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 further includes a plurality of surface recesses extending inwardly from the first major surface, wherein the distribution of the surface recesses is uniform or substantially uniform. The available fraction of 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.

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. BRIEF DESCRIPTION OF THE DRAWINGS

[0002] Figure 1 are photomicrographs comparing antimicrobial pressure sensitive adhesives.

[0003] Figure 2 is a photomicrograph of an antimicrobial pressure sensitive adhesive according to some embodiments of the present disclosure.

[0004] Figure 3 is a photomicrograph of an antimicrobial pressure sensitive adhesive according to some embodiments of the present disclosure.

[0005] Figure 4 is a photomicrograph of a wet antimicrobial pressure sensitive adhesive according to some embodiments of the present disclosure.

[0006] Figure 5 is a micrograph of a comparative wet antimicrobial pressure sensitive adhesive. DETAILED DESCRIPTION

[0007] 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.

[0008] 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. What is needed is a pressure sensitive adhesive capable of carrying and delivering chlorhexidine gluconate, octenidine hydrochloride, or a combination thereof.

[0009] 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.

[0010] 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.

[0011] However, it was subsequently discovered that compositions having such hydrophobic plasticizers, while initially providing a strong availability of chlorhexidine gluconate or octenidine at the working surface of the adhesive (or the surface of the adhesive closest to the patient's skin, or the adhesive / release liner interface prior to affixation to the patient), decrease significantly over time. Therefore, there is a need for compositions and methods for increasing the available surface concentration and / or minimizing the decrease in the available surface concentration over time.

[0012] In this work, the following combinations of substances were surprisingly found:

[0013] (i) PSA with a certain HLB value;

[0014] (ii) an aqueous antimicrobial component having an amount of water (e.g., an aqueous chlorhexidine salt component);

[0015] Combined with a mixing technique in which an aqueous antimicrobial component is mixed with a solvent adhesive solution for a relatively short time before the mixture is applied to a substrate (e.g., an adhesive backing or a release liner), an antimicrobial-impregnated adhesive having very high working surface concentrations of the antimicrobial component can be produced. 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 performance of the antimicrobial-impregnated adhesive even under fluid challenge.

[0016] As used herein, "acid" refers to a carboxylic acid group, ie, -CO2H.

[0017] 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.

[0018] 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:

[0019]

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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).

[0025] 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.

[0026] 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.

[0027] 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.

[0028] In some embodiments, the pressure sensitive adhesive may be characterized by a glass transition temperature (T g In 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 .

[0029] 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.

[0030] 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.

[0031] 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.

[0032] In various embodiments, the aqueous antimicrobial composition can comprise water and one or more antimicrobials. Suitable antimicrobials can include any antimicrobial that is selectively soluble in water (that is, soluble in secondary phase / aqueous phase but insoluble in main phase / organic phase). It should be noted that the flexibility of suitable antimicrobials represents the advantage of the antimicrobial adhesive of the present disclosure. That is to say, although existing antimicrobial adhesives are formulated to exclude water especially by drying the water in the commercially available aqueous antimicrobial drug before incorporation, dissolving the drug in advance in the hydrophobic plasticizer or utilizing organic soluble antimicrobials, the concept and advantages of the present disclosure can be realized with any selective water-soluble antimicrobial. In some embodiments, suitable water-soluble antimicrobials (and it selectively dissolves in water) can include chlorhexidine gluconate (CHG), chlorhexidine acetate, octenidine hydrochloride, polyhexamethylene biguanide salt (PHMB), quaternary ammonium salt, chlorhexidine salt, silver salt, water-soluble iodophor, triclosan or their combination.

[0033] 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).

[0034] 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.

[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 g In 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 or around the depressions

[0046] The 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) 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 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] 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.

[0049] 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.

[0050] 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.

[0051] In some embodiments, the substrate (or adhesive carrier) can be a polymer film. The polymer film can be woven or nonwoven.

[0052] 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.

[0053] 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.

[0054] In some embodiments, medical articles can be configured into a variety of shapes, including custom shapes for fitting over contoured surfaces.

[0055] In some embodiments, the medical article may be in the form of a sheet or a roll.

[0056] In some embodiments, the antimicrobial article is a strip or a wrap.

[0057] 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.

[0058] In some embodiments, the medical article is an intravenous dressing.

[0059] In some embodiments, the medical article is a surgical drape.

[0060] 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.

[0061] 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 collecting near the bottom surface of the main organic surface) (the useful "shelf life" of the suspension also depends on the viscosity of the solvent-based pressure-sensitive adhesive, wherein a solution with a higher viscosity generally provides a 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.

[0062] 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.

[0063] 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.

[0064] 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).

[0065] In various embodiments, a method for preparing a medical article is provided. The method may include preparing an antimicrobial adhesive as described above, wherein the substrate is a backing material or a release liner of the medical article. In some embodiments, the substrate may be a polymer backing material, such as a thermoplastic polyurethane (e.g., manufactured by Lubrizol Inc. under the trade name ESTANE ® In other embodiments, the substrate can be a release liner, which can be made of a variety of materials, such as paper, poly-coated paper, polyester film, high-density polyethylene film, silicone, etc. In embodiments where the substrate can be a polymer backing material, the method can also include contacting the dry antimicrobial adhesive with the release liner.

[0066] In embodiments where the substrate is a release liner, the method may further include laminating the dry antimicrobial adhesive to a polymeric backing material. Lamination may be performed using a nip roller at room temperature.

[0067] In various embodiments, a method for disinfecting a surface is described. The method may include providing a medical product as described herein, and contacting the medical product 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 greater than 15mcg / 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 aforementioned values, such as about 30 to about 50, about 20 to about 60, etc. The amount of any of the above antimicrobial agents or combinations thereof delivered to the surface can be determined using the surface availability analysis described herein.

[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] Unless otherwise indicated, all parts, percentages, ratios, etc. in the examples and the remainder of the specification are by weight. Unless otherwise indicated, the 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. HLB refers to hydrophilic / lipophilic balance. PSA refers to pressure sensitive adhesive. A mil is one thousandth of an inch. The terms "weight %", "% by weight", and "wt %" are used interchangeably.

[0078]

[0079] Elution test :

[0080] By placing a 3.14cm 2 The adhesive portion of each sample was uniformly exposed to 750 μl of water for 30 min, diluted 3-fold in water, the UV absorbance of each antimicrobial agent in the diluted extract was measured in a microcuvette at a unique wavelength (254 nm for chlorhexidine, 236 nm for PHMB, 209 nm for benzalkonium chloride, and 282 nm for octenidine), and the elution of the antimicrobial agent from the adhesive sample was measured by determining the concentration according to the calibration curve. The concentration of the extract was measured as 3.14 cm in 50 μl of extract. 2 The units are reformulated.

[0081] Available score tests :

[0082] 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 antimicrobial agent present in the coated adhesive per area is then ratioed to calculate the available fraction.

[0083] Release rate test :

[0084] Multiple samples were tested for elution at increasing exposure intervals ranging from 5 minutes to 90 minutes. The release rate is defined as the shortest time in which the entire available fraction of the antimicrobial agent is eluted.

[0085] Example 1: Effect of Water on the Release of Chlorhexidine Acetate from Prepared PSA Membranes .

[0086] This example demonstrates the amplifying effect of adding water to a hydrophobic solvent adhesive on the antimicrobial release profile. The antimicrobial chlorhexidine acetate is available in powder form and is soluble in methanol. Therefore, it is easily incorporated into an adhesive-containing solution that can tolerate small amounts of methanol.

[0087]

[0088] Sample 1: Parts A and B were prepared separately as provided in Table 2 and mixed just before coating on a Ioban EZ polyethylene release liner at 9 mil wet thickness. The wet pressure sensitive adhesive coating was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. The liner was removed prior to testing.

[0089] Sample 2: Parts A and B were prepared separately as provided in Table 2 and mixed just before coating on the Ioban EZ liner at 9 mil wet thickness. The wet pressure sensitive adhesive coating was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. The liner was removed before testing.

[0090] Sample 3: Parts A and B were prepared separately and then mixed. Part C was added to the mixed Parts A and B just before coating on the Ioban EZ liner at 9 mil wet thickness. The wet pressure sensitive adhesive coating was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. The liner was removed before testing.

[0091] The elution test was used to measure the elution of chlorhexidine acetate from all three samples. The results are provided in Table 3.

[0092]

[0093] The large effect of adding water to the hydrophobic PSA precursor solution is obvious. Surprisingly, adding water directly to the composition containing CHA and PSA gives the same results. The reason for the increased elution is Figure 1-Figure 3 This is evident from the micrographs of the three adhesives provided in Figure 1. The addition of water pulls CHA out to the adhesive surface as a separate phase. This separate phase appears as Figure 2 and Figure 3 The surface characteristics on the membrane surface, and Figure 1 The surface of the film surface shown has no surface features.The maximum possible release from the adhesive was 3100 ppm, with samples 2 and 3 showing releases of 46% of the maximum.

[0094] Example 2: Effect of Water on the Release of CHG from Prepared PSA Films .

[0095] This example highlights the effect of the amount of water in the composition on the amount of antimicrobial agent chlorhexidine gluconate released.

[0096] Part A and Part B provided in Table 4 were prepared separately and mixed just before coating on the Ioban EZ liner at 9 mil wet thickness. The wet adhesive was dried at 170° F. and laminated to a 0.8 mil thick polyurethane film. The liner was removed before testing.

[0097]

[0098] The CHG of all five samples was measured using the elution test. The results are provided in Table 5.

[0099]

[0100] The significant effect of water content is immediately apparent. The identity of the alcohol co-solvent has relatively little effect on the elution of CHG.

[0101] Example 3: Release rate of CHG from prepared PSA films .

[0102] This example demonstrates that substantially all of the CHG released from the exemplified CHG binders is immediately available.

[0103] Parts A and B of the formulation provided in Table 6 were prepared separately and mixed just before coating on the Ioban EZ liner at 9 mil wet thickness. The wet adhesive was dried at 170° F. and laminated to a 0.8 mil thick polyurethane film. The liner was removed before testing.

[0104]

[0105] After the release rate test, the CH elution of multiple samples was measured at different time points. The results are provided in Table 7.

[0106]

[0107] The data in Table 7 show that all CHG release occurred immediately from the surface. The slight increases evident at 60 and 90 minutes can be attributed to the evaporation of water from the sample extraction device over time.

[0108] Example 4: CHG Release from PSA Films Prepared with and Without Plasticizer .

[0109] This example demonstrates that the plasticizer (Priplast 3197) in the PSA composition has no effect on the release of chlorhexidine gluconate.

[0110] Parts A and B of the formulation provided in Table 8 were prepared separately and mixed just before coating on the Ioban EZ liner at 9 mil wet thickness. The wet adhesive was dried at 170° F. and laminated to a 0.8 mil thick polyurethane film. The liner was removed before testing.

[0111]

[0112] The CHG elution of the samples was measured using the Elution Test. The results are provided in Table 9; the plasticizer effect was not significant:

[0113]

[0114] Example 5: Release of CHG from PSA films prepared with different HLB values .

[0115] This example demonstrates the importance of the HLB of the base polymer in the enhancement of the release of antimicrobial agents from PSA films upon water addition. Acrylic PSAs are produced by copolymerization of hydrophobic monomers (which enable viscous flow) with hydrophilic comonomers (which enable cohesion and elasticity). The HLB of a polymer is defined here according to the Griffin method described in 1954 for nonionic surfactants from the hydrophilic content of the polymer from the total monomer composition as follows:

[0116]

[0117] Among them, M h A is the molecular weight of the hydrophilic portion of the molecule, and M is the molecular weight of the entire molecule.

[0118] The adhesive used in this example is a copolymer of isooctyl acrylate (IOA) and a mixture of N-vinyl pyrrolidone (NVP), acrylamide (ACM) and vinyl acetate (VAc).

[0119] These copolymers were incorporated into solutions using ethyl acetate, propyl acetate, and heptane as solvents and used as Part A in a Part A / Part B mixture as per Example 2. The Part B used was Sample 4 in Example 2 and Part B of the sample prepared using the method described above. The CHG elution of the samples was measured using the Elution Test. The results are provided in Table 10.

[0120]

[0121] When HLB values ​​are above 5, the elution value of CHG drops significantly. The reason for the increase in elution value at low HLB seems to be related to the droplet size of the hydroalcoholic antimicrobial phase. Higher HLB polymers tend to stabilize the droplets at a much smaller size close to 1 micron or lower, while low HLB polymers form droplets that are typically 10 microns or larger. During the drying process, larger droplets can settle to the surface of the release liner under gravity, thereby preferentially spreading a high level of antimicrobial agent on the adhesive surface. On the other hand, smaller droplets tend to remain evenly distributed in the adhesive, resulting in a low incidence of antimicrobial agent at the surface. Figure 4 and Figure 5 Micrographs of wet adhesive mixtures in low and high HLB polymer solutions, respectively.

[0122] Example 6: Antimicrobial activity against Candida albicans .

[0123] This example demonstrates the excellent antimicrobial activity of 3 different batches of samples coated with antimicrobial CHG adhesive film prepared using the method described in Example 2. Part A was combined with Part B2 from Example 2 and film samples were prepared using the procedure described in the previous example.

[0124] A 0.5 McFarland equivalent turbidity standard was used at 1 × 10 8 A suspension of Candida albicans was prepared at a concentration of CFU (colony forming units) / milliliter (mL). Using an Eppendorf pipette, 50 microliters (µL) of this suspension was transferred as a single drop to the adhesive surface of a 2.5 cm diameter section of the prepared adhesive film. The drop was spread evenly under a sterile 20 mm diameter glass coverslip. These inoculated samples were then incubated at room temperature (23 + / - 2°C) for 5 minutes to 30 minutes. After incubation, the samples were placed in 20 mL of neutralization buffer and sonicated for one minute, followed by vortexing for two minutes. Portions of the resulting solution were serially diluted with phosphate buffered water. The pure solution and the dilutions were each plated onto a 3M PETRIFILM aerobic counting plate (3M Company) and incubated for at least 24 hours. The 3M PETRIFILM plates were then counted using a 3M PETRIFILM plate reader (Model 6499, 3M Company). The results presented in Table 11 demonstrate nearly complete killing of the inoculum at the shortest time point, again indicating rapid, burst release of CHG from the adhesive. The inoculum concentration in 50 µL was 6.8 log of yeast. Log reductions were performed in triplicate. The placebo sample showed no killing.

[0125]

[0126] Example 7: Release of CHG from non-acrylic adhesives .

[0127] This example demonstrates the utility of the suspension coating method in terms of its applicability to additional adhesive chemistries. The adhesives used were a heptane solution of a tackified Kraton adhesive and a heptane / toluene / isopropanol mixture solution of a tackified silicone polyurea adhesive. These adhesives were used as Part A and were mixed separately with Part B5 in Example 2 and coated, dried and laminated as described in Example 2. The elution results from the coated adhesives demonstrate the versatility of the present invention in providing CHG release from different types of adhesives.

[0128]

[0129] Example 8: Release of water-soluble antimicrobial agents from prepared PSA films .

[0130] This example demonstrates the utility of the present invention in terms of its applicability to other water-soluble antimicrobial agents.

[0131] The following parts A and B were prepared separately and mixed just before coating on the Ioban EZ liner at 9 mil wet thickness. The wet adhesive was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. The release liner was removed prior to testing.

[0132] Table 13: Release of other water-soluble antimicrobial agents from PSA films .

[0133]

[0134]

[0135] Note that octenidine hydrochloride was used at a lower loading relative to the other antimicrobial agents. The elution procedure was performed as in the previous example. Each antimicrobial agent had its own calibration curve, and UV measurements were performed at 236 nm for sample 11, 209 nm for sample 12, and 282 nm for sample 13. The elution results are provided in Tables 14 and 15.

[0136]

[0137]

[0138] The maximum elutable antimicrobial concentration was 3000 ppm in Samples 11 and 12, and 300 ppm in Sample 13. The high initial elution levels demonstrate the versatility of the suspension binder approach for producing high burst elution delivery compositions.

Claims

1. An antimicrobial agent-impregnated adhesive sheet, the antimicrobial agent-impregnated adhesive sheet comprising: Antimicrobial agents; and Pressure sensitive adhesives; wherein the sheet comprises a first major surface and a second major surface; wherein the sheet includes a plurality of surface depressions extending inwardly from the first major surface; and wherein the 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.

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 for 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 and an antimicrobial 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, polyhexamethylene biguanide 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 water is present in the aqueous antimicrobial composition in an amount of 20 to 80 wt %, based on the total weight of the aqueous antimicrobial composition.

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