ITEMS CONCENTRATED WITH AN ACTIVE INGREDIENT ON THE SUBSTRATE CONTACT SURFACE AND ASSOCIATED PROCEDURES

Description

FIELD

[0001] The present invention relates to a method of incorporating an active agent to an adhesive article for delivery of the active agent to a substrate.BACKGROUND

[0002] Many products use adhesives for affixing the product to a substrate. As will be appreciated, it is desirable in some circumstances for the product to deliver an active agent to a region of interest on a substrate. For example, it may be desirable to deliver an active agent to a wound in skin in order to prevent or at least minimize microbial growth or reproduction along the interface between adhesive and skin, because such microbes can readily lead to infection and other undesirable conditions.

[0003] Accordingly, artisans have incorporated a wide range of antimicrobial agents and other active agents with medical products or materials. Although a limited number of such agents have been incorporated into adhesives, release of such agents from an adhesive composition presents a formidable technical challenge because it is difficult to efficiently and controllably release such agents from the adhesive. Further, such incorporation often negatively affects the bonding strength of the adhesive and a significant portion of the active agent is not transferred to the skin but remains in the adhesive. In this context, US 5,965,154 describes a transdermal patch made by the process of: depositing an active layer of at least one active substance on an adhesive matrix located on a backing layer of a pressure sensitive adhesive tape, wherein said at least one active substance comprises at least one of a powder, a liquid and a gel; bringing a release liner into contact with the adhesive matrix; and applying pressure to the adhesive matrix to drive the active substance into the adhesive matrix.SUMMARY

[0004] The difficulties and drawbacks associated with previously known compositions, products, and practices are addressed by the present invention.

[0005] In particular, the present invention provides a method of incorporating an active agent to an adhesive article for delivery of the active agent to a substrate. The adhesive article includes an adhesive layer defining a substrate contacting surface adapted to adhere the adhesive article to the substrate. The method comprises applying an active agent to the substrate contacting surface such that the active agent is disposed between the substrate and the adhesive layer when the adhesive article is adhered to the substrate, wherein the active agent is applied to the substrate contacting surface of the adhesive as a dry powder, and wherein applying comprises disposing the active agent to a release liner, and bringing the release liner into contact with the adhesive layer such that the active agent is positioned between the substrate contacting surface of the adhesive layer and the release liner.

[0006] The scope of the present invention is only limited by the appended claims. That is, the drawings and description are to be regarded as illustrative and not restrictive.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] These, as well as other features, aspects, and advantages of the present invention, will be more completely understood and appreciated by referring to the following more detailed description of the exemplary embodiments of the present invention in conjunction with the accompanying drawings. FIG. 1 is a schematic process flow diagram of a method in accordance with the present invention. FIG. 2 is a schematic process flow diagram of another method not in accordance with the present invention. FIG. 3 is a cross-sectional diagram of an adhesive article applied to a substrate. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0008] The method of the present invention is adapted to effectively deliver an active agent to a region of interest, as defined by the claims. In accordance with the present invention, effective delivery of an active agent to a region of interest is accomplished by disposing the active agent on the substrate contacting surface of the adhesive layer used to bond the article to the substrate.

[0009] Adhesives, and particularly pressure sensitive adhesives, are routinely used in conjunction with a wide array of medical articles to attach or retain articles to human skin. Adding active agents, particularly at effective concentration levels, within an adhesive material typically impairs bonding strength of the adhesive, while relatively large amounts of active agent are required produce a desired effect. Accordingly, it would be desirable to provide an adhesive article for releasing one or more active agents, such as chlorhexidine gluconate, from a medical product such as a dressing or tape, wherein the agent is controllably and efficiently released to a region of interest such as a wound or other biological area without the difficulties associated with traditional methods.

[0010] In conventional delivery systems, chlorhexidine gluconate for example is dispersed in adhesives and used as an antimicrobial agent in an adhesive article for delivery to a wound or infection in human skin. Chlorhexidine gluconate has a broad antimicrobial spectrum, is safe, and is well accepted in the market. However for a variety of reasons, it is difficult to controllably and efficiently release this and other active agents to a region of interest at effective concentration levels in an adhesive, while at the same time maintaining sufficient bonding strength in the adhesive.

[0011] Thus, in order to address these concerns and to obtain sufficiently high efficacy for the active agent and to maintain adequate adhesive properties in the adhesive layer of the product, the coat weight of the adhesive is conventionally increased. Increased coat weight of the adhesive yields higher active agent concentration per surface area and promotes maintenance of adequate adhesion in the adhesive layer. However, increasing adhesive coat weight may impair various properties of the adhesive product, such as moisture vapor transmission rates or conformability of the adhesive article, among others. Increased adhesive coat weights also increases the cost associated with the product.

[0012] When dispersing the active agent in the adhesive, such as is conventionally done, high concentrations of active agent can be required in order to obtain adequate efficacy for the active agent and thus increase the material cost of the product. This is because in order for the active agent to adequately release to the region of interest, the active agent must migrate through the mass of the adhesive layer to reach the substrate. In many circumstances, a large portion of the active agent remains in the adhesive layer and is never released to the region of interest, thereby resulting in decreased efficiency of the active agent and requiring a larger amount of active agent. Further, increasing active agent concentrations may produce undesired results, such as toxicity to the skin, for example. Certain active agents, chlorhexidine being one of them, are also unstable over time and / or at temperatures typically required to process certain adhesives, such as solvent adhesive processing temperatures or hot melt adhesive processing temperatures. The instability of chlorhexidine is evident by the generation of para chloroaniline or p-chloroaniline. It is therefore advantageous to configure an adhesive product such that the active agent is not subject to the typical processing temperatures for the adhesive, and thereby remains stable and does not degrade.

[0013] Other problems associated with the inclusion of chlorhexidine gluconate into solvent based adhesives are due to certain physical and chemical properties of chlorhexidine gluconate. For example, chlorhexidine gluconate is strongly hydrophilic and is only soluble in methanol and acetone. In addition, chlorhexidine gluconate is typically commercially available as a 20% or 40% by weight in water formulation. Aqueous compositions cannot be readily combined with solvent based adhesives. Chlorhexidine gluconate is sensitive to high temperatures thereby limiting its subsequent processing as would otherwise likely be necessary in any adhesive incorporation. And, when dried by evaporation, the compound does not readily disperse in solvents typically used in solvent based adhesives.

[0014] The present invention provides unique strategies for incorporating active agents, such as chlorhexidine gluconate, onto adhesive layers comprising for example, solvent based acrylic adhesive products which are widely used in medical and surgical applications. The method of the present invention incorporates active agents onto a substrate contacting surface of the adhesive layer of an adhesive product. When the adhesive article is an article used to deliver the active agent to human skin, for example a medical bandage or tape, the substrate contacting surface of the adhesive article will be understood to be the skin contacting surface of an adhesive layer of the article.

[0015] The method of the present invention includes incorporating the active agent on the substrate contacting surface of the adhesive layer by disposing the active agent to a substrate contacting surface of the adhesive layer, in an operation that is separate and apart from processing of the adhesive layer. In one aspect, this includes incorporating the active agent on the substrate contacting surface after the adhesive material is processed and formed into an adhesive layer. This is beneficial in many respects. For instance, it avoids exposing the active agent to possible undesirable processing conditions relating to the adhesive, such as increased temperatures used to process adhesives (e.g. hot melt adhesives). Further, efficacy of the active agent can be maintained or increased, even though the amount of active agent can be decreased in comparison to higher loadings used in conventional adhesive articles where the active agent is dispersed throughout the mass of the adhesive layer. Improved efficacy of the active agent reduces material costs by decreasing the required quantity of active agent necessary to produce a desired result. In the case where micro regions of the active agent are disposed on the substrate contacting surface of the adhesive layer and spaced from one another, the adhesive layer is able to maintain an adequately high bonding strength for adhering to the substrate, while still providing adequate delivery of the active agent to a region of interest on the substrate. The method of the present invention does not require that the adhesive layer coating weight be increased to accommodate for problems commonly associated with conventional active agent delivery systems; such as the low delivery rate of the active agent through the mass of the adhesive layer or the loss in bonding strength of the adhesive resulting from the required increased levels of active agent. In this regard, relatively low coating weights of adhesive can be used. Low adhesive coating weights can provide improved conformability to contoured substrates, such as to the contours of human skin, when compared to higher coating weights.

[0016] More specifically, in accordance with the present invention, the active agent is disposed on the substrate contacting surface of the adhesive layer, wherein the release of the active agent from the adhesive article to the region of interest is efficiently accomplished because of the close proximity of the active agent to the substrate. The active agent, because it lies between the adhesive layer and the substrate, can easily be delivered to the region of interest, thereby increasing the efficiency of the active agent and allowing for a decreased amount of active agent to be used while at the same time providing adequate efficacy. In contrast, conventional adhesive articles have the active agent dispersed within the mass of the adhesive layer. This configuration requires an increased amount of active agent to produce a desired result because the active agent must migrate through the adhesive layer before being delivered to the region of interest.

[0017] The present invention provides active agents incorporated on the surface of the adhesive layer as a dry powder. Particular aspects of the present invention will be described in more detail below.Active Agents

[0018] A wide array of active agents can be used in accordance with the present invention. Any active, active agent, or combination of actives and / or active agents which are biologically active and which can be incorporated on the substrate contacting surface of the adhesive layer in a stable manner or form, can be utilized.

[0019] The active agents can be hydrophilic. Herein, the active agents are in solid form to promote processing and incorporation into the adhesive articles.

[0020] An active in solid form comprises a powder with particles of nearly any size or shape. Non-limiting examples of such shapes include flake and spherical. In several aspects, the particle size distribution of the dry powder active agent has a median diameter of from about 1 micron (µm) to about 500 µm. This particular median diameter range for the particle size distribution of the powder can result in more homogeneous coverage to the substrate contacting surface and increased efficacy of the active agent.

[0021] In the present invention, the active agent is disposed as a powder on the substrate contacting surface of the adhesive article. In other words, the active agent is not disposed on the substrate contacting surface using a liquid or gel vehicle. In this regard, the dry powder active agent is applied in the absence of a liquid or gel vehicle.

[0022] One suitable type of active agent is an antimicrobial agent and can include one or more chlorhexidine salts such as chlorhexidine gluconate (CHG). Chlorhexidine is a chemical antiseptic and generally used as an antimicrobial agent. It is effective on both Gram-positive and Gram-negative bacteria, although it is less effective with some Gram-negative bacteria. It has both bactericidal as well as bacteriostatic mechanisms of action, the mechanism of action being membrane disruption and not ATPase inactivation as previously thought. It is also useful against fungi and enveloped viruses, though this has not been extensively investigated. Products containing chlorhexidine in high concentrations should be kept away from eyes and the ears, due to the risk of damage to those organs. However, chlorhexidine is safely used in very low concentrations, for example in some contact lens solutions.

[0023] Chlorhexidine gluconate (also known as chlorhexidine digluconate) is a salt of chlorhexidine and gluconic acid. The structural formula of chlorhexidine gluconate is:

[0024] Although this compound is actually a digluconate compound, it is commonly referred to as chlorhexidine gluconate.

[0025] Thus, the term chlorhexidine gluconate as used herein encompasses the digluconate compound. Also, the terms "chlorhexidine gluconate" and "chlorhexidine digluconate" are used interchangeably herein. Other pharmaceutically acceptable chlorhexidine salts that may be used as antimicrobial agents according to the present invention include, but are not limited to, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate, chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidine di-acid phosphate, chlorhexidine difluorophosphate, chlorhexidine diformate, chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlorhexidine di-n-valerate, chlorhexidine dicaproate, chlorhexidine malonate, chlorhexidine succinate, chlorhexidine malate, chlorhexidine tartrate, chlorhexidine dimonoglycolate, chlorhexidine monodiglycolate, chlorhexidine dilactate, chlorhexidine di-alpha-hydroxyisobutyrate, chlorhexidine diglucoheptonate, chlorhexidine di-isothionate, chlorhexidine dibenzoate, chlorhexidine dicinnamate, chlorhexidine dimandelate, chlorhexidine di-isophthalate, chlorhexidine di-2-hydroxynapthoate, and chlorhexidine embonate. Chlorhexidine free base is a further example of an antimicrobial agent.

[0026] Additional examples of other antimicrobial agents include but are not limited to other biguanide compounds such as polyhexamethylene biguanide (PHMB); silver; triclosan; penicillins; tetracyclines; aminoglycosides, such as gentamicin and Tobramycin ™< ; polymyxins; rifampicins; bacitracins; erythromycins; vancomycins; neomycins; chloramphenicols; miconazole; quinolones, such as oxolinic acid, norfloxacin, nalidixic acid, pefloxacin, enoxacin, and ciprofloxacin; sulfonamides; nonoxynol 9; fusidic acid; cephalosporins; and combinations of such compounds and similar compounds. The additional antimicrobial compounds provide for enhanced antimicrobial activity. Additional examples of antimicrobial agents include, but are not limited to, benzalkonium chloride (BZK), or iodopropynylbutyl carbamate (IPBC; Germall plus). Further examples of antimicrobial agents include, but are not limited to, iodophors, iodine, benzoic acid, dihydroacetic acid, propionic acid, sorbic acid, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, cetrimide, quaternary ammonium compounds, including but not limited to benzethonium chloride (BZT), dequalinium chloride, chloroeresol, chlorxylenol, benzyl alcohol, bronopol, chlorbutanol, ethanol, phenoxyethanol, phenylethyl alcohol, 2,4-dichlorobenzyl alcohol, thiomersal, clindamycin, benzoyl peroxide, mupirocin, parachlorometaxylene, foscarnet, fluconazole, itriconazole, ketoconazole, and pharmaceutically acceptable salts thereof.

[0027] It will be appreciated that in addition to, or instead of an antimicrobial agent, additional active agents can be disposed on the substrate contacting surface of the adhesive layer. In certain aspects, the actives can comprise for example the pain relievers or analgesics fentanyl, butorphanol, morphine, buprenorphine, naloxone, codeine, menthol, methyl salicylate, camphor, capsaicin, acetylsalicylic acid; local anesthetics such as lidocaine; anti-acne drugs like retinoic acid; anti-angina drugs like nitroglycerin, isosorbide dinitrate, nifedipine, nicardipine; antiarrhythmics like timolol; antibacterials like amikacin, cephalosporins, macrolides, tetracyclines, quinolones, nitrofurantoin; anti-convulsives like carbamazepine, phenobarbital, nitrazepam; antidepressants like tricyclics, bupropion, sertraline, pergolide, fluoxetine; anti-rheumatics like diclofenac, ibuprofen, piroxicam, ketoprofen, thiocolchicoside, methotrexate; sex hormones like progesterone, testosterone, estradiol, levonorgestrel; anti-fungals like clotrimazole, miconazole; anti-hypertensives like sotalol, alprenolol, captopril, enalapril, felodipine, nicardipine, reserpine; anti-hypothyroid drugs like thyroxine; anti-malarials like artemesine, cinchonidine, primaquine; anti-migraine drugs like ergotamine, sumatriptan, rizatriptan; anti-nausea drugs like domperidone, chlorpromazine, methoclopramide, scopolamine, tetrahydrocannabinoids; skin lighteners like hydroquinone, hydroquinine; dopamine receptor antagonists like pergolide, bromocriptine; muscle relaxants like thiocolchicoside, diazepam; sclerosing agents like ethanolamine, sodium ricinoleate; vitamins like A, B, C, E and precursors or various agents like oxybutynin, finasteride, erythropoetine. Combinations of one or more actives are also contemplated including combinations of these agents with still other ingredients.

[0028] The active agents can also contain any combination of additional medicinal compounds. Such medicinal compounds include, but are not limited to, antibiotics, antiviral agents, antithrombogenic agents, anesthetics, anti-inflammatory agents, anticancer agents, vasodilation substances, wound healing agents, angiogenic agents, angiostatic agents, immune boosting agents, growth factors, and other biological agents.

[0029] The active agent is used in an effective amount. The term "effective amount" or "efficacy" as used herein refers to any amount of the active agent such that when incorporated onto the substrate contacting surface of the adhesive layer, the presence of the agent released to the region of interest suitably achieves its intended purpose. For example, an effective amount of antimicrobial agent kills or at least prevents growth or reproduction of microbes.

[0030] When an antimicrobial agent is used, substrate contacting surfaces of the adhesive layer are rendered resistant to microbial growth. Some of the microbes which can be resisted include single cell organisms, e.g., bacteria, fungi, algae, and yeast, and mold. The bacteria can include both gram positive and gram negative bacteria. Some examples of gram positive bacteria include, for example, bacillus cereus, micrococcus luteus, and staphylococcus aureus. Some examples of gram negative bacteria include, for example, escherichia coli, enterobacter aerogenes, enterobacter cloacae, and proteus vulgaris. Strains of yeast include, for example, saccharomyces cerevisiae. It will be appreciated that one embodiment of the present invention is directed toward killing or reducing growth and / or reproduction of a wide array of other microbes and microorganisms. In no way is the present invention limited to the particular examples of microbes presented herein.

[0031] The specific levels of each component can be adjusted to achieve the desired performance. The final concentration of the total additive package is highly dependent on product design and target properties.

[0032] Thus, the present invention provides a method for incorporating one or more active agents and particularly chlorhexidine gluconate to the substrate contacting surface of an adhesive layer comprising for example, a solvent based adhesive such as an acrylic adhesive. Although the present invention is particularly directed to the incorporation of chlorhexidine gluconate, the present invention is applicable to other active agents. Generally, any chlorhexidine salt that is provided as a dry powder is suitable for use.

[0033] Typically for many chlorhexidine salts, they are commercially available in an aqueous solution and in a concentration of from about 1% to about 60%. In aqueous form, water and / or any other solvents or liquids can be removed and separated from the chlorhexidine salt(s) by one or more active or passive drying operations to attain a dry powder.Adhesives

[0034] Generally, the adhesives used in the adhesive layer can comprise any type of adhesive including drying adhesives, pressure sensitive adhesives (PSAs), contact adhesives, hot melt adhesives, and reactive adhesives. The adhesive can be included on a backing layer at a coating weight from about 10 g / m 2< to about 500 g / m 2< to form an adhesive layer on the backing layer. In one embodiment, the adhesive layer is free of intentionally added active agent other than the active agent disposed on the substrate contacting surface of the adhesive layer. That is, active agent is disposed on the substrate contacting surface and is not intentionally added within the mass of the adhesive layer such that at least a portion of the adhesive layer is free of active agent dispersed therein. In one aspect, the active agent is only disposed at the substrate contacting surface of the adhesive layer. In other embodiments, the adhesive layer has intentionally added active agent dispersed therein along with active agent disposed on the substrate contacting surface of the adhesive layer.

[0035] In several embodiments, the adhesive layer comprises PSAs. Various PSAs can be used to form an adhesive layer on an article of interest or a portion of the article such as on a backing layer to render the article adhesive. For example, PSAs may be formulated to offer good skin adhesion characteristics, offer excellent conformability, and provide a gentle release from the skin and wound site. The PSA layer can be continuous, discontinuous, pattern coated, or melt-blown, and have a substrate contacting surface for bonding the adhesive article to a substrate, such as skin.

[0036] The adhesive compositions can include nearly any type of pressure sensitive adhesive (PSA) component such as acrylic-based adhesives, silicone-based adhesives, rubber-based adhesives, polyurethane-based adhesives, and other types or combinations of adhesives.

[0037] The acrylic adhesive for use in the present invention is typically a solvent-based acrylic adhesive and may be any pressure sensitive acrylic adhesive that is capable of adhering to mammalian skin and in one aspect is free of ingredients known to cause undue irritation or toxicity to mammals. These adhesives typically include one or more acrylate copolymers.

[0038] Useful acrylate copolymers may or may not be self-crosslinking and are formed from at least two monomers chosen from: (1) hydroxyalkyl esters of acrylic or methacrylic acid in which the alkyl group comprises 2 to 4 carbon atoms, such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate and 2-hydroxypropyl methacrylate; (2) alkyl esters of acrylic or methacrylic acid in which the alkyl group of the ester comprises 4 to 18 carbon atoms, such as n-butyl acrylate or methacrylate, isopropyl acrylate or methacrylate, n-hexyl methacrylate and 2-ethylhexyl acrylate; (3) α,β-unsaturated monocarboxylic or dicarboxylic acids, their anhydrides and their alkyl or alkenyl esters in which the alkyl group contains from 1 to 3 carbon atoms and the alkenyl group contains from 2 to 5 carbon atoms, such as acrylic acid, itaconic acid, maleic acid, maleic anhydride, alkyl methacrylate and the diethyl esters of fumaric or maleic acid; (4) vinyl monomers, such as vinyl acetate, acrylonitrile, vinyl propionate, vinylpyrrolidone and styrene; (5) monomers containing a functional group selected from amido, amino and epoxy groups, for example, acrylamide, N-butylacrylamide, alkylaminoalkyl and aminoalkyl derivatives of acrylic or methacrylic acid, such as amino-ethyl acrylate, aminoethyl methacrylate and 2-(dimethylamino) ethyl methacrylate, glycidyl methacrylate and glycidyl acrylate; (6) 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; and (7) hexamethylene glycol dimethacrylate.

[0039] As these copolymers can be self-crosslinking, 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.

[0040] These adhesive acrylate copolymers may take the form of solutions in a solvent system including a single organic solvent or a mixture of several solvents, which contain about 25% to about 55% by weight copolymers. Examples of suitable solvents include aromatic solvents such as toluene, xylene, etc. Suitable aliphatic solvents include esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, etc.; ketones such as methyl ethyl ketone, acetone, etc.; and aliphatic hydrocarbons such as heptanes, hexane, pentane, etc.

[0041] Silicone PSAs include two major components, a polymer or gum, and a tackifying resin. The polymer is typically a high molecular weight polydimethylsiloxane or polydimethyldiphenylsiloxane, that contains residual silanol functionality (SiOH) on the ends of the polymer chain, or a block copolymer including polydiorganosiloxane soft segments and urea terminated hard segments. The tackifying resin is generally a three-dimensional silicate structure that is endcapped with trimethylsiloxy groups (OSiMe 3 ) and also contains some residual silanol functionality. Examples of tackifying resins include SR 545, from General Electric Co., Silicone Resins Division, Waterford, NY, and MQD-32-2 from Shin-Etsu Silicones of America, Inc., Torrance, CA. Manufacture of typical silicone PSAs is described in US 2,736,721. Manufacture of silicone urea block copolymer PSA is described in US 5,214,119, for example.

[0042] Examples of rubber-based adhesives may include those comprising solid rubbers such as linear or radial A-B-A block copolymers or mixtures of these A-B-A block copolymers with simple A-B block copolymers. However, the proportion of A-B block copolymers, relative to the A-B-A block copolymers, typically ranges up to about 85% by weight of the (total) block copolymers. These block copolymers can be based on styrene-butadiene, styrene-isoprene, and hydrogenated styrene-diene copolymers such as styrene ethylene-butylene. Suitable styrene-diene copolymers are exemplified by a blend of linear styrene-isoprene-styrene triblock copolymer and linear styrene-isoprene diblock copolymer. Such a material is available from Kraton Polymers as KRATON ®< D-1161 K and has a bound styrene content of about 15% and a diblock content of 17%. A second example is a blend of linear styrene-isoprene-styrene triblock copolymer and linear styrene-isoprene diblock copolymer available from Shell Chemical as KRATON ®< D-1117 and which has a bound styrene content of about 17% and a diblock content of 33%.

[0043] An example of a suitable hydrogenated styrene-diene copolymer is a thermoplastic elastomer comprising a blend of clear linear triblock and diblock copolymer-based on styrene and ethylene-butylene with a bound styrene of 14% mass. Such a material is commercially available from Shell Chemical Company as KRATON ®< G-1657. Another example is KRATON ®< G-1652 from Shell Chemical Company, which is a thermoplastic elastomer comprised of a clear linear triblock copolymer-based on styrene and ethylene-butylene, S-E / B-S, with a bound styrene content of about 30% by weight. Also suitable are polymers in which there is a combination of chemically saturated blocks and chemically unsaturated blocks. For example, a branched copolymer consisting of two polyisoprene chains attached to the rubber midblock of a styrene / ethylene-butylene / styrene triblock copolymer. Such a material, for example, is available from Shell Chemical Company having a styrene content of 18%, and isoprene content of 36% and an ethylene-butylene content of 46% by weight. Also, a low styrene synthetic copolymer of butadiene and styrene, commonly called SBR rubber, can be used as a solid rubber.

[0044] In one embodiment, liquid rubbers may be added to the adhesive material to adjust or control the adhesive or other characteristics. Liquid rubbers useful in this embodiment of the present invention include synthetic liquid isoprene rubber, depolymerized natural rubber, various functionally terminated synthetic liquid isoprene-styrene rubbers and liquid isoprene rubbers, liquid isoprene-styrene copolymer, liquid isoprene-butadiene copolymer, liquid butadiene-styrene copolymer and hydrogenated versions of these materials such as liquid ethylene-propylene-styrene. These liquid rubbers are generally compatible with the solid rubber. The liquid rubbers typically have a molecular weight of 25,000 to 50,000, a glass transition temperature of less than -50° C, and a viscosity at 38° C of 50 to 10,000 Pas. A block copolymer of styrene and isoprene having a styrene content of about 13% and an isoprene content of about 87%, a glass transition of about -60° C, a melt viscosity of about 240 Pas at 50° C and which is commercially available from Shell Chemical Company as LIR310, is particularly useful in the practice of the present invention. Within the adhesive material, in one embodiment, the weight ratio of solid rubber to liquid rubber is in the range from about 100:1 to about 1:2, and is varied in order to obtain the desired degree of adhesiveness and tackiness.

[0045] In one embodiment, the weight ratio of solid rubber to liquid rubber is in the range from about 50:1 to about 5:1, and in another embodiment, from about 20:1 to about 10:1.

[0046] Optionally, an elastomeric polymer such as butyl rubber or high molecular weight polyisobutylene may also be blended into the adhesive material. The optional butyl rubber may be used in the viscosity average molecular weight range of 200,000 to 600,000 and is exemplified by the grades Butyl 065 or Butyl 077, both available from Exxon Chemical. The optional high molecular weight polyisobutylene may be used in the viscosity average molecular weight range of 800,000 to 2,500,000 and is exemplified by the VISTANEX ®< MM series of products, available from Exxon Chemical, with the MM L-80 grade being a suitable grade for the optional high molecular weight polyisobutylene. The optional high molecular weight rubbers, blended as described herein, may be added in amounts suitable to modify various properties of the final formulation and may be from 0% to about 50% of the total weight of the adhesive material, and in one embodiment from about 0.5% to about 25% of the total weight of the adhesive material, and in one embodiment from about 5% to about 10% of the total weight of the adhesive material. The optional low molecular weight polybutenes and / or mineral oil may be added in amounts from 0% to about 20% of the weight of the adhesive material and in one embodiment from about 0.5% to about 10% of the total weight of the adhesive material, and in one embodiment from about 0.5% to about 5% of the total weight of the adhesive material.

[0047] Another useful class of PSAs can include polyurethanes. Polyurethanes may be produced by reacting a polyisocyanate with a polyalcohol (polyol). As described herein, a polyisocyanate is a molecule with two or more isocyanate functional groups and a polyalcohol is a molecule with two or more hydroxyl functional groups. The reaction product is a polymer containing urethane linkages. The functional groups can be alkanes, esters, ethers, and other components.

[0048] Isocyanates can be classed as aromatic, such as diphenylmethane diisocyanate (MDI) or toluene diisocyanate (TDI); or aliphatic, such as hexamethylene diisocyanate (HDI) or isophorone diisocyanate (IPDI). An example of a polymeric isocyanate is polymeric diphenylmethane diisocyanate, which is a blend of molecules with two-, three-, and four- or more isocyanate groups, with an average functionality of 2.7. Isocyanates can be further modified by partially reacting them with a polyol to form a prepolymer. A quasi-prepolymer is formed when the stoichiometric ratio of isocyanate to hydroxyl groups is greater than 2:1. A true prepolymer is formed when the stoichiometric ratio is equal to 2:1. Important characteristics of isocyanates include the molecular backbone, % NCO content, functionality, and viscosity.

[0049] Polyols are distinguished from short chain or low-molecular weight glycol chain extenders and cross linkers such as ethylene glycol (EG), 1,4-butanediol (BDO), diethylene glycol (DEG), glycerin, and trimethylol propane (TMP). Polyols are formed by base-catalyzed addition of propylene oxide (PO), ethylene oxide (EO) onto a hydroxyl or amine containing initiator, or by polyesterification of a di-acid, such as adipic acid, with glycols, such as ethylene glycol or dipropylene glycol (DPG). The choice of initiator, extender, and molecular weight of the polyol greatly affect its physical state, and the physical properties of the polyurethane polymer. Important characteristics of polyols include the molecular backbone, initiator, molecular weight, % primary hydroxyl groups, functionality, and viscosity. Examples of suitable polyurethanes adhesives include those described in US 7,160,976; US 6,642,304; and US 6,518,359.

[0050] In other embodiments, the adhesive or adhesive component is a hot melt adhesive. In certain aspects, the adhesive compositions comprise a hot melt pressure sensitive adhesive.

[0051] The adhesive may be based on for example polyisobutylene, butyl rubber, polyacrylates, polyurethanes, silicone gum, natural gum rubber, SBR rubber or polyvinyl ether. Thermoplastic elastomers such as styrene-isoprene-styrene block copolymers and styrene-ethylene / propylene-styrene block copolymers may be used, and these may require optional tackifiers and plasticizers. Blends or mixtures of elastomers may be more easily employed.

[0052] Also particularly suitable are acrylic pressure sensitive adhesives, exemplified by an acrylic hot melt adhesive manufactured by Schenectedy Chemicals and having the designation Durotac 401. Another example is an acrylic solvent adhesive from Avery Chemicals called Polytex 7600.

[0053] Where the adhesive article is to be contacted to a human skin for delivery of the active agent thereto, the adhesive layer can comprise a skin friendly PSA, such as for example I-807, which is a solvent acrylic adhesive supplied by Avery Dennison Corporation.Release Liner

[0054] According to the present invention, the active agent is disposed on a release liner as depicted in FIG. 1. In accordance with the present invention, the release liner is not particularly limited and may be formed of any material that is suitable for a particular purpose.

[0055] The adhesive article includes a release liner on the substrate contacting surface of the adhesive layer, which is retained in place prior to use and is removed just prior to application to the substrate, for example to a patient's skin. The release liner may be any release liner known in the art which is compatible with the particular adhesive selected for use in the adhesive article.

[0056] The release liner may comprise a substrate sheet of paper, polymer film or combinations thereof coated with a release agent. The typical release agent used in the industry is a silicone-based molecule which can be cured either thermally or with irradiation energy such as ultraviolet light or electron beam. Paper substrates are useful because of the wide variety of applications in which they can be employed. Paper is also relatively inexpensive and has desirable properties such as antiblocking, antistatic, dimensional stability, and can potentially be recycled. Any type of paper having sufficient tensile strength to be handled in conventional paper coating and treating apparatus can be employed as the substrate sheet for the release liner. Thus, any type of paper can be used depending upon the end use and particular personal preferences. Included among the types of paper which can be used is paper, clay coated paper, glassine, polymer coated paper, paperboard from straw, bark, wood, cotton, flax, cornstalks, sugarcane, bagasse, bamboo, hemp, and similar cellulose materials prepared by such processes as the soda, sulfite or sulfate processes, the neutral sulfide cooking process, alkali-chlorine processes, nitric acid processes, semi-chemical processes, etc. Although paper of any weight can be employed as a substrate sheet for the release liner, paper having weights in the range of from about 49 to about 195 g / m 2< (about 30 to about 120 pounds per ream) are useful, and papers having weights in the range of from about 98 to about 163 g / m 2< (about 60 to about 100 pounds per ream) are suitable. The term "ream" as used herein equals 3000 square feet.

[0057] Alternatively, the substrate sheet for the release liner may be a polymer film, and examples of polymer films include polyolefin, polyester, polyvinyl chloride, polyvinyl fluoride (PVF), polyvinylidene difluoride (PVDF), etc., and combinations thereof. The polyolefin films may comprise polymer and copolymers of monoolefins having from 2 to 12 carbon atoms or from 2 to about 4 or 8 carbon atoms per molecule. Examples of such homopolymers include polyethylene, polypropylene, poly-1-butene, etc. The examples of copolymers within the above definition include copolymers of ethylene with from about 1% to about 10% by weight of propylene, copolymers of propylene with about 1% to about 10% by weight of ethylene or 1-butene, etc. Films prepared from blends of copolymers or blends of copolymers with homopolymers also are useful. In addition films may be extruded in mono or multilayers.

[0058] A third type of material used as the substrate sheet for the release liner is a polycoated kraft liner which is basically comprised of a kraft liner that is coated on either one or both sides with a polymer coating. The polymer coating, which can be comprised of high, medium, or low density polyethylene, propylene, polyester, and other similar polymer films, is coated onto the substrate surface to add strength and / or dimensional stability to the release liner. The weight of these types of liners ranges from 49 to 163 g / m 2< (30 to 100 pounds per ream), with 65 to 153 g / m 2< (40 to 94 pounds per ream) representing a typical range. In total, the final liner is comprised of between 10% and 40% polymer and from 60% to 90% paper. For two sided coatings, the quantity of polymer is approximately evenly divided between the top and bottom surface of the paper.

[0059] The release coating which is contained on the substrate sheet to form the release-coated liner, may be any release coating known in the art. Silicone agent release coatings are particularly useful, and any of the silicone agent release coating compositions which are known in the art can be used. In one embodiment, a release coating having a smooth surface is used.Incorporation of Active Agents in Adhesive Articles

[0060] In accordance with the present invention, a method is provided for making adhesive articles configured to deliver an active agent to an area of interest, as defined by the claims. The adhesive articles comprise an adhesive layer, the adhesive layer including a substrate contacting surface adapted to adhere the adhesive article to the substrate. The method includes transferring the active agent to the substrate contacting surface of an adhesive layer such that the active agent will be disposed between the substrate and the adhesive layer when the adhesive article is adhered to the substrate for delivery of the active agent to the substrate. The active agent can comprise an antimicrobial agent, for example chlorhexidine gluconate.

[0061] For incorporating an active agent to an adhesive article, a dry powder active is applied to the release liner to obtain an active transfer liner, followed by laminating the active transfer liner to an adhesive or coating an adhesive onto the active transfer liner.

[0062] As the active agent is disposed on the release liner, the combination is referred to herein as an "active transfer liner." The adhesive layer may be adjoined to the active transfer liner by laminating the active transfer liner to the adhesive layer of the adhesive article such as an existing medical tape, or by coating an adhesive directly onto the active transfer liner.

[0063] A method in accordance with the present invention for incorporating the active agent in an adhesive article is depicted in FIG. 1 (in FIG. 2, similar features have the same reference number). In FIG. 1, an active agent 1 is applied to an adhesive contacting surface 11 of a release liner 10 to produce an active transfer liner 12. The active agent 1 is in powder and can be disposed in one or more micro regions that are spaced from one another. The active agent 1 is applied as an active agent layer 2 having voids or discontinuities as shown, and is not a continuous layer. That is, the active agent layer 2 is shown in FIG. 1 to be layer of isolated micro regions or islands on the adhesive contacting surface 11 of the release liner 10. A backing layer 20, having an adhesive layer 30 thereon, is brought into contact with the active transfer liner 12 such that a substrate contacting surface 31 of the adhesive layer 30 is mated with the adhesive contacting surface 11 of the release liner 10 with the active agent 1 disposed therebetween. The release liner 10 can be laminated to the adhesive layer 30 using pressure and / or heat to at least partially press and / or promote migration of the active agent 1 into the adhesive layer 30. When it is desired to apply the resulting adhesive article 40 to a substrate, the release liner 10 is removed from the adhesive layer 30 and the active agent 1 is substantially transferred or has been substantially transferred from the release liner 10 to the substrate contacting surface 31 of the adhesive layer 30 for the delivery of the active agent 1 to a region of interest.

[0064] An alternative embodiment to FIG. 1, which, however, does not form part of the present invention, is depicted in FIG. 2, wherein an active agent 1 is directly applied to substrate contacting surface 31 of the adhesive layer 30 that is disposed on a backing layer 20. A release liner 10 is brought into contact with the adhesive layer 30 such that the adhesive contacting surface 11 of the release liner 10 is mated with the substrate contacting surface 31 of the adhesive layer 30 with the active agent 1 disposed therebetween. The release liner 10 can be laminated to the adhesive layer 30 using pressure and / or heat to at least partially press and / or promote migration of the active agent 1 into the adhesive layer 30. When it is desired to apply the adhesive article 40 to a substrate, the release liner 10 is removed from the adhesive layer 30 and the active agent 1 remains substantially disposed on the substrate contacting surface 31 of the adhesive layer 30 for the delivery of the active agent 1 to a region of interest.

[0065] It will be understood that the method depicted in FIG. 1 is merely descriptive. In addition, it will be appreciated that the active agent may be applied or exist as a continuous layer or substantially so.

[0066] Herein, the active agent is applied to the adhesive layer as a dry powder. That is, the active agent is not delivered to the substrate contacting surface of the adhesive layer using a liquid or gel vehicle. FIG. 1 will be understood to include the application of active agent 1 as a dry powder.

[0067] In the embodiment shown in FIG. 1, the powder active agent is not directly applied to the substrate contacting surface, but rather is first applied to a release liner to produce an active transfer liner, which is then brought into contact with an adhesive layer such that the powder active agent is positioned between the substrate contacting surface of the adhesive layer and the release liner and is thereby disposed on the substrate contacting surface of the adhesive layer.

[0068] According to the invention, the powder active agent is first applied to a release liner. An adhesive material is then applied over the powder active agent on the release liner to thereby form an adhesive layer, such that the powder active agent is positioned between the formed adhesive layer and the release liner and the powder active agent is disposed on the substrate contacting surface of the adhesive layer. A backing layer, such as a polyurethane film, is then disposed on the adhesive layer wherein the adhesive layer is positioned between the backing layer and the powder active agent.

[0069] The method can include the application of pressure for a certain time to sandwich the structures, thereby laminating the release liner to the adhesive layer and pressing and / or promoting migration of the powder active agent particles at least partially into the adhesive layer.

[0070] Being applied in powder form, the particles of the active agent may not substantially diminish the bonding strength of the adhesive layer. This is because a certain amount of active agent powder is applied to the substrate contacting surface such that when the substrate contacting surface is brought into contact with a substrate, the active agent particles do not occupy the entire interface between the substrate contacting surface and the substrate. That is, a certain percentage of the area of the substrate contacting surface of the adhesive layer, after having powder active agent disposed thereon, is still able to contact a substrate and sufficiently adhere to a substrate to which it is applied. In this regard, and in accordance with the present invention, the powder active agent can be applied to the substrate contacting surface of the adhesive layer in a weight of from about 0.1 g / m 2< to about 25 g / m 2< . Lower application weights of powder active agent may not be effective in producing an antimicrobial or other desired result, while higher application weights may interfere with the ability of the underlying adhesive layer to bond with a substrate.

[0071] It is also contemplated that the powder chlorhexidine gluconate or other chlorhexidine salt can be optionally processed in one or more size reducing operations if needed to attain a particle size distribution with a median diameter of from about 1 µm to about 500 µm. The powder chlorhexidine gluconate is applied first to a release liner, which is then subsequently laminated using heat and / or pressure, to the substrate contacting surface of an adhesive layer of an adhesive article.

[0072] The adhesive layer can be part of an adhesive article comprising a backing layer, such as an existing medical tape or dressing.

[0073] The layer of active agent can range in thickness from about 1 to 1000 µm, more particularly from 10 to 500 µm, and in one embodiment from about 20 µm to about 100 µm.

[0074] In one embodiment, powder chlorhexidine gluconate and / or other chlorhexidine salt are optionally processed in one or more size reducing operations.Articles

[0075] 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, surgical dressings, 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 (NPWT) components, surgical drains, wound draining components, IV site dressings, prostheses, stoma pouches, buccal patches, transdermal patches, dentures, hairpieces, bandages, diapers, medical padding for example liposuction padding, hygiene pads, corn and callous pads, toe cushioning pads, and pads for protecting and cushioning tube sites such as tracheotomy tubes.

[0076] The medical articles generally include a backing layer or material such as a polyurethane film layer. An adhesive layer is disposed on at least one side of the backing layer. The adhesive layer includes a substrate contacting surface configured to bond the adhesive article to a substrate, for example to a biological surface. The active agent and related active agent compositions are applied to the substrate contacting surface of the adhesive layer, such that when the adhesive article is adhered to a user's skin for example, the active agent will be disposed between the skin and the skin contacting surface of the adhesive layer. As in other embodiments, the active agent can comprise an antimicrobial agent such as chlorhexidine gluconate and is applied as a dry powder.

[0077] Sifting or forming a layer, coating, or other region of active agent on a portion of the substrate contacting surface of an article enables the article to be adhered to a wide range of surfaces, including biological surfaces such as skin, while still delivering a relatively high dose of active agent to an area of interest. It will be understood that the present invention is not limited to any of these articles. Instead, the present invention includes the use of active agent on the substrate contacting surface of an adhesive layer in articles other than those specifically listed herein. The medical articles also include one or more layers covering the adhesive layer, such as a release liner.

[0078] Various articles that include the active agent compositions are described herein. The articles can be in a variety of different forms and configurations. In one embodiment, the articles are medical articles adapted for covering a biological surface such as for example a wound or other region undergoing healing. In one embodiment, the article comprises a backing layer such as a fabric, mesh, or film. The article also comprises one or more layers or regions of an adhesive composition disposed on at least a portion of the backing. The adhesive includes an active agent on a substrate contacting surface as described herein. In one aspect, the active agent comprises at least one antimicrobial agent in dry powder form. Upon application of the adhesive article to a substrate, the active agent is delivered to a region of interest.

[0079] The method of the present invention can be used to incorporate for example, chlorhexidine salts such as chlorhexidine gluconate, onto a substrate contacting surface of a wide array of adhesives, and in one aspect a solvent based adhesive. Non-limiting adhesives include acrylic adhesives, rubber adhesives, silicone adhesives, polyurethane adhesives, and variants and combinations thereof. Generally, the resulting chlorhexidine salt, which can be chlorhexidine gluconate, is incorporated onto the substrate contacting surface of nearly any non-aqueous based adhesive. In one aspect, the adhesive is a solvent based adhesive, for example a solvent based acrylic adhesive.

[0080] It is also contemplated that in combination with the method described herein, that one or more active agents can be incorporated into the mass of the adhesive layer by combining a liquid solution, mixture or dispersion containing an active agent into an adhesive used for the adhesive layer.

[0081] As shown in FIG. 1, the active transfer liner is configured to transfer the active agent in powder to a substrate contacting surface of an adhesive layer of an adhesive article. The active agent is applied to an adhesive contacting surface of the release liner, which is then brought into contact with a substrate contacting surface of an adhesive layer in order to transfer the active agent to the substrate contacting surface. When the active transfer liner is removed from the adhesive article, the active agent is substantially retained on the substrate contacting surface of the adhesive layer. The adhesive product can then be applied to a substrate such that the active agent is disposed between the substrate contacting surface of the adhesive layer and the substrate, in order that the active agent is delivered to a region of interest.

[0082] As in other embodiments, the active agent is applied in dry powder form to the release liner such that the adhesive contacting surface of the release liner is not completely covered by, or is free of, the active agent compositions. In one embodiment, the active agent compositions are applied to the release liner as a layer having voids.Delivering Active Agents to a Region of Interest

[0083] Methods of delivering active agent to a region of interest, such as a biological surface, are also described herein. The biological surface can include human skin. The methods include providing an adhesive article that includes an adhesive layer defining a substrate contacting surface. The article can be an article applied to skin of an animal, including human skin, for delivery of the active agent to a region of interest, such that the substrate contacting surface defines a skin contacting surface.

[0084] The substrate contacting surface of the adhesive article has an active agent disposed thereon in the form of a dry powder. The method includes adhering the adhesive article to the biological surface by bringing the skin contacting surface of the adhesive layer into abutment with the biological surface. When this is done, the active agent is positioned between the biological surface and the substrate contacting surface of the adhesive layer such that the active agent is able to be released to the region of interest.

[0085] One example of this is shown in FIG. 3, wherein an adhesive article 40 comprising a backing layer 20, adhesive layer 30, and active agent 1, is adhered to a surface 51 of a substrate 50, which may for example be biological skin. As depicted, the active agent 1 is disposed on the substrate contacting surface 31 of the adhesive layer 30, and forms an active agent layer 2 having voids 3 such that a portion of the substrate contacting surface 31 of the adhesive layer 30 can come into contact with and adhere to the surface 51 of the substrate 50 at the article-substrate interface 60. Further, the active agent 1 is also disposed at the article-substrate interface 60 and between the adhesive layer 30 and the substrate 50 so that the active agent can be efficiently delivered to an area of interest on the surface 51 of the substrate 50. It will be understood that the portions of the active agent 1 separated by the voids 3 depicted in FIG. 3, are one or more particles of powder active agent 1. Also depicted in FIG. 3 is the active agent 1 at least partially pressed into the adhesive layer 30. In further embodiments, the active agent 1 is not partially pressed into the adhesive and resides on the surface of the adhesive 30.

[0086] In one embodiment, the active agent comprises an antimicrobial agent such as chlorhexidine gluconate.

[0087] The adhesive article comprises a backing and a release liner, wherein the adhesive layer is disposed on the backing and the release liner is covering the skin contacting surface of the adhesive layer and the active agent. The method comprises removing the release liner from the adhesive article so that the skin contacting surface of the adhesive layer and the active agent are exposed and can be brought into contact with the substrate. The adhesive article is configured, such that upon removal of the release liner from the adhesive article, the active agent in powder form remains substantially disposed on the skin contacting surface of the adhesive layer for delivery to a region of interest on a substrate.

[0088] As described hereinabove, the present invention solves many problems associated with previous strategies, systems and / or devices.

Claims

1. A method of incorporating an active agent to an adhesive article for delivery of the active agent to a substrate, the adhesive article including an adhesive layer defining a substrate contacting surface adapted to adhere the adhesive article to the substrate, the method comprising: applying an active agent to the substrate contacting surface such that the active agent is disposed between the substrate and the adhesive layer when the adhesive article is adhered to the substrate, wherein the active agent is applied to the substrate contacting surface of the adhesive as a dry powder, and wherein applying comprises disposing the active agent to a release liner, and bringing the release liner into contact with the adhesive layer such that the active agent is positioned between the substrate contacting surface of the adhesive layer and the release liner.

2. The method of claim 1, further including laminating the release liner to the adhesive layer using pressure such that the active agent is at least partially pressed into the adhesive layer.