BACKGROUND

Antiseptic-impregnated adhesives are discussed in, for example, U.S. Patents 4,323,557, 9,713,659, and 9,764,059.

BRIEF DESCRIPTION OF THE FIGURES

Figure l is a micrograph of a comparative antimicrobial pressure sensitive adhesive.

Figure 2 is a micrograph of an antimicrobial pressure sensitive adhesive according to some embodiments of the present disclosure.

Figure 3 is a micrograph of an antimicrobial pressure sensitive adhesive according to some embodiments of the present disclosure.

Figure 4 is a micrograph of a wet antimicrobial pressure sensitive adhesive according to some embodiments of the present disclosure.

Figure 5 is a micrograph of a comparative wet antimicrobial pressure sensitive adhesive.

DETAILED DESCRIPTION

Despite advances made in infection-control practices, surgical-site infections (SSIs) remain a substantial cause of morbidity, prolonged hospitalization, and death. In fact, SSIs are associated with a mortality rate of 3% and 75% of SSI-related deaths are directly attributable to the SSL Surgeons currently rely on surgical drapes having iodine-impregnated adhesives to mitigate contact with pathogenic microbes. While povidone -iodine is a widely effective antiseptic, there are drawbacks to its use. For example, povidone -iodine may cause skin irritations in some individuals, and use with large wounds may lead to kidney problems, high blood sodium, and metabolic acidosis. Furthermore, the use of povidone-iodine is not recommended for those that are less than 32 weeks pregnant, those that are prescribed lithium, or those with thyroid problems. Chlorhexidine gluconate and octendine hydrochloride are a viable alternative that is not associated with the aforementioned fallbacks.

Developing antiseptic-impregnated adhesives (e.g., chlorhexidine gluconate- and octenidine hydrochloride-impregnated adhesives) would help reduce surgical-site infection rates, meanwhile potentially avoiding the side effects associated with povidone-iodine. What is needed are pressure-sensitive adhesives capable of carrying and delivering chlorhexidine gluconate, octenidine hydrochloride, or a combination thereof

Efforts to develop antiseptic-impregnated adhesives have been met with significant challenges. Chlorhexidine gluconate (“CHG”) and octenidine hydrochloride (“octenidine”), each being highly polar compounds, tend to precipitate from hydrophobic adhesive compositions. The lack of CHG solubility or octenidine solubility in the adhesive effectively immobilizes CHG or octenidine such that it is unavailable for adequate transfer to a surface. Moreover, blending additives like CHG and CHG-solubilizing vehicles often compromise the strength of the adhesive, which leads to premature adhesive failure. In terms of surgical drapes, this premature adhesive failure is called ‘drape drift. ’ When surgical drapes move or ‘drift,’ the patient experiences a greater exposure to microbes and becomes more vulnerable to infection. The present disclosure is directed toward water soluble antimicrobial-based (e.g., chlorhexidine gluconate-based or octenidine hydrochloride-based) compositions for inclusion within pressure-sensitive adhesive (PSA) formulations, and medical articles made therefrom. Initially, it was believed that hydrophilic (polar) vehicles were required to render chlorhexidine gluconate or octenidine hydrochloride compatible with adhesives It was later found that hydrophobic (non-polar) vehicles having vicinal (i e , separated by two atoms; adjacent), or otherwise proximate (i.e., separated by three atoms), hydrogenbonding groups were effective at solubilizing chlorhexidine gluconate and octenidine hydrochloride, which in turn compatibilized the hydrophobic chlorhexidine gluconate solutions and hydrophobic octenidine solutions with hydrophobic pressure-sensitive adhesives (see WO 2014/035981). Still later it was found that chlorhexidine gluconate and octenidine, despite being polar compounds, are readily soluble in hydrophobic plasticizers that have hydrogen-bonding groups spaced more than three atoms apart, and that hydrophobic vehicles bearing vicinal hydrogen-bonding groups can be detrimental to adhesive integrity as compared to compositions that are void of said hydrophobic vehicles.

It was then discovered, however, that compositions having such hydrophobic plasticizers, while initially providing strong availability of the chlorhexidine gluconate or octenidine at the working surface of the adhesive (or surface of the adhesive nearest the skin of the patient or, prior to securement to a patient, the adhesive/release liner interface) (the “available surface concentration”), dropped significantly over time. Consequently, compositions and methods for increasing the available surface concentration and/or minimizing the reduction overtime in available surface concentration, are desirable.

In this work, surprisingly, it was discovered that the combination of:

(i) a PSA having certain HLB values;

(ii) an aqueous-antimicrobial component (e g., aqueous -chlorohexadine salt component) having certain amounts of water; in combination with a mixing technique whereby the aqueous-antimicrobial component is combined with a solvent adhesive solution a relatively short period before coating the mixture onto a substrate (e.g., adhesive backing or release liner) can produce antimicrobial-impregnated adhesives having very high working surface concentrations of the antimicrobial component. It was further discovered that that presence of these very high working surface concentrations (and, as will be discussed in greater detail below, the associated surface features at or near the working surface) did not negatively impact the adhesive properties of the antimicrobial -impregnated adhesives even under fluid challenge.

As used herein, “acid” refers to a carboxylic acid group, i.e., -CO2H.

As used herein, “disinfecting” refers to a reduction in the number of active microorganisms present on a surface being disinfected. Disinfecting may kill or prevent microorganisms from growing or proliferating.

As used herein, “hydrophilic-lipophilic balance” or “HLB” values are calculated using the method of Griffin (Griffin WC; I. Soc. of Cosmetic Chemists 5, 259 (1954)). Thus, as used herein, the “HLB Method” involves a calculation based on the following:

HLB=20 * Mh / M where Mh is the molecular mass of the hydrophilic portion of the molecule, and M is the molecular mass of the whole molecule, giving a result on a scale of 0 to 20. An HLB value of 0 corresponds to a completely lipophilic/hydrophobic molecule, and a value of 20 corresponds to a completely hydrophilic/lipophobic molecule.

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, decrease viscosity, and/or decrease friction of a substance to which it is added.

As used herein, “polymer” refers to a substance having one or more repeating monomer units. The chemical identities of the polymeric substances herein are at times described in terms of the monomers to which the polymer is derived. A skilled artisan would readily understand the reactivity profile of the recited monomers and how the monomers could synthetically be joined to form the polymer.

As used herein, “pressure -sensitive adhesive” refers to a non-reactive, self-stick adhesive that forms a bond when pressure is applied. No solvent, water, or heat is requiredto activate a pressure-sensitive adhesive

When referring to “solubility,” or “to solubilize” it should be understood that the solubility of a component A in a component B refers to conditions in which only component A and component B are present, e.g., no added salts, compounds, or the like. Furthermore, any solubility values provided herein are with regard to a temperature range of about 20 °C to about 23 °C at atmospheric pressure (i.e., 760 mm/Hg).

In some embodiments, the present disclosure is directed to antimicrobial adhesives. The antimicrobial adhesives may be formed by the combination of a solvent-based pressure sensitive adhesive solution and an aqueous antimicrobial composition.

In some embodiments, the solvent -based pressure sensitive adhesive solution may include a solvent and a pressure sensitive adhesive. Suitable solvents may include any organic solvent that is miscible with the pressure -sensitive adhesive. For example, the solvent may include ethyl acetate, heptane, toluene, and methyl ethyl ketone, propyl acetate, butyl acetate, acetone, methyl propyl ketone, methyl isobutyl ketone, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, hexanes, petroleum ether, tetrahydrofiiran, lower alcohols, glycol ethers, xylenes, a combination thereof, or the like.

In some embodiments, the pressure-sensitive adhesive may be selected from an acrylic polymer or copolymer. In some embodiments, the acrylic polymer or copolymer may be the reaction product one of monomers selected from an alkyl (meth)acrylate, N-vinyl pyrrolidone, N-vinyl caprolactam, (alkyl- substituted)acrylamide, (alkyl-substituted)methacrylamide, 2 -hydroxy ethyl (meth)acrylate or and a combination thereof. In some embodiments, the pressure -sensitive adhesive may be selected from a rubber polymer or copolymer Suitable mbber polymers include natural mbber, polybutadiene, and polyisobutylene. Suitable rubber copolymers include styrenic block copolymers such as styrene-butadiene- styrene, styrene-isoprene-styrene, and styrene-ethylene-butadiene-styrene. In some embodiments, the pressure -sensitive adhesive may be selected from atackified silicone polymer. In some embodiments, the pressure-sensitive adhesive may be characterized by a glass transition temperature (T _g ) of about -70 °C to about 20 °C. In some embodiments, the pressure-sensitive adhesive may be characterized by a T _g 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 preceding values, for example, between about -20 and about 5, between about -50 and about -30, or the like

As discussed above, it was discovered that pressure sensitive adhesives having HLB values within a certain range may, in part, contribute to the formation of antimicrobial adhesives having very high working surface antimicrobial concentrations. Generally, it is believed that such certain HLB values contribute to the generation of discrete secondary phase regions, which are discussed in greater detail below, that are relatively large. In this regard, in some embodiments, the pressure sensitive adhesives may have an HLB value that is less than 5, less than 4 6, or less than 4.5.

In some embodiments, pressure sensitive adhesive solution may include pressure sensitive adhesive 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 preceding values, for example, between 15 and 50 wt.-% or 15 and 30-wt.-%, based on the total weight of the pressure sensitive adhesive solution In some embodiments, pressure sensitive adhesive solution may include solvent in an amount of 30 wt.-%, 40 wt.- %, 50 wt.-%, 60 wt.-%, 70 wt.-%, 80 wt.-%, 90 wt-%, 95 wt.-%, or a value within a range between any of the preceding values, for example, between 50 and 90 wt-% or 50 and 80-wt.-%, based on the total weight of the pressure sensitive adhesive solution.

In some embodiments, in addition to pressure sensitive adhesive and solvent, the pressure sensitive adhesive solution may include a plasticizer. Any suitable plasticizer may be used as long as it does not unacceptably affect the properties of the pressure sensitive adhesive solution or the PSA made therefrom. Such a plasticizer may be optimally selected to be compatible with (i.e., miscible with) the other components in the adhesive composition. Potentially suitable plasticizers include various esters, e.g. adipic acid esters, formic acid esters, phosphoric acid esters, benzoic acid esters, phthalic acid esters, esters of dimer diacids with dimer diols; sulfonamides, and naphthenic oils. Other potentially suitable plasticizers include e.g. hydrocarbon oils (e.g., those that are aromatic, paraffinic, or naphthenic), vegetable oils, hydrocarbon resins, polyterpenes, rosin esters, phthalates, phosphate esters, dibasic acid esters, fatty acid esters, polyethers, and combinations thereof; plant fats and oils such as olive oil, castor oil, and palm oil; animal fats and oils such as lanolin; fatty acid esters of polyhydric alcohols such as a glycerin fatty acid ester and a propylene glycol fatty acid ester; and, fatty acid alkyl esters such as ethyl oleate, isopropyl palmitate, octyl palmitate, isopropyl myristate, isotridecyl myristate, and ethyl laurate, esters of a fatty acid. Any of the above plasticizers may be used alone or in combination (and/or in combination with any other additive mentioned herein). Plasticizer, if present, may 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 preceding values, for example, between 10 and 50 wt.-% or 15 and 30-wt.-%, based on the total weight of the pressure sensitive adhesive solution. In various embodiments, the aqueous antimicrobial composition may include water and one or more antimicrobials. Suitable antimicrobials may include any antimicrobials that are selectively soluble in water (i.e., that are soluble in a minor/water phase but not in a major/organic phase). It is noted that the flexibility in suitable antimicrobials represents an advantage of the antimicrobial adhesives of the present disclosure That is, while prior antimicrobial adhesives were formulated to specifically exclude water by drying water from a commercial aqueous antimicrobial drug prior to incorporation, predissolving the drug in a hydrophobic plasticizer, or utilizing organic soluble antimicrobials, the concepts and advantages of the present disclosure may be accomplished with any selectively water-soluble antimicrobial. In some embodiments, suitable water-soluble antimicrobials (and that are selectively soluble in water) may include chlorhexidine gluconate (CHG), chlorohexidine acetate, octenidine hydrochloride, polyhexamethylene biguanide salts (PHMB), quat ammonium salts, chlorohexidine salts, silver salts, water-soluble iodophors, triclosan, or combinations thereof.

In some embodiments, water-soluble antimicrobials may be present in the aqueous antimicrobial composition in an amount of at least about 0.05 wt-%, based on the total weight of the aqueous antimicrobial composition. In some embodiments, water-soluble antimicrobials may be present in the aqueous antimicrobial composition in an amount of no more than about 5 wt-%, based on the total weight of the aqueous antimicrobial composition. In some embodiments, water-soluble antimicrobials may be present in the aqueous antimicrobial composition in an amount (wt-% with respect to the total weight of the aqueous antimicrobial composition.) 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 a range of any of the preceding values, for example, between about 0.2 and about 4.0 or between about 2.0 and about 3.0.

In some embodiments, the aqueous antimicrobial composition may include water. As discussed above, it was discovered that the presence of water within a certain range that is higher than that which has been conventionally employed with respect to antimicrobial adhesives may, in part, contribute to the formation of antimicrobial adhesives having very high working surface antimicrobial concentrations. More specifically, and as will be discussed further below, it was discovered that the presence of water at higher concentrations than conventionally employed, at least in part, contributes to the formation of larger discrete aqueous phase regions (e.g., droplets) upon combination of the solvent-based pressure sensitive adhesive solution and the aqueous antimicrobial composition. In this regard, in some embodiments, water may be present in the aqueous antimicrobial composition in an amount of between 20 and 80 wt-%, between 30 and 70 wt-%, or between 40 and 60 wt-%, based on the total weight of the aqueous antimicrobial composition.

In some embodiments, in addition to water and antimicrobials, the aqueous antimicrobial composition may include one or more co -solvents . Generally, any water miscible solvent may be employed as a cosolvent Suitable cosolvents may include methanol, ethanol, isopropanol, butanol, acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glycol ethers, or the like. Co-solvents, if present, may be present in an amount of 20 wt.-%, 30 wt.-%, 40 wt.-%, 50 wt.-%, 60 wt.-%, 70 wt.-%, 80 wt.-%, or a value within a range between any of the preceding values, for example, between 20 and 80 wt.-% or 30 and 50-wt.-%, based on the total weight of the aqueous antimicrobial composition.

In some embodiments, the antimicrobial adhesives of the present disclosure may further include one or more of a tackifier, antioxidant, pigment, reinforcing filler, cross-linker, or electrolyte.

In some embodiments, the antimicrobial adhesive may be characterized by a glass transition temperature (T _g ) of about -90 °C to about 10 °C. 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 preceding values, for example, between about - 30 and about -5, between about -70 and about 0, or the like.

As discussed above, it was discovered the above-described solvent-based pressure sensitive adhesive solutions and aqueous antimicrobial compositions could be combined to produce antimicrobial- impregnated adhesives having very high working surface concentrations of the antimicrobial component. Further regarding this discovery, it was observed that when the above-described solvent-based pressure sensitive adhesive and aqueous antimicrobial compositions are combined, a two-phase composition is formed. More specifically, it was observed that a primary or major organic phase that includes at least the pressure sensitive adhesive and solvent, and a secondary or minor aqueous phase that includes at least water and the water-soluble antimicrobial, are formed. It was further observed that, in some embodiments, at least initially, the discrete aqueous phase regions are relatively large and tend to descend (in the direction of gravitational force) into the organic phase such that the discrete aqueous phase regions collect at or near a bottom surface of the organic phase (which, as discussed below, may correspond to the working surface of the adhesive).

In some embodiments, the discrete aqueous phase regions may have a shape that is spherical. In relation to the discrete aqueous phase regions (or discrete surface features as described below), “spherical” refers to a geometric shape that is perfectly spherical, or a spherical shape within ±10% or ±5% (that is, the eccentricity in either direction does not exceed 5% or 10%), or any portion of such geometric shape (e.g., hemispherical). In some embodiments, the discrete aqueous phase regions may have shapes that are spherical or elliptical.

In some embodiments, the discrete aqueous phase regions may have an average longest dimension (e.g., diameter) of between 4 and 100 micrometers, between 10 and 60 micrometers, or between 15 and 50 micrometers. Further regarding the size of the discrete aqueous phase regions, it was discovered that the higher the size of the discrete aqueous phase regions (e.g., droplets), the higher the probability that such discrete phase migrates through the organic phase and to a bottom surface thereof. Still further, it was discovered that the size of the discrete aqueous phase regions is a function of, at least in part, the amount of water that is present in the aqueous antimicrobial compositions (although it was also observed that increasing the amount of water beyond a certain point can cause coagulation of the pressure sensitive adhesive in the continuous organic phase).

It was further observed that after settling of the discrete aqueous phase regions into the organic phase and subsequent drying (i.e., removal or partial removal of water and solvent), the dried down equivalent of the discrete aqueous phase regions remains on the bottom surface of the pressure sensitive adhesive as depressions or dimples (having the same or substantially the same shape, size, and distribution of the discrete aqueous phase regions prior to drying) having the antimicrobial contained therein (likely in the form of a coating that coats the surface of the depressions).

In this regard, in some embodiments, the present disclosure is directed to antimicrobial- impregnated adhesives that are formed from diying down the composition that results from combining the above-described solvent-based pressure sensitive adhesive solution and the aqueous antimicrobial composition, and which have been combined utilizing the techniques of the present disclosure (e.g., a technique whereby the aqueous-antimicrobial component is combined with the solvent adhesive a relatively short period before the combined composition is coated onto a substrate). Such antimicrobial-impregnated adhesives may have any one, any combination, or all of the following properties:

• Discrete surface depressions (e g., dimples)

• Uniform or substantially uniform distribution of surface depressions

• Antimicrobial material in or around the depressions

• An available fraction of antimicrobial at the working surface (which can be considered as the amount of antimicrobial that is available for antimicrobial action at the adhesive working surfacecontact surface of the patient (e.g., skin) interface), of 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 in the adhesive. For purposes of the present disclosure, the available fraction of antimicrobial at the working surface is as determined in accordance the Available Fraction Test of the Examples.

• A rate of antimicrobial release (which can be considered as the time required for release of the available antimicrobial microbial upon exposure to an aqueous solution/the contact surface of a patient), of no more than 10 minutes, no more than 7 minutes, or no more than 5 minutes. For purposes of the present disclosure, the rate of antimicrobial release is as determined in accordance the Rate of Release Test of the Examples.

Further regarding the discrete surface depressions, in some embodiments, the antimicrobial- impregnated adhesives of the present disclosure may be characterized as adhesive sheets having at least one topologically microstructured major surface that includes a plurality of micro-dimples or micro-craters protruding inwardly from the major surface, and which are distributed uniformly (or substantially uniformly) about such major surface. As discussed above, the surface depressions may generally conform to the discrete aqueous phase regions prior to drying of the antimicrobial-impregnated adhesive.

In some embodiments, the discrete surface depressions (or micro-dimples or micro-craters) may have an average size (in terms of average longest dimension) of between 4 and 100 micrometers, between 10 and 60 micrometers, or between 15 and 50 micrometers. In some embodiments, the discrete surface depressions may be uniformly distributed such that the number of discrete surface depressions about the major surface, per square millimeter, differs by no more than 10% or no more than 5%. As described above, the discrete surface depressions may have a shape that is spherical In some embodiment, the regions of the working surface of the adhesive having discrete surface depressions may account for between 3 and 40%, between 5 and 20 %, between 6 and 18 %, between 7 and 15 %, or between 8 and 12 %, of the total surface area of the major surface of the adhesive sheet (the total surface area being made up of the discrete surface depressions and the planar (or nearly planar) regions that extend between discrete surface depressions It is noted that in the present work, it was confirmed that presence of discrete surface depressions at the adhesive working surface-contact surface of the patient (e.g., skin) interface did not negatively impact adhesive properties even under fluid challenge.

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

In some embodiments, the substrate (or adhesive carrier) may be a polymeric film. The polymeric film may be woven or nonwoven.

In some embodiments, the medical article may further include a release liner in contact with the antimicrobial adhesive. The release liner may protect the antimicrobial adhesive from coming into contact with foreign matter prior to use. The release liner may further facilitate application of the medical article to a surface. In some embodiments, the major surface of the antimicrobial adhesive having a high concentration of antimicrobial may be nearest the release liner (as opposed to the substrate). In this regard, once the release liner is removed and the antimicrobial adhesive applied to the skin of the patient, the major surface of the antimicrobial adhesive having a high concentration of antimicrobial may be in contact with the skin of the patient.

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

In some embodiments, the medical article may be configured in various shapes, including custom shapes for fitting over contoured surfaces.

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

In some embodiments, the antimicrobial article is a tape or wrap.

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

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

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

In various embodiments, a method for preparing the antimicrobial adhesives described herein is provided. The method may include contacting an aqueous antimicrobial composition described herein and a solvent-based pressure sensitive adhesive solution described herein to form an antimicrobial adhesive precursor. In some embodiments, the step of contacting aqueous antimicrobial composition and a solventbased pressure sensitive adhesive solution may include, for example, combining the two parts via a mixing tube as described in U.S. Patent 3,865,352, which is herein incorporated by reference in its entirety, or by combining the two parts in a suitable vessel and then maintaining the suspension through constant agitation. Of course, any other conventional methods of combining components of a mixture may be employed without deviating from the scope of the present disclosure.

In some embodiments, the methods of the present disclosure may then include, shortly after the step of contacting the aqueous antimicrobial composition and the solvent-based pressure sensitive adhesive solution, 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). Generally, it was observed that if too much time elapses between the step of contacting and the step of depositing the antimicrobial adhesive precursor (may alternatively be referred to as a wet pressure sensitive adhesive), the discrete aqueous phase regions can collapse into the bulk, or major organic phase (as opposed to collecting near a bottom surface of the major organic surface) (the useful “pot-life” of the suspension is also dependent on the viscosity of the solvent-based pressure sensitive adhesive with higher viscosity solutions generally affording higher suspension stability). In this regard, in some embodiments, the methods of the present disclosure may include depositing the antimicrobial adhesive precursor within 30 minutes, within 10 minutes, or within 2 minutes of contacting the aqueous antimicrobial composition and the solvent-based pressure sensitive adhesive solution. In some embodiments, depositing the antimicrobial adhesive onto the substrate may include any conventional deposition technique such as such as dip coating, knife coating, extrusion coating, spin coating, slide hopper coating, curtain coating, or the like.

In some embodiments, the antimicrobial adhesive precursor may be deposited onto the substrate at a generally uniform thickness. In some embodiments, the antimicrobial adhesive precursor may be deposited onto the substrate at a thickness of between 5 micrometers and 100 micrometers, between 10 micrometers and 50 micrometers, or between 15 micrometers and 40 micrometers. The antimicrobial adhesive precursor may be deposited onto the substrate as a continuous coating or a series of discrete or patterned coatings.

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 step of drying may include one or more of heating; vacuum, including roto-evaporating or freeze-pump- thaw techniques, distillation or azeotropic distillation, molecular sieves, or the like. 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 a range of any of the preceding values, for example, between 40 and 60, between 50 and 70, or the like. In some embodiments, the heating may be conducted under vacuum. In some embodiments, heating may be carried out for a period of about 1 min to about 10 min.

In some embodiments, after drying, the antimicrobial adhesive may be bome on a surface of the substrate at a thickness of (in microns) 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or 525, or avalue between any ofthe preceding values, for example, between 100 and 200, between 75 and 350, or the like.

In various embodiments, a method for preparing a medical article is provided. The method may include preparing an antimicrobial adhesive as described above, where the substrate is backing material or release liner for a medical article. In some embodiments, the substrate may be a polymeric backing material, such as thermoplastic polyurethanes (e.g., as sold by Lubrizol Inc. under the tradename ESTANE®). In other embodiments, the substrate may be a release liner, which can be made from a variety of materials such as paper, poly-coated paper, polyester fdm, high-density polyethylene film, silicone, or the like In embodiments wherein the substrate may be a polymeric backing material, the method may further include contacting the dried antimicrobial adhesive to a release liner.

In embodiments where the substrate is a release liner, the method may further include laminating the dried antimicrobial adhesive to a polymeric backing material. The laminating may be performed using nip rollers at room temperature.

In various embodiments, a method for disinfecting a surface is described. The method may include providing a medical article described herein, and contacting the medical article to the surface for a period. In some embodiments, the surface may be skin or tissue. In some embodiments, the skin or tissue is mammalian skin ortissue. In some embodiments, the tissues may be selected from mucosal tissues, chronic wounds, acute wounds, bums, or the like. In some embodiments, the skin or tissue may be intact, i.e., undamaged. In some embodiments, the skin or tissue may be wounded or otherwise damaged In some embodiments, the skin or tissue may be intact upon contacting and may remain in contact upon subjecting the skin to damage, e.g., cutting, piercing, or the like.

In other embodiments, the surface may be a medical surface, for example, surgical devices (e.g., scalpel, scissors, blades, forceps, drapes, orthe like), medical devices (e.g., catheters, stents, artificial joints, dental implants, or the like), floor tiles, countertops, tubs, dishes, gloves, swabs, cloth, sponges, foams, nonwovens, and paper products.

In some embodiments, the medical articles may be effective against various microorganisms types, e.g., Gram positive bacteria, Gram negative bacteria, fungi, protozoa, mycoplasma, yeast viruses, lipid- enveloped viruses, or the like. For example, the antimicrobial adhesives and medical articles made therefrom may be effective at reducing the number of microorganisms present on the surface and/or preventing the growth of such microorganisms, e.g., 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, vancomycin-resistant Enterococcus (VRE), Pseudomonas aeruginosa, Esherichia coli, Aspergillus niger, Aspergillus fumiga ts, Aspergillus clavatus, Fusarium solani, Fusarium oxysporum, Fusarium chlamydosporum, Candida albicans, Candid glabrata, Candida krusei, or the like.

In some embodiments, the medical article may contact the surface for a period in minutes of about 30, 60, 90, 120, 150, 180, or 210 or a value between any of the preceding values, for example, between about 30 and about 120, between about 90 and about 180, or the like In other embodiments, the antimicrobial article may contact the surface for a period in hours of greater than about 1 , 2, 3, 4, 5 , 12, or 24, or a value between any of the preceding values, for example between about 2 and about 5, between about 12 and about 24, or the like. In some embodiments, the antimicrobial article may contact the surface for a period in days of about 1, 2, 3, 4, 5, 6, or 7, or a value between any of the preceding values, for example, between about 1 and about 2, between about 2 and about 5, or the like.

In some embodiments, the method may be effective to deliver any of the above-described antimicrobials or a combination thereof to the surface at an average rate of greater than 15 mcg/sq in per hour For example, the method may be effective to deliver any of the above-described antimicrobials or a combination thereof to the surface at an average rate (mcg/sq. in per hour) of about 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100, or a value between any of the preceding values, for example, between about 30 and about 50, between about 20 and about 60, or the like. The amount of any of the above-described antimicrobials or a combination thereof delivered to the surface may be determined using the Surface Availability Analysis described herein.

In some embodiments, the method may be a method for preparing a surface for incision, e.g., surgery. In some embodiments, the method may be a method for preparing a surface for needle penetration, e g., to administer intravenous pharmaceuticals or fluids, withdraw fluids, or the like.

In various embodiments, a kit is described. The kit may include a medical article described herein and a set of instructions directing a user to disinfect a surface according to the methods described herein.

In various embodiments, a kit is described. The kit may include a medical article described herein and a set of instruction directed a user to prepare a surface for surgery according to the methods described herein.

EXAMPLES

Objects and advantages of this disclosure are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this disclosure. These examples are merely for illustrative purposes only and are not meant to be limiting on the scope of the appended claims.

All parts, percentages, ratios, etc. in the examples and the rest of the specification are by weight, unless noted otherwise. Solvents and other reagents used were obtained from MilliporeSigma, St. Louis, MO, unless otherwise noted. 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.

Table 1: Materials.

Elution Test:

Antimicrobial elution from adhesive samples is measured by exposing the adhesive portion of each sample having 3.14 cm ² area uniformly to 750 microliters of water for 30 minutes, diluting 3-fold in water, measuring the UV absorbance in a microcuvette at a unique wavelength for each antimicrobial (254 nm for chlorhexidine, 236 nm for PHMB, 209 nm for benzalkonium chloride, and 282 nm for octenidine) of this dilute extract, and determining concentration from a calibration curve. The extracted concentration is reexpressed in units of3.14 cm ² extracted in 50 microliters.

Available Fraction Test:

The available fraction is calculated by ratioing the weight of extracted antimicrobial in the Elution Test to the theoretical weight of antimicrobial present in 3.14 cm ² area of coated adhesive.

Rate of Release Test:

The Elution Test is performed on multiple samples over increasing exposure intervals ranging from 5 minutes to 90 minutes. The rate of release is defined as the shortest time at which the entire available fraction of antimicrobial is eluted.

Example 1: Effect of water on release of chlorhexidine acetate release from prepared PSA film.

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

Table 2: Formulations used to prepare samples 1, 2, and 3.

Sample 1: Parts A and B were prepared separately as provided in Table 2 and combined immediately prior to coating at 9 mils wet thickness on an loban EZ polyethylene release liner. 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.

Sample 2: Parts A and B were prepared separately as provided in Table 2 and combined immediately prior to coating at 9 mils wet thickness on an loban EZ liner. 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.

Sample 3: Parts A and B were prepared separately and then combined. Part C was added to the combined parts A and B immediately prior to coating at 9 mils wet thickness on an loban EZ liner. 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.

Chlorhexidine acetate elution from all three samples was measured using the Elution Test. The results are provided in Table 3.

Table 3: Elution of chlorhexidine from samples 1, 2, and 3.

The outsized influence of water addition to the hydrophobic PSA precursor solution is clearly apparent. Surprisingly, addition of water directly to a composition containing CHA and PSA gives the same result. The reason for the increase in elution is apparent from the micrographs of the three adhesives provided in Figs. 1-3. The addition of water draws out the CHA to the adhesive surface as a separate phase. This separate phase appears as surface features on the film surfaces of Figs. 2 and 3 and surface features are absent from the surface of the film surface shown in Fig. 1. The maximum release possible from the adhesive is 3100 ppm, samples 2 and 3 show a release of 46% of the maximum value. Example 2: Effect of water on CHG release from prepared PSA films.

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

Part A and parts B as provided in Table 4 were prepared separately and combined immediately prior to coating at 9 mils wet thickness on an loban EZ liner The wet adhesive was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. The liner was removed before testing.

Table 4: Formulations used to prepare samples 4-8.

All five samples were measured for CHG using the Elution Test. The results are provided in Table 5.

Table 5: CHG eluted from PSA films prepared according to Table 4

The dramatic effect of water content is immediately apparent. The identity of the alcohol co-solvent has relatively little impact on the elution of CHG Example 3: Rate of CHG release from prepared PSA films.

This example demonstrates that essentially all of the CHG released from the exemplified CHG adhesive is immediately available. Parts A and B of the formulation provided in Table 6 were prepared separately and combined immediately prior to coating at 9 mils wet thickness on an loban EZ liner. The wet adhesive was dried at 170°F and laminated to a 0.8 mil thick polyurethane fdm. The liner was removed before testing.

Table 6: Formulation of CHG-containing PSA preparation for Example 3.

Multiple samples were measured for CH elution at different timepoints following the Rate of

Release Test. The results are provided in Table 7

Table 7: Elution of CHG from a PSA film over time.

The data in Table 7 shows that all the CHG release occurs immediately from the surface. The apparent slight increase at 60 and 90 minutes can be ascribed to water evaporation occurring from the sample extraction set-up overtime.

Example 4: CHG release from PSA films prepared with and without plasticizer.

This example demonstrates the lack of influence of plasticizer (Priplast 3197) in the PSA composition on the release of chlorhexidine gluconate, Parts A and B of the formulation provided in Table 8 were made separately and mixed immediately prior to coating at 9 mils wet thickness on an loban EZ liner. The wet adhesive was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. The liner was removed before testing. Table 8: Formulation of CHG-containing PSA preparation for Example 4.

The samples were measured for CHG elution using the Elution Test. The results are provided in Table 9; no influence of the plasticizer is apparent:

Table 9: Elution of CHG from PSA films with and without plasticizer.

Example 5: Release of CHG from prepared PSA films have different values of HLB.

This Example demonstrates the importance of the HLB of the base polymer in the enhancement effect of water addition to the antimicrobial agent release from the PSA film. Acrylic PSAs are created by the copolymerization of hydrophobic monomers (that enable viscous flow) with hydrophilic co -monomers (that enable cohesion and elasticity) The HLB of the polymer is defined here by the hydrophilic content of the polymer from the total monomer composition according to Griffin's method for non-ionic surfactants as described in 1954 as follows:

HLB=20*M _h /M where Mh is the molecular mass of the hydrophilic portion of the molecule, and M is the molecular mass of the whole molecule.

The adhesives employed in this Example were copolymers of isooctyl acrylate (IO A) with mixtures of N-vinyl pyrrolidone (NVP), acrylamide (ACm), and vinyl acetate (Vac).

These copolymers were incorporated into solution utilizing ethyl acetate, propyl acetate, and heptane as solvents and utilized as part A in a Part A / Part B mix as per Example 2. The part B used was that of Sample 4 in Example 2 and the samples prepared using the processes described above. The samples were measured for CHG elution using the Elution Test. The results are provided in Table 10. Table 10: Effect of HLB of adhesive copolymer on elution of CHG from prepared film samples.

At HLB values above 5, these is a clear and precipitous reduction in the eluted values of CHG. The reason for the enhancement in elution values at low HLB appears to be related to the droplet size of the hydroalcoholic antimicrobial phase. Higher HLB polymers tend to stabilize the droplets at much smaller sizes approaching 1 micrometer or lower while the low HLB polymers form droplets that are typically 10 micrometers or larger. During the drying process, the larger droplets can gravitationally settle onto the surface of the release liner, thereby preferentially seeding the adhesive surface with high levels of antimicrobial agent. Smaller droplets, on the other hand, tend to remain uniformly distributed in the adhesive, leading to a low incidence of antimicrobial at the surface. Figs. 4 and 5 are micrographs of the wet adhesive mixtures in low and high HLB polymer solutions, respectively.

Example 6: Antimicrobial activity against Candida albicans.

This Example demonstrates the excellent antimicrobial activity of 3 different lots of antimicrobial CHG adhesive film coated samples made using the method described in Example 2. Part A was combined with part B2 from Example 2 and film samples were prepared using the procedures described in the previous examples.

A suspension of C. albicans was prepared at a concentration of 1 * 10 ⁸ CFU (colony forming units) per milliliter (mL) in phosphate buffered water (pbw) using a 0.5 McFarland Equivalence Turbidity Standard. Using an Eppendorf pipette, 50 microliters (pL) of this suspension was transferred as a single droplet to the adhesive surface of a 2.5 cm diameter section of the prepared adhesive film. The droplet was evenly spread under a sterile 20 mm diameter glass coverslip. These inoculated specimens were then incubated at room temperature (23+/-2°C) for 5-30 minutes. After incubation, the specimens were placed in 20 mL of neutralizing 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 neat solution and dilutions were each plated to 3M PETRIFILM aerobic count plates (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 provided in Table 11 indicate almost complete kill of the inoculum at the shortest time point, once again pointing to the rapid, burst release of CHG from the adhesive. The inoculum concentration in 50 LIL was 6.8 logs of yeast. The log reductions were performed in triplicate. The placebo sample shows no kill. Table 11: Log reduction of C. albicans on CHG-containing film samples.

Example 7: CHG release from non-acrylic adhesives.

This Example demonstrates the utility of the suspension coating method in its applicability to additional adhesive chemistries. The adhesives utilized were a tackified Kraton adhesive in heptane and a tackified silicone polyurea adhesive in a heptane/toluene/isopropanol mix. These adhesives were used as parts A and individually mixed with part B5 in Example 2 and coated, dried and laminated as described in Example 2. The elution results from the coated adhesives confirm the versatility of the current invention to provide release of CHG from different types of adhesives.

Table 12: Elution of CHG from prepared adhesive film samples.

Example 8: Release of the water-soluble antimicrobial agents from prepared PSA films.

This example demonstrates the utility of the invention in its applicability to additional water- soluble antimicrobial agents.

The following parts A and B were made separately and mixed immediately prior to coating at 9 mils wet thickness on an loban EZ liner. The wet adhesive was dried at 170°F and laminated to a 0.8 mil thick polyurethane film. The release liner was removed before testing.

Table 13: Release of other water-soluble antimicrobial agents from PSA film.

Note that octenidine hydrochloride was used at a lower loading relative to the other antimicrobial agents. The elution procedure was performed as per the previous examples Each antimicrobial had its own calibration curve, and the UV measurements were conducted 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.

Table 14: Release of PHMB (sample 11) and benzalkonium chloride (sample 12) from prepared PSA films. Table 15: Release of octenidine dihydrochloride (sample 13) from prepared PSA films.

The maximum elutable antimicrobial agent concentration in samples 11 and 12 is 3000 ppm, and the maximum elutable antimicrobial agent concentration is 300 ppm in sample 13. The high initial elution levels are proof of the universality of the suspension adhesive approach for creation of high burst elution delivery compositions.