Patent Description:
The present disclosure relates generally to adhesives particularly useful for the quick release of antimicrobial agents from medical dressings and drapes, resulting in the rapid onset of antimicrobial activity.

Adhesives, and particularly pressure sensitive adhesives, are routinely used in conjunction with a wide array of medical articles to attach or retain these articles to human skin. For example, hydrocolloid containing dressings and adhesive articles are commonly used in the treatment of wounds. In many instances, the hydrocolloid containing dressings and adhesive articles may comprise a variety of dressings, drapes including but not limited to surgical incise drapes, and sealing components that may be used in various medical applications. In some instances, the hydrocolloid containing dressings and adhesive articles may be used in negative pressure wound therapy (NPWT). In such treatment therapies, dressings, drapes, and sealing components are placed over a desired area of a patient's body, for example a wound area, to form a sealed area to be subjected to reduced pressure. Dressings and drapes may be provided with an adhesive coating along their underside for adhering and sealing the dressing or drape to the patient's skin.

In some cases, attempts have been made to use antimicrobial adhesives with such medical articles. However, there are several challenges associated with the incorporation of antimicrobial agents into adhesive compositions, and with the effective release of these agents from the adhesive. For example, adding antimicrobial agent to an adhesive typically impairs adhesion. Thus, in order to obtain sufficiently high antimicrobial efficacy and necessary adhesive properties, the coat weight of the adhesive must be increased. Although increased coat weight can yield higher antimicrobial concentration per surface area and promote maintenance of adequate adhesion, the increase in adhesive coat weight can also interfere with the stability or release of the antimicrobial agent from the adhesive if the adhesive component binds to or otherwise negatively interacts with the antimicrobial agent.

In addition, to obtain adequate antimicrobial efficacy of the medical adhesive article, high concentrations of antimicrobial agents can be required in conventional adhesive medical articles. This high concentration can tend to generate toxicity to the skin. It is therefore challenging for conventional antimicrobial adhesives to generate a high reduction of microbial activity without generating cytotoxic side effects. <CIT> describes an antibacterial pressure sensitive adhesive composition for medical applications. The adhesive composition comprises silver sulfadiazine as antibacterial agent (<NUM>-<NUM> wt %), internally crosslinked sodium carboxymethylcellulose or microcrystalline cellulose as a release aid (<NUM>-<NUM> wt%) and a solid hydrophobic acrylic adhesive (<NUM>-<NUM> wt%).

In view of these challenges with the use of conventional medical adhesive technologies, the need therefore remains for improved adhesive compositions having enhanced antimicrobial agent release characteristics as well as other advantages.

The scope of this invention is defined by the claims. Embodiments in the description relating to methods of treatment are not covered by the claims. Any "embodiment" or "example" which is disclosed in the description but is not covered by the claims should be considered as presented for illustrative purpose only.

The present invention relates to an adhesive composition comprising <NUM> wt% to <NUM> wt% of at least one adhesive, wherein the adhesive comprises at least one adhesive of an alcohol-functionalized acrylic adhesive and an alcohol-functionalized silicone adhesive; <NUM> wt% to <NUM> wt% of at least one phase-separated hydrophilic material, wherein at least one phase-separated hydrophilic material comprises silicon dioxide, zinc dioxide, titanium dioxide, calcium carbonate, crospovidone, clay, or combinations thereof; and at least one bioactive compound. In most embodiments, the concentration of the bioactive compound in the adhesive composition ranges from about <NUM> wt% to about <NUM> wt%. In many embodiments, the bioactive compound is an antimicrobial agent. In some embodiments, the release rate of the bioactive compound into water is at least about <NUM>µg/cm<NUM> within <NUM> minutes of contact of the adhesive composition with water. In some embodiments, the release rate of the bioactive compound into water is at least about <NUM>µg/cm<NUM> within <NUM> minutes of contact of the adhesive composition with water. In some embodiments, the release rate of the bioactive compound into water is at least about <NUM>µg/cm<NUM> within <NUM> minutes of contact of the adhesive composition with water. In some embodiments, the release rate of the bioactive compound into water is at least about <NUM>µg/cm<NUM> within <NUM> minutes of contact of the adhesive composition with water. In some embodiments, the adhesive composition has antimicrobial activity resulting in at least a <NUM> log reduction in a Pseudomonas aeruginosa, Staphylococcus epidermidis, Enterococcus faecalis (VRE), Enterobacter aerogenes, Escherichia coli, Staphylococcus aureus, or Candida albicans population within <NUM> minutes of contact of the adhesive composition with the population. In other embodiments, the adhesive composition has antimicrobial activity resulting in at least a <NUM> log reduction in an Aspergillus brasilienis population within <NUM> minutes of contact of the adhesive composition with the population. In other embodiments, the adhesive composition has antimicrobial activity resulting in at least a <NUM> log reduction in an Aspergillus brasilienis population within <NUM> minutes of contact of the adhesive composition with the population. In many embodiments, the adhesive composition has a grade <NUM> cytotoxicity. In some embodiments, the adhesive composition has a grade <NUM> cytotoxicity. In some embodiments, the adhesive composition has a grade <NUM> cytotoxicity. In many embodiments, the adhesive composition has a cytotoxicity grade of less than or equal to <NUM>. In other embodiments, the adhesive composition has a Primary Irritation Index value of less than or equal to <NUM>.

The present invention also relates to an adhesive product. The adhesive product comprises a substrate layer, and an adhesive layer disposed on at least a portion of a surface of the substrate layer. The adhesive layer comprises the adhesive composition as defined here above. In many embodiments, the substrate layer may comprise a polyethylene film, a polyurethane film, a polyvinylchloride film, a polyethylene foam, a polyurethane foam, a polyvinylchloride foam, nonwoven polyurethane, nonwoven elastomeric polyester, knitted fabric, woven fabric, or combinations thereof. In some embodiments, the substrate layer comprises a waterproof, flexible, non-adhesive film. In other embodiments, the adhesive product is configured for conformable topical application to biological skin. In many embodiments, the adhesive product is a pressure sensitive adhesive bandage, a wound covering, a medical dressing, a surgical dressing, a surgical drape, a surgical tape, or a medical tape.

The present invention further relates to an adhesive product as defined here above for use in delivering a bioactive compound to a subject by contacting the adhesive layer of the adhesive product to a biological skin surface of the subject, thereby delivering the bioactive compound of the adhesive product to the subject. In some embodiments, the biological skin surface is proximate to a wound or surgical site of the subject. In many embodiments, the subject is human.

The present invention further provides a method for producing an adhesive composition as defined here above. The method comprises providing an adhesive wherein the adhesive is at least one of an alcohol-functionalized acrylic adhesive and an alcohol-functionalized silicone adhesive, at least one phase-separated hydrophilic material wherein at least one phase-separated hydrophilic material comprises silicon dioxide, zinc oxide, titanium dioxide, calcium carbonate, crospovidone, clay, or combinations thereof, and at least one bioactive compound. The method further comprises combining the adhesive, the phase-separated hydrophilic material(s), and the bioactive compound(s) to produce the adhesive composition.

The present disclosure generally relates to adhesive compositions that, when employed for example in medical applications, provide advantageous improvements, inter alia, in the release of desired bioactive compounds from the adhesive composition. It would be beneficial for an adhesive material applied to a target site to quickly deliver chemical treatments to the site. For example, it would be beneficial for medical adhesive products to rapidly supply antimicrobial agents to a wound or surgical site, quickly facilitating the onset of antimicrobial activity shortly after application of the adhesive product. The ability of adhesive medical products to quickly provide an antimicrobial effect can advantageously reduce the occurrence or severity of microbial infections, and can improve patient outcomes.

In certain applications, it is desirable that the adhesives achieve relatively high release rates and/or extents of release of antimicrobial agents incorporated in the adhesive. High release rates and/or extents of release of antimicrobial agents in relatively short time periods can be a prerequisite to using an adhesive in, for example, medical incise films or peripheral IV dressings.

There are challenges associated with balancing the above needs for an adhesive formulation to not inhibit bioactive compound release with further needs for the adhesive to meet requirements for dermal application. These requirements include good adhesion to skin, no to low toxicity to a patient, and minimal irritation caused by application of the medical adhesive product. As noted above, an increase in the amount of antimicrobial agent in an adhesive formulation typically results in a decrease in the adhesive properties of the formulation. Generally speaking, adhesive formulation characteristics that help to achieve some of these goals, however, are in opposition to other goals. It has been found difficult for an adhesive composition to simultaneously address each of these demands.

Disclosed herein are certain adhesive compositions that beneficially provide for a synergistic combination of both dermal application and the quick release of compounds, e.g., bioactive compounds such as antimicrobial agents, into a surrounding aqueous medium such as that of a wound or surgical site. In particular, it has been found that by utilizing alcohol-functionalized ("OH-functionalized") adhesives in the adhesive compositions described herein, the resulting adhesive composition can surprisingly release compounds at a faster rate and with a higher activity.

Also, it has been discovered that the use of particular phase-separated hydrophilic materials in the adhesive composition can surprisingly lead to the creation of micron-scale hydrophilic channels with the adhesive with minimal or no water absorption. These channels can also act to enhance the release of bioactive compounds from within the adhesive composition. Importantly, some of the phase-separated hydrophilic materials of the disclosed adhesive compositions also advantageously provide the adhesive with improved stability in various different sterilization procedures that can be used in preparing the adhesive for medical application. These sterilization procedures can include, for example, gamma radiation and ethylene oxide gas treatment. According to the claimed invention, the phase-separated hydrophilic materials are selected from silicon dioxide, zinc oxide, titanium dioxide, calcium carbonate, crospovidone, clay, or a combination thereof.

In one embodiment, an adhesive composition is disclosed. The adhesive composition may include at least one adhesive, at least one phase-separated hydrophilic material, and at least one bioactive compound. The adhesive composition comprises at least one adhesive of an alcohol-functionalized acrylic adhesive and an alcohol-functionalized silicone adhesive. A adhesive may be a hybrid comprising at least one silicone adhesive and/or at least one acrylic adhesive as defined here above. In some embodiments, at least one adhesive may be a pressure sensitive adhesive.

In some embodiments according to the claimed invention, the adhesive comprises an acrylic adhesive, wherein the acrylic adhesive is an alcohol-functionalized acrylic adhesive. In other embodiments according to the claimed invention, the adhesive comprises a silicone adhesive, wherein the silicone adhesive is an alcohol-functionalized silicone adhesive. In many embodiments, the adhesive composition may also comprise at least one adhesive of an alcohol-functionalized acrylic adhesive and an alcohol-functionalized silicone adhesive.

According to the claimed invention, the concentration of the adhesive ranges from <NUM> wt% to <NUM> wt% of the adhesive composition. Besides the adhesive, the adhesive composition also comprises at least one phase-separated hydrophilic material and at least one bioactive compound. The selection and concentration of these materials within the adhesive composition provide it with advantageous properties associated with the rapid release of the bioactive compound from the adhesive composition when contacted with water. This rapid release results in an increased bioactive compound release rate, particularly during the first <NUM>-<NUM> hours of adhesive application. The rapid release also results in the overall delivery of a greater percentage of the bioactive compound from within the composition, both during the initial hours of application, and during the overall application lifetime of the adhesive composition.

In some cases, the alcohol-functionalized adhesive can be selected to provide, for example, good skin adhesion characteristics, conformability to skin surfaces, and gentle release from a skin or wound site. The adhesive for use in the present subject matter can be an aqueous-based or a solvent-based adhesive.

Further, the adhesive composition disclosed herein may also comprise both alcohol-functionalized adhesive and carboxyl-functionalized adhesives. In some embodiments, the adhesive may comprise at least one acrylic adhesive. In other embodiments, the adhesive may comprise at least one silicone adhesive. In some embodiments, the adhesive may comprise at least one acrylic adhesive and at least one silicone adhesive.

Useful acrylate copolymers may or may not be self-crosslinking and can be formed from at least two monomers. The monomers of the alcohol-functionalized acrylic adhesive can, for example, include hydroxyalkyl esters of acrylic or methacrylic acid in which the alkyl group comprises <NUM> to <NUM> carbon atoms, such as <NUM>-hydroxyethyl acrylate, <NUM>-hydroxyethyl methacrylate, <NUM>-hydroxypropyl acrylate, <NUM>-hydroxypropyl acrylate, and <NUM>-hydroxypropyl methacrylate. The monomers of the alcohol-functionalized acrylic adhesive can include alkyl esters of acrylic or methacrylic acid in which the alkyl group of the ester comprises <NUM> to <NUM> carbon atoms, such as n-butyl acrylate or methacrylate, isopropyl acrylate or methacrylate, n-hexyl methacrylate, and <NUM>-ethylhexyl acrylate. The monomers of the alcohol-functionalized acrylic adhesive can include α,β-unsaturated monocarboxylic or dicarboxylic acids, their anhydrides, and their alkyl or alkenyl esters in which the alkyl group contains from <NUM> to <NUM> carbon atoms and the alkenyl group contains from <NUM> to <NUM> carbon atoms, such as acrylic acid, itaconic acid, maleic acid, maleic anhydride, alkyl methacrylate, and the diethyl esters of fumaric or maleic acid. The monomers of the alcohol-functionalized acrylic adhesive can include vinyl monomers, such as vinyl acetate, acrylonitrile, vinyl propionate, vinylpyrrolidone, and styrene. The monomers of the alcohol-functionalized acrylic adhesive can include monomers containing a functional group selected from amido, amino, and epoxy groups, for example, acrylamide, N-butylacrylamide, alkyl amino alkyl and aminoalkyl derivatives of acrylic or methacrylic acid, such as aminoethyl acrylate, aminoethyl methacrylate and <NUM>-(dimethylamino) ethyl methacrylate, glycidyl methacrylate, and glycidyl acrylate. The monomers of the alcohol-functionalized acrylic adhesive can include alkoxyalkyl esters of acrylic or methacrylic acid, for example methoxyethyl acrylates or methacrylates, butoxyethyl acrylates or methacrylates. methoxypropylene glycol acrylates or methacrylates, and methoxypolyethylene glycol acrylates or methacrylates. The monomers of the alcohol-functionalized acrylic adhesive can include, but are not limited to, hexamethylene glycol dimethacrylate. The monomers of the carboxyl-functionalized acrylic adhesive can include, but are not limited to, acrylic acid, methacrylic acid, and maleic acid.

In cases where these copolymers are crosslinkable or at least partially crosslinked, they may also contain a crosslinking agent selected from those generally used by those skilled in the art, for example, organic peroxides, polyisocyanates, chelates or metals such as titanium or aluminum, or metal acetylacetonates, such as those of zinc, magnesium, and aluminum.

These adhesive acrylate copolymers can take the form of solutions in a solvent system including a single organic solvent or a mixture of several solvents, which contain about <NUM>% to about <NUM>% by weight (wt) copolymers. Examples of suitable solvents include aromatic solvents such as toluene, xylene, and other solvents Suitable aliphatic solvents may include, but are not limited to, esters such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; ketones such as methyl ethyl ketone, and acetone; and aliphatic hydrocarbons such as heptanes, hexane, and pentane. Other suitable solvents may also include alcohols such as, but not limited to, methanol, ethanol, and isopropyl alcohol.

In many embodiments, useful silicone adhesives comprise silicone-based monomers. Examples of suitable commercial silicone-based adhesives are described herein. These products are exemplary and are not meant to limit the scope of the silicone adhesives.

Where the monomer is a silicone-based monomer, the monomer may be a single polymer species or a mixture of two or more polymers, as long as at least one of the polymers is a silicone-based polymer. In many embodiments, the silicone adhesive has a siloxane backbone. In many embodiments, the silicone adhesive is comprised of polydimethylsiloxane (PDMS). For the silicone PSA, weight average molecular weight (Mw), Mw distribution, MQ resin type, and other polymer compositional factors may affect the properties of the silicone adhesive.

The silicone-based monomer of the silicone-based polymer may comprise, but are not limited to, siloxanes, silanes, silatrane glycols, and mixtures thereof. Other suitable silicone-based monomers include, <NUM>,<NUM>-Bis[dimethyl[<NUM>-(<NUM>-norbornen-<NUM>-yl)ethyl]silyl]benzene; <NUM>,<NUM>-Dicyclohexyl-<NUM>,<NUM>,<NUM>,<NUM>-tetrakis(dimethylsilyloxy)disiloxane; <NUM>,<NUM>-Dicyclohexyl-<NUM>,<NUM>,<NUM>,<NUM>-tetrakis(dimethylvinylsilyloxy)disiloxane; <NUM>,<NUM>-Dicyclohexyl-<NUM>,<NUM>,<NUM>,<NUM>-tetrakis[(norbornen-<NUM>-yl)ethyldimethylsilyloxy]disiloxane; <NUM>,<NUM>-Divinyltetramethyldisiloxane; <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-Hexamethyl-<NUM>,<NUM>-bis[<NUM>-(<NUM>-norbornen-<NUM>-yl)ethyl]trisiloxane; <NUM>,<NUM>,<NUM>,<NUM>-Tetramethyl-<NUM>,<NUM>-bis[<NUM>-(<NUM>-norbornen-<NUM>-yl)ethyl]disiloxane; <NUM>,<NUM>,<NUM>,<NUM>-Tetramethyl-<NUM>,<NUM>,<NUM>,<NUM>-tetravinylcyclotetrasiloxane; N-[<NUM>-(Trimethoxysilyl)propyl]-N'-(<NUM>-vinylbenzyl)ethylenediamine; <NUM>-[Tris(trimethylsiloxy)silyl]propyl vinyl carbamate; and mixtures thereof. Combinations of these monomers may be polymerized to form the silicone-based adhesive.

Suitable commercially available silicone-based products, e.g., that contain silicone polymer, include but are not limited to, products from KRT <NUM> (Shin Etsu), PSA <NUM> (Momentive), Q2-<NUM> (Dow Corning), DC <NUM> (Dow Corning), DC 280A (Dow Corning), DC <NUM> (Dow Corning), DC <NUM> (Dow Corning), BioPSA (Dow Corning), Q2-<NUM> (Dow Corning), KRT <NUM> (Shin Etsu), KRT <NUM> (Shin Etsu), KRT <NUM> (Shin Etsu), KRT <NUM> (Shin Etsu), KR <NUM> (Shin Etsu), KCT <NUM> (Shin Etsu), KR <NUM> (Shin Etsu), PSA <NUM> (Momentive), PSA <NUM> (Momentive), PSA <NUM> (Momentive), PSA 610e (Momentive), Bluestar PSA <NUM>, and PSA <NUM> (Bluestar).

It will be appreciated that the present subject matter is not limited to any particular silicone polymer component, and includes a wide array of such components.

Further, the adhesive composition described herein may comprise at least one adhesive that is a pressure-sensitive adhesive (PSA), including any pressure sensitive adhesive that is capable of adhering to mammalian skin and that is free of ingredients known to cause undue irritation or toxicity to mammals. One well known means of identifying PSAs is the Dahlquist criterion. This criterion defines a PSA as an adhesive having a <NUM> second creep compliance of greater than <NUM>×<NUM>-<NUM> cm<NUM>/dyne as described in <NPL>. Alternatively, since modulus is, to a first approximation, the inverse of creep compliance, PSAs may be defined as adhesives having a Young's modulus of less than <NUM>×<NUM><NUM> dynes/cm<NUM>. Another well-known means of identifying a PSA is that it is aggressively and permanently tacky at room temperature and firmly adheres to a variety of dissimilar surfaces upon mere contact without the need of more than finger or hand pressure, and which may be removed from smooth surfaces without leaving a residue as described in <NPL>. Another suitable definition of a suitable PSA is that it preferably has a room temperature storage modulus within the area defined by the following points as plotted on a graph of modulus versus frequency at <NUM>° C : a range of moduli from approximately <NUM>×<NUM><NUM> to <NUM>×<NUM><NUM> dynes/cm<NUM> at a frequency of approximately <NUM> radians/sec (<NUM>), and a range of moduli from approximately <NUM>×<NUM><NUM> to <NUM>×<NUM><NUM> dynes/cm<NUM> at a frequency of approximately <NUM> radians/sec (<NUM>) (for example see FIG. <NUM>-<NUM> on p. Any of these methods of identifying a PSA may be used to identify suitable PSAs for use in accordance with the present subject matter.

Additionally, at least one adhesive may be a hybrid adhesive. The hybrid adhesive may be a hybrid comprising at least one silicone adhesive and/or at least one acrylic adhesive.

In some embodiments, the adhesive may not be tacky at room temperature, but may be a tacky PSA after the addition of a tackifier.

The adhesive can include a wide array of additive materials. Additives, such as certain pigments, ultraviolet light absorbers, ultraviolet stabilizers, antioxidants, post curing agents, and the like can be blended into the adhesive to modify its properties.

The combined concentration of at least one adhesive of an alcohol-functionalized acrylic adhesive and an alcohol-functionalized silicone adhesive ranges from <NUM> wt% to <NUM> wt%.

In terms of upper limits, the concentration of the alcohol-functionalized acrylic adhesive(s) is less than <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt% or less than about <NUM> wt%. In terms of lower limits, the concentration of the alcohol-functionalized acrylic adhesive(s) is at least <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, or at least about <NUM> wt%.

In terms of upper limits, the concentration of the alcohol-functionalized silicone adhesive(s) is less than <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt% or less than about <NUM> wt%. In terms of lower limits, the concentration of the alcohol-functionalized silicone adhesive(s) is at least <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt% or at least about <NUM> wt%.

The adhesive composition includes one or more phase-separated hydrophilic materials. The phase-separated hydrophilic materials are not dissolved in the adhesive but are instead phase-separated from the adhesive. Phase-separated hydrophilic materials may be agents added to compositions to promote the breakup or disintegration of the composition into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of one or more hydrophilic active agents or substances contained in the composition. Further, phase-separated hydrophilic materials may allow water or other solvents or liquids to move into the matrix to extract one or more active agents more efficiently. In many embodiments, the phase-separated hydrophilic materials may be solid, plasma, liquid, gel, or some other form. In certain aspects, the phase-separated hydrophilic material of the disclosed adhesive composition is a medical or pharmaceutical grade material. In certain aspects, the phase-separated hydrophilic material is crospovidone. In certain aspects, the phase-separated hydrophilic material is clay. In certain aspects, the phase-separated hydrophilic material is silicon dioxide. In other embodiments, the phase-separated hydrophilic material is silicon dioxide, zinc oxide, titanium dioxide, calcium carbonate, crospovidone, clay, or a combination thereof.

For the adhesive composition described herein, the use of the disclosed phase-separated hydrophilic material unexpectedly provides at least some of the described advantages when used as a partial or complete replacement for cellulose phase-separated hydrophilic materials of conventional medical adhesives.

The combined concentration of the one or more phase-separated hydrophilic materials in the adhesive composition ranges from <NUM> wt% to <NUM> wt%. In terms of upper limits, the phase-separated hydrophilic material concentration can be less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt% or less than about <NUM> wt%. In terms of lower limits, the phase-separated hydrophilic material concentration can be at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt% or at least about <NUM> wt%.

Generally, the phase-separated hydrophilic material(s) are uniformly dispersed within the composition but not dissolved within the composition. However, the present subject matter contemplates the use of non-uniform dispersions of the phase-separated hydrophilic material(s). For example, for certain applications it may be advantageous to provide a relatively high concentration of phase-separated hydrophilic material(s) along or proximate to a face of the adhesive layer, and a lower concentration of phase-separated hydrophilic material(s) within other regions spaced from the contacting face of the adhesive. Adhesive layers having concentration gradients of phase-separated hydrophilic materials within the layer, such as across a thickness of the layer, are also included in the present subject matter.

As used herein, the term "bioactive" refers to a compound having a physiological effect on a biological system or subject as compared to a biological system or subject not exposed to the compound. The bioactive compound of the present disclosure can be an antibacterial agent, an antifungal agent, an analgesic agent, a tissue healant agent, a local anesthetic agent, an antibleeding agent, an enzyme, or a vasoconstrictor. The bioactive compound can be pharmaceutically active components such as, for example, an anti-inflammatory agent, analgesic agent, anesthetic, other pharmaceutically acceptable compound, or combinations thereof. The bioactive compound can be included in the adhesive composition in a pharmaceutically effective amount.

Examples of bioactive compounds include anionic agents such as those selected from antibacterials including fusidic acid, pseudomonic acid, and Ceftriaxone (Rocephin); antifungals including nafcillin, Nystatin, and undecylenic acid; analge sics including salicylic acid, salicylsulfonic acid, and nicotinic acid; and antibleeding agents including adenosine diphosphate. Further examples of bioactive compounds include cationic agents such as those selected from antibacterials including chlorhexidine, Bacitracin, Chlortetracycline, Gentamycin, Kanamycin, Neomycin B, Polymyxin B, Streptomycin, and Tetracycline; antifungals including Amphotericin B, ClotrimaZole, and MiconaZole; tissue healants including cysteine, glycine and threonine; local anesthetics such as Lidocaine; enzymes including trypsin, Streptokinase, plasmin (Fibrinolysin), and Streptodornase; deoxyribonuclease; and cationic vasoconstrictors including epinephrine and serotonin. Such biologically active agents can be used in the form of their salts. One or more bioactive compounds can be combined in the adhesive compositions of the present disclosure.

In certain aspects, the bioactive compound comprises an antimicrobial agent. As used herein. the terms "antimicrobial" and "inhibiting microbial growth" refer to the killing of, as well as the inhibition of or control of, the growth of bacteria, yeasts, fungi, and algae. Enhancement of antimicrobial efficacy refers to increasing the rate of kill and/or decreasing the amount of necessary antimicrobial agent to achieve antimicrobial control.

Non-limiting examples of antimicrobial agents include diiodomethyl-para-tolylsulfone (DIMTS, Amical®), ortho-phenylphenol (OPP), sodium pyrithione (NaPT), zinc pyrithione (ZPT), <NUM>-iodo-<NUM>-propynylbutylcarbamate (IPBC), <NUM>-methyl-<NUM>-isothiazolin-<NUM>-one (MIT), <NUM>,<NUM>-benzisothiazolin-<NUM>-one (BIT), <NUM>-n-octyl-<NUM>-isothiazolin-<NUM>-one (OIT), <NUM>-(<NUM>-chloroallyl)-<NUM>,<NUM>,<NUM>-triaza-<NUM>-azoniaadamantane chloride (CTAC. Dowicil <NUM>), <NUM>-(<NUM>-thiazolyl)-benzimidazole (TBZ, thiabendazole), β-bromo-β-nitrostyrene (BNS), <NUM>,<NUM>,<NUM>'-trichloro-<NUM>-hydroxyphenyl ether (Triclosan), chloroxylenol (PCMX), chlorocresol (PCMC), para-tert-amylphenol (PTAP), N-(<NUM>-chlorophenyl)-N'-(<NUM>-dichlorophenyl)-urea (Trichlocarban), para-hydroxybenzoic acid esters (parabens), and mixtures thereof. A partial listing of antimicrobial agents may include, but are not limited to, DIMTS, OPP, NaPT, ZPT, IPBC, BIT, and OIT. In certain embodiments the antimicrobial agent is a bis-biguanide salt and particularly chlorhexidine or a chlorhexidine salt thereof. In some embodiments, the chlorhexidine salt may comprise chlorhexidine digluconate.

Non-volatile, water-soluble antimicrobial agents include natural components including botanical compounds such as aloe, acids such as anisic acid, hydroxy acids such as lactic acid, polypeptides such as N-cocoyl-L-arginine ethyl ether DL-pyrrolidone carboxylate CAE, enzymes such as lactoperoxidase, polysaccharides such as chitosan, and proteins such as ionic lysostaphin; synthetic components including metal salts such as copper acetate and silver sulfadiazine, phenol derivatives such as phenoxyethanol, sulfur-containing compounds such as mafenide acetate, surfactants such as Nonoxynol-<NUM>, aminoglycosides such as streptomycin, iodine complexes such as povidone-iodine, hydric solvents such as benzyl alcohol, alkyl guanidines such as dodecylguanidine hydrochloride (DGH), anionic polymers such as polystyrene sulfonate, cationic polymers such as polytrimethoxysilyl propyldimethyloctadecyl ammonium chloride (AEM 5700TM), and cationic nitrogen-containing organic compounds such as bis-biguanide salts and quaternary ammonium salts such as poly[(dimethylimino)-<NUM>-butene-<NUM>-diylchloride] and [<NUM>-tris(<NUM>-hydroxyethyl)ammonio]-<NUM>-butenyl-w-[tris(<NUM>-hydroxyethyl)ammonio]dichloride available as Polyquatemium-<NUM>. In certain embodiments, it is contemplated that in addition to the metal salts noted herein, other metal salts with antimicrobial metallic ions, for example mercury, could be used and furthermore that nonmetallic ions having antibacterial properties could also be utilized. Additional examples of other quaternary ammonium compounds which can be used as antimicrobial agents include but are not limited to Cetremide, Domiphen Bromide, polymeric quaternaries, and iodophores such as Povidone Iodine.

Bis-biguanide salts include hexamethylene biguanide hydrochloride (available as Vantocil <NUM>), polyhexamethylene biguanide hydrochloride (also known as PHMB, available as Cosmocil CQ®), bis-biguanide alkanes, and mixtures thereof. In some embodiments, the bis-biguanide salt is <NUM>'-hexamethylene bis(<NUM>-(p-chlorophenyl)biguanide) salt commonly known as chlorhexidine salt. This form includes chlorhexidine acetate, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine diphosphanilate, or chlorhexidine digluconate, which mainly differ in their solubility profiles in various solvents and in their application. In certain aspects, the antimicrobial agent of the adhesive composition is chlorhexidine digluconate, i.e., chlorhexidine gluconate (CHG). The CHG can be present in an amount ranging from about <NUM>%, and more particularly from about <NUM>%, to about <NUM>% by weight (wt) of total solids, even more particularly from about <NUM>% to about <NUM>% by weight (wt) of total solids, and most particularly from about <NUM>% to about <NUM>% by weight (wt) of total solids.

The concentration of the bioactive compound in the adhesive composition can, for example, range from about <NUM> wt% to about <NUM> wt%, e.g., from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, or from about <NUM> wt% to about <NUM> wt%.

In certain aspects, within <NUM> minutes of contact of the adhesive composition with water, the adhesive composition has a cumulative release rate of the bioactive compound into the water that is at least about <NUM>µg/cm<NUM>, e.g., at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, at least about <NUM>µg/cm<NUM>, or at least about <NUM>µg/cm<NUM>. The release rate of the bioactive compound into water within <NUM> minutes of contact can, for example, range from about <NUM>µg/cm<NUM> to about <NUM>µg/cm<NUM>, from about <NUM>µg/cm<NUM> to about <NUM>µg/cm<NUM>, from about <NUM>µg/cm<NUM> to about <NUM>µg/cm<NUM>, from about <NUM>µg/cm<NUM> to about <NUM>µg/cm<NUM>, or from about <NUM>µg/cm<NUM> to about <NUM>µg/cm<NUM>.

In certain aspects, within <NUM> minutes of contact of the adhesive composition with water, the percentage of the adhesive composition bioactive compound that is released into the water is at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>%. The percentage of bioactive compound released into water within <NUM> minutes of contact can, for example, range from about <NUM>% to about <NUM>%, from about <NUM>% to about <NUM>%, from about <NUM>% to about <NUM>%, from about <NUM>% to about <NUM>%, or from about <NUM>% to about <NUM>%.

In some embodiments, the adhesive compositions exhibit antimicrobial efficacy against a broad spectrum of microbes, including but not limited to gram-positive bacteria, gram-negative bacteria, yeasts, fungi, and other microbes. Non-limiting examples may include gram-positive bacteria such as Propionibacterium acnes, Streptococcus pyogenes, Staphlococcus epidermidis, Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium, Non-limiting examples may include gram negative bacteria such as Burkholderia cepacia, Proteus mirabilis, Enterobacteriaceae β-lactamases, Acinetobacter baumannii, Serratia marcescens, Escherichia coli, Enterobacter aerogenes, Klebsiella pneumonia, and Pseudomonas aeruginosa. Other examples may include clinical isolates such as methicillin-resistant Staphylococcus aureus (MRSA), Carbapenem resistant Klebsiella pneumonia (CRE), and vancomycin-resistant Enterococcus faecium (VRE). The above noted bacteria can typically be found in a hospital environment. Additional non-limiting examples of additional microorganisms to which the present subject matter is directed may include Candida albicans, Candida parapsilosis, and Aspergillus brasiliensiss.

The adhesive composition can be effective in preventing or reducing the severity of infections by bacteria such as Pseudomonas aeruginosa. aeruginosa is a Gram-negative, rod-shaped bacterium associated with serious illnesses including hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes. Because it thrives on moist surfaces, P. aeruginosa can also be found on and in medical equipment, including catheters, causing cross-infections in hospitals and clinics. One measure of the efficacy of an antimicrobial treatment is the reduction of the number of viable microorganisms in a test population, e.g., a P. aeruginosa population, within a period of time as a result of application of the treatment. This reduction in microorganism viability can be expressed in terms of log reduction, wherein a log reduction of <NUM> indicates a <NUM>-<NUM>, or <NUM>%, probability that an individual microorganism of the test population remains viable and nonsterile. The log reduction of a microbial population in response to an antimicrobial agent can be measured according to, for example, the standard protocol ASTM E2315 - <NUM>. In certain aspects, within <NUM> minutes of contact of the adhesive composition with a population of P. aeruginosa, the adhesive composition causes a log reduction in the P. aeruginosa population that is at least about <NUM>, e.g., at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. The log reduction of the P. aeruginosa population within <NUM> minutes of contact can, for example, range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

The adhesive composition can be effective in preventing or reducing the severity of infections by bacteria such as Escherichia coli. coli is a Gram-negative, facultatively anaerobic, rod-shaped, coliform bacterium, some virulent strains of which can cause gastroenteritis, urinary tract infections, neonatal meningitis, hemorrhagic colitis, and Crohn's disease. In certain aspects, within <NUM> minutes of contact of the adhesive composition with a population of E. coli, the adhesive composition causes a log reduction in the E. coli population that is at least about <NUM>, e.g., at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. The log reduction of the E. coli population within <NUM> minutes of contact can, for example, range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

The adhesive composition can be effective in preventing or reducing the severity of infections by bacteria such as Staphylococcus aureus. aureus is a common cause of a range of illnesses, from minor skin infections, such as pimples, impetigo, boils, cellulitis, folliculitis, carbuncles, scalded skin syndrome, and abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome, bacteremia, and sepsis. aureus is one of the most common causes of hospital-acquired infections and is often the cause of wound infections following surgery. In certain aspects, within <NUM> minutes of contact of the adhesive composition with a population of S. aureus, the adhesive composition causes a log reduction in the S. aureus population that is at least about <NUM>, e.g., at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. The log reduction of the S. aureus population within <NUM> minutes of contact can, for example, range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

The adhesive composition can be effective in preventing or reducing the severity of infections by yeast such as Candida albicans, Candida tropicalis, Candida parapsilosis, or Candida glabrata. albicans is a pathogenic yeast that is a common member of the human gut flora. Individuals at particular risk of C. albicans infections are those who are immunocompromised, or those who have recently undergone surgery, a transplant, or are in an Intensive Care Unit (ICU). In certain aspects, within <NUM> minutes of contact of the adhesive composition with a population of C. albicans, the adhesive composition causes a log reduction in the C. albicans population that is at least about <NUM>, e.g., at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. The log reduction of the C. albicans population within <NUM> minutes of contact can, for example, range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

The adhesive composition can be effective in preventing or reducing the severity of infections by fungal molds such as Aspergillus brasiliensis, Aspergillus tubingensis, Aspergillus foetidus, Aspergillus carbonarius, or Aspergillus awamori. brasiliensis is a common cause of fungal infections of the lung and ear. In certain aspects, within <NUM> minutes of contact of the adhesive composition with a population of Pseudomonas aeriginosa, the adhesive composition causes a log reduction in the P. aeriginosa population that is at least about <NUM>, e.g., at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. The log reduction of the P. aeriginosa population within <NUM> minutes of contact can, for example, range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

When an adhesive is to be used in the treatment of patients, it can be advantageous for the adhesive to have low to minimal cytotoxicity. The cytotoxicity of a material can be measured according to, for example, the standard protocol ISO <NUM>-<NUM>:<NUM>. Generally, materials having a cytotoxicity grade of <NUM> are classified as having severe reactivity, a cytotoxicity grade of <NUM> are classified as having moderate reactivity, a cytotoxicity grade of <NUM> are classified as having mild reactivity, a cytotoxicity grade of <NUM> as having slight reactivity, and a cytotoxicity grade of <NUM> as having no reactivity. In certain aspects, the adhesive composition of the present disclosure has less than a grade <NUM> cytotoxicity. In certain aspects, the adhesive composition of the present disclosure has a grade <NUM> cytotoxicity. In certain aspects, the adhesive composition has a grade <NUM> cytotoxicity. In certain aspects, the adhesive composition has a grade <NUM> cytotoxicity. In many embodiments, the adhesive composition described herein has a cytotoxicity grade of less than or equal to <NUM>. In many embodiments, the adhesive composition described herein has a cytotoxicity grade of less than <NUM>.

It can further be advantageous for an adhesive intended for dermal application to produce low to minimal skin irritation. The skin irritation caused by a material can be measured according to, for example, standard protocol ISO <NUM>-<NUM>:<NUM>. Generally, materials having Primary Irritation index values between <NUM> and <NUM> are classified are severe irritants, between <NUM> and <NUM> are classified as moderate irritants, between <NUM> and <NUM> are classified as mild irritants, and between <NUM> and <NUM> are classified as minimal irritants or non-irritants. In certain aspects, the disclosed adhesive composition has a Primary Irritation Index value that is less than <NUM>, e.g., less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, or less than <NUM>. The Primary Irritation Index value of the adhesive composition can, for example, range from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, or from <NUM> to <NUM>.

Also provided are adhesive products using the disclosed adhesive composition. The adhesive products include a substrate layer and an adhesive layer disposed on at least a portion of a surface of the substrate layer, wherein the adhesive layer includes the disclosed adhesive composition. In certain aspects, the adhesive product is configured for conformable topical application to biological skin. In some embodiments, the biological skin surface is proximate to a wound or surgical site of the subject. As used herein, the term "subject" refers to animals such as mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.

The adhesive compositions described herein can be used in association with a wide array of medical articles. Non-limiting examples of such articles include wound dressings or coverings, medical dressings, incise films or drapes, surgical dressings or drapes, medical tapes, athletic tapes, surgical tapes, sensors, electrodes, ostomy appliances, or related components such as sealing rings, catheters, connector fittings, catheter hubs, catheter adapters, fluid delivery tubes, electrical wires and cables, negative pressure wound therapy components, surgical drains, wound draining components, IV site dressings such as peripheral IV dressings, prostheses, stoma pouches, buccal patches, transdermal patches, dentures, hairpieces, bandages, diapers, and medical padding such as liposuction padding, hygiene pads, corn and callous pads, toe cushioning pads, and pads for protecting and cushioning tube sites such as tracheotomy tubes. The adhesive product may include one or more faces, regions, and/or surfaces to which the adhesive compositions of the present subject matter are applied. Forming a layer, coating, or other region of adhesive on an article enables the article to be adhered to a wide range of surfaces, including skin. It will be understood that the present subject matter is not limited to any of these articles. Instead, the subject matter includes the use of the adhesive compositions with other articles besides those noted herein.

In certain aspects, the adhesive product is a dressing or drape. Dressings and drapes can include a uniform coating of the adhesive and can be non-patterned in at least one region, along an underside or face of the substrate layer. Dressings and drapes can be cut or otherwise appropriately sized by a medical practitioner prior to application. Dressings and drapes, prior to cutting, can be available in a wide range of sizes such as square shapes of <NUM> by <NUM>, or larger or rectangular shapes of <NUM> by <NUM> or larger. The term "drape" as used herein can refer to even larger articles. In some embodiments, the adhesive product is a surgical tape. In other embodiments, the adhesive product is used for wound care.

The adhesive layer is disposed on at least a portion of the substrate layer, wherein the term "disposed" is not intended to imply that that the adhesive layer and the substrate layer are in direct contact with one another. In certain aspects, one or more intervening layers are located between the adhesive layer and the substrate layer within the adhesive product. In certain aspects, at least a portion of the adhesive layer directly contacts at least a portion of the substrate layer.

In certain versions, the adhesive product includes a continuous adhesive layer, i.e., the adhesive layer covers the entirety of the substrate layer or adhesive product face. In other versions the adhesive product includes a non-continuous adhesive layer, such that at least one region of adhesive is disposed on a face of the substrate layer and at least one adhesive-free region is defined on the face. In certain versions using a non-continuous adhesive layer, an adhesive region in the form of a strip or band is provided that extends around at least a periphery of a face of the substrate layer. One or more adhesive-free regions may be defined on other areas of the substrate layer face such as within a central or interior region of the substrate layer. The adhesive layer can be pattern coated. The adhesive layer can also be melt-blown.

The coat weight of the adhesive layer of the adhesive product can, for example, range from about <NUM> gram/m<NUM> (gsm) to about <NUM> gsm, e.g., from about <NUM> gsm to about <NUM> gsm, from about <NUM> gsm to about <NUM> gsm, from about <NUM> gsm to about <NUM> gsm, from about <NUM> gsm to about <NUM> gsm, or from about <NUM> gsm to about <NUM> gsm. In terms of upper limits, the adhesive layer coat weight can be less than about <NUM> gsm, e.g., less than about <NUM> gsm, less than about <NUM> gsm, less than about <NUM> gsm, less than about <NUM> gsm, less than about <NUM> gsm, less than <NUM> gsm, less than about <NUM> gsm, less than about <NUM> gsm, less than about <NUM> gsm. In terms of lower limits, the adhesive coat weight is at least about <NUM> gsm, at least about <NUM> gsm, at least about <NUM> gsm, at least about <NUM> gsm, at least about <NUM> gsm, at least about <NUM> gsm, at least about <NUM> gsm, at least about <NUM> gsm, or at least about <NUM> gsm. Higher coat weights, e.g., at least about <NUM> gsm, and lower coat weights, e.g., less than about <NUM> gsm, are also contemplated.

In certain aspects, the adhesive composition is formulated as a wet blend prior to coating. The wet blend can include an organic solvent. In some embodiments, the organic solvent is methanol. The concentration of solvent in the wet blend can, for example, range from about <NUM> wt% to about <NUM> wt%, e.g., from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, or from about <NUM> wt% to about <NUM> wt%. In terms of upper limits, the solvent concentration in the wet blend can be less than about <NUM> wt%, e.g., less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, or less than about <NUM> wt%. Higher solvent concentrations, e.g., at least about <NUM> wt%, and lower solvent concentrations, e.g., less than about <NUM> wt%, are also contemplated.

The concentrations of solids in the wet blend can, for example, range from about <NUM> wt% to about <NUM> wt%, e.g., from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, from about <NUM> wt% to about <NUM> wt%, or from about <NUM> wt% to about <NUM> wt%. In terms of upper limits, the solids concentration in the wet blend can be less than about <NUM> wt%, e.g., less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, less than about <NUM> wt%, or less than about <NUM> wt%. In terms of lower limits, the solids concentration in the wet blend can be at least about <NUM> wt%, e.g., at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, or at least about <NUM> wt%. Higher solids concentrations, e.g., at least about <NUM> wt%, and lower solids concentrations, e.g., less than about <NUM> wt%, are also contemplated.

The adhesive layer of the adhesive product can be applied using standard coating techniques, such as curtain coating, gravure coating, reverse gravure coating, offset gravure coating, roller coating, brushing, knife-over roll coating, air knife coating metering rod coating, reverse roll coating, doctor knife coating, dipping, die coating, spraying, and the like. The application of these coating techniques is well known in the industry and can effectively be implemented by one skilled in the art. Co-extrusion techniques can also be utilized.

In certain aspects, the coating of the adhesive layer involves the use of a coating rod or bar positioned across from the substrate layer at a particular gap distance. The bar gap used during coating of the adhesive layer can, for example, range from about <NUM> mil to about <NUM> mil, e.g., from about <NUM> mil to about <NUM> mil, from about <NUM> mil to about <NUM> mil, from about <NUM> mil to about <NUM> mil, from about <NUM> mil to about <NUM> mil, or from about <NUM> mil to about <NUM> mil. In terms of upper limits, the bar gap can be less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, or less than about <NUM> mil. In terms of lower limits, the bar gap can be at least about <NUM> mil, e.g., at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, or at least about <NUM> mil. Larger bar gaps, e.g., at least about <NUM> mil, and smaller bar gaps, e.g., less than about <NUM> mil, are also contemplated. Hereby a mil equals <NUM>.

After coating the wet blend of the adhesive composition, the adhesive layer can be dried by evaporating, for example, the solvent component of the wet blend. In some embodiments, the adhesive layer is dried at room temperature for a first period of time, such as for example approximately <NUM> minutes, and then dried at an elevated temperature, such as for example <NUM> °F (<NUM>), for a second period of time, such as for example <NUM> minutes. The temperature for drying for a second period of time may also be <NUM> °F (<NUM>), <NUM> °F (<NUM>), <NUM> °F (<NUM>), or <NUM> °F (<NUM>).

The materials and configuration of the substrate layer can be selected to provide a thin and flexible layer that can optionally be permeable to water vapor. In some embodiments, the substrate layer includes a water-proof, flexible, non-adhesive film. In certain aspects the substrate layer includes a polyethylene film, a polyurethane film, a polyvinylchloride film, a polyethylene foam, a polyurethane foam, a polyvinylchloride foam, nonwoven polyurethane, nonwoven elastomeric polyester, knitted fabric, woven fabric, or combinations thereof.

The substrate layer can be sufficiently conformable to conform to the contours of skin to which it will be applied. The substrate layer can be porous, non-porous, woven or nonwoven or a foam film. The substrate layer can include, for example, non-woven meshes; woven meshes of fiberglass or acetate; gauze; polyurethane foams; polymeric films including polyolefins (linear and branched), halogenated polyolefins, polyamides, polystyrenes, nylon, polyesters, polyester copolymers, polyurethanes, polysulfones, styrene-maleic anhydride copolymers, styrene-acrylonitrile copolymers, ionomers based on sodium or zinc salts of ethylene methacrylic acid, polymethyl methacrylates, cellulosics, acrylic polymers and copolymers, polycarbonates, polyacrylonitriles, and ethylene-vinyl acetate copolymers; composite wound dressings, and adhesive-coated, thin-film dressings.

The substrate layer can include an untreated film that is amenable to adsorption. Alternatively, the substrate layer can be treated by first exposing the layer to an electron discharge treatment, e.g., corona treatment, at a surface. A surface of the substrate layer can be plasma treated, chemically treated or solvent washed. Examples of pretreated films suitable for use in the substrate layer of the disclosed adhesive product include the PET films available from DuPont Teijin Films under the designation ST504 (one side treated) and ST505 (both sides treated).

In some embodiments, a surface of the substrate layer is roughened to improve adhesion and to increase the surface area of the substrate surface. With increased surface area, such as with roughened surfaces and foamed substrates, the adhesion of the adhesive layer or activity of the bioactive compound can be increased.

The substrate layer can be a single-layered film or it can itself be a multi-layered construction. The multi-layered construction can include, for example, coextruded films and laminated films. The multi-layered constructions have two or more layers. In some embodiments, the substrate layer includes from two to seven layers. In some embodiments, the substrate layer includes from three to five layers. The layers of such multi-layered constructions and polymer films can have the same composition and/or size as one another, or they can be different.

The thickness of the substrate layer can, for example, range from about <NUM> microns to about <NUM> microns, e.g., from about <NUM> microns to about <NUM> microns, from about <NUM> microns to <NUM> microns, from about <NUM> microns to about <NUM> microns, from about <NUM> microns to about <NUM> microns, or from about <NUM> microns to about <NUM> microns. In terms of upper limits, the substrate layer thickness can be less than about <NUM> microns, e.g., less than about <NUM> microns, less than about <NUM> microns, less than about <NUM> microns, less than about <NUM> microns, less than about <NUM> microns, less than about <NUM> microns, less than about <NUM> microns, less than about <NUM> microns, or less than about <NUM> microns. In terms of lower limits, the substrate layer thickness can be at least about <NUM> microns, e.g., at least about <NUM> microns, at least about <NUM> microns, at least about <NUM> microns, at least about <NUM> microns, at least about <NUM> microns, at least about <NUM> microns, at least about <NUM> microns, at least about <NUM> microns, or at least about <NUM> microns. Larger thicknesses, e.g., at least about <NUM> microns, and smaller thicknesses, e.g., less than about <NUM> microns, are also contemplated.

In some embodiments, the adhesive product further comprises a release liner. One face of the release liner can be directly adjacent to the adhesive layer, or there can be one or more intervening layers between the adhesive layer and the release liner. In some cases, one face of the adhesive layer is directly adjacent to the release liner, and an opposite face of the adhesive layer is directly adjacent to the substrate layer.

The releasable liner can function as a protective cover such that the release liner remains in place until the adhesive is ready for attachment to a subject. If a liner or release liner is included in the adhesive product, a wide array of materials and configurations can be used for the liner. In many embodiments, the liner is a paper or paper-based material. In many other embodiments, the liner is a polymeric film of one or more polymeric materials. Typically, at least one face of the liner is coated with a release material such as a silicone or silicone-based material. As will be appreciated, the release coated face of the liner is placed in contact with the otherwise exposed face of the outer adhesive layer. Prior to application of the label to a surface of interest, the liner is removed to thereby expose the adhesive layer of the adhesive product. The liner can be in the form of a single sheet. Alternatively, the liner can be in the form of multiple sections or panels.

The thickness of the release liner can, for example, range from about <NUM> mil to about <NUM> mil, e.g., from about <NUM> mil to about <NUM> mil, from about <NUM> mil to about <NUM> mil, from about <NUM> mil to about <NUM> mil, from about <NUM> mil to about <NUM> mil, or from about <NUM> mil to about <NUM> mil. In terms of upper limits, the release liner thickness can be less than about <NUM> mil, e.g., less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, less than about <NUM> mil, or less than about <NUM> mil. In terms of lower limits, the release liner thickness can be at least about <NUM> mil, e.g., at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, at least about <NUM> mil, or at least about <NUM> mil. Larger thicknesses, e.g., at least about <NUM> mil, and smaller thicknesses, e.g., less than about <NUM> mil, are also contemplated. Hereby a mil equals <NUM>.

Also provided is the adhesive product as described herein for use in delivering a bioactive compound to a subject by contacting the adhesive layer of the adhesive product to a biological skin surface of the subject, thereby delivering the bioactive compound of the adhesive product to the subject. In some embodiments, the biological skin surface is at or proximate to a wound or surgical site of the subject.

Also provided are methods for producing the disclosed adhesive compositions. The methods include providing: <NUM>) at least one adhesive wherein the adhesive is at least one of an alcohol-functionalized acrylic adhesive and an alcohol-functionalized silicone adhesive, <NUM>) a phase-separated hydrophilic material, wherein at least one phase-separated hydrophilic material comprises silicon dioxide, zinc oxide, titanium dioxide, calcium carbonate, crospovidone, clay, or combinations thereof, and <NUM>) a bioactive compound. The methods also include: <NUM>) providing the adhesive, the phase-separated hydrophilic material, and the bioactive compound; and <NUM>) combining at least one adhesive, the phase-separated hydrophilic material, and the bioactive compound to produce the adhesive composition. In some embodiments, the combining comprises blending the components in solvents, such as alcohols, toluene, heptanes, and the like, until a homogeneous blend is obtained. The blending time can be, for example, approximately <NUM> hours. Various methods of blending are known in the art, and any method that produces a homogeneous blend can be suitable for use in producing the adhesive composition.

The following examples are added to illustrate the benefits of disclosed adhesive compositions and are non-limiting. Hereby Examples <NUM>-<NUM> are according to the claimed invention. Example <NUM> and the Comparative Examples are provided for illustrative purposes.

The adhesives of Examples <NUM>-<NUM> and Comparative Examples A - C were laminated between a stiff polyester layer and a <NUM>-gsm polyurethane layer. This configuration allowed the adhesive composition to remain unfolded and un-sticky during testing with a rigid acrylic adhesive tape attached to the polyurethane film for the reinforcement. Samples measuring <NUM> inches (<NUM>) by <NUM> inch (<NUM>) were place in <NUM> demineralized water on a shaker. At regular time points, <NUM>µl of solution was removed and analyzed by UV-spectrophotometry. Spectrophotometric readings at a wavelength of <NUM> were used to measure the CHG concentration.

The antimicrobial agent release results shown in Table 1A below demonstrate that the disclosed adhesive compositions demonstrated significantly higher release rates and release percentages of the antimicrobial agent as compared to those of the comparative examples.

Additional adhesive compositions described in Table 1C were prepared in accordance with Table 1B.

The antimicrobial efficacies of these adhesive compositions were measured according to the standard protocol ASTM E2315 - <NUM>. Square pieces of adhesive <NUM> × <NUM> were aseptically cut. Microorganisms were grown with tryptic soy agar (TSA) at <NUM> for <NUM> to <NUM> hours, and then harvested with sterile water to achieve a final concentration between <NUM>×<NUM><NUM> cfu/ml to <NUM>×<NUM><NUM> cfu/ml, wherein "cfu" refers to colony forming units. Under a class-<NUM> biological cabinet, the <NUM> × <NUM> adhesive films were inoculated with <NUM>µl of the prepared challenge organism to achieve an inoculum of <NUM>×<NUM><NUM> to <NUM>×<NUM><NUM> cfu of the samples. The inoculated samples were covered with a <NUM> diameter sterile glass to assure that the inoculum was in intimate contact with the adhesive and that the inoculum did not spread beyond the edge of the test sample. The inoculated test sample was held at <NUM>-<NUM>. and <NUM>% relative humidity. The identical procedure is performed on a placebo (identical adhesive not containing the CHG).

After a <NUM>-minute contact time, the glass covers were carefully separated from both the placebo and inoculated samples, and were placed into <NUM> of Dey-Engley Neutralizing Broth and sonicated for <NUM> minutes. Enumeration of the recovered microorganisms was performed by pour plating onto TSA (bacterial) or SDA (yeast and mold) 2x10-ml aliquots (<NUM>-<NUM> dilution), 2x <NUM>-ml aliquots (<NUM>-<NUM> dilution), 2x <NUM>-ml aliquots (<NUM>-<NUM> dilution), <NUM>-µl aliquots (<NUM>-<NUM> dilution), and <NUM> into <NUM> D/E broth aliquots (<NUM>-<NUM> dilution). The log reduction was then calculated by subtracting the log<NUM> cfu from the test sample to contact and the log<NUM> cfu from the test sample after <NUM> minutes of contact.

The antimicrobial efficacy results shown in Table 2A below demonstrate that of the materials tested, only the exemplary adhesive composition was surprisingly effective in reducing both the populations of the tested bacterial and yeast cultures by a factor at least about log <NUM>, and the population of the tested fungal mold by a factor at least about log <NUM>. The comparative examples were unable to reduce both the populations of the tested bacterial and yeast cultures and the population of the tested fungal mold in the same manner.

Additional adhesive compositions were prepared in accordance with Table 2B.

The cytotoxicities of these adhesive compositions were measured according to standard protocol ISO10993-<NUM>:<NUM> using mouse fibroblast cell line L-<NUM>. The cells were incubated in <NUM>-cm<NUM> wells to obtain sub-confluent monolayers of cells. The growth medium was then replaced in each well by <NUM> of agarose. Test articles prepared in a square were placed on the solidified agarose surface. The wells were incubated for a period of <NUM> hours and then observed under a microscope.

The cytotoxicity results shown in Table <NUM> below demonstrate that the disclosed adhesive composition showed no evidence of causing cell lysis or other cytotoxicity effects to the tested cells, indicating that the adhesive composition meets requirements associated with medical products.

For the cytotoxicity test, the release liner was removed and excluded from the preparation. Based on the USP ratio of <NUM>":<NUM>, a <NUM> portion of the test article was covered with <NUM> of single strength Minimum Essential Medium supplemented with <NUM>% serum and <NUM>% antibiotics (IX MEM). A single preparation was extracted with agitation at <NUM> for <NUM> hours. The IX MEM extraction method was conducted in the presence of serum to optimize extraction of both polar and non-polar components. For the testing extract after <NUM> hours, Comp. C had a <NUM>% lysis and a rating for cytotoxic effect (CTE) score of non-toxic (N).

The likelihood of skin irritation caused by the adhesive composition was measured according to standard protocol ISO10993-<NUM>:<NUM>, with results shown in Table <NUM> below. The results demonstrate that application of the adhesive composition to each of the test animals resulted in no to very slight erythema, and no edema, indicating only a slight irritation response.

Claim 1:
An adhesive composition comprising:
<NUM> wt% to <NUM> wt% of at least one adhesive, wherein the adhesive comprises at least one adhesive of an alcohol-functionalized acrylic adhesive and an alcohol-functionalized silicone adhesive;
<NUM> wt% to <NUM> wt% of at least one phase-separated hydrophilic material, wherein at least one phase-separated hydrophilic material comprises silicon dioxide, zinc oxide, titanium dioxide, calcium carbonate, crospovidone, clay, or combinations thereof; and
at least one bioactive compound.