a water-soluble complexing agent;

[0011] In combination with a mixing technique (wherein an aqueous antimicrobial component is combined with a solvent adhesive solution for a relatively short time before the mixture is applied to a substrate (e.g., an adhesive backing or release liner)), an antimicrobial-impregnated adhesive can be produced that (i) has an initial very high initial working surface concentration of the antimicrobial component, and (ii) has the ability to maintain or substantially maintain such a high working surface concentration over time in storage. It has been further discovered that the presence of these very high working surface concentrations (and, as will be discussed in more detail below, the associated surface features at or near the working surface) do not adversely affect the adhesive properties of the antimicrobial-impregnated adhesive even under fluid challenge.

[0012] As used herein, "acid" refers to a carboxylic acid group, i.e., -CO 2 H.

[0013] As used herein, "complexing agent" refers to a compound having at least two hydrogen bonding functional groups and capable of cooperative intermolecular hydrogen bond formation. Cooperative action means the inherent ability to form multiple hydrogen bonds.

[0014] As used herein, "disinfection" refers to reducing the number of active microorganisms present on the surface being disinfected. Disinfection can kill or prevent the growth or proliferation of microorganisms.

[0015] As used herein, "hydrophile-lipophile balance" or "HLB" values ​​are calculated using the Griffin method (Griffin WC; J. Soc. of Cosmetic Chemists 5, 259 (1954)). Thus, as used herein, the "HLB method" involves a calculation based on:

[0016]

[0017] Among them, M h HLB is the molecular weight of the hydrophilic portion of the molecule and M is the molecular weight of the entire molecule, giving results ranging from 0 to 20. An HLB value of 0 corresponds to a completely lipophilic / hydrophobic molecule and an HLB value of 20 corresponds to a completely hydrophilic / lipophobic molecule.

[0018] As used herein, "plasticizer" refers to a substance or combination of substances that lowers the glass transition temperature of another substance (e.g., a pressure sensitive adhesive). Plasticizers effectively soften, increase flexibility, increase plasticity, reduce viscosity, and / or reduce friction of the substance to which the plasticizer is added.

[0019] As used herein, "polymer" refers to a substance having one or more repeating monomeric units. The chemical properties of polymeric substances herein are sometimes described in terms of the monomers from which the polymer is derived. The skilled artisan will readily understand the reactive characteristics of the monomers and how the monomers can be synthetically joined to form a polymer.

[0020] As used herein, "pressure sensitive adhesive" refers to a non-reactive, self-adhesive adhesive that forms a bond when pressure is applied. No solvent, water, or heat is required to activate the pressure sensitive adhesive.

[0021] When referring to "solubility" or "solubilization", it is understood that the solubility of component A in component B refers to the conditions where only component A and component B are present, e.g., no added salts, compounds, etc. In addition, any solubility values ​​provided herein are referenced to a temperature range of about 20°C to about 23°C at atmospheric pressure (i.e., 760 mm / Hg).

[0022] In some embodiments, the present disclosure relates to an antimicrobial adhesive.The antimicrobial adhesive can be formed by mixing a solvent-based pressure sensitive adhesive solution and an aqueous antimicrobial composition.

[0023] In some embodiments, solvent-based pressure-sensitive adhesive solution can comprise solvent and pressure-sensitive adhesive.Suitable solvent can comprise any organic solvent that can be miscible with pressure-sensitive adhesive.For example, solvent can comprise ethyl acetate, heptane, toluene and methyl ethyl ketone, propyl acetate, butyl acetate, acetone, methyl propyl ketone, methyl isobutyl ketone, dimethylacetamide, dimethyl formamide, dimethyl sulfoxide, N-Methyl pyrrolidone, hexane, sherwood oil, tetrahydrofuran, lower alcohol, glycol ether, dimethylbenzene and their combination etc.

[0024] In some embodiments, pressure-sensitive adhesive can be selected from acrylic polymer or copolymer.In some embodiments, acrylic polymer or copolymer can be the reaction product of one of the monomers selected from (methyl) alkyl acrylate, N-vinyl pyrrolidone, N-vinyl caprolactam, (alkyl substituted) acrylamide, (alkyl substituted) methacrylamide, (methyl) 2-hydroxyethyl acrylate or and their combination.In some embodiments, pressure-sensitive adhesive can be selected from rubber polymer or copolymer.Suitable rubber polymer includes natural rubber, polybutadiene and polyisobutylene.Suitable rubber copolymer includes styrene block copolymer, such as styrene-butadiene-styrene, styrene-isoprene-styrene and styrene-ethylene-butadiene-styrene.In some embodiments, pressure-sensitive adhesive can be selected from the organosilicon polymer of tackification.

[0025] In some embodiments, the pressure sensitive adhesive may be characterized by a glass transition temperature (T gIn some embodiments, the pressure sensitive adhesive may be characterized by a T in °C of about -70, -60, -50, -40, -30, -20, -10, -5, 0, 5, 10, or 20, or a value within a range between any of the foregoing values, such as about -20 to about 5, about -50 to about -30, etc. g .

[0026] As mentioned above, it has been found that pressure sensitive adhesives having HLB values ​​within a certain range can partially contribute to the formation of antimicrobial adhesives having very high working surface antimicrobial concentrations. Generally speaking, it is believed that such certain HLB values ​​contribute to the generation of relatively large discrete secondary phase regions, which will be discussed in more detail below. In this regard, in some embodiments, the pressure sensitive adhesive may have an HLB value of less than 5, less than 4.6, or less than 4.5.

[0027] In some embodiments, the pressure-sensitive adhesive solution may include 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, or a value in a range between any of the foregoing values, such as 15 wt% to 50 wt% or 15 wt% to 30 wt% of the pressure-sensitive adhesive. In some embodiments, the pressure-sensitive adhesive solution may include 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, or a value in a range between any of the foregoing values, such as 50 wt% to 90 wt% or 50 wt% to 80 wt% of the solvent, based on the total weight of the pressure-sensitive adhesive solution.

[0028] In some embodiments, in addition to pressure-sensitive adhesive and solvent, the pressure-sensitive adhesive solution can also include a plasticizer. Any suitable plasticizer can be used, as long as it can not unacceptably affect the pressure-sensitive adhesive solution or the property of the PSA made therefrom. This plasticizer can be optimally selected to be compatible (that is, miscible) with other components in the adhesive composition. Potentially suitable plasticizers include various esters, such as esters of adipic acid esters, formates, phosphates, benzoates, phthalates, dimer diacids and dimer glycol; Sulfonamides and naphthenic oils. Other possible suitable plasticizers include, for example, hydrocarbon oils (e.g., those of aromatic, paraffinic or cycloparaffinic hydrocarbons), vegetable oils, hydrocarbon resins, polyterpenes, rosin esters, phthalates, phosphates, dibasic acid esters, fatty acid esters, polyethers, and combinations thereof; vegetable fats and oils, such as olive oil, castor oil, and palm oil; animal fats and oils, such as lanolin; fatty acid esters of polyols, such as glycerol fatty acid esters and propylene glycol fatty acid esters; and fatty acid alkyl esters, such as ethyl oleate, isopropyl palmitate, octyl palmitate, isopropyl myristate, isotridecyl myristate, and ethyl laurate, fatty acid esters. Any of the above plasticizers may be used alone or in combination (and / or in combination with any other additives mentioned herein). The plasticizer, if present, can be present in an amount of 10 wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt %, 50 wt %, or a value within a range between any of the foregoing values, e.g., 10 wt % to 50 wt % or 15 wt % to 30 wt %, based on the total weight of the pressure-sensitive adhesive solution.

[0029] In various embodiments, aqueous antimicrobial compositions may include one or more antimicrobial agents, water, and one or more water-soluble complexing agents.

[0030] In some embodiments, suitable antimicrobial agents can include any antimicrobial agent that is selectively soluble in water (that is, soluble in the secondary phase / aqueous phase but insoluble in the primary phase / organic phase). It should be noted that the flexibility of suitable antimicrobial agents represents the advantages of the antimicrobial adhesive of the present disclosure. That is, although existing antimicrobial adhesives are formulated to exclude water in particular by drying the water in the commercially available aqueous antimicrobial drug before incorporation, dissolving the drug in a hydrophobic plasticizer in advance, or utilizing an organic soluble antimicrobial agent, the concepts and advantages of the present disclosure can be realized with any selective water-soluble antimicrobial agent. In some embodiments, suitable water-soluble antimicrobial agents (and they are selectively soluble in water) can include chlorhexidine gluconate (CHG), chlorhexidine acetate, octenidine hydrochloride, polyhexamethylenediamine biguanide salt (PHMB), quaternary ammonium salts, chlorhexidine salts, silver salts, water-soluble iodophors, triclosan, or a combination thereof.

[0031] In some embodiments, based on the total weight of the aqueous antimicrobial composition, the water-soluble antimicrobial agent can be present in the aqueous antimicrobial composition in an amount of at least about 0.05% by weight. In some embodiments, based on the total weight of the aqueous antimicrobial composition, the water-soluble antimicrobial agent can be present in the aqueous antimicrobial composition in an amount of no more than about 5% by weight. In some embodiments, the water-soluble antimicrobial agent can be present in the aqueous antimicrobial composition in an amount of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, or a value within the range of any of the foregoing values, for example, about 0.2 to about 4.0 or about 2.0 to about 3.0 (wt % relative to the total weight of the aqueous antimicrobial composition).

[0032] In some embodiments, the aqueous antimicrobial composition can comprise water.As discussed above, find that the existence of water higher than the conventional use of about the antimicrobial adhesive in a certain range can partly help to form an antimicrobial adhesive with very high working surface antimicrobial concentration.More specifically, and as will be discussed further below, find that water exists at least partly to help to form larger discrete water region (for example, droplet) when solvent-based pressure-sensitive adhesive solution and the aqueous antimicrobial composition mix with the concentration higher than the conventional use.In this respect, in some embodiments, based on the gross weight of the aqueous antimicrobial composition, water can be present in the aqueous antimicrobial composition in the amount of 20 % by weight to 80 % by weight, 30 % by weight to 70 % by weight or 40 % by weight to 60 % by weight.

[0033] In some embodiments, the aqueous antimicrobial composition can comprise one or more water-soluble complexing agents.Usually, it is found that comprising this type of complexing agent helps to significantly reduce (or retain increase) the reduction of available surface concentration over time.It is believed that this type of reduction can be attributed to the ability of complexing agents, that is, complexing agents combine with preservatives and suppress it to move into the adhesive body after the composition drying produced by combining the above-mentioned solvent-based pressure-sensitive adhesive solution with the aqueous antimicrobial composition.Suitable water-soluble complexing agents can include any water-soluble compound falling in the complexing agent definition provided above. In some embodiments, suitable water-soluble complexing agents can include monomeric polyhydroxylated compounds (charged or uncharged) (e.g., glycerol, erythritol, sorbitol, xylitol, sodium gluconate, maltitol, trehalose), polymeric polyhydroxylated compounds (e.g., polyglycerol, poly(vinyl alcohol), dextrin, cyclodextrin, partially hydrolyzed poly(vinyl acetate), carrageenan, polyethylene glycol, starch, hyaluronic acid, xanthan gum, polyglucitol), carbodiamides (e.g., urea, hydroxyethyl urea, hydroxypropyl urea), lactams (e.g., poly(vinyl pyrrolidone), poly(N-vinyl caprolactam)), amides (e.g., acetamide, propionamide, butyramide), or combinations thereof.

[0034] In some embodiments, the water-soluble complexing agent can be present in the aqueous antimicrobial composition in an amount of 0.1 wt % to 10 wt %, 0.2 wt % to 5 wt %, or 0.5 wt % to 2 wt %, based on the total weight of the aqueous antimicrobial composition.

[0035] In some embodiments, except water and antimicrobial agent, aqueous antimicrobial composition can comprise one or more cosolvents.Generally speaking, any solvent miscible with water can be used as cosolvent.Suitable cosolvent can comprise methyl alcohol, ethanol, isopropanol, butanols, acetone, tetrahydrofuran (THF), dimethylformamide, dimethyl sulfoxide (DMSO), glycol ether etc.Based on the gross weight of aqueous antimicrobial composition, cosolvent (if present) can be 20 weight %, 30 weight %, 40 weight %, 50 weight %, 60 weight %, 70 weight %, 80 weight %, or the value in the scope between any aforementioned value, for example 20 weight % to 80 weight % or 30 weight % to 50 weight % amount exists.

[0036] In some embodiments, the antimicrobial adhesives of the present disclosure may further include one or more of a tackifier, an antioxidant, a pigment, a reinforcing filler, a cross-linking agent, or an electrolyte.

[0037] In some embodiments, the antimicrobial adhesive may be characterized by a glass transition temperature (T gIn some embodiments, the antimicrobial adhesive may be characterized by a glass transition temperature (°C) of about -90, -80, -70, -60, -50, -40, -30, -20, -10, -5, 0, 5, or 10, or a value within a range between any of the foregoing values, such as about -30 to about -5, about -70 to about 0, etc.

[0038] As discussed above, find that above-mentioned solvent-based pressure-sensitive adhesive solution and aqueous antimicrobial composition can mix to produce the antimicrobial-impregnated adhesive of the working surface concentration with very high antimicrobial component.Further about this discovery, observe when above-mentioned solvent-based pressure-sensitive adhesive and aqueous antimicrobial composition mix, form two-phase composition.More specifically, observe to form the primary or main organic phase that at least comprises pressure-sensitive adhesive and solvent, and the secondary or minor aqueous phase that at least comprises water and water-soluble antimicrobial.Further observe, in some embodiments, at least initially, the discrete water phase region is relatively large and tends to descend (in the direction of gravity) in the organic phase, makes the discrete water phase region be collected at the bottom surface of the organic phase or near (as described below, it can correspond to the working surface of adhesive).

[0039] In some embodiments, the discrete aqueous phase regions can have a spherical shape. With respect to discrete aqueous phase regions (or discrete surface features as described below), "spherical" refers to a geometry that is a perfect sphere, or a sphere within ±10% or ±5% (i.e., the eccentricity in any direction does not exceed 5% or 10%), or any portion of such a geometry (e.g., a hemisphere). In some embodiments, the discrete aqueous phase regions can have a spherical or ellipsoidal shape.

[0040] In some embodiments, the discrete aqueous phase regions may have an average longest dimension (e.g., diameter) of 4 to 100 microns, 10 to 60 microns, or 15 to 50 microns. Further with respect to the size of the discrete aqueous phase regions, it was found that the larger the size of the discrete aqueous phase regions (e.g., droplets), the higher the probability that such discrete phases migrate through the organic phase and reach its bottom surface. In addition, it was found that the size of the discrete aqueous phase regions varies at least in part with the amount of water present in the aqueous antimicrobial composition (although it was also observed that increasing the amount of water beyond a certain point can cause the pressure-sensitive adhesive to coagulate in the continuous organic phase).

[0041] It was further observed that after the discrete aqueous phase regions settled into the organic phase and subsequently dried (i.e., the water and solvent were removed or partially removed), the dried equivalents of the discrete aqueous phase regions remained on the bottom surface of the pressure sensitive adhesive as depressions or indentations (having the same or substantially the same shape, size, and distribution as the discrete aqueous phase regions prior to drying) containing the antimicrobial agent therein (possibly in the form of a coating coating the surface of the depressions).

[0042] In this regard, in some embodiments, the present disclosure relates to an antimicrobial agent-impregnated adhesive formed by drying a composition resulting from mixing the above-described solvent-based pressure-sensitive adhesive solution and an aqueous antimicrobial composition, and which has been mixed using the techniques of the present disclosure (e.g., a technique in which the aqueous antimicrobial component is mixed with the solvent adhesive for a relatively short time before the mixed composition is applied to a substrate). Such antimicrobial agent-impregnated adhesives may have any one, any combination, or all of the following characteristics:

[0043] Discrete surface depressions (e.g., dents)

[0044] ●Uniform or substantially uniform distribution of surface depressions

[0045] Antimicrobial materials in and / or around the depressions

[0046] The initial available fraction of the antimicrobial agent at the working surface (which can be considered as the amount of antimicrobial agent available for antimicrobial action at the adhesive working surface-contacting surface of the patient (e.g., skin) interface within a relatively short time (e.g., 24 hours) after the adhesive sheet is formed) is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%, based on the total amount of antimicrobial agent in the adhesive. For purposes of this disclosure, the initial available fraction of the antimicrobial agent at the working surface is determined according to the Available Fraction Test of the Examples.

[0047] An antimicrobial release rate of no more than 10 minutes, no more than 7 minutes, or no more than 5 minutes (which can be considered the time required to release available antimicrobial microorganisms when exposed to an aqueous solution / patient contact surface). For purposes of this disclosure, the antimicrobial release rate is determined according to the Release Rate Test of the Examples.

[0048] After accelerated aging, at least 50%, at least 60%, at least 70%, or at least 80%, at least 90%, or at least 100% of the initial available antimicrobial agent fraction is retained at the working surface. For purposes of this disclosure, accelerated aging refers to the accelerated aging conditions of the embodiments - elevated humidity and elevated temperature for at least 3 months. For purposes of this disclosure, the Available Fraction Test of the embodiments (and comparing the initial available fraction to the available fraction after accelerated aging) is used to determine the percentage retention of the initial available fraction of the antimicrobial agent at the working surface.

[0049] Further with respect to discrete surface depressions, in some embodiments, the antimicrobial agent-impregnated adhesive of the present disclosure may be characterized as an adhesive sheet having at least one topologically microstructured major surface, the topologically microstructured major surface comprising a plurality of micro-dimples or micro-pits protruding inwardly from the major surface, and the plurality of micro-dimples or micro-pits being uniformly (or substantially uniformly) distributed around such major surface. As discussed above, prior to drying the antimicrobial agent-impregnated adhesive, the surface depressions may generally coincide with discrete aqueous phase regions.

[0050] In some embodiments, the discrete surface depressions (or micro-dents or micro-pits) may have an average size (in terms of the average longest dimension) of 4 microns to 100 microns, 10 microns to 60 microns, or 15 microns to 50 microns. In some embodiments, the discrete surface depressions may be evenly distributed so that the number of discrete surface depressions per square millimeter around the main surface differs by no more than 10% or no more than 5%. As described above, the discrete surface depressions may have a spherical shape. In some embodiments, the area of ​​the working surface of the adhesive with discrete surface depressions may account for 3% to 40%, 5% to 20%, 6% to 18%, 7% to 15%, or 8% to 12% of the total surface area of ​​the main surface of the adhesive sheet (the total surface area is composed of discrete surface depressions and plane (or nearly plane) areas extending between discrete surface depressions). It should be noted that in this work, it was confirmed that the presence of discrete surface depressions at the adhesive working surface-contact surface of the patient (e.g., skin) interface does not negatively affect the adhesive performance even under fluid challenges.

[0051] In various embodiments, a medical article is described. The medical article may include a substrate (or adhesive carrier) having a first surface and a second surface opposite the first surface, and any antimicrobial adhesive described herein disposed on the first surface.

[0052] In some embodiments, the substrate (or adhesive carrier) can be a polymer film. The polymer film can be woven or nonwoven.

[0053] In some embodiments, the medical article can also include a release liner in contact with the antimicrobial adhesive. The release liner can protect the antimicrobial adhesive from contacting with foreign matter before use. The release liner can further help the medical article to be applied to the surface. In some embodiments, the major surface of the antimicrobial adhesive with a high concentration of antimicrobial agent can be closest to the release liner (relative to substrate). In this respect, once the release liner is removed and the antimicrobial adhesive is applied to the patient's skin, the major surface of the antimicrobial adhesive with a high concentration of antimicrobial agent can contact the patient's skin.

[0054] In some embodiments, the medical article may further include a delivery system disposed on the second surface. The delivery system may be, for example, paper releasably secured to the second surface with an adhesive. The delivery system may provide structural integrity to the medical article to facilitate application of the medical article to the surface.

[0055] In some embodiments, medical articles can be configured into a variety of shapes, including custom shapes for fitting over contoured surfaces.

[0056] In some embodiments, the medical article may be in the form of a sheet or a roll.

[0057] In some embodiments, the antimicrobial article is a strip or a wrap.

[0058] In some embodiments, the medical article is a wound dressing.The medical article can be in the shape of any wound dressing known in the art.

[0059] In some embodiments, the medical article is an intravenous dressing.

[0060] In some embodiments, the medical article is a surgical drape.

[0061] In various embodiments, a method for preparing antimicrobial adhesive as described herein is provided. The method may include contacting the aqueous antimicrobial composition as described herein with a solvent-based pressure-sensitive adhesive solution as described herein to form an antimicrobial adhesive precursor. In some embodiments, the step of contacting the aqueous antimicrobial composition with a solvent-based pressure-sensitive adhesive solution may include, for example, mixing the two parts via a mixing tube as described in U.S. Patent 3,865,352 (which is incorporated herein by reference in its entirety), or by mixing the two parts in a suitable container, then keeping the suspension by constant stirring. Of course, without departing from the scope of the present disclosure, any other conventional method of the components of the combined mixture may be adopted.

[0062] In some embodiments, the method of the present disclosure may then include depositing (e.g., coating) the resulting composition (or antimicrobial adhesive precursor or wet pressure-sensitive adhesive) onto a substrate (e.g., a release liner or carrier) shortly after the step of contacting the aqueous antimicrobial composition with the solvent-based pressure-sensitive adhesive solution. Generally speaking, it is observed that if too much time passes between the contacting step and the step of depositing the antimicrobial adhesive precursor (alternatively referred to as the wet pressure-sensitive adhesive), the discrete aqueous phase region may collapse into a block or a main organic phase (contrary to collection near the bottom surface of the main organic surface) (the useful "use life" of the suspension also depends on the viscosity of the solvent-based pressure-sensitive adhesive, wherein higher viscosity solutions generally provide higher suspension stability). In this regard, in some embodiments, the method of the present disclosure may include depositing the antimicrobial adhesive precursor within 30 minutes, 10 minutes, or 2 minutes of contacting the aqueous antimicrobial composition with the solvent-based pressure-sensitive adhesive solution. In some embodiments, depositing the antimicrobial adhesive onto the substrate may include any conventional deposition techniques, such as dip coating, scraping, extrusion coating, spin coating, slide bucket coating, curtain coating, etc.

[0063] In some embodiments, the antimicrobial adhesive precursor can be deposited onto the substrate with a generally uniform thickness. In some embodiments, the antimicrobial adhesive precursor can be deposited onto the substrate with a thickness of 5 microns to 100 microns, 10 microns to 50 microns, or 15 microns to 40 microns. The antimicrobial adhesive precursor can be deposited onto the substrate as a continuous coating or a series of discrete or patterned coatings.

[0064] In some embodiments, the method may further include drying (to reduce or remove solvent and water) the antimicrobial adhesive precursor to form the antimicrobial adhesive. In some embodiments, the drying step may include one or more of the following: heating; vacuum, including rotary evaporation or freeze-pump-thaw technology, distillation or azeotropic distillation, molecular sieves, etc. In some embodiments, drying may include heating the precursor to a temperature (°C) of 30, 40, 50, 60, 70, 80, 90, 100, or a value within the range of any of the aforementioned values, such as 40 to 60, 50 to 70, etc. In some embodiments, heating may be performed under vacuum. In some embodiments, heating may be performed for a time of about 1 minute to about 10 minutes.

[0065] In some embodiments, after drying, the antimicrobial adhesive can be carried on the surface of the substrate at a thickness of 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or 525, or a value between any of the foregoing values, e.g., 100 to 200, 75 to 350, etc. (in micrometers).

[0066] In various embodiments, a method for preparing medical products is provided. The method may include preparing an antimicrobial adhesive as described above, wherein substrate is a backing material or a release liner of a medical product. In some embodiments, substrate may be a polymer backing material, such as thermoplastic polyurethane (for example, sold by Lubrizol Inc. with trade name ESTANE). In other embodiments, substrate may be a release liner, which may be made of various materials, such as paper, polymer coated paper (poly-coated paper), polyester film, high-density polyethylene film, silicone etc. In the embodiment in which substrate may be a polymer backing material, the method may also include contacting a dry antimicrobial adhesive with a release liner. In the embodiment in which substrate is a release liner, the method may also include laminating a dry antimicrobial adhesive to a polymer backing material. Rollers may be used to carry out lamination at room temperature.

[0067] In various embodiments, a method for disinfecting a surface is described. The method may include providing a medical article as described herein, and contacting the medical article with a surface for a period of time. In some embodiments, the surface may be skin or tissue. In some embodiments, the skin or tissue is mammalian skin or tissue. In some embodiments, the tissue may be selected from mucosal tissue, chronic wounds, acute wounds, burns, etc. In some embodiments, the skin or tissue may be intact, i.e., undamaged. In some embodiments, the skin or tissue may be injured or otherwise damaged. In some embodiments, the skin or tissue may be intact when in contact, and may remain in contact when the skin is damaged (e.g., cut, punctured, etc.).

[0068] In other embodiments, the surface can be a medical surface, such as, for example, surgical instruments (e.g., scalpels, scissors, blades, forceps, drapes, etc.), medical devices (e.g., catheters, stents, artificial joints, dental implants, etc.), floor tiles, countertops, basins, trays, gloves, cotton swabs, cloths, sponges, foams, nonwovens, and paper products.

[0069] In some embodiments, the medical article can be effective against various types of microorganisms, such as Gram-positive bacteria, Gram-negative bacteria, fungi, protozoa, mycoplasmas, yeast viruses, lipid enveloped viruses, and the like. For example, the antimicrobial adhesive and medical articles made therefrom can effectively reduce the number of microorganisms present on the surface and / or prevent the growth of such microorganisms, such as Staphylococcus spp., Streptococcus spp., Pseudomonas spp., Enterococcus spp., Escherichia spp., Aspergillus spp., Fusarium spp., Candida spp., Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, Staphylococcus aureus, ... faecalis), vancomycin-resistant Enterococcus (VRE), Pseudomonas aeruginosa, Escherichia coli, Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Fusarium solani, Fusarium oxysporum, Fusarium chlamydosporum, Candida albicans, Candida glabrata, Candida krusei, etc.

[0070] In some embodiments, the medical article can contact the surface for a period of time in minutes of about 30, 60, 90, 120, 150, 180, or 210, or a value between any of the foregoing values, such as about 30 to about 120, about 90 to about 180, etc. In other embodiments, the antimicrobial article can contact the surface for a period of time in hours of greater than about 1, 2, 3, 4, 5, 12, or 24, or a value between any of the foregoing values, such as about 2 to about 5, about 12 to about 24, etc. In some embodiments, the antimicrobial article can contact the surface for a period of time in days of about 1, 2, 3, 4, 5, 6, or 7, or a value between any of the foregoing values, such as about 1 to about 2, about 2 to about 5, etc.

[0071] In some embodiments, the method can be effective to deliver any of the above antimicrobial agents or combinations thereof to the surface at an average rate of greater than 15 mcg / sq. / hour. For example, the method can be effective to deliver any of the above antimicrobial agents or combinations thereof to the surface at an average rate (mcg / sq. / hour) of about 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100, or any value between the foregoing values, such as about 30 to about 50, about 20 to about 60, etc.

[0072] In some embodiments, the method can be a method for preparing a surface for incision (e.g., surgery). In some embodiments, the method can be a method for preparing a surface for needle penetration, e.g., for administering intravenous drugs or fluids, withdrawing fluids, etc.

[0073] In various embodiments, a kit is described. The kit may include a medical article as described herein and a set of instructions for instructing a user to disinfect a surface according to the methods described herein.

[0074] In various embodiments, a kit is described. The kit may include a medical article as described herein and a set of instructions for directing a user to prepare a surface for surgical use according to the methods described herein.

[0075] Example

[0076] The following examples further illustrate the objects and advantages of the present disclosure, but the specific materials and amounts thereof listed in these examples, as well as other conditions and details, should not be construed to unduly limit the present disclosure. These examples are for illustrative purposes only and are not meant to limit the scope of the appended claims.

[0077] These examples are for illustrative purposes only and are not intended to limit the scope of the appended claims. Unless otherwise noted, all parts, percentages, ratios, etc. in the examples and the remainder of the specification are by weight. Unless otherwise noted, solvents and other reagents used were obtained from MilliporeSigma, St. Louis, MO. The following abbreviations are used: cm = centimeter; g = gram; nm = nanometer; ppm = parts per million. PSA refers to pressure sensitive adhesive. Mil is one thousandth of an inch. RH is for relative humidity. The terms "weight %", "% by weight", and "wt %" are used interchangeably.

[0078] Elution test :

[0079] By placing a 3.14cm 2 The elution of the antimicrobial agent from the adhesive sample was measured by uniformly exposing the adhesive portion of each sample to 750 μl of water for 30 min, diluting 3-fold in water, measuring the UV absorbance of the diluted extract at 254 nm in a microcuvette, and determining the concentration according to the calibration curve. The concentration of the extract was calculated as 3.14 cm in 50 μl of extract. 2 The units are reformulated.

[0080] Available score tests :

[0081] The weight of the antimicrobial agent extracted in the elution test was compared with the weight of the 3.14 cm 2 The theoretical weight of the antimicrobial present in the coating adhesive of the area is compared to calculate the available fraction. Before the elution test, the coating adhesive is incubated at room temperature for less than 24 hours. The weight of the antimicrobial extracted is the initial available amount, and can be expressed as the fraction or weight percentage of the theoretical weight of the antimicrobial present. If the theoretical weight of the antimicrobial present is 1000mg and 500mg has been extracted, this provides 50% of the initial available fraction.

[0082] Accelerated aging conditions :

[0083] Accelerated aging refers to exposing samples to elevated temperatures and humidity for a desired period of time prior to testing. To simulate a one-year shelf life, the standard accelerated aging conditions for pharmaceutical products are 40°C and 75% relative humidity (40°C / 75% RH) for three months. Acceptable product performance after exposure to these accelerated aging conditions predicts a one-year shelf life at room temperature. Testing after exposure to the standard conditions of 40°C and 75% relative humidity (40°C / 75% RH) for three months can be referred to as accelerated aging testing.

[0084] Incubation :

[0085] Incubation refers to keeping the sample at a specific temperature and humidity for a specific time. The combination of temperature, humidity and time used for incubation is not the condition used for accelerated aging conditions.

[0086] reserve :

[0087] Retention refers to comparing the elution of the antimicrobial agent from a sample that has been subjected to accelerated aging or incubation to the elution from a sample that has not been subjected to accelerated aging or incubation. Retention can be calculated by dividing the initial available fraction of the sample exposed to accelerated aging or incubation by the initial available fraction of the sample that has not been subjected to accelerated aging or incubation. Retention can be expressed as a percentage.

[0088] Table 1: Materials.

[0089]

[0090] Example 1

[0091] This example demonstrates the effect of two different water-soluble complexing agents on the retention of CHG at the adhesive surface. For each sample type, the following parts A and B were made separately as provided in Table 2 and mixed just before being coated on the Ioban EZ liner with a wet thickness of 9 mils. The wet adhesive was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. In addition to the control adhesive, adhesive samples containing 10% sorbitol and 2% polyglycerol-3 (based on the weight percentage of solids) were also made.

[0092] Table 2: Adhesive formulations.

[0093]

[0094] A portion of the three coated samples were incubated at 80°C / 75% RH for 3 days. Samples from each of the three sample groups were measured for CHG elution freshly prepared and after incubation. Freshly prepared samples served as controls. 2 The elution of the antimicrobial agent from the adhesive sample was measured by uniformly exposing the adhesive portion of each sample to 750 μl of water for 30 min, diluting 3-fold in water, measuring the UV absorbance of the diluted extract at 254 nm in a microcuvette, and determining the concentration according to the calibration curve. The concentration of the extract was calculated as 3.14 cm in 50 μl of extract. 2 The results are provided in Table 3.

[0095] Table 3: CHG elution from freshly prepared and incubated (3d) adhesive samples.

[0096]

[0097] Both complexing agents were found to exert a protective effect on CHG release from the adhesive surface. The results indicate that lower levels of complexing agents close to the CHG concentration are sufficient for protection.

[0098] Example 2

[0099] This example expands the selection of complexing agents to demonstrate the generality of the effect. Both ionic (sodium gluconate) and polymeric (polyvinyl pyrrolidone or PVP) complexing agents are included.

[0100] A control adhesive was made, coated, and laminated as in Example 1. Complexed samples were made by adding complexing agent to Part B, replacing the 4% complexing agent sample with all of the water in water and part of the isopropanol in isopropanol. The 8% complexing agent sample was also replaced with part of the isopropanol in isopropanol. A portion of the laminated samples was incubated at 80°C / 75% RH for 3 days, and all samples were tested for CHG elution as in Example 1 using an elution time of 30 minutes. The results are provided in Table 4.

[0101] Note that there is a sharp drop in the control and 8% PVP samples. All remaining complexing agents, including the lower 4% PVP, exhibit a significant protective effect on stabilizing CHG at the adhesive surface.

[0102] Table 4: CHG elution from samples of Example 2.

[0103]

[0104] Example 3

[0105] This example demonstrates the protective effect of the complexing agent when the experiment was performed at a lower incubation temperature under the same elevated humidity as the previous example. Incubations were performed for longer periods of time and additional concentrations of the caging agent were explored.

[0106] A control adhesive was made, coated and laminated as in Example 1. Complexed samples were made by adding complexing agent to Part B, replacing the 4% complexing agent sample with all the water and part of the isopropyl alcohol. Samples with lower levels of complexing agent had only a portion of the water replaced. Portions of the laminated samples were incubated at 40°C / 75% RH for 1 and 3 weeks, and all samples were tested for CHG elution as in Example 1 using an elution time of 30 minutes. The results are provided in Table 5.

[0107] At lower temperatures and extended times, the reduction in CHG release rate continued unabated in the control. All complexing agents showed improved CHG release from the incubated adhesive compared to the control. PVP showed some reduction at a very low dosage of 0.25%.

[0108] Table 5: CHG elution from samples of Example 3.

[0109]

[0110] Example 4

[0111] This example utilizes room temperature incubation at ambient humidity to demonstrate improved CHG release from incubated adhesive samples compared to controls, while the protective effect of the water-soluble complexing agent continues to remain viable.

[0112] A control adhesive was made, coated and laminated as in Example 1. Complexed samples were made by adding complexing agent to Part B, replacing the 4% complexing agent sample with all of the water and a portion of the isopropyl alcohol. Samples with lower levels of complexing agent had only a portion of the water replaced. A portion of the laminated samples was incubated at room temperature for 6 weeks, and CHG elution was measured for all samples as in Example 1 using an elution time of 30 minutes. The results are provided in Table 6.

[0113] Table 6: CHG elution from samples of Example 4.

[0114]

[0115] Example 5

[0116] This example uses standard accelerated aging conditions for pharmaceuticals. When the sample passes the test after 3 months of accelerated aging, these accelerated aging conditions predict a shelf life of 1 year at room temperature. The control adhesive and the adhesive containing the complexing agent were manufactured, coated and laminated as in the previous example. Accelerated aging was performed for 3 months at 40°C / 75% RH. Before reaching the accelerated aging conditions, the samples were also removed by removing the samples after one week and three weeks of incubation. Using a 30-minute elution time, the CHG elution of the initial (as prepared) sample, the sample exposed to the accelerated aging conditions, and the sample incubated for one week and three weeks was tested as in the previous example. The results in Table 7 clearly show that for the control, the reduction of elutable CHG at the surface is as much as 95%. The use of xylitol as a complexing agent at both 1% and 2% of the composition has exerted an excellent protective effect. Under these conditions, polyglycerol-3 is also shown to be a protective agent.

[0117] Table 7: CHG elution from samples of Example 5.

[0118]

[0119] Example 6

[0120] This example explores the effect of multiple ethylene oxide sterilization cycles on the availability of CHG at the adhesive surface. Complexed samples were made, coated, and laminated as in the previous examples, and subjected to 3 commercial ethylene oxide sterilization cycles. The samples were tested for eluted CHG as in the previous examples, using an elution time of 30 minutes. The results are provided in Table 8.

[0121] Note that EO sterilization appears to significantly impair the protective effect of PVP, whereas xylitol and polyglycerol-3 samples remain unaffected.

[0122] Table 8: CHG elution from samples of Example 6.

[0123]

Claims

1. An antimicrobial agent-impregnated adhesive sheet comprising: Antimicrobial agents; as well as Pressure sensitive adhesives; wherein the antimicrobial agent-impregnated adhesive sheet comprises a first major surface and a second major surface; wherein the antimicrobial agent impregnated adhesive sheet comprises a plurality of surface depressions extending inwardly from the first major surface; and wherein the initial available fraction of the antimicrobial agent at the first major surface is at least 30% based on the total amount of antimicrobial agent in the antimicrobial agent-impregnated adhesive sheet; and wherein the antimicrobial agent impregnated adhesive sheet exhibits retention of at least 50% of the initial available fraction of the antimicrobial agent at the first major surface after accelerated aging.

2. The antimicrobial agent-impregnated adhesive sheet according to claim 1, wherein the surface depressions are distributed on the first major surface such that the number of surface depressions per square millimeter differs by no more than 10%.

3. The antimicrobial agent impregnated adhesive sheet according to any one of the preceding claims, wherein the antimicrobial agent impregnated adhesive sheet exhibits an antimicrobial agent release rate of no more than 10 minutes.

4. The antimicrobial agent impregnated adhesive sheet according to any one of the preceding claims, wherein the plurality of surface depressions have an average longest dimension of 4 micrometers to 100 micrometers.

5. The antimicrobial agent impregnated adhesive sheet according to any one of the preceding claims, wherein the surface depressions may have a spherical shape.

6. The antimicrobial agent impregnated adhesive sheet according to any one of the preceding claims, wherein the antimicrobial agent impregnated adhesive sheet has a thickness of 5 to 100 microns.

7. The antimicrobial agent impregnated adhesive sheet according to any one of the preceding claims, wherein the pressure sensitive has an HLB value of less than 5.

8. The antimicrobial agent-impregnated adhesive sheet according to any one of the preceding claims, wherein the pressure sensitive adhesive comprises an acrylic polymer or copolymer, a natural or synthetic rubber polymer or copolymer, or a silicone polymer.

9. A medical product, comprising: a substrate having a first surface and a second surface opposite to the first surface; and An antimicrobial agent-impregnated adhesive sheet according to any one of claims 1 to 8 is disposed on the first surface.

10. The medical article of claim 9, wherein the substrate is a polymer film.

11. The medical article of any one of claims 9 to 10, further comprising a release liner in contact with the antimicrobial agent-impregnated adhesive sheet.

12. The medical article of any one of claims 9 to 11 which is a surgical drape.

13. A method of disinfecting a surface, the method comprising: contacting the medical article according to any one of claims 9 to 12 with the surface; as well as The medical article is maintained in contact with the surface for a period of time.

14. The method of claim 13, wherein the surface is the skin of a patient and the method prepares the skin for a surgical incision.

15. A method according to any one of claims 13 to 14, wherein the surface is the skin of a patient and the method prepares the skin for needle penetration.

16. A method for preparing an antimicrobial agent-impregnated adhesive sheet according to any one of claims 1 to 8, the method comprising: providing a solvent-based pressure-sensitive adhesive solution comprising a solvent and a pressure-sensitive adhesive, wherein the pressure-sensitive adhesive has an HLB value of less than 5; Providing an aqueous antimicrobial composition comprising water, an antimicrobial agent, and a water-soluble complexing agent, wherein the water is present in the aqueous antimicrobial composition in an amount of 20 wt % to 80 wt % based on the total weight of the aqueous antimicrobial composition; and The solvent-based pressure sensitive adhesive solution and the aqueous antimicrobial composition are contacted to form an antimicrobial agent-impregnated adhesive precursor.

17. The method for preparing an antimicrobial agent-impregnated adhesive sheet according to claim 16, further comprising depositing the antimicrobial agent-impregnated adhesive precursor on a substrate.

18. The method for preparing an antimicrobial agent impregnated adhesive sheet according to any one of claims 16 to 17, wherein depositing the antimicrobial adhesive precursor occurs within 30 minutes of contacting the aqueous antimicrobial composition and the solvent-based pressure-sensitive adhesive solution.

19. The method for preparing an antimicrobial agent impregnated adhesive sheet according to any one of claims 16 to 18, further comprising drying the antimicrobial agent impregnated adhesive precursor to form the antimicrobial agent impregnated adhesive sheet.

20. The method for preparing an antimicrobial agent-impregnated adhesive sheet according to any one of claims 16 to 19, wherein the antimicrobial agent comprises chlorhexidine gluconate, chlorhexidine acetate, octenidine hydrochloride, hexamethonium salts, quaternary ammonium salts, chlorhexidine salts, silver salts, water-soluble iodophors or triclosan.

21. The method for preparing an antimicrobial agent-impregnated adhesive sheet according to any one of claims 16 to 20, wherein the water-soluble complexing agent comprises a polyhydroxylated compound, a polymer polyhydroxylated compound, a carbodiamide, a lactam, an amide, or a combination thereof.

22. The method for preparing an antimicrobial agent-impregnated adhesive sheet according to any one of claims 16 to 21, wherein the water-soluble complexing agent is present in the aqueous antimicrobial composition in an amount of 0.1 wt% to 10 wt%, based on the total weight of the aqueous antimicrobial composition.

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