Compositions and methods for articles comprising therapeutic agents

Abstract

The present disclosure relates to polymer adhesive systems, articles, compositions or patches comprising a water-insoluble polymer matrix that contains a compound, whereupon application of an occluded patch to the mammalian skin, results in the release of the compound on to the skin and an into the skin. In one aspect, the rate of release of the compound can be fully or partially solubilized by water miscible and immiscible excipients, liposomes and lipid nanoparticles, and where the released compound is available in the treatment of immune related diseases such as atopic dermatitis, psoriasis, alopecia areata, acne and hyperpigmentation.

Description

ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) COMPOSITIONS AND METHODS FOR ARTICLES COMPRISING THERAPEUTIC AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Provisional Application No. 63 / 696,079, filed on September 18, 2024, which is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE

[0002] The present disclosure relates generally to articles comprising a disclosed formulation of water insoluble polymers comprising a water-soluble or water-insoluble compound, e.g., a therapeutic agent, wherein the compound is released from the polymer composition and onto, into and across the skin surface of an animal or human skin for the purpose of treating a clinical condition, i.e., treatment of a clinical condition via topical, cutaneous, and / or trans. BACKGROUND

[0003] Wounds are commonplace from childhood to old age. Wounds are a significant problem among the geriatric and nursing home population, especially at the end of life. Pressure ulcers alone exact a significant human and financial toll, costing on average more than $1,200 per patient per month to treat. CDC data indicates that from about 2% to 28% of nursing home residents have pressure ulcers. Diabetic ulcers similarly result in significant morbidity and costs, with diabetics accounting for approximately 82,000 amputations annually in the U.S., averaging $30,000 per amputation. Other wounds plaguing the nursing home and end of life population are ulcers resulting from arterial and venous insufficiency, as well as traumatic wounds, and non-healing surgical wounds.

[0004] Any penetration of the skin carries with it the risk of potential infection. This risk pertains to simple wounds incurred by accident or negligence; to surgical procedures performed under controlled conditions which utilize different biomaterials for the closure and dressing of incisions and / or wounds; and to a diverse range of in-vivo implantable textile fabrics, configured textile articles, and textile-containing mechanical appliances and devices which are surgically introduced into the body for diagnostic, therapeutic and / or prosthetic purposes.

[0005] Standard wound care involves debridement, cleansing and covering the wound with any of a variety of commercially available dressings. There are many special dressings available which are designed to keep wounds moist or absorb exudates. Some specialty dressings have silver impregnated in the dressing to prevent infection. Typically, dressings are attached either with self-adhesive or tape, or in some cases are applied with a compression wrap. Recent high-tech approaches are available for wound care using thermalATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) wound treatments and vacuum pumps. While these can be effective, they are very expensive and healing times are still measured in weeks or months. As such, it is desired to have an inexpensive wound treatment method and composition which reduces the time required for wounds to heal.

[0006] The rational use of antimicrobial agents against infection, particularly for simple wound treatment, has been advocated generally and has been previously reviewed in detail [Rodgers, K. G., Emer. Med. Clin. N. Am. 10: 753 (1992)]. Similarly, the major concerns regarding the ever-growing incidence of infections resulting from biocompatible textiles, articles and devices implanted in the body—espite recent advances in sterile procedures used in the clinical / surgical setting—have been considered and reviewed as the primary purpose and focus of a FDA / EPA / CDC / AAMI joint conference [Proceedings, Infection Control Symposium: Influence Of Medical Device Design, U.S. Dept. of Health and Human Services, Bethesda, Md., January 1995]. Moreover, the use of antibiotics and of mechanisms for delivering antimicrobial agents generally, particularly via slow-release delivery systems over time, to prevent or reduce severity of infection for implanted biodegradable materials has been reviewed [Sasmor et al., J. Vasc. Sur.14: 521 (1993)]. All of these considerations lead to the same conclusion: Infection, with or without the use of antibiotics, must be prevented or be controlled for all implantable biomaterials (including textiles, articles and devices) regardless of need or medical purpose.

[0007] A further clinical indication of unmet need is atopic dermatitis. Associated with changes in living environment and eating habits, the number of people suffering from atopic dermatitis has been increasing rapidly. It is one of the representative skin diseases shown in people with a history of allergy disorders. It is a chronic skin disease which has immunologic responses and thus often occurs together with other atopic diseases such as urticaria, metal allergy, allergic asthma, or allergic rhinitis etc, and its main skin symptoms are dryness and itch. In addition, it is believed to have a hereditary component, and often runs in families whose members also have atopic disease.

[0008] The pathogenetic mechanism of atopic dermatitis has not been clarified in many aspects and methods for treating atopic dermatitis have not yet been established. Although of unknown etiology, there is genetic predisposition and it is also related to abnormalities in the immune system. In addition, it is known as an inflammatory skin disease with a complex etiology that encompasses dry skin, increased susceptibility to irritation compared with normal human skin, cutaneous infection with bacteria, virus, fungus, etc., emotional factors, environmental factors and the like. Main skin symptoms of atopic dermatitis are severe itching, dryness, rash, redness, weeping crusting, scaling and the like. It has been known that there is no fundamental treatment for atopic dermatitis even with contemporary medical science,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) and thus the patients just have to avoid atopic dermatitis inducing factors and use therapies or therapeutic agents that help reduce the symptoms although they could not provide fundamental treatment.

[0009] Atopic dermatitis is a very common skin disease which affects 0.5-1% of the population as a whole, and 5~10% of children, and starts 2~6 months after birth, particularly, occurs most often within a year after birth, and 85% of children with atopic dermatitis manifest the disease before the age of 5 years. In 50% of atopic patients, it resolves spontaneously by the time the patient reaches age 2, however, the symptoms do not improve in 25% of the patients until they reach adolescence and the rest 25% of the patients has some degree of eczema that occurs throughout their lifetime.

[0010] The common early treatment for atopic dermatitis involves the use of topical steroids such as hydrocortisone. Such treatments require repeated daily applications to control irritations, itchiness and inflammations.

[0011] Oral or injectable administration of drugs to treat skin ailments do not provide immediate relief.

[0012] Despite advances in wound care, treatment of inflammation, and atopic dermatitis research, there is still a scarcity of articles, products and systems that meet the needs for adequate and effective wound treatment, treatment of inflammation, and treatment of atopic dermatitis. These needs and other needs are satisfied by the present disclosure. SUMMARY

[0013] In accordance with the purpose(s) of the disclosure, as embodied and broadly described herein, the disclosure, discloses a polmer adhesive article, a polymer adhesive patch or a polymer adhesive system that comprises polymer adhesive and a natural or synthetic compound or compounds, wherein upon contact with the skin, the article, the patch or the system provides occlusion and / or continuous delivery of medication, sustained relief, and ease of application, and minimal side effects when administered to a subject. The disclosed patches or systems provide an improved treatment modality for skin affected with an inflammatory condition such as atopic dermatitis, which is very sensitive and may not respond well to harsh pressure sensitive adhesives. The combination of GAc, GA, and / or derivatives thereof with the two-part silicone adhesives and excipients described herein, produce a mild and adhesion with a soothing feel to the inflamed skin.

[0014] In various further aspects, the present disclosure relates to articles that are therapeutic coverings and wraps comprising a substrate and a releasable therapeutic agent in contact with or attached to one another. In various aspects, the articles comprisingATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) therapeutic coverings and wraps are useful for treatment of atopic dermatitis. In other aspects, the articles are dermal or wound coverings, patches, wraps, dressings and bandages that are useful for treatment of wounds and other clinical conditions as disclosed herein.

[0015] In a further aspect, the substrate comprises a textile having hydroxyl groups in the textile yarn or filament, e.g., a textile comprising a yarn or filament comprising cotton, rayon, silk, or combinations thereof. It is understood that substrates can comprise other materials and is not limited to textile materials. Moreover, a substrate can comprise a composite material, e.g., a bilayer material wherein a first layer comprises a substrate and a releasable therapeutic agent in contact with or attached to one another and a second layer does not. In a further aspect, the therapeutic agent interacts with or is attached to the substrate via non- covalent interactions, e.g., van der Waals forces, ionic interactions, and combinations thereof, or via a covalent linkage that can release the therapeutic agent under normal use with a subject.

[0016] In a further aspect, the articles comprising a substrate and a releasable therapeutic agent in contact with or attached to one another provide for tunable release of the therapeutic agent such that the therapeutic agent can be released in a short time frame (or immediate release) on the order of minutes to hours to longer time frames (or delayed release) on the order of hours to days or longer by varying the mode of interaction between the substrate and the releasable therapeutic agent from non-covalent interactions of different types to covalent interactions involving linkers of different length and chemical reactivities to mixtures of chemistries and covalent / non-covalent interactions between the releasable therapeutic agent and substrate.

[0017] Disclosed are articles comprising a substrate and a therapeutic agent.

[0018] Also disclosed are methods of making the disclosed articles.

[0019] Also disclosed are methods of treating a subject using the disclosed articles.

[0020] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described aspects are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described aspects are combinable and interchangeable with one another.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) BRIEF DESCRIPTION OF THE FIGURES

[0021] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0022] FIG.1 shows representative data for release of a therapeutic agent from a disclosed substrate comprising a therapeutic agent attached thereto.

[0023] FIG.2 shows a representative chromatogram of 18β-glycyrrhetinic Standard at 1 µg / mL in 30% ethanol in water.

[0024] FIGs. 3A-3B show representative schematic cross-sectional view of a disclosed article, e.g., a topical skin patch, showing the different layers of the article comprising a backing material layer (10), a matrix layer (20), and a liner layer (30). It should be noted that the relative layer thicknesses are not necessarily to scale and can vary as disclosed herein. FIG.3A shows a schematic cross-sectional view of a disclosed article, e.g., a topical skin patch, showing the different layers of the article comprising a backing material layer (10), a matrix layer (20), and a liner layer (30), wherein the matrix layer comprises a disclosed polymer adhesive system and a therapeutic agent mixture. FIG. 3B shows a schematic cross-sectional view of a disclosed article, e.g., a topical skin patch, showing the different layers of the article comprising a backing material layer (10), a matrix layer (20), and a liner layer (30), wherein the matrix layer comprises a disclosed polymer adhesive system and a therapeutic agent mixture.

[0025] FIGs.4A-4B shows representative data relating to the in-vitro release profile of GA or 18 beta-Glycyrrhetinic acid from different patch formulations. FIG.4A shows representative data comparing release of 18β-glycyrrhetinic (GA) from MG7-9850 or MG7-9900 soft skin adhesives. FIG.4B shows representative data comparing release of 18β-glycyrrhetinic (GA) from MG7-9850 soft skin adhesives containing triethanolamine, oleic acid and oleyl alcohol.

[0026] FIGs. 5A-5B show representative photographs of two formulations of disclosed patches. FIG.5A shows a photograph of a formulation comprising 8 wt% having relatively increased tack and residue as evidenced when pulled from a surface that the patch was applied to. FIG. 5B shows a photograph of a formulation comprising 4 wt% relatively decreased tack and residue as evidenced when pulled from a surface that the patch was applied to.

[0027] FIGs. 6A-6B show representative data for release of therapeutic agent, 18β- glycyrrhetinic acid, from disclosed patches as a function of drug loading in the patch orATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) temperature at which the patch was cured. FIG. 6A shows representative data for in vitro release of 18β-glycyrrhetinic acid from patches made with different amounts of drug as indicated in the figure. FIG. 6B shows representative data for in vitro release of 18β- glycyrrhetinic acid from patches cured at different temperatures and having different drug loading as indicated in the figure.

[0028] FIGs.7 shows representative data for release of therapeutic agent, cannabidiol, from disclosed patches as a function of drug loading in the patch as indicated in the figure.

[0029] FIG.8 shows a representative study scheme for patch treatment for MC-903 induced AD in mice as further discussed in the examples herein.

[0030] FIG.9 shows representative data showing efficacy of a disclosed patch comprising 18β- glycyrrhetinic (GA) in the atopic dermatitis MC903 model in mouse (n=5, mean ± SEM) as further discussed in the examples herein.

[0031] FIG.10 shows representative data showing concentration of 18β-glycyrrhetinic (GA) in animal skin (ng / g) (Mean, ± SD, n=5 or 6) as further discussed in the examples herein.

[0032] Additional advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the disclosure. The advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed. DETAILED DESCRIPTION

[0033] Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0034] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0035] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and featuresATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) which may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure.

[0036] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0037] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0038] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0039] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0040] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. A. DEFINITIONSATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0041] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0042] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. Expressions such as “at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0043] Reference to "a" chemical therapeutic agent refers to one or more molecules of the chemical therapeutic agent rather than being limited to a single molecule of the chemical compound. Furthermore, the one or more molecules may or may not be identical, so long as they fall under the category of the chemical compound. Thus, for example, "a" chemical therapeutic agent is interpreted to include one or more molecules of the chemical, where the molecules may or may not be identical (e.g., different isotopic ratios, enantiomers, and the like).

[0044] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a therapeutic agent,” “a substrate,” or “a wrap,” includes, but is not limited to, two or more such therapeutioc agents, substrates, or wraps, and the like.

[0045] Reference to "a / an" therapeutic agent chemical compound, protein, and antibody each refers to one or more molecules of the chemical compound, protein, and antibody rather than being limited to a single molecule of the chemical compound, protein, and antibody. Furthermore, the one or more molecules may or may not be identical, so long as they fall under the category of the chemical compound, protein, and antibody. Thus, for example, "an" antibody is interpreted to include one or more antibody molecules of the antibody, where the antibody molecules may or may not be identical (e.g., different isotypes and / or different antigen binding sites as may be found in a polyclonal antibody).

[0046] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of theATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one-particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0047] When a range is expressed, a further aspect includes from the one-particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0048] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0049] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at orATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0050] The term “contacting” as used herein refers to bringing a disclosed therapeutic agent, compound, chemical, substrate, or material in proximity to another disclosed therapeutic agent, compound, chemical, substrate, or material as indicated by the context. For example, a therapeutic agent contacting a substrate refers to the therapeutic agent being in proximity to the substrate by the therapeutic agent interacting and binding to the substrate via ionic, dipolar and / or van der Waals interactions. In some instances, contacting can comprise both physical and chemical interactions between the indicated components. It is to be understood that chemical interactions can comprise a combination of covalent and non-covalent interactions, including one or more of ionic, dipolar, van der Waals interactions, and the like. For example, a therapeutic agent contacting a substrate is understood to mean that the therapeutic agent in physical and chemical contact with the substrate that can comprise covalent, ionic, and non- covalent interactions.

[0051] In a further aspect, the term "contacting" in the specific context of a therapeutic agent contacting a clinically relevant target can refer to bringing a disclosed therapeutic agent in proximity to a tissue, an organ, a cell, a target protein, or other biological entity together in such a manner that the disclosed therapeutic agent or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent. In a more specific instance, “contacting” can refer to bring a therapeutic agent in proximity to or contact with a wound, injury, inflammatory site, or skin of a subject.

[0052] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0053] As used herein, the term “patch”, “system” when used with respect to a polymer or compound described herein, or components thereof, refers to delivery system that is capable of delivering a medication on to the skin surface.

[0054] As used herein, the term "wound" includes any defect or disruption in the skin whichATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) may result from physical, chemical or thermal damage, or as a result of an underlying medical or physiological condition. Wounds may be classified as acute or chronic wounds.

[0055] As used herein, “therapeutic agent mixture” refers to one or more therapeutic agent, as disclosed herein, dispersed in a matrix layer.

[0056] As used herein, “administering” can refer to an administration of a therapeutic agent that is associated or in contact with a substrate. Administration can be continuous, releasable over specific time intervals, and / or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0057] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those therapeutic agents or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes therapeutic agents or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, anti-Parkinson agents, anti-tardive dyskinesia agents, analgesics, local anesthetics, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics;ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) antispasmodics, cardiovascular preparations (including calcium channel blockers, beta- blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single- stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0058] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0059] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, troubleshooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents and are meant to include future updates.

[0060] As used herein, “attached” can be used in lieu of and interchangeably with “contacting”, and “attached” refers to covalent or non-covalent interaction between two or moreATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, π-π interactions, cation-π interactions, anion-π interactions, polar π-interactions, and hydrophobic effects.

[0061] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and juvenile subjects, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0062] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as an infection. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a wound, including a wound without apparent infection, infection, or injury in a subject, as well as, radiation-induced skin damage, inflammation, atopic dermatitis, psoriasis and other clinical conditions, particularly said clinical conditions in a human and can include any one or more of the following: (a) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease or condition, i.e., arresting its development; and (c) relieving the disease or condition, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. In particular aspects, the terms “treatment”, “treat” and “treating” refer to a course of action (such as administering a system as describedATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) herein or pharmaceutical composition comprising a polymer patch and compound (as described herein) so as to prevent, eliminate, or reduce a symptom, aspect, or characteristics of a disease or condition. Such treating need not be absolute to be useful. In one aspect, treatment includes a course of action that is initiated concurrently with or after the onset of a symptom, aspect, or characteristics of a disease or condition. In another aspect, treatment includes a course of action that is initiated before the onset of a symptom, aspect, or characteristics of a disease or condition.

[0063] The term “in need of treatment” refers to a judgment made by a caregiver that a patient requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the patient is ill, or will be ill, as the result of a disease or condition that is treatable by a method or compound of the disclosure.

[0064] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units, e.g., mg therapeutic agent per gram substrate or mg therapeutic agent per unit area of substrate, suitable for use in treating a subject, each unit containing a predetermined quantity of a disclosed therapeutic agent thereof calculated to produce the desired response or responses in association with its administration.

[0065] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0066] As used herein, the term “effective amount” refers to an amount that is sufficient to achieve the desired modification of a physical property of the composition or material. For example, an “effective amount” of a therapeutic agent refers to an amount that is sufficient to achieve the desired improvement or outcome associated with the referenced component, e.g., achieving the desired clinical result and / or rate of therapeutic agent release. The specific level in terms of wt% or mol% in a composition required as an effective amount will depend upon a variety of factors including the amount and type of substrate, amount and type of mode of the interaction between the substrate and therapeutic agent, chemical structure of the linker, if present, and type of therapeutic agent. In a further aspect, “effective amount” can refer to the amount of a disclosed therapeutic agent or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.

[0067] As used herein, the term “release” refers to a drug or therapeutic agent leaving,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) desorbing, and / or diffusing from a disclosed article, e.., a disclosed patch, under in vitro or in- vivo under physiological conditions of the subject. The release, unless specified otherwise, refers to continuous release of a drug over a period of ≥0.5 hour, ≥1 hour, ≥2 hours, ≥3 hours, ≥4 hours, ≥5 hours, ≥6 hours, ≥12 hours, ≥24 hours, ≥48 hours, and the like.

[0068] As used herein. “continuous release” refers to any mechanism of drug or therapeutic agent release that occurs over the course of a period of time in which the release of the drug or therapeutic agent during that period is continuous and essentially zero order release kinetics over the period of time. For example, continuous release may be a constant release profile in contrast to a release profile that may have an initial burst of release followed by constant release thereafter or a variable release profile having periodic release bursts throughout the release period.

[0069] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific therapeutic agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific therapeutic agent employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition. That is, “therapeutically effective amount” refers to an amount of drug in the system, either alone or as a part of a pharmaceutical system, that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease or condition. Such effect need not be absolute to be beneficial.

[0070] For example, it is well within the skill of the art to start doses of a therapeutic agent at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single doseATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0071] A response to a therapeutically effective dose of a disclosed therapeutic agent and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed therapeutic agent and / or pharmaceutical composition, by changing the disclosed therapeutic agent and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0072] As used herein, the term "prophylactically effective amount" refers to an amount effective for preventing onset or initiation of a disease or condition.

[0073] As used herein, the term "prevent" or "preventing" refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0074] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0075] The term "pharmaceutically acceptable salts", as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When therapeutic agents of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such therapeutic agents with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceuticallyATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When therapeutic agents of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such therapeutic agents with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, trifluoracetate, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0076] The term "pharmaceutically acceptable ester" refers to esters of therapeutic agents of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent therapeutic agent or a salt thereof. Examples of pharmaceutically acceptable, non-toxic esters of the present disclosure include C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred. Esters of disclosed therapeutic agents can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the therapeutic agent that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of therapeutic agents containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from therapeutic agents containing the carboxylic acid groups by reaction of the therapeutic agent with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the therapeutic agent with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0077] The term "pharmaceutically acceptable amide" refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed therapeutic agents can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from therapeutic agentsATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) containing primary or secondary amine groups by reaction of the therapeutic agent that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of therapeutic agents containing carboxylic acid groups, the pharmaceutically acceptable amides are prepared from therapeutic agents containing the carboxylic acid groups by reaction of the therapeutic agent with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the therapeutic agent with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a therapeutic agent of the present disclosure in the form of a pharmaceutically acceptable prodrug.

[0078] The term "pharmaceutically acceptable prodrug" or "prodrug" represents those prodrugs of the therapeutic agents of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent therapeutic agent having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0079] The terms “carrier” and “pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.

[0080] As used herein, the term "derivative" refers to a therapeutic agent having a structure derived from the structure of a parent therapeutic agent (e.g., a therapeutic agent disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0081] As used herein, “purified water” refers to water (H2O) that is at least about 99.95% (w / w) pure.

[0082] Certain compounds contained in the compositions of the present disclosure may exist in particular geometric or stereoisomeric forms. In addition, compounds contained in the compositions of the present disclosure may also be optically active. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0083] As used herein, “enoxolone”, “18 beta-Glycyrrhetinic acid”, “18-β glycyrrhetinic acid”, and “GA” which can be used interchangeably, refer to a compound having a structure represented by a formula: . Unless otherwiseand metabolites, and is inclusive of pharmaceutically acceptable salts thereof.

[0084] As used herein, “glycyrrhizic acid” or “GAc”, which can be used interchangeably, refer to a compound having a structure represented by a formula:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) . Unlessmetabolites, and is inclusive of pharmaceutically acceptable salts thereof.

[0085] As used herein, “curcumin”, “diferuloylmethane” and “(E,E)-1,7-bis(4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione” can be used interchangeably, refer to a compound having a structure represented by a formula: . Unlessderivatives, and metabolites, and is inclusive of pharmaceutically acceptable salts thereof.

[0086] As used herein, “methylnissolin”, “10-Methoxymedicarpin”, and “9,10-dimethoxy- 6a,11a-dihydro-6H-[1]benzofuro[3,2-c]chromen-3-ol” can be used interchangeably, refer to a compound having a structure represented by a formula: . Unlesscan analogues,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) derivatives, and metabolites, and is inclusive of pharmaceutically acceptable salts thereof.

[0087] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E / Z specification, and the like. One of skill in the art can readily ascertain the structure of a therapeutic agent if given a name, either by systemic reduction of the therapeutic agent structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

[0088] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e., one atmosphere).

[0089] Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0090] Described herein are articles or systems, e.g., comprising dermal or wound coverings, patches, wraps, dressings, and bandages, that comprise at least one polymer adhesive and at least one natural or synthetic compound or compounds, wherein upon contact with the skin, the article, the patch or the system provides continuous delivery of medication, sustained relief, and ease of application, and minimal side effects when administered to a subject. The disclosed patches or systems provide an improved treatment modality for skin affected with an inflammatory condition such as atopic dermatitis, which is very sensitive and may not respond well to harsh pressure sensitive adhesives. The combination of GAc, GA, and / or derivatives thereof with the two-part silicone adhesives and excipients described herein, produce a mild and adhesion with a soothing feel to the inflamed skin.

[0091] Also described herein are articles comprising dermal or wound coverings, patches, wraps, dressings and bandages, comprising a substrate and a releasable therapeutic agent in contact with one another. Also described herein are methods of administering the articles to a subject in need thereof. In various aspects, the subject can have a wound, injury, or infection. Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0092] Also described herein are articles comprising a backing material layer, a matrix layer, and a liner layer; wherein the matrix layer comprises a polymer adhesive system and therapeutic agent mixture in contact with a substrate.

[0093] Also described herein are articles article comprising a backing material layer, a matrix layer, and a liner layer; wherein the matrix layer comprises a polymer adhesive system and therapeutic agent mixture in contact with a substrate; and wherein the polymer adhesive system is a self-adhesive, a pressure adhesive, or a combination thereof. B. POLYMER ADHESIVE SYSTEMS

[0094] In one aspect, the disclosure relates to articles comprising a substrate and a releasable therapeutic agent in contact with or attached to one another. In a further aspect, the present disclosure provides a polymer adhesive system comprising a water-insoluble polymer and a compound. In one aspect, the compound is soluble in the polymer system via use of one more excipient. In one aspect, the compound is dispersed or suspended in the polymer system, such that in-vivo under physiological conditions in the body of a subject, such as, but not limited to, a human, the compound is released from the polymer after administration of the polymer system to the subject.

[0095] The polymer portion of the disclosed polymer conjugates may take on a variety of forms. In certain aspects, the polymer is a poly(dimethylsiloxane), a polyacrylate, a poly(hydroxypropylmethacrylate), a polydextran, a polyethylene glycol, polyglutamic acid, a polylactic-polyglutamic acid mixture, a polysialic acid, a polycaprolactone, a polyvinylpyrrolidone, a glycosaminoglycans, a poly(oxazoline), a polyglycerol, a poly(acryloyloxyethylphosphorylcholine), or a methacrylate-based co-polymer with synthetic forms of phosphorylcholine; combinations of the foregoing are also included.

[0096] In one aspect, wherein the water insoluble polymer is a co-polymer, the co-polymer may be manufactured by reacting one of more monomer units of a first water soluble polymer and one or more monomer units of at least a second polymer (which may optionally be a water soluble polymer). Such a co-polymer includes both block co-polymers and random co- polymers. In a particular aspect, the co-polymer comprises a siloxane polymer and at least a second polymer. In a particular aspect, the co-polymer comprises a siloxane polymer and at least a second polymer, wherein the siloxane polymer portion comprises greater than 25%, 50%, 75%, 85%, 95%, 98%, 99%, or 99.5% of the polymer (on a weight-to-weight basis with regard to the total polymer components). In a particular aspect, the co-polymer comprises a siloxane polymer and at least a second polymer, wherein the siloxane polymer is comprises greater than 25%, 50%, 75%, 85%, 95%, 98%, 99%, or 99.5% of the polymer (on a weight to weight basis with regard to the total polymer components) and at least one of the additionalATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) polymers is a water soluble polymer. In any of the foregoing, the additional water insoluble polymer(s) may be any water insoluble polymer described above. In any of the foregoing, the additional polymer(s) may be polyethylene glycol, dextran, polyoxazoline and / or dextran modified by oxidation. In a particular aspect, the co-polymer comprises a siloxane polymer and at least a second polymer, wherein the siloxane polymer comprises greater than 25%, 50%, 75%, 85%, 95%, 98%, 99%, or 99.5% of the polymer (on a weight-to-weight basis) and the additional polymer(s) is not a water-soluble polymer.

[0097] In various aspects, the polymer adhesive system is a self adhesive (SSA) and pressure adhesive (PSA) composition.

[0098] The pharmaceutical active ingredients or therapeutic agents that are used in the polymer adhesive system can be selected from a class of compounds used to treat atopic dermatitis, acne, skin cancer and other topical diseases. Non-limiting examples of water insoluble compounds include methotrexate, cis-retinoic acid, dapsone, adapalene, isotretinoin, tretinoin, spironolactone, 18-beta-glycyrrhetinic acid, azelaic acid, and the like.

[0099] In one aspect, water-soluble compounds include sodium or ammonium salt forms of 18-beta-glycyrrhetinic acid and azelaic acid; NSAIDs such as ibuprofen, naproxen, and diclofenac; peldesine; anthralin; acitretin; ixekizumab; secukinumab; ruxolitinib; and the like.

[0100] In a further aspect, the disclosed polymer adhesive can be a drug-in-adhesive (DIA) single-layer topical patch of varying sizes for the treatment of skin conditions in adults and children. In a still further aspect, the drug or therapeutic agent (e.g., GAc, Ga, and / or a derivatie thereof) can be combined with the adhesive and potentially skin penetration enhancers and potentially emollients.

[0101] In a further aspect, the disclosed polymer adhesive can be a single-layer topical patch comprising a 4" x 5.5" drug-in-adhesive (DIA) single-layer topical patch for the treatment of mild to moderate atopic dermatitis and psoriasis in adults and children (> 3 months old). Each patch will be individually packaged. The regimen will be one patch per day for 7 to 28 days. To apply, patients will open a package, peel off the release liner, and apply to the affected area.

[0102] In a further aspect, the disclosed polymer adhesive can be a single-layer topical patch comprising a drug-in-adhesive (DIA) single-layer topical patch comprising about 0.5% - 6% of a disclosed therapeutic agent, e.g., GAc, GA, or a derivative thereof (compared to weight of dry adhesive), 0.5% - 5% skin penetration enhancers such as isopropyl myristate, glycerin, propylene glycol, eucalyptol, isoprene, limonene, menthol, camphor and adhesives such as: amylopectin-carbomer, acrylic copolymer, polyisobutylene, and silicone based (e.g., Liveo MG 7-9800) biocompatible adhesives. These ingredients can be solubilized with solvents such asATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) ethyl acetate or as two-part adhesive mix, followed by complete evaporation of the solvent if needed.

[0103] In a further aspect, the disclosed polymer adhesive can be a single-layer topical patch comprising a drug-in-adhesive (DIA) single-layer topical patch comprising can be manufactured in a controlled environment to ensure quality and purity using raw materials and equipment used in the process qualified and validated per their monographs listed in USP. In a still further aspect, mixing and casting can be performed under controlled conditions to ensure uniformity of the bandage; and drying can be performed at a specific temperature and humidity to ensure the integrity and stability of the bandage.

[0104] In a further aspect, the disclosed polymer adhesive can be a single-layer topical patch comprising a drug-in-adhesive (DIA) single-layer topical patch can comprise a backing material comprising polyurethane or polyester.

[0105] In a further aspect, the disclosed polymer adhesive can be a single-layer topical patch comprising a drug-in-adhesive (DIA) single-layer topical patch can comprise a release liner comprising a low-density polyethylene.

[0106] In a further aspect, the disclosed polymer adhesive system can comprise a two-part adhesive such as, for example, but not limited to, Dupont Softskin MG7-9850 adhesive ingredients comprisng: Part A: dimethyl siloxane, dimethylvinylsiloxy-terminated / 68083-19-2, siloxanes and silicones, dimethyl / 6148-62-9; and Part B: dimethyl siloxane, dimethylvinylsiloxy-terminated / 68083-19-2, siloxanes and silicones, di-Me, hydrogen- terminated / 70900-21-9, siloxanes and silicones, dimethyl / 63148-62-9; octamethyl clyclotetrasiloxane / 556-67-2.

[0107] In a further aspect, the disclosed polymer adhesive system can comprise a two-part adhesive such as, for example, but not limited to, Dupont Softskin MG7-9900 adhesive ingredients comprisng: Part A: dimethyl siloxane, dimethylvinylsiloxy-terminated / 68083-19-2, octamethyl clyclotetrasiloxane / 556-67-2; and Part B: dimethyl siloxane, dimethylvinylsiloxy- terminated / 68083-19-2, siloxanes and silicones, di-Me, hydrogen-terminated / 70900-21-9, octamethyl clyclotetrasiloxane / 556-67-2. C. DISCLOSED ARTICLES COMPRISING A SUBSTRATE AND A THERAPEUTIC AGENT

[0108] In one aspect, the disclosure relates to articles comprising a backing material layer, a matrix layer, and a liner layer; wherein the matrix layer comprises a polymer adhesive system and therapeutic agent mixture in contact with a substrate.

[0109] In a further aspect, the disclosure relates to articles article comprising a backing material layer, a matrix layer, and a liner layer; wherein the matrix layer comprises a polymerATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) adhesive system and therapeutic agent mixture in contact with a substrate; and wherein the polymer adhesive system is a self-adhesive, a pressure adhesive, or a combination thereof.

[0110] In various aspects, the disclosed articles can be fabricated as wound coverings, skin or dermal patches, wraps, dressings and bandages.

[0111] In a further aspect, the therapeutic agent is releasable from the matrix layer comprising the adhesive polymer system system, e.g., via diffusion.

[0112] In a further aspect, the therapeutic agent not covalkently linked to the adhesive polymer system. In a still further aspect, the therapeutic agent is releasable from the adhesive polymer system system, e.g., via diffusion.

[0113] In a futher aspect, the substracte is, but, but not limited to, a patch, a bandage, a film, or the like.

[0114] In a still further aspect, the article comprises the polymer adhesive system as disclosed herein.

[0115] The present disclosure provides an article comprising a polymer adhesive system and therapeutic agent mixture in contact with a substrate. The polymer adhesive system, article, composition, or patch may include an adhesive polymer that is an adhesive water insoluble polymer. The therapeutic agent may be in solution or suspended or emulsified in the matrix. The therapeutic agent may be micronized or size reduced. The therapeutic agent may be mixed with an excipient or solvent that is hydrophilic (e.g., a polyol) or hydrophobic (e.g., an oleic acid).

[0116] In other embodiments, the adhesive polymer system system is an elastomeric silicone adhesive. The elastomeric silicone adhesive may be a platinum-catalyzed two-part elastomeric silicone adhesive. The therapeutic agent may be in a salt form or counter-ion complex. The therapeutic agent may be incorporated in a liposome or lipid nanoparticle vesicle prior to mixing with a matrix. The therapeutic agent may be emulsified with an oil, aqueous- polyol and surfactant prior to mixing with the matrix.

[0117] In various aspects, the therapeutic agent may comprise glycyrrhizic acid, enoxolone, a derivative and / or pharmaceutically acceptable salt thereof, or any combination thereof. In a further aspect, the therapeutic agent comprises 18β-glycyrrhetinic acid.

[0118] In a further aspect, the therapeutic agent may be glycyrrhizic acid, 18β-glycyrrhetinic acid, enoxolone, adapalene, a cannabinoid, curcumin, methylnissolin, a derivative and / or pharmaceutically acceptable salt thereof, and combinations of one or more of the foregoing.

[0119] It is understood throughout herein that reference to a therapeutic agent is inclusive ofATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) pharmaceutically acceptable salts thereof.

[0120] The therapeutic agent may be present in an amount from 0.1 to 10.0% w / w, from 0.5 to 8.0% w / w, from 1.0 to 6.0% w / w, from 2.0 to 5.0% w / w, or from 2.5 to 4.5% w / w. The polymer adhesive and therapeutic agent mixture may further comprise a penetration enhancer. The polymer adhesive may be an elastomeric polymer adhesive, which may be derived from a two- part catalyzed system comprising a component A and a component B. The catalyst may be a platinum catalyst. The elastomeric polymer adhesive may be cured, and may be cured via catalysis of a component A and component B, thereby forming the elastomeric polymer adhesive.

[0121] The soft skin adhesive may be present in an amount from 90.0 to 99.9% w / w, from 92.0 to 99.5% w / w, from 94.0 to 99.0% w / w, from 95.0 to 98.5% w / w, or from 96.0 to 98.0% w / w. The soft skin adhesive may comprise Liveo MG7-9850 or MG7-9900.

[0122] The article may further comprise a weak base selected from triethanolamine, 2- amino-2-hydroxymethyl-propane-1,3-diol (TRIS), and an amino acid. In a still further aspect, if the weak is an amino acid, it can be selected from any suitable amino acid useful as a weak base, e.g., lysine, histidine, and the like. The weak base may be present in an amount from 0 to 200 mM, from 6 to 190 mM, from 30 to 90 mM, from 40 to 80 mM, or from 50 to 70 mM.

[0123] The article may further comprise a fatty acid selected from oleic acid, linoleic acid, palmitic acid, stearic acid, myristic acid, lauric acid, capric acid, caprylic acid, caproic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and combinations thereof. The fatty acid may specifically be oleic acid, linoleic acid, palmitic acid, stearic acid, myristic acid, lauric acid, capric acid, caprylic acid, caproic acid, arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid. The fatty acid may be present in an amount from 0 to 1.0% w / w, from 0.05 to 0.5% w / w, from 0.05 to 0.25% w / w, from 0.08 to 0.20% w / w, or from 0.10 to 0.15% w / w.

[0124] The article may further comprise a fatty alcohol selected from oleyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, behenyl alcohol, arachidyl alcohol, lignoceryl alcohol, ceryl alcohol, montanyl alcohol, melissyl alcohol, and combinations thereof. The fatty alcohol may specifically be oleyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, behenyl alcohol, arachidyl alcohol, lignoceryl alcohol, ceryl alcohol, montanyl alcohol, or melissyl alcohol. The fatty alcohol may be present in an amount from 0 to 1.0% w / w, from 0.05 to 0.5% w / w, from 0.05 to 0.25% w / w, from 0.08 to 0.20% w / w, or from 0.10 to 0.15% w / w.

[0125] The article may further comprise a fatty acid ester selected from isopropyl myristate, ethyl oleate, methyl palmitate, propyl stearate, butyl laurate, isopropyl palmitate, ethylATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) stearate, methyl oleate, propyl myristate, butyl palmitate, isopropyl stearate, ethyl myristate, methyl stearate, propyl oleate, butyl myristate, isopropyl oleate, ethyl palmitate, methyl myristate, propyl palmitate, butyl stearate, isopropyl laurate, ethyl laurate, methyl laurate, propyl laurate, butyl oleate, and combinations thereof. The fatty acid ester may specifically be any one of the listed esters. The fatty acid ester may be present in an amount from 0 to 1.0% w / w, from 0.05 to 0.5% w / w, from 0.05 to 0.25% w / w, from 0.08 to 0.20% w / w, or from 0.10 to 0.15% w / w.

[0126] The article may further comprise a glycol selected from propylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, neopentyl glycol, 2-methyl-1,3-propanediol, 3-methyl-1,5-pentanediol, 2-ethyl-2-methyl-1,3-propanediol, and combinations thereof. The glycol may specifically be any one of the listed glycols. The glycol may be selected from propylene glycol, ethylene glycol, diethylene glycol, and polyethylene glycol, or from propylene glycol, dipropylene glycol, and polypropylene glycol, or from 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol. The propylene glycol may be present in an amount from 0 to 1.0% w / w, from 0.05 to 0.5% w / w, from 0.05 to 0.25% w / w, from 0.08 to 0.20% w / w, or from 0.10 to 0.15% w / w.

[0127] The article may further comprise glycerin, which may be present in an amount from 0 to 1.0% w / w, from 0.05 to 0.5% w / w, from 0.05 to 0.25% w / w, from 0.08 to 0.20% w / w, or from 0.10 to 0.15% w / w. The article may further comprise diethylene glycol monoethyl ether, which may be present in an amount from 0 to 1.0% w / w, from 0.05 to 0.5% w / w, from 0.05 to 0.25% w / w, from 0.08 to 0.20% w / w, or from 0.10 to 0.15% w / w. The article may further comprise purified water, which may be present in an amount from 0 to 1.0% w / w, from 0.005 to 0.25% w / w, from 0.01 to 0.10% w / w, or from 0.02 to 0.08% w / w.

[0128] The article may further comprise a second therapeutic agent, which may be selected from a therapeutic agent. The second therapeutic agent may be selected from an antibiotic, an antifungal, an antimicrobial, an NSAID, and a corticosteroid, or combinations thereof. The second therapeutic agent may be an antibiotic or an antimicrobial agent, an NSAID, or a corticosteroid.

[0129] In a further aspect, the adhesive polymer system system is an elastomeric adhesive polymer. In a yet further aspect, the elastomeric adhesive polymer is a two-part catalyzed elastomeric adhesive polymer. In a still further aspect, the two-part catalyzed elastomeric adhesive polymer is a platinum catalyzed elastomeric adhesive polymer. In a yet further aspect, the two-part catalyzed elastomeric adhesive polymer comprises two-parts of similarATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) viscosity in a weight ration of about 0.1:1 to about 5:1. In an even further aspect, the two-part catalyzed elastomeric adhesive polymer comprises two-parts of similar viscosity in a weight ration of about 0.7:1 to about 1.3:1. In a still further aspect, the two-part catalyzed elastomeric adhesive polymer comprises two-parts of similar viscosity in a weight ration of about 0.9:1 to about 1.1:1. In a still further aspect, the two-part catalyzed elastomeric adhesive polymer comprises two-parts of similar viscosity in a weight ration of about 0.95:1 to about 1.05:1. In a yet further aspect, the two-part catalyzed elastomeric adhesive polymer comprises two-parts of similar viscosity in a weight ration of about 0.99:1 to about 1.01:1.

[0130] In a further aspect, the adhesive polymer system system, upon curing, is a cured adhesive polymer consisting essentially of no cure by-products.

[0131] In a further aspect, the adhesive polymer system is a silicone gel adhesive. Silicone gel adhesives of the present disclosure comprise a skin-contacting silicone adhesive gel. Silicone gel adhesives are known in the art, e.g., as detailed in WO 2008 / 057155, they are lightly crosslinked silicone polymers that have a viscoelastic, jelly-like consistency. They are typically formed using a hydrosilation reaction between an alpha-omega vinyl terminated polydimethyl siloxane and a Si-H containing siloxane catalyzed by a platinum catalyst. Further details on their formulation and properties are disclosed, for example, in U.S. Pat. Nos. 4,991,574 and 5,145,933.

[0132] In various aspects, a silicone gel adhesive precursor can be coated onto the substrate, and then the silicone gel adhesive precursor can then be cured. Alternatively, in a further aspect, the silicone gel adhesive precursor can be cured on a suitable release liner and laminated to the substrate.

[0133] In a further aspect, the silicone gel adhesive is based on platinum catalyzed two component addition cure chemistry. In a yet further aspect, such materials prior to curing typically have viscosities of about 1000 mPa·s to about 6000 mPa·s.

[0134] In a further aspect, further non-limiting examples of suitable silicone adhesive systems include those available from DuPont de Nemours, Inc. (hereinafter referred to as “DuPont”; Wilmington, Delaware), or their affiliates, under the brand name of DuPont™ Liveo™ Soft Skin Adhesives, and exemplary suitable silicone adhesives of said polymers include MG 7-9850, MG 7-9800, MG 7-9900, MG 7-9700, MG 7-9960 and related organopolysiloxanes from DuPont.

[0135] In a further aspect, further non-limiting examples of suitable commercially available silicone gel precursors include Blue Star Silicones Silbione™ RT Gel 4317; the two component MED-6345™ tacky silicone gel by Nusil Technology LLC, CA, USA; and Wacker SILPURAN® 2112 A / B, 2120 A / B and 2130 A / B, two-part, addition-curing silicone compositions curing toATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) soft, tacky silicone adhesives by Wacker Chemie GmbH, Munich, Germany. Components A and B of SILPURAN® 2110 A / B and 2120 A / B, e.g., which are mixed homogeneously in a ratio A:B=1:1 and cure rapidly at temperatures over 100° C.

[0136] In a further aspect, the coating weight of the adhesive polymer system and therapeutic agent on the substrate, in aggregate, is from about 20 g / m2to about 150 g / m2or from about 40 g / m2to about 120 g / m2. In a still further aspect, the adhesive polymer system and therapeutic agent is coated on the substrate from about 0.8 to about 6 mils thick.

[0137] In the foregoing, the therapeutic agent can be present in the adhesive polymer system to provide an amount of from about 1 to about 20 mg / cm2of the substrate. Each range described herein is intended to include all numerical values encompassed by the range. Furthermore, additional ranges may be formed from any lower limits and / or upper limits described herein. For example, the therapeutic agent is present in an amount within a range having a lower limit and / or an upper limit. The range may include or exclude the lower limit and / or the upper limit. By way of example and not limitation, a lower limit and / or an upper limit may be selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90 and 100 mg / cm2. A range formed from a single lower limit includes at least the lower limit and all numerical values greater than the lower limit regardless of whether the values are explicitly recited in this disclosure. A range formed from a single upper limit includes at least the upper limit and all numerical values less than the upper limit regardless of whether the values are explicitly recited in this disclosure. A range formed from a combination of a lower limit and an upper limit includes at least the lower limit, the upper limit, and all numerical values therebetween regardless of whether the values are explicitly recited in this disclosure. For example, based on the set of exemplary upper limits and lower limits explicitly recited above, the therapeutic agent can be present in the adhesive polymer system to provide an amount of from: about 1 to about 100 mg / cm2, less than about 1 mg / cm2, greater than about 1 mg / cm2, less than about 100 mg / cm2, or greater than about 100 mg / cm2, etc. All such ranges are contemplated and are intended to be explicitly disclosed and recited. Each value recited is intended to be modified by the term “about.”

[0138] In a further aspect, the therapeutic agent and polymer adhesive may further comprise a penetration enhancer, including, but not limited to, one or more of cocoyl caprylocaprate, decyl oleate, dimethyl sulfoxide, oleyl alcohol, octyldodecanol, propylene glycol, isopropyl myristate, and triacetin.

[0139] In a further aspect, the therapeutic agent may be present in the polymer adhesive n the form of one or more of particles. The particles may include microparticles and / or nanoparticles. The microparticles and / or nanoparticles may be milled or micro-milled. TheATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) particles may have an average particle size of from about 100 nanometers to about 700 micrometers. In other words, according to various aspects, the particles may have an average particle size of from about 0.1 to about 700 micrometers. Each range described herein is intended to include all numerical values encompassed by the range. Furthermore, additional ranges may be formed from any lower limits and / or upper limits described herein. For example, the particles may have an average particle size within a range having a lower limit and / or an upper limit. The range may include or exclude the lower limit and / or the upper limit. By way of example and not limitation, a lower limit and / or an upper limit may be selected from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900 and 1000 micrometers. A range formed from a single lower limit includes at least the lower limit and all numerical values greater than the lower limit regardless of whether the values are explicitly recited in this disclosure. A range formed from a single upper limit includes at least the upper limit and all numerical values less than the upper limit regardless of whether the values are explicitly recited in this disclosure. A range formed from a combination of a lower limit and an upper limit includes at least the lower limit, the upper limit, and all numerical values therebetween regardless of whether the values are explicitly recited in this disclosure. For example, based on the set of exemplary upper limits and lower limits explicitly recited above, the particles may have an average particle size of: about 0.1 to about 1000 micrometers, less than about 0.1 micrometers, greater than about 0.1 micrometers, less than about 1000 micrometers, or greater than about 1000 micrometers, etc. All such ranges are contemplated and are intended to be explicitly disclosed and recited. Each value recited is intended to be modified by the term “about.” According to various embodiments, microparticles may have an average particle size in a range of from about 0.7 to about 700 micrometers in diameter. According to various embodiments, nanoparticles may have an average particle size of from about 100 to about 2,500 nm in diameter.

[0140] In one aspect, the disclosure relates to articles comprising a substrate and a releasable therapeutic agent in contact with or attached to one another.

[0141] In a further aspect, the textile is a woven fabric, a knitted fabric, a non-woven fabric, or combinations thereof. It is understood that substrates can comprise other materials and is not limited to textile materials. Moreover, a substrate can comprise a composite material, e.g., a bilayer material wherein a first layer comprises a substrate and a releasable therapeutic agent in contact with or attached to one another and a second layer does not. In a further aspect, the therapeutic agent interacts with or is attached to the substrate via non-covalent interactions, e.g., van der Waals forces, ionic interactions, and combinations thereof, or via a covalent linkage that can release the therapeutic agent under normal use with a subject.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0142] In a further aspect, the articles comprising a substrate and a releasable therapeutic agent in contact with or attached to one another provide for tunable release of the therapeutic agent such that the therapeutic agent can be released in a short time frame (or immediate release) on the order of minutes to hours to longer time frames (or delayed release) on the order of hours to days or longer by varying the mode of interaction between the substrate and the releasable therapeutic agent from non-covalent interactions of different types to covalent interactions involving linkers of different length and chemical reactivities to mixtures of chemistries and covalent / non-covalent interactions between the releasable therapeutic agent and substrate.

[0143] In one aspect, the disclosure relates to articles comprising medical or therapeutic wraps, coverings, and devices comprising a substrate and a releasable therapeutic agent in contact with or attached to one another that can be used of treatment of inflammation, atopic dermatitis and other clinical conditions associated with the skin and muscle.

[0144] In one aspect, the disclosure relates to articles comprising dermal or wound coverings, patches, wraps, dressings and bandages comprising a substrate and a releasable therapeutic agent in contact with or attached to one another.

[0145] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate. In a still further aspect, the substrate comprises one or more hydroxyl groups. In a yet further aspect, the therapeutic agent is in contact with or attached to the substrate via non-covalent bonds comprising hydrogen bond interactions with the one or more hydroxyl groups of the substrate. In an even further aspect, the therapeutic agent is in contact with or attached to the substrate via covalent bonds comprising a covalent bond with one or more oxygen atom derived from the one or more hydroxyl groups associated with the substrate.

[0146] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below:In the foregoing, a specific therapeutic agent is depicted, glycyrrhetinic acid, but other therapeutic agents as described in the present disclosure capable of hydrogen bonding interactions with the substrate can be used in addition to or in lieu of glycyrrhetinic acid.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Exemplary, but non-limiting therapeutic agents that could be used in addition to or in lieu of glycyrrhetinic acid in the article depicted above include penicillins (e.g., amoxicillin, flucoxacillin, and the like); cephalosporins (e.g., cefepime, cefalexin, and the like); streptomycin; neomycin; kanamycin; paromomycin; vancomycin; ciprofloxacin; linezolid; and combinations thereof. In the aspect shown above, the substrate can be a fabric or textile material comprising cotton, rayon, silk, and other substrate materials comprising one or more hydroxyl groups as described in the present disclosure such as synthetic fibers (e.g., polyester or polyamides) that are blends comprising cotton, rayon, silk, and other materials comprising one or more hydroxyl group. The article depicted above can be prepared by the disclosed methods.

[0147] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below:. In the foregoing, a specific therapeutic agent is depicted, glycyrrhetinic acid, but other therapeutic agents as described in the present disclosure capable of hydrogen bonding interactions with the substrate can be used in addition to or in lieu of glycyrrhetinic acid. Exemplary, but non-limiting therapeutic agents that could be used in addition to or in lieu of glycyrrhetinic acid in the article depicted above include penicillins (e.g., amoxicillin, flucoxacillin, and the like); cephalosporins (e.g., cefepime, cefalexin, and the like); streptomycin; neomycin; kanamycin; paromomycin; vancomycin; ciprofloxacin; linezolid; and combinations thereof. In the aspect shown above, the substrate can be a fabric or textile material comprising cotton, rayon, silk, and other substrate materials comprising one or more hydroxyl groups as described in the present disclosure such as synthetic fibers (e.g., polyester or polyamides) that are blends comprising cotton, rayon, silk, and other materials comprisingATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) one or more hydroxyl group. Articles comprising the therapeutic agent in contact or attached to a substrate having the structure shown in the formula above can be prepared by the disclosed methods.

[0148] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below: .is depicted, glycyrrhetinic acid, but other therapeutic agents as described in the present disclosure capable of hydrogen bonding interactions with the substrate can be used in addition to or in lieu of glycyrrhetinic acid. Exemplary, but non-limiting therapeutic agents that could be used in addition to or in lieu of glycyrrhetinic acid in the article depicted above include penicillins (e.g., amoxicillin, flucoxacillin, and the like); cephalosporins (e.g., cefepime, cefalexin, and the like); streptomycin; neomycin; kanamycin; paromomycin; vancomycin; ciprofloxacin; linezolid; and combinations thereof. In the aspect shown above, the substrate can be a fabric or textile material comprising cotton, rayon, silk, and other substrate materials comprising one or more hydroxyl groups as described in the present disclosure such as synthetic fibers (e.g., polyester or polyamides) that are blends comprising cotton, rayon, silk, and other materials comprising one or more hydroxyl group. Articles comprising the therapeutic agent in contact or attached to a substrate having the structure shown in the formula above can be prepared by the disclosed methods.

[0149] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below: ,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) wherein A is OH or a moiety having a structure shown in the formula: an7, 8.9, and 10.

[0150] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below: ,;a structure shown in the formula: ;from O, NH, and S; wherein m is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8.9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; wherein n is an integer selected from 1, 2, and 3; and wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8.9, and 10.

[0151] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) .agent is depicted, glycyrrhetinic acid, but other therapeutic agents as described in the present disclosure capable of hydrogen bonding interactions with the substrate can be used in addition to or in lieu of glycyrrhetinic acid. Exemplary, but non-limiting therapeutic agents that could be used in addition to or in lieu of glycyrrhetinic acid in the article depicted above include penicillins (e.g., amoxicillin, flucoxacillin, and the like); cephalosporins (e.g., cefepime, cefalexin, and the like); streptomycin; neomycin; kanamycin; paromomycin; vancomycin; ciprofloxacin; linezolid; and combinations thereof. In the aspect shown above, the substrate can be a fabric or textile material comprising cotton, rayon, silk, and other substrate materials comprising one or more hydroxyl groups as described in the present disclosure such as synthetic fibers (e.g., polyester or polyamides) that are blends comprising cotton, rayon, silk, and other materials comprising one or more hydroxyl group. Articles comprising the therapeutic agent in contact or attached to a substrate having the structure shown in the formula above can be prepared by the disclosed methods.

[0152] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) .depicted, glycyrrhetinic acid, but other therapeutic agents as described in the present disclosure capable of hydrogen bonding interactions with the substrate can be used in addition to or in lieu of glycyrrhetinic acid. Exemplary, but non-limiting therapeutic agents that could be used in addition to or in lieu of glycyrrhetinic acid in the article depicted above include penicillins (e.g., amoxicillin, flucoxacillin, and the like); cephalosporins (e.g., cefepime, cefalexin, and the like); streptomycin; neomycin; kanamycin; paromomycin; vancomycin; ciprofloxacin; linezolid; and combinations thereof. In the aspect shown above, the substrate can be a fabric or textile material comprising cotton, rayon, silk, and other substrate materials comprising one or more hydroxyl groups as described in the present disclosure such as synthetic fibers (e.g., polyester or polyamides) that are blends comprising cotton, rayon, silk, and other materials comprising one or more hydroxyl group. Articles comprising the therapeutic agent in contact or attached to a substrate having the structure shown in the formula above can be prepared by the disclosed methods.

[0153] In a further aspect, the disclosed articles comprise a therapeutic agent in contact or attached to a substrate having the structure shown in the formula below:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) .therapeutic agent is depicted, glycyrrhetinic acid, but other therapeutic agents as described in the present disclosure capable of hydrogen bonding interactions with the substrate can be used in addition to or in lieu of glycyrrhetinic acid. Exemplary, but non-limiting therapeutic agents that could be used in addition to or in lieu of glycyrrhetinic acid in the article depicted above include penicillins (e.g., amoxicillin, flucoxacillin, and the like); cephalosporins (e.g., cefepime, cefalexin, and the like); streptomycin; neomycin; kanamycin; paromomycin; vancomycin; ciprofloxacin; linezolid; and combinations thereof. In the aspect shown above, the substrate can be a fabric or textile material comprising cotton, rayon, silk, and other substrate materials comprising one or more hydroxyl groups as described in the present disclosure such as synthetic fibers (e.g., polyester or polyamides) that are blends comprising cotton, rayon, silk, and other materials comprising one or more hydroxyl group. Articles comprising the therapeutic agent in contact or attached to a substrate having the structure shown in the formula above can be prepared by the disclosed methods. D. SUBSTRATES

[0154] In various aspects, the present disclosure comprises a therapeutic agent in contact or attached to a substrate.

[0155] In a further aspect, the substrate can be a textile material or a fabric comprising a yarn, a fiber and / or a filament optionally comprising one or more hydroxyl groups. In a still further aspect, the fabric can be a woven fabric, a knit fabric, a non-woven fabric, and combinations thereof.

[0156] In a further aspect, the substrate can be a textile material or a fabric comprising a yarn, a fiber and / or a filament comprising one or more hydroxyl groups. In a still further aspect, the fabric can be a woven fabric, a knit fabric, a non-woven fabric, and combinations thereof.

[0157] In a further aspect, the substrate can be a textile material or a fabric comprising a yarn, a fiber and / or a filament without one or more hydroxyl groups. In a still further aspect, the fabric can be a woven fabric, a knit fabric, a non-woven fabric, and combinations thereof.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0158] In a further aspect, the textile material or the fabric can comprise a yarn, a fiber, and / or a filament comprising plant fibers, animal fibers or synthetic fibers. In a still further aspect, the textile material or the fabric can comprise a yarn, a fiber, and / or a filament comprising cotton, rayon staple, flax, wool, viscose, silk and / or synthetic fibers. In a yet further aspect, the textile material or the fabric can comprise a yarn, a fiber, and / or a filament comprising polyamide, polyester, polypropylene, polyacrylics, and combinations thereof provided that comprise one or more hydroxyl group or moiety in the polymer backbone or within a graft or sidechain linked to the polymer backbone.

[0159] In a further aspect, the textile material is selected from cotton, silk, polyester, wool, rayon, nylon, pre-printed textile fabric, woven-fabric, dyed-woven fabric, raw fiber, non-woven fabric, silk, synthetic textile or bandage cloth, woven fabric or non- woven fabric and yarn, and combinations thereof. E. THERAPEUTIC AGENTS

[0160] In various aspects, the present disclosure comprises a therapeutic agent in contact or attached to a substrate. In a further aspect, the therapeutic agent is an antimicrobial therapeutic agent, antibiotic therapeutic agent, antibacterial therapeutic agent, antifungal therapeutic agent, an anti-inflammatory therapeutic agent such as a non-steroidal anti- inflammatory agent (“NSAID”) or a steroid, an anti-pain therapeutic agent, analgesic therapeutic agent, an antiallegic therapeutic agent, an anesthetic therapeutic agent, an antihistamine therapeutic agent, and combinations thereof.

[0161] In a further aspect, the therapeutic agent can be glycyrrhizic acid (also referred to herein throughout as “GAc”), having a chemical structure shown by the formula below, or a derivative thereof. CH3COOH .ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0162] In a further aspect, the GAc can be classified as a Non-Botanical Drug because of its high level of purity, its production under Good Manufacturing Practices and its registration in the European Pharmacopoeia.

[0163] In a further aspect, GAc can be metabolized in vivo via hydrolysis or further processed by hydrolysis to provide enoxolone (also referred to herein as GA or 18-β Glycyrrhetinic Acid) as shown below.structure shown by the formula immediately below, or a derivative thereof..

[0165] In a further aspect, enoxolone can be sourches from a variety of sources, including,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) for example, from a Mafco Worldwide approved and audited facility in China (i.e., Gansu Fanzhi Pharmaceutical Co., Gaolan County, Lanzhou Gansu, China 730299) and Alchem International Private, LLC in Ballabgrh, Faridabad, Haryana, India 110030.

[0166] Enoxolone has been registered in the European Pharmacopoeia. One supplier, Mafco Worldwide has registered this product with US FDA under the requirements of the FDA Bioterrorism Act. Other suppliers such as Alchem International Pvt Ltd provide enoxolone for the European market. Enoxolone is supplied as micronized powder, where the particle size distribution or PSD can be below 100, 50, 25 or 10 microns.

[0167] In a further aspect, the therapeutic agent can be an analog or derivative of enoxolone. The therapeutic agent can be represented by a formula having the structure, or a derivative thereof: wherein R1acan be =O,acetyloxy, an ester, an alkoxy, an aryloxy, oxy-glucopyranose (Glc), or an amine; R1bcan be hydrogen, a halogen, hydroxy, an ether, a nitrile, or an alkoxy; R1aand R1bcan be covalently bonded and, together with intermediate atoms, comprise an optionally substituted 5- to 7-membered fused heteroaryl; R1ccan be hydrogen or hydroxy; R1band R1ccan be covalently bonded and, together with at least one intermediate oxygen, comprise an optionally substituted 3- to 5- membered spiroheterocycloalkyl; R1dcan be hydrogen or hydroxy; R2acan be hydrogen or a halide; R2bcan be hydrogen, hydroxy, or a linear or branched C1-C6 alkyl; R2ccan be selected from hydrogen, hydroxy, =O, a linear or branched C1-C6 alkyl; R2dcan be selected from hydrogen, hydroxy, a halogen, =O, or a linear or branched C1-C6 alkyl; R3acan be hydrogen, =O, hydroxy, or ester; R3bcan be hydrogen or =O; R3ccan be hydrogen or an alkoxy; R3dcan be hydrogen, hydroxy, or a linear or branched C1-C6 alkyl; R5acan be α-hydrogen or β- hydrogen; R5bcan be an alkyl, an amine, an amide, a ketone, an ester, or a nitrile. The dashed line in this and other structures presented herein indicates the presence of a single bond or a double bond, together with the solid line, as allowed. For a generic substituent (e.g., R)ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) attached by a solid line together with a dashed line, the presence of a double bond is indicated using “=” in combination with the substituent. For example, “=O” indicates that the substituent is a doubly bonded oxygen.

[0168] In another aspect, the therapeutic agent can be represented by a formula having the structure, or a derivative thereof: wherein R71, R72, andC6 linear or branched alkyl group, an oligomer of ethylene glycol, or another water-soluble polymer.

[0169] In another aspect, the therapeutic agent can be represented by a formula having the structure, or a derivative thereof: wherein R81can be a

[0170] In another aspect, the therapeutic agent can be represented by a formula having the structure, or a derivative thereof:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) wherein R91can be and R92can be selected from carboxylic acid, an ester, an

[0171] In a further aspect, the therapeutic agent can be represented by a formula having the structure, or a derivative thereof:

[0172] wherein R1aacetamide, an alkoxy, an aryloxy, or an ester; R1bcan be hydrogen, hydroxy, or an alkoxy; R3acan be hydrogen or =O; R51can be hydrogen, hydroxy, or an alkyl; R52can be a hydrogen, hydroxy, an alkyl, an amide, an amine, an imine, a thioamide, a thioketone, an aryl, or a heteroaryl; R51and R52can be covalently bonded and, together with at least one intermediate nitrogen, comprise an optionally substituted 5- to 8- membered heterocycloalkyl or an optionally substituted 5- to 8- membered heteroaryl; Z can be CHR53, wherein R53can be hydrogen or a C1-C6 linear or branched alkyl; and n can be an integer selected from 0, 1, 2, and 3. In another further aspect, n is 0 and R51and R52can be covalently bonded and, together with at least one intermediate nitrogen, comprise a piperazine ring substited with an optionall substituted phenyl group.

[0173] In another further aspect, the therapeutic agent can be represented by a formula having the structure, or a derivative thereof:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0174] wherein R1aan ester, an alkoxy, an acetyloxy, an aryl, an aryloxy, or oxy-glucopyranose (Glc); R1bcan be hydrogen, hydroxy, nitrile, a halogen, or an alkoxy; R1aand R1bcan be covalently bonded and, together with intermediate atoms, comprise an optionally substituted 5- to 7-membered fused heteroaryl; R1ccan be hydrogen or hydroxy; R1band R1ccan be covalently bonded and, together with at least one intermediate oxygen, comprise an optionally substituted 3- to 5- membered spiroheterocycloalkyl; R1dcan be hydrogen or hydroxy; R2acan be hydrogen or a halogen; R2bcan be hydrogen, hydroxy, or a linear or branched C1-C6 alkyl; R2ccan be hydrogen, hydroxy, =O, or a linear or branched C1-C6 alkyl; R2dcan be hydrogen, hydroxy, a halogen, =O, or a linear or branched C1-C6 alkyl; R3acan be hydrogen, hydroxy, or =O; R3bcan be hydrogen or =O; R3ccan be hydrogen or an alkoxy; R3dcan be hydrogen, hydroxy, or a linear or branched C1-C6 alkyl; R61can be hydrogen, an alkyl, an alkenyl, an ester, an alkoxy, an aryl, or an aryloxy; L can be CHR62, wherein R62can be hydrogen or a C1-C6 linear or branched alkyl; and m can be an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0175] In another further aspect, the therapeutic agent can be represented by a formula having the structure, or a derivative thereof:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) wherein, R1acan be hydrogen, hydroxy, =O, acetyloxy, an ester, an alkyl, a C1-C18 alkylcarbonyl, an alkoxy, an aryloxy, or oxy-glucopyranose (Glc); R1bcan be hydrogen, hydroxy, nitrile, a halogen, or an alkoxy; R1aand R1bcan be covalently bonded and, together with at least one intermediate nitrogen, comprise an optionally substituted 5- to 7-membered fused heteroaryl; R1ccan be hydrogen or hydroxy; R1band R1ccan be covalently bonded and, together with at least one intermediate oxygen, comprise an optionally substituted 3- to 5- membered spiroheterocycloalkyl; R1dcan be hydrogen or hydroxy; R2acan be hydrogen or a halogen; R2bcan be hydrogen, a hydroxy, or a linear or branched C1-C6 alkyl; R2ccan be hydrogen, hydroxy, =O, or a linear or branched C1-C6 alkyl; R2dcan be hydrogen, hydroxy, =O, a halogen, or a linear or branched C1-C6 alkyl; R3acan be hydroxy, =O or an alkoxy; R3bcan be hydrogen or =O; R3ccan be hydrogen or an alkoxy; R3dcan be hydrogen, a hydroxy, or a linear or branched C1-C6 alkyl; R65can be hydrogen, an unsubstitued C1-C18 linear or branched alkyl, an unsubstituted C1-C18 alkoxy, an unsubstituted C1-C18 aryloxy, or a substituted or unsubstitued C1-C6 aryl.In a further aspect, the therapeutic agent is an antimicrobial therapeutic agent, antibiotic therapeutic agent, antibacterial therapeutic agent, and / or antifungal therapeutic agent.

[0176] In a further aspect, the therapeutic agent can be a cannabinoid such as cannabidiol (CBD) or cannabigerol (CBG).

[0177] In a still further aspect, the therapeutic agent can be a cannabinoid having a chemical structure shown by the formula immediately below, or a derivative thereof..

[0178] In a further aspect, the cannabinoid is selected from tetrahydrocannabivarin, cannabidivarin, cannabigerol, cannabidiolic acid, cannabigerolic acid, cannabinol, combinations thereof. In a still further aspect, the cannabinoid is selected from cannabidiol, cannabigerol, cannabichromene, cannabinol, tetrahydrocannabinol, cannabidiolic acid, cannabigerolic acid, cannabichromenic acid, cannabinolic acid, tetrahydrocannabinolic acid, cannabidivarin, cannabigerovarin, cannabichromevarin, cannabinolivarin,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) tetrahydrocannabivarinol, cannabicyclol, cannabielsoin, cannabitriol, and combinations thereof. In a yet further aspect, the cannabinoid is selected from cannabidiol or cannabigerol.

[0179] In a still further aspect, the therapeutic agent can be curcumin having a chemical structure shown by the formula immediately below, or a derivative thereof.

[0180] Curcuma longa L., which is a member of the Zingiberaceae family. The spice turmeric is extracted from the rhizomes of Curcuma longa L.

[0181] As used herein, curcumin analogues are those compounds which due to their structural similarity to curcumin, exhibit anti-proliferative, pro-apoptotic effects, and / or other biochemical and cellular effects to that of curcumin. Curcumin analogues useful as a therapeutic agent with the disclosed articles with effects similar to curcumin include Ar- tumerone, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, 1,7- bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin1), 1,7-bis(piperonyl)- 1,6-heptadiene-3,5-dione (piperonyl curcumin) 1,7-bis(2-hydroxy naphthyl)-1,6-heptadiene- 2,5-dione (2-hydroxyl naphthyl curcumin), 1,1-bis(phenyl)-1,3,8,10 undecatetraene-5,7-dione (cinnamyl curcumin) and the like (Araujo and Leon, 2001; Lin et al., 2001; John et al., 2002; see also Ishida et al., 2002). Curcumin analogues may also include isomers of curcumin, such as the (Z,E) and (Z,Z) isomers of curcumin. In a related embodiment, curcumin metabolites which have similar to curcumin can also be used in the present disclosure. Known curcumin metabolites include glucoronides of tetrahydrocurcumin and hexahydrocurcumin, and dihydroferulic acid. In certain aspects, curcumin analogues or metabolites can be formulated as metal chelates, especially copper chelates. Other appropriate derivatives of curcumin, curcumin analogues and curcumin metabolites appropriate for use in the present invention will be apparent to one of skill in the art.

[0182] In a further aspect, the therapeutic agent can be methylnissolin, an IL-12 inhibitor and anti-inflammatory agent from Lathyrus nissolia, Dalbergia odorifera and Astragalus mongholicus, having a structure as shown below.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0183] In atherapeutic agent, antibiotic agent, agent is selected from the group consisting of chloramphenicol, tetracyclines, synthetic and semi-synthesic penicillins, beta-lactames, quinolones, fluoroquinolnes, macrolide antibiotics, peptide antibiotics, cyclosporines and combinations thereof. In a still further aspect, the therapeutic agent is an antimicrobial therapeutic agent, antibiotic therapeutic agent, and / or antibacterial therapeutic agent and is selected from the group consisting of cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine, cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef, imipenem, erythromycin (and erythromycin salts such as estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycoin, dirithromycin, troleanomycin, penicillin V, peniciliin salts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and clavulanate potassium, ampicillin, bacampicillin, carbenicillin indanyl sodium (and other salts of carbenicillin) mezlocillin, piperacillin, piperacillin and taxobactam, ticarcillin, ticarcillin and clavulanate potassium, clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine, ethambutol HC 1 and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine, sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine, sulfadiazine, sulfmethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, co- triamoxazole, pentamidine, and trimetrexate, and combinations thereof. In an yet further aspect, the therapeutic agent is an antimicrobial therapeutic agent, antibiotic therapeutic agent, and / or antibacterial therapeutic agent and is selected from the group consisting of azoleaic acid, erythromycin, bacitracin, zinc bacitracin, polymyxin, neomycin, chloramphenicol, tetracycline, minocycline, clindamycin, doxycycline, undecylenic acid and salts thereof, propionic acid and salts thereof, caprylic acid and salts thereof, ciprofloxacin, cephalosporins, benzoic acid, ciclopirox olamine, clotrimazole, econazole nitrate, metronidazole, miconazol nitrate, ketaconazole, oxiconazole, tolnaftate and combinations thereof.

[0184] In a further aspect, the therapeutic agent is an antimicrobial therapeutic agent,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) antibiotic therapeutic agent, and / or antibacterial therapeutic agent and is selected from the group consisting of glycyrrhetinic acid or derivative thereof; a penicillin or derivative thereof, such as amoxicillin and / or flucoxacillin; a cephalosporin such as cefepime and / or cefalexin; streptomycin; neomycin; kanamycin; paromomycin; vancomycin; ciprofloxacin; linezolid; and combinations thereof.

[0185] In a further aspect, the therapeutic agent is an an antifungal therapeutic agent. In a yet further aspect, the therapeutic agent is an antifungal therapeutic agent and is selected from the group consisting of amphotericin B, flucytosine, fluconazole, griseofulvin, miconazole nitrate, terbinafine hydrochloride, ketoconazole, itraconazole, undecylenic acid and chloroxylenol, ciclopirox, clotrimazole, butenafine hydrochloride, nystatin, naftifine hydrochloride, oxiconazole nitrate, selenium sulfide, econazole nitrate, terconazole, butoconazole nitrate, carbol- fuchsin, clioquinol, methylrosaniline chloride, sodium thiosulfate, sulconazole nitrate, terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and undecylenate salts (calcium undecylenate, copper undecylenate, zinc undecylenate) The following are representative examples of some antivirals that may be used in the invention: Acyclovir, Amantadine, Amprenavir, Cidofovir, Delavirdine, Didanosine, Famciclovir, Foscarnet, Ganciclovir, Indinavir, Interferon, Lamivudine, Nelfinavir, Nevirapine, Palivizumab, Penciclovir, Ribavirin, Rimantadine, Ritonavir, Saquinavir, Stavudine, Trifluridine, Valacyclovir, Vidarabine, Zalcitabine, Zidovudine The following are representative examples of agents for the treatment of cancer that may be used in accordance with the invention: carboplatin, busulfan, cisplatin, thiotepa, melphalan hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, mechlorethamine hydrochloride, carmustine, lomustine, streptozocin, polifeprosan 20, dexrazoxane, dronabinol, granisetron hydrochloride, fluconazole, erythropoietin, octreotide acetate, pilocarpine hydrochloride, etidronate disodium, pamidronate disodium, allopurinol sodium, amifostine, filgrastim, mesna, ondansetron hydrochloride, dolasetron mesylate, leucovorin calcium, sargramostim, levamisole hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, mitomycin, daunorubicin citrate, plicamycin, daunorubicin hydrochloride, bleomycin sulfate, mitoxantrone hydrochloride, valrubicin, dactinomycin, fludarabine phosphate, cytarabine, mercaptopurine, thioguanine, methotrexate sodium, cladribine, floxuridine, capecitabine, anastrozole, bicalutamide, tamoxifen citrate, testolactone, nilutamide, methyltestosterone, flutamide, toremifene citrate, goserelin acetate, estramustine phosphate sodium, ethinyl estradiol, esterified estrogen, leuprolide acetate, conjugated estrogens, megestrol acetate, aldesleukin, medroxyprogesterone acetate, dacarbazine, hydroxyurea, etoposide phosphate, megestrol acetate, paclitaxel, etoposide, teniposide, trastuzumab, rituximab, vinorelbine tartrate, denileukin diftitox, gemcitabine hydrochloride, vincristine sulfate, vinblastine sulfate,ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) asparaginase, edrophonium chloride, bacillus calmette and guerin, irinotecan hydrochloride, pegaspargase, docetaxel, interferon alfa-2a, recombinant, tretinoin, porfimer sodium, interferon alfa-2b, recombinant, procarbazine hydrochloride, topotecan hydrochloride, altretamine, fluorouracil, prednisolone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone sodium sulfate, dexamethasone acetate, hydrocortisone sodium phosphate, hydrocortisone, prednisolone, methylprednisolone sodium succinate, betamethasone sodium phosphate, betamethasone acetate, letrozole, mithramycin, mitotane, pentostatin, perfosfamide, raloxifene, and combinations thereof.

[0186] In a further aspect, the therapeutic agent is a prodrug or compound that can release a therapeutically useful peroxide, e.g., a benzoyl peroxide.

[0187] In a further aspect, therapeutic agent is an NSAID. In a still further aspect, the NSAID is selected from piroxicam, aspirin, carprofen, diclofenac, fenoprofen, flufenamic acid, flurbiprofen, ibufenac, ibuprofen, indomethacin, isoxicam, ketoprofen, meclofenamic acid, naproxen, oxaprozin, pranoprofen, tenoxicam, zomepirac, diflunisal, sulindac and tolmetin and combinations thereof. In a yet further aspect, the NSAID can be a salicylic acid derivative, such as, but not limited to, aspirin, sodium salicylate, choline magnesium trislicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine. In a still further aspect, the NSAID can be a para-aminophenol derivative such as acetaminophen. In an even further aspect, the NSAID can be an indole and indole acetic acid such as indomethacin, sulindac, etodolac. In a yet further aspect, the NSAID can be an aryl acetic acid such as tolmetin, diclofenac, ketorolac. In a still further aspect, the NSAID can be an arylpropionic acid such as ibuprofen, naproxen, flubiprofen, ketoprofen, fenoprofen, oxaprozin. In an even further aspect, the NSAID can be an anthranilic acid or fenamate such as mefenamic acid or meclofenamic acid. In a yet further aspect, the NSAID can be an enolic acids such as an oxicam, including, but not limited to, piroxicam or tenoxicam, or a pyrazolidinedione, including, but not limited to phenylbutazone or oxyphenthratrazone. In a still further aspect, the NSAID can be an alkenone such as nabumetone.

[0188] In a further aspect, therapeutic agent is a dopamine agonist or monamine modulating agent. In a still further aspect, the dopamine agonist or monoamine modulating agent is selected from rotigotine, pramipexole, ropinirole, tetrabenazine, valbenazine, deutetetrabenazine, dihydoxybenazine and prodrugs of the same.

[0189] The disclosed therapeutic agents encompass their pharmaceutical salts and derivatives or analogues, including bioisosteric equivalents.

[0190] In various aspects, it is contemplated herein that the disclosed therapeutic agents further comprise their biosteric equivalents. The term “bioisosteric equivalent” refers toATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) therapeutic agents or groups that possess near equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical and biological properties. Examples of such equivalents are: (i) fluorine vs. hydrogen, (ii) oxo vs. thia, (iii) hydroxyl vs. amide, (iv) carbonyl vs. oxime, (v) carboxylate vs. tetrazole. Examples of such bioisosteric replacements can be found in the literature and examples of such are: (i) Burger A, Relation of chemical structure and biological activity; in Medicinal Chemistry Third ed., Burger A, ed.; Wiley-Interscience; New York, 1970, 64-80; (ii) Burger, A.; “Isosterism and bioisosterism in drug design”; Prog. Drug Res.1991, 37, 287-371; (iii) Burger A, “Isosterism and bioanalogy in drug design”, Med. Chem. Res.1994, 4, 89-92; (iv) Clark R D, Ferguson A M, Cramer R D, “Bioisosterism and molecular diversity”, Perspect. Drug Discovery Des.1998, 9 / 10 / 11, 213-224; (v) Koyanagi T, Haga T, “Bioisosterism in agrochemicals”, ACS Symp. Ser. 1995, 584, 15-24; (vi) Kubinyi H, “Molecular similarities. Part 1. Chemical structure and biological activity”, Pharm. Unserer Zeit 1998, 27, 92-106; (vii) Lipinski C A.; “Bioisosterism in drug design”; Annu. Rep. Med. Chem. 1986, 21, 283-91; (viii) Patani G A, LaVoie E J, “Bioisosterism: A rational approach in drug design”, Chem. Rev. (Washington, D.C.) 1996, 96, 3147-3176; (ix) Soskic V, Joksimovic J, “Bioisosteric approach in the design of new dopaminergic / serotonergic ligands”, Curr. Med. Chem.1998, 5, 493-512 (x) Thornber C W, “Isosterism and molecular modification in drug design”, Chem. Soc. Rev.1979, 8, 563-80.

[0191] In further aspects, bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered substantially identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density. Preferred bioisosteres of esters, amides or carboxylic acids are therapeutic agents containing two sites for hydrogen bond acceptance. In one aspect, the ester, amide or carboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring, such as an optionally substituted 1H-imidazolyl, an optionally substituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionally substituted [1,2,4]oxadiazolyl.

[0192] In various aspects, it is contemplated herein that the disclosed therapeutic agents further comprise their isotopically labelled or isotopically-substituted variants, i.e., therapeutic agents identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into therapeutic agents of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Cl, respectively. Therapeutic agents further comprise prodrugs thereof, and pharmaceutically acceptable salts of said therapeutic agents or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled therapeutic agents of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled therapeutic agents of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.

[0193] In various aspects, the disclosed therapeutic agents can possess at least one center of asymmetry, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers. The stereoisomers can be present in the mixtures in any arbitrary proportions. In various aspects, provided this is possible, the disclosed therapeutic agents can be present in the form of the tautomers.

[0194] Thus, methods which are known per se can be used, for example, to separate the disclosed therapeutic agents which possess one or more chiral centers and occur as racemates into their optical isomers, i.e., enantiomers or diastereomers. The separation can be effected by means of column separation on chiral phases or by means of recrystallization from an optically active solvent or using an optically active acid or base or by means of derivatizing with an optically active reagent, such as an optically active alcohol, and subsequently cleaving off the residue.

[0195] In various aspects, the disclosed therapeutic agents can be in the form of a co-crystal. The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g., “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Preferred co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0196] The term “pharmaceutically acceptable co-crystal” means one that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0197] In a further aspect, the disclosed therapeutic agents can be isolated as solvates and, in particular, as hydrates of a disclosed compound, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the therapeutic agents according to the invention to form solvates and hydrates.

[0198] The disclosed therapeutic agents can be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug therapeutic agent with a suitable pharmaceutically acceptable base. The salts can be prepared in situ during the final isolation and purification of the therapeutic agents of the present disclosure; or following final isolation by reacting a free base function, such as a secondary or tertiary amine, of a disclosed therapeutic agent with a suitable inorganic or organic acid; or reacting a free acid function, such as a carboxylic acid, of a disclosed therapeutic agent with a suitable inorganic or organic base.

[0199] Acidic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting moieties comprising one or more nitrogen groups with a suitable acid. In various aspects, acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. In a further aspect, salts further include, but are not limited, to the following: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p- toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate), nicotinate, 2-naphthalenesulfonate, oxalate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, undecanoate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. Also, basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, andATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

[0200] Basic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In further aspects, bases which may be used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N- methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2- hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide. F. METHODS OF MAKING THE DISCLOSED ARTICLES

[0201] In various aspects, the disclosed articles can be prepared by the methods disclosed herein.

[0202] In a further aspect, a disclosed article comprising:, can be prepared by incubating a substrate, e.g., fabric or textile material as disclosed herein, with a solution of the therapeutic agent, e.g., glycyrrhetinic acid as shown above, in a suitable solvent, e.g., water or dichloromethane, at a suitable concentration, e.g., about 100-350 mg of an activated form of therapeutic agent per milliliter of solvent, e.g., an acyl halide analogue of the therapeutic agent such as the acyl chloride analogue of glycyrrheticinic acid. In someATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) instances, the solvent can further comprise a catalyst, e.g., 0.1 w / v% DMSO. The solution of therapeutic agent can then be applied to the substrate in an amount of 100-1000 μL of the solution per square centimeter of substrate, or in an amount of therapeutic agent of from about 1 mg per cm2of substrate to about 100 mg per cm2of substrate. In a still further aspect, the substrate can be washed prior to incubation with the solution comprising the therapeutic agent, e.g., washed with water and / or a detergent, then washed with isopropanol, then dried under a vacuum at a temperature of about 20 °C to about 30 °C. The solution and substrate can be incubated together for a suitable period of time at a suitable temperature. In a further aspect, the article depicted above can be prepared by exposing the substrate to a solution comprising the therapeutic agent, and incubated for a suitable period of time, such as from about 1 minute to about 24 hours, at a suitable temperature, such as from about 10 °C to about 40 °C. In a yet further aspect, the article depicted above can be prepared by exposing the substrate to a solution comprising the therapeutic agent, and incubated for a suitable period of time, such as from about 1 minute to about 24 hours, at a suitable temperature, such as a gradual temperature ramp from about -10 °C to about 25 °C In a still further aspect, the temperature during incubation can be gradual temperature ramp from about -10 °C to about 30 °C. Following incubation, the substrate is removed from the solution and washed with a suitable solvent, e.g., dichloromethane, and vacuum dried at a suitable temperature, e.g., about 25 °C. Appropriate storage conditions can be determined by the skilled artisan, e.g., storage in an airtight or evacuated container can improve stability of the foregoing article.

[0203] In a further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:10. In a still further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:2 to about 1:7. In a yet further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:3.

[0204] In a further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 100 mg therapeutic agent to about 1 cm2of substrate. In a still further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 50 mg therapeutic agent to about 1 cm2of substrate. In a yet further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 25 mg therapeutic agent to about 1 cm2of substrate. In an even further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 10 mg therapeutic agent to about 1 cm2of substrate.

[0205] In a further aspect, a disclosed article comprising:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02), can be prepared by incubating a substrate, e.g., fabric or textile material as disclosed herein, with a solution of the therapeutic agent, e.g., glycyrrhetinic acid as shown above, in a suitable solvent, e.g., water and / or DMSO, a suitable concentration, e.g., about 100-350 mg of therapeutic agent per milliliter of solvent. The solution of therapeutic agent can then be applied to the substrate in an amount of 100-1000 μL of the solution per square centimeter of substrate, or in an amount of therapeutic agent of from about 1 mg per cm2of substrate to about 100 mg per cm2of substrate. In various aspects, the therapeutic agent may be formed into a paste by grinding with water and then spread onto the substrate. In a still further aspect, the substrate can be washed prior to incubation with the solution comprising the therapeutic agent, e.g., washed with water and / or a detergent, then washed with isopropanol, then dried under a vacuum at a temperature of about 20 °C to about 30 °C. The solution and substrate can be incubated together for a suitable period of time at a suitable temperature. In a further aspect, the article depicted above can be prepared by exposing the substrate to a solution comprising the therapeutic agent, and incubated for a suitable period of time, such as from about 1 minute to about 24 hours, at a suitable temperature, such as from about 10 °C to about 40 °C. In a still further aspect, the temperature during incubation can be from about 20 °C to about 30 °C.

[0206] In a further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:10. In a still further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:2 to about 1:7. In a yet further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:3 to about 1:5.

[0207] In a further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 100 mg therapeutic agent to about 1ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) cm2of substrate. In a still further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 50 mg therapeutic agent to about 1 cm2of substrate. In a yet further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 25 mg therapeutic agent to about 1 cm2of substrate. In an even further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 10 mg therapeutic agent to about 1 cm2of substrate.

[0208] In a further aspect, a disclosed article comprising: ,e.g., fabric or textile material as disclosed herein, with a solution of the therapeutic agent, e.g., glycyrrhetinic acid as shown above, in a suitable solvent, e.g., DMSO, a suitable concentration, e.g., about 100-350 mg of therapeutic agent per milliliter of solvent comprising about 0.01 v / v% ammonia to about 1% v / v% ammonia. The solution of therapeutic agent can then be applied to the substrate in an amount of 100-1000 μL of the solution per square centimeter of substrate, or in an amount of therapeutic agent of from about 1 mg per cm2of substrate to about 100 mg per cm2of substrate. In a still further aspect, the substrate can be washed prior to incubation with the solution comprising the therapeutic agent, e.g., washed with water, then washed with isopropanol, then dried under a vacuum at a temperature of about 20 °C to about 30 °C, and then rinsed with a 1% aqueous ammonia solution, followed by draining excess ammonia before incubating with the solution comprising the therapeutic agent. The solution and substrate can be incubated together for a suitable period of time at a suitable temperature. In a further aspect, the article depicted above can be prepared by exposing the substrate to a solution comprising the therapeutic agent, and incubated for a suitable period of time, such as from about 1 minute to about 24 hours, at a suitable temperature, such as from about 10 °C to about 40 °C. In a still further aspect, the temperature during incubation can be from about 20 °C to about 30 °C.

[0209] In a further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:10. In a still further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:2 to about 1:7. In a yet further aspect, the ratioATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) of substrate to therapeutic agent on a weight basis can be from about 1:3 to about 1:5.

[0210] In a further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 100 mg therapeutic agent to about 1 cm2of substrate. In a still further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 50 mg therapeutic agent to about 1 cm2of substrate. In a yet further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 25 mg therapeutic agent to about 1 cm2of substrate. In an even further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 10 mg therapeutic agent to about 1 cm2of substrate.

[0211] In a further aspect, a disclosed article comprising: ,material as disclosed herein, can be prepared by incubating as shown in the reaction schemes as disclosed herein.

[0212] In a further aspect, a disclosed method of making a disclosed article is provided in the following reaction scheme:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)the formula: ; wherein X is a halogen; wherein Y is a moiety having a structure; wherein n is an integer selected from 1, 2, and 3; wherein m is an an1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; and wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0213] In a further aspect, the above generalized reaction scheme can be carried out as shown below, although other methods and conditions are suitable as determined by the skilled artisan:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) HO OOHshown above invoves: (a) reaction of the substrate with a suitable alkoxy silyl amine; (b) reaction the substrate comprising a covalently linked alkoxy silyl amine with a suitable linker; and (c) reaction of the material generated in the previous step with an activated form of the therapeutic agent. In a still further aspect, the substrate can be washed prior to incubation with the solution comprising the alkoxy silyl amine, e.g., washed with water, then washed with isopropanol, then dried under a vacuum at a temperature of about 20 °C to about 30 °C. A silyl amine solution comprising the suitable alkoxy silyl amine, e.g., 3-(triethoxysilyl) propane-1-amine, is prepared in a suitable solvent, e.g., THF, at an appropriate concentration, e.g., 1 part alkoxy silyl amine with 2 parts solvent. The substrate is immersed in the silyl amine solution and allowed to react, e.g., heating at about 60 °C to about 90 °C for a suitable period of time, e.g., about 1 hr to about 6 hours. The substrate is removed from the silyl amine solution, and allowed to dry, e.g., at room temperature, with protection from light. A suitable linker solution is prepared comprising a suitable linker, e.g., aconitic anhydride acyl chloride, in a suitable solvent, e.g., dichloromethane. The linker solution can further comprise a suitable catalyst, e.g., DMSO in about 0.1 v / v% to about 1% v / v%. The linker solution is added in a sufficient amount to provide, on a weight basis, a substrate:linker ratio of about 1:1 to about 1:10, and in a particular instance about 1:4 to about 1:6. The reaction can be carried out under an inert atmosphere, e.g., nitrogen or argon. The substrate is separated from the linker solution, and washed, e.g., washed with excess solvent such as used to prepare the linker solution. The substrate can then be dried under a vacuum at ambient temperature. In the last step, the substrate comprising the alkoxy silyl amine and linker is reacted with a suitable therapeutic agent that isATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) chemically activated, e.g., an acyl chloride derivative of the therapeutic agent. In the reaction depicted above, the therapeutic agent is glycyrrhetinic acyl chloride. In this last step, an activated therapeutic agent solution is prepared, e.g., glycyrrhetinic acyl chloride in dichloromethane as a solvent. The activated therapeutic agent solution can further comprise a catalytic amount of a second agent, e.g., DMSO in about 0.1 v / v% to about 1% v / v%. The reaction is carried out under an inert atmosphere, e.g., nitrogen or argon. The activated therapeutic agent solution is added in a sufficient amount to provide, on a weight basis, a substrate: activated therapeutic agent ratio of about 1:1 to about 1:10, and in a particular instance a ratio of about 1:4 to about 1:6. The reacted substrate comprising a covalently linked alkoxy silyl amine linked to a linker group and further comprising a releasable therapeutic agent is then washed and dried under a vacuum at ambient temperature, e.g., about 20 °C to about 30 °C. The therapeutic agent, e.g., glycyrrhetinic acid as shown above, in an amount of therapeutic agent of from about 1 mg per cm2of substrate to about 25 mg per cm2of substrate.

[0214] In a further aspect, a disclosed method of making a disclosed article is provided in the following reaction scheme:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) wherein A is hydroxy or a moiety having a structure represented by the formula: ; wherein X is a halogen; wherein Y is a moiety having a structure; wherein n is an integer selected from 1, 2, and 3; wherein m is an an 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; and whereinfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0215] In a further aspect, the above generalized reaction scheme can be carried out as shown below, although other methods and conditions are suitable as determined by the skilled artisan:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Briefly, sequence for preparation of the article comprising the composition shown above invoves: (a) reaction of the substrate with a suitable alkoxy silyl amine; (b) reaction the substrate comprising a covalently linked alkoxy silyl amine with a suitable linker; and (c) reaction of the material generated in the previous step with an activated form of the therapeutic agent. In a still further aspect, the substrate can be washed prior to incubation with the solution comprising the alkoxy silyl amine, e.g., washed with water, then washed with isopropanol, then dried under a vacuum at a temperature of about 20 °C to about 30 °C. A silyl amine solution comprising the suitable alkoxy silyl amine, e.g., 3-(triethoxysilyl) propane-1-amine, is prepared in a suitable solvent, e.g., THF, at an appropriate concentration, e.g., 1 part alkoxy silyl amine with 2 parts solvent. The substrate is immersed in the silyl amine solution and allowed to react, e.g., heating at about 60 °C to about 90 °C for a suitable period of time, e.g., about 1 hr to about 6 hours. The substrate is removed from the silyl amine solution, and allowed to dry, e.g., at room temperature, with protection from light. A suitable linker solution is prepared comprising a suitable linker, e.g., aconitic anhydride acyl chloride, in a suitable solvent, e.g., dichloromethane. The linker solution can further comprise a suitable catalyst, e.g., DMSO in about 0.1 v / v% to about 1% v / v%. The linker solution is added in a sufficient amount to provide, on a weight basis, a substrate:linker ratio of about 1:1 to about 1:10, and in a particular instance about 1:4 to about 1:6. The reaction can be carried out under an inert atmosphere, e.g., nitrogen or argon. The substrate is separated from the linker solution, and washed, e.g., washed with excess solvent such as used to prepare the linker solution. The substrate can then be dried under a vacuum at ambient temperature. In the last step, the substrate comprising the alkoxy silyl amine and linker is reacted with a suitable therapeutic agent that is chemically activated, e.g., an acyl chloride derivative of the therapeutic agent. In the reaction depicted above, the therapeutic agent is glycyrrhetinic acyl chloride. In this last step, an activated therapeutic agent solution is prepared, e.g., glycyrrhetinic acyl chloride in dichloromethane as a solvent. The activated therapeutic agent solution can further comprise a catalytic amount of a second agent, e.g., DMSO in about 0.1 v / v% to about 1% v / v%. The reaction is carried out under an inert atmosphere, e.g., nitrogen or argon. The activated therapeutic agent solution is added in a sufficient amount to provide, on a weight basis, a substrate: activated therapeutic agent ratio of about 1:1 to about 1:10, and in a particular instance a ratio of about 1:4 to about 1:6. The reacted substrate comprising a covalently linked alkoxy silyl amine linked to a linker group and further comprising a releasable therapeutic agent is then washed and dried under a vacuum at ambient temperature, e.g., about 20 °C to about 30 °C. The therapeutic agent, e.g., glycyrrhetinic acid as shown above, in an amount of therapeutic agent of from about 1 mg per cm2of substrate to about 25 mg per cm2of substrate.

[0216] In a further aspect, the ratio of substrate to alkoxy silyl amine on a weight basis canATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) be from about 1:1 to about 1:10. In a still further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:0 to about 1:7. In a yet further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:6. In an even further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:2 to about 1:6.

[0217] In a further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:10. In a still further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:0 to about 1:5. In a yet further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:0 to about 1:3. In an even further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:2.

[0218] In a further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 100 mg therapeutic agent to about 1 cm2of substrate. In a still further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 50 mg therapeutic agent to about 1 cm2of substrate. In a yet further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 25 mg therapeutic agent to about 1 cm2of substrate. In an even further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 10 mg therapeutic agent to about 1 cm2of substrate.

[0219] In a further aspect, a disclosed article comprising: ,a e.g., or as disclosed herein, can be prepared byATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) incubating as shown in the following reaction scheme: .Briefly, sequence for preparation of the article comprising the composition shown above invoves: (a) reaction of the substrate with a suitable alkoxy silyl amine; (b) reaction the substrate comprising a covalently linked alkoxy silyl amine with a suitable linker; and (c) reaction of the material generated in the previous step with an activated form of the therapeutic agent. In a still further aspect, the substrate can be washed prior to incubation with the solution comprising the alkoxy silyl amine, e.g., washed with water, then washed with isopropanol, then dried under a vacuum at a temperature of about 20 °C to about 30 °C. A silyl amine solution comprising the suitable alkoxy silyl amine, e.g., 3-(triethoxysilyl) propane-1-amine, is prepared in a suitable solvent, e.g., THF, at an appropriate concentration, e.g., 1 part alkoxy silyl amine with 2 parts solvent. The substrate is immersed in the silyl amine solution and allowed to react, e.g., heating at about 60 °C to about 90 °C for a suitable period of time, e.g., about 1 hr to about 6 hours. The substrate is removed from the silyl amine solution, and allowed to dry, e.g., at room temperature, with protection from light. A suitable linker solution is prepared comprising a suitable linker, e.g., maleic anhydride acyl chloride, in a suitable solvent, e.g., dichloromethane. The linker solution can further comprise a suitable catalyst, e.g., DMSO in about 0.1 v / v% to about 1% v / v%. The linker solution is added in a sufficient amount to provide, on a weight basis, a substrate:linker ratio of about 1:1 to about 1:10, and in a particular instance about 1:4 to about 1:6. The reaction can be carried out under an inert atmosphere, e.g., nitrogen or argon. The substrate is separated from the linker solution, and washed, e.g., washed with excess solvent such as used to prepare the linker solution. The substrate can then be dried under a vacuum at ambient temperature. In the last step, the substrate comprising the alkoxy silyl amine and linker is reacted with a suitable therapeutic agent that is chemically activated, e.g., an acyl chloride derivative of the therapeutic agent. In the reaction depicted above, the therapeutic agent is glycyrrhetinic acyl chloride. In this last step, an activated therapeutic agent solution is prepared, e.g., glycyrrhetinic acyl chloride inATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) dichloromethane as a solvent. The activated therapeutic agent solution can further comprise a catalytic amount of a second agent, e.g., DMSO in about 0.1 v / v% to about 1% v / v%. The reaction is carried out under an inert atmosphere, e.g., nitrogen or argon. The activated therapeutic agent solution is added in a sufficient amount to provide, on a weight basis, a substrate: activated therapeutic agent ratio of about 1:1 to about 1:10, and in a particular instance a ratio of about 1:6 to about 1:8. The reacted substrate comprising a covalently linked alkoxy silyl amine linked to a linker group and further comprising a releasable therapeutic agent is then washed and dried under a vacuum at ambient temperature, e.g., about 20 °C to about 30 °C. The therapeutic agent, e.g., glycyrrhetinic acid as shown above, in an amount of therapeutic agent of from about 1 mg per cm2of substrate to about 25 mg per cm2of substrate.

[0220] In a further aspect, the ratio of substrate to alkoxy silyl amine on a weight basis can be from about 1:1 to about 1:10. In a still further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:0 to about 1:7. In a yet further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:6. In an even further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:2 to about 1:6.

[0221] In a further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:10. In a still further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:0 to about 1:5. In a yet further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:0 to about 1:3. In an even further aspect, the ratio of substrate to therapeutic agent on a weight basis can be from about 1:1 to about 1:2.

[0222] In a further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 100 mg therapeutic agent to about 1 cm2of substrate. In a still further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 50 mg therapeutic agent to about 1 cm2of substrate. In a yet further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 25 mg therapeutic agent to about 1 cm2of substrate. In an even further aspect, the amount of therapeutic agent to the substrate is about 1 mg therapeutic agent to about 1 cm2of substrate to about 10 mg therapeutic agent to about 1 cm2of substrate.

[0223] In a further aspect, a disclosed article comprising:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) ,or textile material as disclosed herein, can be prepared by incubating as described above with omission of the reaction step comprising reaction with the alkoxy silyl amine. G. METHODS OF TREATING A SUBJECT

[0224] In various aspects, present disclosure relates to use of the disclosed articles for methods of treatment of a subject. In a further aspect, the subject is a patient diagnosed with having atopic dermatitis. In a still further aspect, the subject is a patient diagnosed with having a wound, injury to their skin, radiation-induced skin damage, an infection, an inflammation, topical pain, and combinations thereof. In a further aspect, the present disclosure relates to use of the disclosed articles for methods of treatment of a subject have a clinical condition involving or comprising a microbial infection and / or an inflammatory aspect.

[0225] The present disclosure also provides a method of treating or providing prophylaxis of a clinical condition by administering to a subject an article as described above. The clinical condition may be a wound, radiation-induced skin damage, inflammation, atopic dermatitis, psoriasis, alopecia areata, acne, hyperpigmentation, or dermatitis. When the clinical condition is atopic dermatitis, it may be mild to moderate atopic dermatitis, severe atopic dermatitis, localized atopic dermatitis, or generalized atopic dermatitis. When the clinical condition is psoriasis, it may be plaque psoriasis, mild to moderate psoriasis, severe psoriasis, localized psoriasis, guttate psoriasis, or inverse psoriasis. When the clinical condition is alopecia areata, it may be patchy alopecia areata, alopecia totalis, alopecia universalis, or ophiasis alopecia areata. When the clinical condition is acne, it may be mild to moderate acne, severe acne, inflammatory acne, comedonal acne, cystic acne, or nodular acne. When the clinical condition is hyperpigmentation, it may be melasma, post-inflammatory hyperpigmentation, solar lentigines, age spots, or café-au-lait macules. When the clinical condition is dermatitis, it may be contact dermatitis, seborrheic dermatitis, allergic dermatitis, or irritant dermatitis.

[0226] In the treatment methods, the article may be applied topically to the affected skin area and may provide sustained release of the therapeutic agent over a period of 12 to 72 hours. The article may be applied once daily. The treatment may reduce inflammation in the affectedATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) skin area, improve skin barrier function, or reduce pruritus associated with the clinical condition. For alopecia areata, the treatment may promote hair regrowth. For acne, the treatment may reduce sebum production or reduce comedone formation. For hyperpigmentation, the treatment may reduce melanin production or lighten existing hyperpigmented areas.

[0227] The present disclosure also provides the article for use in a method for the treatment of various conditions including wounds, radiation-induced skin damage, inflammation, atopic dermatitis, psoriasis, alopecia areata, acne, hyperpigmentation, or dermatitis, with the same variations and specifications as described for the treatment methods. In these uses, the adhesive polymer may be an adhesive water insoluble polymer, the therapeutic agent may comprise glycyrrhizic acid, 18β-glycyrrhetinic acid, curcumin, enoxolone, adapalene, cannabinoids, and methylnissolin, a derivative thereof, or any combination thereof, the adhesive polymer may be an elastomeric silicone adhesive, the therapeutic agent may be present in an amount from 0.1 to 10.0% w / w, and the article may further comprise a second therapeutic agent selected from an antibiotic, an antifungal, an antimicrobial, an NSAID, and a corticosteroid, or combinations thereof.

[0228] In a further aspect, the present disclosure relates to use of the disclosed articles for methods of treatment of a subject having atopic dermatitis. In a yet further aspect, the present disclosure relates to use of the disclosed articles for methods of treatment of a subject having atopic dermatitis, wherein the subject has one or more skin excoriations. In a still further aspect, the present disclosure relates to use of the disclosed articles for methods of treatment of a subject having atopic dermatitis, wherein the method comprises administering a disclosed article comprising a substrate contacting or attached to glycyrrhetinic acid.

[0229] In a further aspect, the present disclosure relates to use of the disclosed articles for methods of treatment of a subject having psoriasis.

[0230] In a further aspect, the present disclosure relates to use of the disclosed articles for methods of treatment of a subject having acne.

[0231] In a further aspect, the foregoing method can further comprise co-administration, e.g., simultaneously or sequentially, a further therapeutic agent associated with treatment of atopic dermatitis, e.g., nemolizumab or an equivalent thereof, an IL-13 antagonist, an anti-OX40 antagonist, a anti-TSLP antibody, a ceramide derivative, acetylcholine receptor antagonist, a corticosteroid, an antihistamine, a calcineurin inhibitor, a phosphodiesterase inhibitor, an antimicrobial agent, and other therapeutic agents as known to the skilled artisan. In a still further aspect, the further therapeutic agent can be administered by a suitable route of administration for that agent and the disclosed article is separately administered to the skin orATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) excoriation. In a yet further aspect, the article can further comprise poly-gamma-glutamic acid is used at a concentration of 0.001 to 5 % by weight, and preferably 0.01 to 3 % by weight.

[0232] In a further aspect, the subject has an active infection associated with a bacterium, a fungus, a microbial organism, and combinations thereof. In a still further aspect, the subject has an active infection associated with Pseudomonas aeruginosa, Vancomycin Resistant Enterococci, Klebsiella pneumoniae, Streptococcus pneumoniae, Salmonella sp., Escherichia coli, extensively drug resistant tuberculosis, Acinetobacter baumannii, Neisseria gonorrhaeae, Clostridium difficile, and Candida sp. related infections. In a yet further aspect, the subject has an active infection associated with a macrofungi, such as Ganoderma lucidum (GL) and Pycnoporus sanguineus (PY). In an even further aspect, the subject has an active infection associated with a microfungi, such as Hypocrea rufa (Hr), Phoma foveata (PH), Curvularia sp. (Cur), Fusarium sp. and Pestalotiopsis sp. In a still further aspect, the subject has an active infection associated with an actinomycetes such as Streptomyces species such as Streptomyces sp. (unidentified) Streptomyces cacaoi, and Streptomyces parvulus. In a yet further aspect, the subject has an active infection associated with Pseudomonas sp., Chromobacterium sp., Serratia marcescens, and combinations thereof. In an even further aspect, the subject has an active infection associated with MRSA, VRSA, P. aeruginosa, Vancomycin Resistant Enterococci, Klebsiella pneumoniae, Streptococcus pneumoniae, Salmonella sp., Escherichia coli, extensively drug resistant tuberculosis, Acinetobacter baumannii, Neisseria gonorrhaeae, Clostridium difficile, Candida sp. related infections, and combinations thereof. In a still further aspect, the subject has an active infection associated with Streptococcus pyogenes, Streptococcus aglactiae, Streptococcus pneumonia, Staphylococcus aureus, Neisseria gonorhoeae, Haemophilus influenza, Vibrio cholera, E. coli, Salmonella typhimurium, Shigella dysenteriae, Shigella dysenteriae, Proteus mirabilis, Pseudomonas aeruginosa, Bacillus anthracis, Bacillus anthracis spores, Bacillus cereus, Bacillus cereus spores, Bacillus subtilus, Bacillus subtilus spores, Yersinia enterocolitica, or Yersinia pseudotuberculosis. In a yet further aspect, the subject has an active infection associated with a fungus such as Candida albicans, Candida tropicalis, and combinations thereof. H. ASPECTS

[0233] The following listing of exemplary aspects supports and is supported by the disclosure provided herein.

[0234] Aspect 1: An article comprising a backing material layer, a matrix layer, and a liner layer; wherein the matrix layer comprises a polymer adhesive system and therapeutic agent mixture in contact with a substrate; and wherein the polymer adhesive system is a self-ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) adhesive, a pressure adhesive, or a combination thereof.

[0235] Aspect 2: The article of Aspect 1, wherein the polymer adhesive system is an adhesive water insoluble polymer.

[0236] Aspect 3: The article of Aspect 2, wherein the therapeutic agent is in solution or suspended or emulsified in the matrix.

[0237] Aspect 4: The article of Aspect 2 or Aspect 3, wherein the therapeutic agent is micronized or size reduced.

[0238] Aspect 5: The article of any of Aspects 2-4, wherein the therapeutic agent is mixed with an excipient or solvent.

[0239] Aspect 6: The article of Aspect 1, wherein the polymer adhesive system is an elastomeric silicone adhesive.

[0240] Aspect 7: The article of Aspect 6, wherein the elastomeric silicone adhesive is selected from a one-part elastomeric silicone adhesive and a two-part silicone adhesive.

[0241] Aspect 7a: The article of Aspect 7, wherein the elastomeric silicone adhesive is a one-part elastomeric silicone adhesive.

[0242] Aspect 7b: The article of Aspect 6, wherein the elastomeric silicone adhesive is a two-part silicone adhesive.

[0243] Aspect 7c: The article of Aspect 7b, wherein the elastomeric silicone adhesive is a a platinum-catalyzed two-part elastomeric silicone adhesive.

[0244] Aspect 8: The article of any of Aspects 1-7c, wherein the therapeutic agent is in a salt form or counter-ion complex.

[0245] Aspect 9: The article of any of Aspects 1-8, wherein the therapeutic agent is incorporated in a liposome or lipid nanoparticle vesicle prior to mixing with the polymer adhesive system.

[0246] Aspect 10: The article of any of Aspects 1-9, wherein the therapeutic agent is emulsified with an oil, aqueous-polyol and surfactant prior to mixing with the matrix layer.

[0247] Aspect 11: The article of any of Aspects 1-10, wherein the therapeutic agent comprises glycyrrhizic acid, enoxolone, a derivative thereof, or any combination thereof.

[0248] Aspect 12: The article of Aspect 11, wherein the therapeutic agent comprises 18β- glycyrrhetinic acid.

[0249] Aspect 13: The article of any of Aspects 1-12, wherein the therapeutic agent isATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) selected from glycyrrhizic acid, 18β-glycyrrhetinic acid, curcumin, enoxolone, adapalene, cannabinoids, and methylnissolin.

[0250] Aspect 14: The article of Aspect 13, wherein the therapeutic agent is glycyrrhizic acid.

[0251] Aspect 15: The article of Aspect 13, wherein the therapeutic agent is 18β- glycyrrhetinic acid.

[0252] Aspect 16: The article of Aspect 13, wherein the therapeutic agent is enoxolone.

[0253] Aspect 17: The article of Aspect 13, wherein the therapeutic agent is adapalene.

[0254] Aspect 18: The article of Aspect 13, wherein the therapeutic agent is a cannabinoid.

[0255] Aspect 18a: The article of Aspect 18, wherein the cannabinoid is selected from cannabidiol, cannabigerol, cannabichromene, cannabinol, tetrahydrocannabinol, cannabidiolic acid, cannabigerolic acid, cannabichromenic acid, cannabinolic acid, tetrahydrocannabinolic acid, cannabidivarin, cannabigerovarin, cannabichromevarin, cannabinolivarin, tetrahydrocannabivarinol, cannabicyclol, cannabielsoin, cannabitriol, and combinations thereof.

[0256] Aspect 19: The article of Aspect 18-18a, wherein the cannabinoid is selected from cannabidiol and cannabigerol.

[0257] Aspect 20: The article of Aspect 18, wherein the cannabinoid is cannabidiol.

[0258] Aspect 21: The article of Aspect 18, wherein the cannabinoid is cannabigerol.

[0259] Aspect 22: The article of Aspect 13, wherein the therapeutic agent is methylnissolin.

[0260] Aspect 22a: The article of Aspect 13, wherein the therapeutic agent is curcumin.

[0261] Aspect 23: The article of any of Aspects 11-22a, wherein the therapeutic agent is present in an amount from 0.1 to 20.0% w / w.

[0262] Aspect 23a: The article of Aspect 23, wherein the therapeutic agent is present in an amount from 0.1 to 10.0% w / w.

[0263] Aspect 24: The article of Aspect 23, wherein the therapeutic agent is present in an amount from 0.5 to 8.0% w / w.

[0264] Aspect 25: The article of Aspect 24, wherein the therapeutic agent is present in an amount from 1.0 to 6.0% w / w.

[0265] Aspect 26: The article of Aspect 25, wherein the therapeutic agent is present in an amount from 2.0 to 5.0% w / w.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0266] Aspect 27: The article of Aspect 26, wherein the therapeutic agent is present in an amount from 2.5 to 4.5% w / w.

[0267] Aspect 28: The article of any of Aspects 1-27, wherein the polymer adhesive system and therapeutic agent mixture further comprises a penetration enhancer.

[0268] Aspect 29: The article of any of Aspects 1-28, wherein the polymer adhesive system is an elastomeric polymer adhesive system.

[0269] Aspect 30: The article of Aspect 29, wherein the elastomeric polymer adhesive system is derived from a two-part catalyzed system comprising a component A and a component B, wherein component A, component B or both comprise a catalyst.

[0270] Aspect 31: The article of Aspect 30, wherein the catalyst is a platinum catalyst.

[0271] Aspect 32: The article of any of Aspects 29-31, wherein the elastomeric polymer adhesive system is cured.

[0272] Aspect 33: The article of Aspect 32, wherein the elastomeric polymer adhesive system is cured via catalysis of a component A and component B, thereby forming the elastomeric polymer adhesive system.

[0273] Aspect 34: The article of any of Aspects 1-33, wherein the polymer adhesive system is present in an amount from 90.0 to 99.9% w / w.

[0274] Aspect 35: The article of Aspect 34, wherein the polymer adhesive system is present in an amount from 92.0 to 99.5% w / w.

[0275] Aspect 36: The article of Aspect 35, wherein the polymer adhesive system is present in an amount from 94.0 to 99.0% w / w.

[0276] Aspect 37: The article of Aspect 36, wherein the polymer adhesive system is present in an amount from 95.0 to 98.5% w / w.

[0277] Aspect 38: The article of Aspect 37, wherein the polymer adhesive system is present in an amount from 96.0 to 98.0% w / w.

[0278] Aspect 39: The article of any of Aspects 1-38, wherein the polymer adhesive system comprises Liveo MG7-9850 or MG7-9900.

[0279] Aspect 40: The article of any of Aspects 1-39, wherein the matrix layer further comprises a weak base selected from triethanolamine or TRIS.

[0280] Aspect 41: The article of Aspect 40, wherein the weak base is present in an amount from 0 to 200 mM.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0281] Aspect 42: The article of Aspect 41, wherein the weak base is present in an amount from 6 to 190 mM.

[0282] Aspect 43: The article of Aspect 42, wherein the weak base is present in an amount from 30 to 90 mM.

[0283] Aspect 44: The article of Aspect 43, wherein the weak base is present in an amount from 40 to 80 mM.

[0284] Aspect 45: The article of Aspect 44, wherein the weak base is present in an amount from 50 to 70 mM.

[0285] Aspect 46: The article of any of Aspects 1-45, wherein the matrix layer further comprises a fatty acid.

[0286] Aspect 47: The article of Aspect 46, wherein the fatty acid is selected from oleic acid, linoleic acid, palmitic acid, stearic acid, myristic acid, lauric acid, capric acid, caprylic acid, caproic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and combinations thereof.

[0287] Aspect 48: The article of Aspect 47, wherein the fatty acid is oleic acid.

[0288] Aspect 49: The article of Aspect 47, wherein the fatty acid is linoleic acid.

[0289] Aspect 50: The article of Aspect 47, wherein the fatty acid is palmitic acid.

[0290] Aspect 51: The article of Aspect 47, wherein the fatty acid is stearic acid.

[0291] Aspect 52: The article of Aspect 47, wherein the fatty acid is myristic acid.

[0292] Aspect 53: The article of Aspect 47, wherein the fatty acid is lauric acid.

[0293] Aspect 54: The article of Aspect 47, wherein the fatty acid is capric acid.

[0294] Aspect 55: The article of Aspect 47, wherein the fatty acid is caprylic acid.

[0295] Aspect 56: The article of Aspect 47, wherein the fatty acid is caproic acid.

[0296] Aspect 57: The article of Aspect 47, wherein the fatty acid is arachidonic acid.

[0297] Aspect 58: The article of Aspect 47, wherein the fatty acid is eicosapentaenoic acid.

[0298] Aspect 59: The article of Aspect 47, wherein the fatty acid is docosahexaenoic acid.

[0299] Aspect 60: The article of any of Aspects 46-59, wherein the fatty acid is present in an amount from 0 to 1.0% w / w.

[0300] Aspect 61: The article of Aspect 60, wherein the fatty acid is present in an amount from 0.05 to 0.5% w / w.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0301] Aspect 62: The article of Aspect 61, wherein the fatty acid is present in an amount from 0.05 to 0.25% w / w.

[0302] Aspect 63: The article of Aspect 62, wherein the fatty acid is present in an amount from 0.08 to 0.20% w / w.

[0303] Aspect 64: The article of Aspect 63, wherein the fatty acid is present in an amount from 0.10 to 0.15% w / w.

[0304] Aspect 65: The article of any of Aspects 1-64, wherein the matrix layer further comprises a fatty alcohol.

[0305] Aspect 66: The article of Aspect 65, wherein the fatty alcohol is selected from oleyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, behenyl alcohol, arachidyl alcohol, lignoceryl alcohol, ceryl alcohol, montanyl alcohol, melissyl alcohol, and combinations thereof.

[0306] Aspect 67: The article of Aspect 66, wherein the fatty alcohol is oleyl alcohol.

[0307] Aspect 68: The article of Aspect 66, wherein the fatty alcohol is cetyl alcohol.

[0308] Aspect 69: The article of Aspect 66, wherein the fatty alcohol is stearyl alcohol.

[0309] Aspect 70: The article of Aspect 66, wherein the fatty alcohol is cetostearyl alcohol.

[0310] Aspect 71: The article of Aspect 66, wherein the fatty alcohol is lauryl alcohol.

[0311] Aspect 72: The article of Aspect 66, wherein the fatty alcohol is myristyl alcohol.

[0312] Aspect 73: The article of Aspect 66, wherein the fatty alcohol is palmityl alcohol.

[0313] Aspect 74: The article of Aspect 66, wherein the fatty alcohol is behenyl alcohol.

[0314] Aspect 75: The article of Aspect 66, wherein the fatty alcohol is arachidyl alcohol.

[0315] Aspect 76: The article of Aspect 66, wherein the fatty alcohol is lignoceryl alcohol.

[0316] Aspect 77: The article of Aspect 66, wherein the fatty alcohol is ceryl alcohol.

[0317] Aspect 78: The article of Aspect 66, wherein the fatty alcohol is montanyl alcohol.

[0318] Aspect 79: The article of Aspect 66, wherein the fatty alcohol is melissyl alcohol.

[0319] Aspect 80: The article of any of Aspects 65-79, wherein the fatty alcohol is present in an amount from 0 to 1.0% w / w.

[0320] Aspect 81: The article of Aspect 80, wherein the fatty alcohol is present in an amount from 0.05 to 0.5% w / w.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0321] Aspect 82: The article of Aspect 81, wherein the fatty alcohol is present in an amount from 0.05 to 0.25% w / w.

[0322] Aspect 83: The article of Aspect 82, wherein the fatty alcohol is present in an amount from 0.08 to 0.20% w / w.

[0323] Aspect 84: The article of Aspect 83, wherein the fatty alcohol is present in an amount from 0.10 to 0.15% w / w.

[0324] Aspect 85: The article of any of Aspects 1-84, wherein the matrix layer further comprises a fatty acid ester.

[0325] Aspect 86: The article of Aspect 85, wherein the fatty acid ester is selected from isopropyl myristate, ethyl oleate, methyl palmitate, propyl stearate, butyl laurate, isopropyl palmitate, ethyl stearate, methyl oleate, propyl myristate, butyl palmitate, isopropyl stearate, ethyl myristate, methyl stearate, propyl oleate, butyl myristate, isopropyl oleate, ethyl palmitate, methyl myristate, propyl palmitate, butyl stearate, isopropyl laurate, ethyl laurate, methyl laurate, propyl laurate, butyl oleate, and combinations thereof.

[0326] Aspect 87: The article of Aspect 86, wherein the fatty acid ester is isopropyl myristate.

[0327] Aspect 88: The article of Aspect 86, wherein the fatty acid ester is ethyl oleate.

[0328] Aspect 89: The article of Aspect 86, wherein the fatty acid ester is methyl palmitate.

[0329] Aspect 90: The article of Aspect 86, wherein the fatty acid ester is propyl stearate.

[0330] Aspect 91: The article of Aspect 86, wherein the fatty acid ester is butyl laurate.

[0331] Aspect 92: The article of Aspect 86, wherein the fatty acid ester is isopropyl palmitate.

[0332] Aspect 93: The article of Aspect 86, wherein the fatty acid ester is ethyl stearate.

[0333] Aspect 94: The article of Aspect 86, wherein the fatty acid ester is methyl oleate.

[0334] Aspect 95: The article of Aspect 86, wherein the fatty acid ester is propyl myristate.

[0335] Aspect 96: The article of Aspect 86, wherein the fatty acid ester is butyl palmitate.

[0336] Aspect 97: The article of Aspect 86, wherein the fatty acid ester is isopropyl stearate.

[0337] Aspect 98: The article of Aspect 86, wherein the fatty acid ester is ethyl myristate.

[0338] Aspect 99: The article of Aspect 86, wherein the fatty acid ester is methyl stearate.

[0339] Aspect 100: The article of Aspect 86, wherein the fatty acid ester is propyl oleate.

[0340] Aspect 101: The article of Aspect 86, wherein the fatty acid ester is butyl myristate.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0341] Aspect 102: The article of Aspect 86, wherein the fatty acid ester is isopropyl oleate.

[0342] Aspect 103: The article of Aspect 86, wherein the fatty acid ester is ethyl palmitate.

[0343] Aspect 104: The article of Aspect 86, wherein the fatty acid ester is methyl myristate.

[0344] Aspect 105: The article of Aspect 86, wherein the fatty acid ester is propyl palmitate.

[0345] Aspect 106: The article of Aspect 86, wherein the fatty acid ester is butyl stearate.

[0346] Aspect 107: The article of Aspect 86, wherein the fatty acid ester is isopropyl laurate.

[0347] Aspect 108: The article of Aspect 86, wherein the fatty acid ester is ethyl laurate.

[0348] Aspect 109: The article of Aspect 86, wherein the fatty acid ester is methyl laurate.

[0349] Aspect 110: The article of Aspect 86, wherein the fatty acid ester is propyl laurate.

[0350] Aspect 111: The article of Aspect 86, wherein the fatty acid ester is butyl oleate.

[0351] Aspect 112: The article of any of Aspects 85-111, wherein the fatty acid ester is present in an amount from 0 to 1.0% w / w.

[0352] Aspect 113: The article of Aspect 112, wherein the fatty acid ester is present in an amount from 0.05 to 0.5% w / w.

[0353] Aspect 114: The article of Aspect 113, wherein the fatty acid ester is present in an amount from 0.05 to 0.25% w / w.

[0354] Aspect 115: The article of Aspect 114, wherein the fatty acid ester is present in an amount from 0.08 to 0.20% w / w.

[0355] Aspect 116: The article of Aspect 115, wherein the fatty acid ester is present in an amount from 0.10 to 0.15% w / w.

[0356] Aspect 117: The article of any of Aspects 1-116, wherein the matrix layer further comprises a glycol.

[0357] Aspect 118: The article of Aspect 117, wherein the glycol is selected from propylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, 1,3-propanediol, 1,4- butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, neopentyl glycol, 2-methyl-1,3-propanediol, 3-methyl-1,5-pentanediol, 2-ethyl-2-methyl-1,3- propanediol, and combinations thereof.

[0358] Aspect 119: The article of Aspect 118, wherein the glycol is propylene glycol.

[0359] Aspect 120: The article of Aspect 118, wherein the glycol is ethylene glycol.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0360] Aspect 121: The article of Aspect 118, wherein the glycol is diethylene glycol.

[0361] Aspect 122: The article of Aspect 118, wherein the glycol is triethylene glycol.

[0362] Aspect 123: The article of Aspect 118, wherein the glycol is tetraethylene glycol.

[0363] Aspect 124: The article of Aspect 118, wherein the glycol is polyethylene glycol.

[0364] Aspect 125: The article of Aspect 118, wherein the glycol is dipropylene glycol.

[0365] Aspect 126: The article of Aspect 118, wherein the glycol is tripropylene glycol.

[0366] Aspect 127: The article of Aspect 118, wherein the glycol is polypropylene glycol.

[0367] Aspect 128: The article of Aspect 118, wherein the glycol is 1,3-propanediol.

[0368] Aspect 129: The article of Aspect 118, wherein the glycol is 1,4-butanediol.

[0369] Aspect 130: The article of Aspect 118, wherein the glycol is 1,5-pentanediol.

[0370] Aspect 131: The article of Aspect 118, wherein the glycol is 1,6-hexanediol.

[0371] Aspect 132: The article of Aspect 118, wherein the glycol is 1,2-butanediol.

[0372] Aspect 133: The article of Aspect 118, wherein the glycol is 1,3-butanediol.

[0373] Aspect 134: The article of Aspect 118, wherein the glycol is 2,3-butanediol.

[0374] Aspect 135: The article of Aspect 118, wherein the glycol is neopentyl glycol.

[0375] Aspect 136: The article of Aspect 118, wherein the glycol is 2-methyl-1,3- propanediol.

[0376] Aspect 137: The article of Aspect 118, wherein the glycol is 3-methyl-1,5- pentanediol.

[0377] Aspect 138: The article of Aspect 118, wherein the glycol is 2-ethyl-2-methyl-1,3- propanediol.

[0378] Aspect 139: The article of Aspect 118, wherein the glycol is selected from propylene glycol, ethylene glycol, diethylene glycol, and polyethylene glycol.

[0379] Aspect 140: The article of Aspect 118, wherein the glycol is selected from propylene glycol, dipropylene glycol, and polypropylene glycol.

[0380] Aspect 141: The article of Aspect 118, wherein the glycol is selected from 1,3- propanediol, 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol.

[0381] Aspect 142: The article of any of Aspects 117-141, wherein the propylene glycol is present in an amount from 0 to 1.0% w / w.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0382] Aspect 143: The article of Aspect 142, wherein the propylene glycol is present in an amount from 0.05 to 0.5% w / w.

[0383] Aspect 144: The article of Aspect 143, wherein the propylene glycol is present in an amount from 0.05 to 0.25% w / w.

[0384] Aspect 145: The article of Aspect 144, wherein the propylene glycol is present in an amount from 0.08 to 0.20% w / w.

[0385] Aspect 146: The article of Aspect 145, wherein the propylene glycol is present in an amount from 0.10 to 0.15% w / w.

[0386] Aspect 147: The article of any of Aspects 1-146, wherein the matrix layer further comprises glycerin.

[0387] Aspect 148: The article of Aspect 147, wherein the glycerin is present in an amount from 0 to 1.0% w / w.

[0388] Aspect 149: The article of Aspect 148, wherein the glycerin is present in an amount from 0.05 to 0.5% w / w.

[0389] Aspect 150: The article of Aspect 149, wherein the glycerin is present in an amount from 0.05 to 0.25% w / w.

[0390] Aspect 151: The article of Aspect 150, wherein the glycerin is present in an amount from 0.08 to 0.20% w / w.

[0391] Aspect 152: The article of Aspect 151, wherein the glycerin is present in an amount from 0.10 to 0.15% w / w.

[0392] Aspect 153: The article of any of Aspects 1-152, wherein the matrix layer further comprises diethylene glycol monoethyl ether.

[0393] Aspect 154: The article of Aspect 153, wherein the diethylene glycol monoethyl ether is present in an amount from 0 to 1.0% w / w.

[0394] Aspect 155: The article of Aspect 154, wherein the diethylene glycol monoethyl ether is present in an amount from 0.05 to 0.5% w / w.

[0395] Aspect 156: The article of Aspect 155, wherein the diethylene glycol monoethyl ether is present in an amount from 0.05 to 0.25% w / w.

[0396] Aspect 157: The article of Aspect 156, wherein the diethylene glycol monoethyl ether is present in an amount from 0.08 to 0.20% w / w.

[0397] Aspect 158: The article of Aspect 157, wherein the diethylene glycol monoethyl etherATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) is present in an amount from 0.10 to 0.15% w / w.

[0398] Aspect 159: The article of any of Aspects 1-158, wherein the matrix layer further comprises purified water.

[0399] Aspect 160: The article of Aspect 159, wherein the purified water is present in an amount from 0 to 1.0% w / w.

[0400] Aspect 161: The article of Aspect 160, wherein the purified water is present in an amount from 0.005 to 0.25% w / w.

[0401] Aspect 162: The article of Aspect 161, wherein the purified water is present in an amount from 0.01 to 0.10% w / w.

[0402] Aspect 163: The article of Aspect 162, wherein the purified water is present in an amount from 0.02 to 0.08% w / w.

[0403] Aspect 164: The article of any of Aspects 1-163, wherein the matrix layer further comprises a second therapeutic agent.

[0404] Aspect 165: The article of Aspect 164, wherein the second therapeutic agent is selected from a therapeutic agent.

[0405] Aspect 166: The article of Aspect 165, wherein the second therapeutic agent is selected from an antibiotic, an antifungal, an antimicrobial, an NSAID, and a corticosteroid, or combinations thereof.

[0406] Aspect 167: The article of Aspect 166, wherein the second therapeutic agent is an antibiotic or an antimicrobial agent.

[0407] Aspect 168: The article of Aspect 166, wherein the second therapeutic agent is an NSAID.

[0408] Aspect 169: The article of Aspect 166, wherein the second therapeutic agent is a corticosteroid.

[0409] Aspect 170: A method of treating or providing prophylaxis of a clinical condition by administering to a subject an article of any of Aspects 1-169.

[0410] Aspect 171: The method of Aspect 170, wherein the clinical condition is selected from a wound, radiation-induced skin damage, and inflammation.

[0411] Aspect 171a: The method of Aspect 171, wherein the wound is a diabetic wound.

[0412] Aspect 172: The method of Aspect 170, wherein the clinical condition is atopic dermatitis.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0413] Aspect 173: The method of Aspect 172, wherein the atopic dermatitis is mild to moderate atopic dermatitis.

[0414] Aspect 174: The method of Aspect 172, wherein the atopic dermatitis is severe atopic dermatitis.

[0415] Aspect 175: The method of Aspect 172, wherein the atopic dermatitis is localized atopic dermatitis.

[0416] Aspect 176: The method of Aspect 172, wherein the atopic dermatitis is generalized atopic dermatitis.

[0417] Aspect 177: The method of Aspect 170, wherein the clinical condition is psoriasis.

[0418] Aspect 178: The method of Aspect 177, wherein the psoriasis is plaque psoriasis.

[0419] Aspect 179: The method of Aspect 177, wherein the psoriasis is mild to moderate psoriasis.

[0420] Aspect 180: The method of Aspect 177, wherein the psoriasis is severe psoriasis.

[0421] Aspect 181: The method of Aspect 177, wherein the psoriasis is localized psoriasis.

[0422] Aspect 182: The method of Aspect 177, wherein the psoriasis is guttate psoriasis.

[0423] Aspect 183: The method of Aspect 177, wherein the psoriasis is inverse psoriasis.

[0424] Aspect 184: The method of Aspect 170, wherein the clinical condition is alopecia areata.

[0425] Aspect 185: The method of Aspect 184, wherein the alopecia areata is patchy alopecia areata.

[0426] Aspect 186: The method of Aspect 184, wherein the alopecia areata is alopecia totalis.

[0427] Aspect 187: The method of Aspect 184, wherein the alopecia areata is alopecia universalis.

[0428] Aspect 188: The method of Aspect 184, wherein the alopecia areata is ophiasis alopecia areata.

[0429] Aspect 189: The method of Aspect 170, wherein the clinical condition is acne.

[0430] Aspect 190: The method of Aspect 189, wherein the acne is mild to moderate acne.

[0431] Aspect 191: The method of Aspect 189, wherein the acne is severe acne.

[0432] Aspect 192: The method of Aspect 189, wherein the acne is inflammatory acne.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0433] Aspect 193: The method of Aspect 189, wherein the acne is comedonal acne.

[0434] Aspect 194: The method of Aspect 189, wherein the acne is cystic acne.

[0435] Aspect 195: The method of Aspect 189, wherein the acne is nodular acne.

[0436] Aspect 196: The method of Aspect 170, wherein the clinical condition is hyperpigmentation.

[0437] Aspect 197: The method of Aspect 196, wherein the hyperpigmentation is melasma.

[0438] Aspect 198: The method of Aspect 196, wherein the hyperpigmentation is post- inflammatory hyperpigmentation.

[0439] Aspect 199: The method of Aspect 196, wherein the hyperpigmentation is solar lentigines.

[0440] Aspect 200: The method of Aspect 196, wherein the hyperpigmentation is age spots.

[0441] Aspect 201: The method of Aspect 196, wherein the hyperpigmentation is café-au- lait macules.

[0442] Aspect 202: The method of Aspect 170, wherein the clinical condition is dermatitis.

[0443] Aspect 203: The method of Aspect 202, wherein the dermatitis is contact dermatitis.

[0444] Aspect 204: The method of Aspect 202, wherein the dermatitis is seborrheic dermatitis.

[0445] Aspect 205: The method of Aspect 202, wherein the dermatitis is allergic dermatitis.

[0446] Aspect 206: The method of Aspect 202, wherein the dermatitis is irritant dermatitis.

[0447] Aspect 207: The method of any of Aspects 172-206, wherein the article is applied topically to the affected skin area.

[0448] Aspect 208: The method of any of Aspects 172-207, wherein the article provides sustained release of the therapeutic agent over a period of 12 to 72 hours.

[0449] Aspect 209: The method of any of Aspects 172-208, wherein the article is applied once daily.

[0450] Aspect 210: The method of any of Aspects 172-209, wherein the treatment reduces inflammation in the affected skin area.

[0451] Aspect 211: The method of any of Aspects 172-210, wherein the treatment improves skin barrier function.

[0452] Aspect 212: The method of any of Aspects 172-211, wherein the treatment reducesATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) pruritus associated with the clinical condition.

[0453] Aspect 213: The method of any of Aspects 184-188, wherein the treatment promotes hair regrowth.

[0454] Aspect 214: The method of any of Aspects 189-195, wherein the treatment reduces sebum production.

[0455] Aspect 215: The method of any of Aspects 189-195, wherein the treatment reduces comedone formation.

[0456] Aspect 216: The method of any of Aspects 196-201, wherein the treatment reduces melanin production.

[0457] Aspect 217: The method of any of Aspects 196-201, wherein the treatment lightens existing hyperpigmented areas.

[0458] Aspect 218: The article of any of Aspects 1-169 for use in a method for the treatment of a wound, radiation-induced skin damage, and inflammation.

[0459] Aspect 219: The article of any of Aspects 1-169 for use in a method for the treatment of atopic dermatitis.

[0460] Aspect 220: The article of Aspect 219, wherein the atopic dermatitis is mild to moderate atopic dermatitis.

[0461] Aspect 221: The article of Aspect 219, wherein the atopic dermatitis is severe atopic dermatitis.

[0462] Aspect 222: The article of Aspect 219, wherein the atopic dermatitis is localized atopic dermatitis.

[0463] Aspect 223: The article of Aspect 219, wherein the atopic dermatitis is generalized atopic dermatitis.

[0464] Aspect 224: The article of any of Aspects 1-169 for use in a method for the treatment of psoriasis.

[0465] Aspect 225: The article of Aspect 224, wherein the psoriasis is plaque psoriasis.

[0466] Aspect 226: The article of Aspect 224, wherein the psoriasis is mild to moderate psoriasis.

[0467] Aspect 227: The article of Aspect 224, wherein the psoriasis is severe psoriasis.

[0468] Aspect 228: The article of Aspect 224, wherein the psoriasis is localized psoriasis.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0469] Aspect 229: The article of Aspect 224, wherein the psoriasis is guttate psoriasis.

[0470] Aspect 230: The article of Aspect 224, wherein the psoriasis is inverse psoriasis.

[0471] Aspect 231: The article of any of Aspects 1-169 for use in a method for the treatment of alopecia areata.

[0472] Aspect 232: The article of Aspect 231, wherein the alopecia areata is patchy alopecia areata.

[0473] Aspect 233: The article of Aspect 231, wherein the alopecia areata is alopecia totalis.

[0474] Aspect 234: The article of Aspect 231, wherein the alopecia areata is alopecia universalis.

[0475] Aspect 235: The article of Aspect 231, wherein the alopecia areata is ophiasis alopecia areata.

[0476] Aspect 236: The article of any of Aspects 1-169 for use in a method for the treatment of acne.

[0477] Aspect 237: The article of Aspect 236, wherein the acne is mild to moderate acne.

[0478] Aspect 238: The article of Aspect 236, wherein the acne is severe acne.

[0479] Aspect 239: The article of Aspect 236, wherein the acne is inflammatory acne.

[0480] Aspect 240: The article of Aspect 236, wherein the acne is comedonal acne.

[0481] Aspect 241: The article of Aspect 236, wherein the acne is cystic acne.

[0482] Aspect 242: The article of Aspect 236, wherein the acne is nodular acne.

[0483] Aspect 243: The article of any of Aspects 1-169 for use in a method for the treatment of hyperpigmentation.

[0484] Aspect 244: The article of Aspect 243, wherein the hyperpigmentation is melasma.

[0485] Aspect 245: The article of Aspect 243, wherein the hyperpigmentation is post- inflammatory hyperpigmentation.

[0486] Aspect 246: The article of Aspect 243, wherein the hyperpigmentation is solar lentigines.

[0487] Aspect 247: The article of Aspect 243, wherein the hyperpigmentation is age spots.

[0488] Aspect 248: The article of Aspect 243, wherein the hyperpigmentation is café-au-lait macules.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0489] Aspect 249: The article of any of Aspects 1-169 for use in a method for the treatment of dermatitis.

[0490] Aspect 250: The article of Aspect 249, wherein the dermatitis is contact dermatitis.

[0491] Aspect 251: The article of Aspect 249, wherein the dermatitis is seborrheic dermatitis.

[0492] Aspect 252: The article of Aspect 249, wherein the dermatitis is allergic dermatitis.

[0493] Aspect 253: The article of Aspect 249, wherein the dermatitis is irritant dermatitis.

[0494] Aspect 254: The article of any of Aspects 218-253, wherein the polymer adhesive system is an adhesive water insoluble polymer.

[0495] Aspect 255: The article of any of Aspects 218-254, wherein the therapeutic agent comprises glycyrrhizic acid, 18β-glycyrrhetinic acid, curcumin, enoxolone, adapalene, cannabinoids, and methylnissolin.

[0496] Aspect 256: The article of any of Aspects 218-255, wherein the polymer adhesive system is an elastomeric silicone adhesive.

[0497] Aspect 257: The article of any of Aspects 218-256, wherein the therapeutic agent is present in an amount from 0.1 to 10.0% w / w.

[0498] Aspect 258: The article of any of Aspects 218-257, wherein the matrix layer further comprises a second therapeutic agent selected from an antibiotic, an antifungal, an antimicrobial, an NSAID, and a corticosteroid, or combinations thereof.

[0499] From the foregoing, it will be seen that aspects herein are well adapted to attain all the ends and objects hereinabove set forth together with other advantages which are obvious and which are inherent to the structure.

[0500] While specific elements and steps are discussed in connection to one another, it is understood that any element and / or steps provided herein is contemplated as being combinable with any other elements and / or steps regardless of explicit provision of the same while still being within the scope provided herein.

[0501] It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations. This is contemplated by and is within the scope of the claims.

[0502] Since many possible aspects may be made without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawings and detailed description is to be interpreted as illustrative and not in a limiting sense.

[0503] It is also to be understood that the terminology used herein is for the purpose ofATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) describing particular aspects only, and is not intended to be limiting. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0504] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. I. EXAMPLES

[0505] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. EXAMPLE 1: FORMULATION OF GLYCYRRHETINIC ACID ON A COTTON FABRIC.

[0506] Glycyrrhetinic acid was solubilized in DMSO to a obtain clear solution. For example, 800 mg of Glycyrrhetinic acid was solubilized in 3 mL of DMSO. A cotton fabric was washed with water and isopropanol and dried in a high vacuum at room temperature, then the Glycyrrhetinic acid DMSO solution, 375 µL was applied to the dried fabric, 2 cm2, then dried using a stream of air at 25 °C to a constant weight.

[0507] The amount of therapeutic agent incorporated into the fabric as follows: a 2 square cm fabric was incubated in 3.0 mL of diluent made up of a phosphate buffer pH 5.5. At specific times, 50 µL of the diluent was removed and analyzed using LC-MS. The LC-MS method utilized an Agilent 1200 LC equipped with 6120 single quad mass spectrometers (detector-UV -Vis 254 nm), using a mobile phase comprising acetonitrile and water, with a gradient of 20% acetonitrile in water to 100% acetonitrile over 11 minutes. The LC-MS column was Infinity poroschell 120EC-C18, 2.1 internal diameter, 75mm length; 2.7-micron particle size.

[0508] The rate of release of therapeutic agent under the above conditions is shown in FIG. 1.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) EXAMPLE 2: ASSAY OF 18β-GLYCYRRHETINIC.

[0509] A reversed phase HPLC method was used to analyze the amount and release of 18^- glycyrrhetinic acid from the formulated silicone patches. An Agilent 1200 series HPLC with a UV detector (254 nm) and a Zorbax Eclipse plus C-181.8 ^m, 4.6 x 75 mm column were used. The mobile phases were 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) using a gradient elution process and a flow rate of 0.7 mL / min. The retention time of 18β-glycyrrhetinic acid was 4.4 minutes. An example of the HPLC chromatogram is shown in FIG.2.

[0510] To assay for the drug content in each patch formulation, one square centimeter area patch samples with backing material were cut and immersed in a vial containing 3 mL of absolute ethanol. A mini-stir bar is introduced into each vial, and the vials were then placed in a sand bath on a hot-plate stirrer. The temperature of the sand bath was maintained at 50°C. The 18β-glycyrrhetinic acid was allowed to extract into the ethanol with slow stirring and over a period of 20 to 24 hours. The vials were removed from the sand bath, and ethanol solutions were then allowed to come to room temperature. The solutions were diluted 10 to 50 times in a diluent containing 30% ethanol in water. The diluted extracts were then assayed for 18β-glycyrrhetinic acid using the method described above. EXAMPLE 3: METHOD 1 TO STUDY IN-VITRO RATE OF RELEASE OF 18β-GLYCYRRHETINIC – PASSIVE DIFFUSION METHOD.

[0511] To study the 18β-glycyrrhetinic acid release from a patch formulation, one square centimeter area patch samples with backing material were cut and immersed in a vial containing 3 mL of dissolution medium composed of 30% ethanol in water. The vials were then placed on the bench at room temperature. Microliter aliquots of the dissolution medium are taken at different time points, diluted two times in blank dissolution medium and assayed for the drug concentration using the above HPLC method. EXAMPLE 4: METHOD 2 TO STUDY IN-VITRO RATE OF RELEASE OF 18β-GLYCYRRHETINIC – VERTICAL DIFFUSION CELL APPARATUS.

[0512] The 9-station vertical Franz cell stirrer system (PermeGear V9-CA-0091) was used. The manifold contains short clear acrylic cell holders into which 9-mm clear glass, 5 mL jacketed Franz cells with O-ring joints (4G-00-00-09-05) were placed. The cells were connected with peristaltic tubing to a circulating water bath so that water was allowed to circulate through the jacket of each Franz cell in order to maintain the dissolution / receptor medium at a temperature of 32°C. The dissolution medium and diluent was a 30% v / v ethanol- water solution.5 mL of this dissolution medium was pipetted into each Franz cell; a mini stir bar was introduced into each receptor cell and allowed to stir at 600 rpm.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0513] A 2 x 2 cm patch formulation was carefully placed to cover the 9 mm orifice of each cell. The patches were positioned so as to avoid any air bubbles and to ensure that the adhesive film was in full contact with the receptor medium. Aliquots of 0.4 mL receptor medium were withdrawn from the center of each cell using the side port and with the aid for a 1 mL syringe and a 3” needle. The aliquots were withdrawn at 30 mins, 2h, 4h, 7h, 24h and 48h. At each time the aliquot volume was replaced with fresh 0.4 mL of 30% v / v ethanol-water solution in order to maintain a constant volume of 5 mL. The sampled aliquot was placed in a HPLC vial and diluted 1:1 with dissolution medium, mixed, screw cap attached to vial and placed in the HPLC autosampler. The solution was assayed for 18β-glycyrrhetinic acid concentration in μg / mL using the HPLC method described above. EXAMPLE 5: FORMULATION OF A TOPICAL PATCH OF 18β-GLYCYRRHETINIC ACID IN SILICONE ELASTOMERS.

[0514] Liveo™ MG7-9850 or MG7-9900 soft skin adhesive (part B) (4.5 gm, 1 eq.) was weighed into a 250 mL beaker. 18β-glycyrrhetinic acid (0.18 g, 2 % by weight) was added, and mixed and blended for 3 minutes with an overhead mixer and stainless-steel pivotal blade paddle, 2½” (OniLab, OS10-Pro). The speed was controlled to minimize the generation of air bubbles. The MG7-9850 or MG7-9900 soft skin adhesive (part A) (4.5 gm, 1 eq.) was added into a 250 mL beaker and the mixing was continued for another 3 minutes until a smooth consistent free-flowing mixture was formed.

[0515] To produce the patch, the PE or PU backing material was first secured to the vacuum plate of an automatic film coater (model MSK-AFA-1, MTI Corporation). The casting knife gap was set manually to 200 μm. The polymer-drug matrix casting solution was manually poured directly over the backing material, and a 10 mm / s drawdown was performed on the matrix. The drug matrix was cured at different temperatures, such as 25°C overnight, 40°C for 4 h, 80°C for 1 h, 100°C for 30 minutes, or 150°C for 5 minutes in a solvent-safe oven. The produced drug matrix film dried at higher temperatures can be slightly thinner than the original casting gap width. The backing and drug matrix was removed from heat and allowed to cool to room temperature. Lastly, a release liner was manually overlaid to the top of the polymer- drug layer to produce the final assembly (FIG.3). Patches were made by cutting the polymer- drug matrix with backing material and liner into different square and rectangular and circular dimensions. The thickness of each patch was measured with a Mitutoyo micrometer (model AWXQ73). The measured thickness of the system (backing material, film and liner) was 0.35 mm ± 0.03 mm and the average cured film thickness alone was 0.2 mm ± 0.025 mm. The release of 18β-glycyrrhetinic acid from the formulated adhesive patches was studied using the method described in Example 3. The % of 18β-glycyrrhetinic acid released over 24 hours isATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) shown in the data in FIG.4. EXAMPLE 6: FORMULATION OF A PATCH OF 18β-GLYCYRRHETINIC ACID AND TRIETHANOLAMINE (TEOA) COUNTER-ION.

[0516] Liveo™ MG7-9850 soft skin adhesive (part B) (5.0 gm, 1 eq.) was weighed into a 100 mL beaker. 18β-glycyrrhetinic acid (0.20 g, 2% by weight) and triethanolamine (20 μL of 6 mM solution in purified water) was added, and mixed and blended for 3 minutes with an overhead stirrer and paddle. The speed was controlled to minimize the generation of air bubbles. The MG7-9850 soft skin adhesive (part A) (5.0 gm, 1 eq.) was added into a 100 mL beaker and the mixing was continued to for another 3 minutes until a smooth consistent free- flowing mixture was formed. The patch was made on PU backing as described in the previous example. The drug matrix was cured at 55°C for 1 h and 80°C for 10 minutes in a solvent- safe oven. The measured thickness of the cured film was 0.2 mm ± 0.025 mm. The release of LDPE liner from the matrix produced no tack or matrix residue. EXAMPLE 7: FORMULATION OF A PATCH OF 18β-GLYCYRRHETINIC ACID, TRIETHANOLAMINE (TEOA) AND OLEIC ACID EXCIPIENT IN SILICONE POLYMERS. (EXPT. REF: TV-2-19 TO 23).

[0517] Liveo™ MG7-9850 soft skin adhesive (part B) (5.0 gm, 1 eq.) was weighed into a 100 mL beaker. 18β-glycyrrhetinic acid (0.20 g, 2% by weight), triethanolamine (20 μL of 6 mM solution in purified water) and oleic acid (0.001 g, 0.01% by weight), were added, and mixed and blended for 3 minutes with an overhead stirrer and paddle. The speed was controlled to minimize the generation of air bubbles. The MG7-9850 soft skin adhesive (part A) (5.0 gm, 1 eq.) was added into a 100 mL beaker and the mixing was continued to for another 3 minutes until a smooth consistent free-flowing mixture was formed. The patch was prepared and cured as described in the previous example. Similar patch formulations were also made with 0.015%, 0.02%, 0.025%, 0.05% and 0.1% by weight of oleic acid. The release of LDPE liner from the matrix produced no tack or matrix residue for the 0.01%, 0.015%, 0.02%, 0.025% oleic acid formulations. However, the 0.05% and 0.1% oleic acid formulations had high tack and poor liner release. The release of 18β-glycyrrhetinic acid from the formulated adhesive patches was studied using the method described in Example 3. The % of 18β-glycyrrhetinic acid released over 24 hours is shown in the data in FIG.4. EXAMPLE 8: FORMULATION OF A PATCH OF 18β-GLYCYRRHETINIC ACID, TRIETHANOLAMINE (TEOA) AND OLEYL ALCOHOL EXCIPIENT IN SILICONE POLYMERS.

[0518] Liveo™ MG7-9850 soft skin adhesive (part B) (5.0 gm, 1 eq.) was weighed into a 100 mL beaker. 18β-glycyrrhetinic acid (0.20 g, 2% by weight), triethanolamine (20 μL of 6 mM solution in purified water) and oleyl alcohol (0.001 g, 0.01% by weight), were added, and mixedATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) and blended for 3 minutes with an overhead stirrer and paddle. The speed was controlled to minimize the generation of air bubbles. The MG7-9850 soft skin adhesive (part A) (5.0 gm, 1 eq.) was added into a 100 mL beaker and the mixing was continued to for another 3 minutes until a smooth consistent free-flowing mixture was formed. The patch was made as described in the previous example. The measured thickness of the cured film was 0.2 mm ± 0.025 mm. The release of LDPE liner from the matrix produced no tack or matrix residue. The release of 18β-glycyrrhetinic acid from the formulated adhesive patches was studied using the method described in Example 3. The % of 18β-glycyrrhetinic acid released over 24 hours is shown in the data in FIG.4. EXAMPLE 9: FORMULATION OF A PATCH OF 18β-GLYCYRRHETINIC ACID CONTAINING GLYCERIN, PROPYLENE GLYCOL OR DIETHYLENE GLYCOL MONOETHYL ETHER, AS EXCIPIENTS, SILICONE POLYMERS (EXPT. REF: TV-2-30 TO 31).

[0519] Liveo™ MG7-9850 soft skin adhesive (part B) (4.5 gm, 1 eq.) was weighed into a 100 mL beaker. 18β-glycyrrhetinic acid (0.18 g, 2% by weight) and propylene glycol (0.09 g, 1% by weight) was added, and mixed and blended for 3 minutes with an overhead stirrer and paddle. The speed was controlled to minimize the generation of air bubbles. The MG7-9850 soft skin adhesive (part A) (4.5 gm, 1 eq.) was added into a 100 mL beaker and the mixing was continued to for another 3 minutes until a smooth consistent free-flowing mixture was formed. The patch was made as described in the previous example. A similar formulation was made by replacing propylene glycol with either glycerin or diethylene glycol monoethyl ether. The release of LDPE liner from the matrix produced no tack or matrix residue for the diethylene glycol monoethyl ether formulation. However, the glycerin and propylene glycol formulations were very sticky, with high tack and poor liner release. EXAMPLE 10: FORMULATION OF PATCHES CONTAINING DIFFERENT AMOUNTS OF 18β- GLYCYRRHETINIC ACID PLUS TRIETHANOLAMINE (TEOA), OLEIC ACID AND DIETHYLENE GLYCOL MONOETHYL ETHER, AS EXCIPIENTS (EXPT. REF: TV-2-45 TO 61).

[0520] Formulations of 18β-glycyrrhetinic acid were prepared at 1, 2, 4, 6, 8 and 10% w / w concentrations. One portion of Liveo™ MG7-9850 soft skin adhesive (part B) (~2.4 gm, 0.5 eq.) was weighed into a 100 mL beaker. 18β-glycyrrhetinic acid (0.10 to 1.0 g, 1-10% by weight) and triethanolamine (10-100 μL of 30 mM solution in purified water) were added, and mixed and blended for 5 minutes at 300 rpm and 5 minutes at 400 rpm with an overhead stirrer and paddle. A second portion of Liveo™ MG7-9850 soft skin adhesive (part B) (~2.4 gm, 0.5 eq.) was weighed into the beaker and oleic acid (0.0022 g, 0.02% by weight), diethylene glycol monoethyl ether (0.025 g, 0.25% by weight) was added, and mixed and blended for 5 minutes at 300 rpm with an overhead stirrer and paddle. The speed was controlled to minimize theATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) generation of air bubbles. The MG7-9850 soft skin adhesive (part A) (4.8 gm, 1 eq.) was added into the 100 mL beaker and the mixing was continued to for another 3 minutes until a smooth consistent free-flowing mixture was formed. The patch was made and cured as described in the previous example. A similar formulation was made by replacing propylene glycol with either glycerin or diethylene glycol monoethyl ether. The release of LDPE liner from the matrix produced no tack or matrix residue for the 1, 2, 4 and 6% formulations. However, the 8 and 10% formulations were very sticky, with high tack and poor liner release (FIG. 5). The rate of release of 18β-glycyrrhetinic acid from each patch formulation was studied using the method described in Example 4. The results are shown in cumulative release plots (FIG.6A). The formulations were also cured at different temperatures i.e.60°C for 20 minutes, 100°C for 3 minutes and 140°C for 1 minute. The effect of curing temperature on the release of drug shows no differences in release rates at concentrations of 2, 4 and 6% (FIG.6B). EXAMPLE 11: FORMULATION OF A PATCH CONTAINING GLYCYRRHIZIN PLUS OLEIC ACID AND DIETHYLENE GLYCOL MONOETHYL ETHER, AS EXCIPIENTS (EXPT. REF: TV-2-92)

[0521] A formulation of glycyrrhizin (3-O-(2-O-β-D-Glucopyranuronosyl-α-D- glucopyranuronosyl)-18-β Glycyrrhetinic acid ammonium salt) was prepared at 2% w / w concentration. One portion of Liveo™ MG7-9850 soft skin adhesive (part B) (~2.44 gm, 0.5 eq.) was weighed into a 100 mL beaker. Glycyrrhizin (0.20 g, 2% by weight) was added to the beaker and blended for 5 minutes at 300 rpm and 5 minutes at 400 rpm with an overhead stirrer and paddle. A second portion of Liveo™ MG7-9850 soft skin adhesive (part B) (~2.44 gm, 0.5 eq.) was weighed into the beaker and oleic acid (0.0022 g, 0.02% by weight), diethylene glycol monoethyl ether (0.025 g, 0.25% by weight) was added, and mixed and blended for 5 minutes at 300 rpm with an overhead stirrer and paddle. The speed was controlled to minimize the generation of air bubbles. The MG7-9850 soft skin adhesive (part A) (4.88 gm, 1 eq.) was added into the 100 mL beaker and the mixing was continued to for another 3 minutes until a smooth consistent free-flowing mixture was formed. The polymer- drug matrix casting solution was manually poured directly over the PE backing material, and an 8 mm / s drawdown was performed on the matrix. The drug matrix was cured at 55°C for 1 hour and then overnight at 30°C. Lastly, a LDPE release liner was manually overlaid on top of the polymer-drug layer to produce the final assembly. The release of LDPE liner from the matrix produced no tack or matrix residue. EXAMPLE 12: FORMULATION OF A PATCHES CONTAINING DIFFERENT AMOUNTS OF CANNABIDIOL PLUS OLEIC ACID AND DIETHYLENE GLYCOL MONOETHYL ETHER, AS EXCIPIENTS (EXPT. REF: TV- 2-104).ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0522] Formulations of Cannabidiol were prepared at 2, 4 and 6% w / w concentrations. One portion of Liveo™ MG7-9850 soft skin adhesive (part B) (~2.4 gm, 0.5 eq.) was weighed into a 100 mL beaker. Cannabidiol (0.20 to 0.60 g, 2-6% by weight) was added and mixed and blended for 5 minutes with an overhead stirrer and paddle. A second portion of Liveo™ MG7- 9850 soft skin adhesive (part B) (~2.4 gm, 0.5 eq.) was weighed into the beaker and oleic acid (0.0028 g, 0.025% by weight), diethylene glycol monoethyl ether (0.025 g, 0.25% by weight) was added, and mixed and blended for 5 minutes with an overhead stirrer and paddle. The speed was controlled to minimize the generation of air bubbles. The MG7-9850 soft skin adhesive (part A) (~4.8 gm, 1 eq.) was added into the 100 mL beaker and the mixing was continued to for another 3 minutes until a smooth consistent free-flowing mixture was formed. The patch was prepared and cured as described in the previous example. The release of LDPE liner from the matrix produced no tack or matrix residue for the 2, 4 and 6% formulations. The rate of release of Cannabidiol from each patch formulation was studied using the method described in Example 5. The results are shown in cumulative release plots (FIG.7). EXAMPLE 13: IN-VIVO RELEASE OF 18-BETA-GLYCYRRHETINIC ACID FROM PATCH - SKIN STRIPPING.

[0523] Patches (2 x 2 cm) were applied to human skin for varying amounts of time. The tape stripping procedure was performed with D-Squame standard sampling 3.8 cm2discs (Clinical and Derm D100) on the section of the skin where the patch was removed. The disc was pressed by rolling a 1 lb. cylinder back and forth 5-times. The disc was removed with a fast vertical motion and placed in 1 ml of 100% ethanol in a 1,5 mL micrtotube. This procedure was repeated a second time with a fresh disc. The surface deposition of GA was tested with 2 tape strips for each patch formulation. The microtube with 2 sampling discs and ethanol was mixed with a vortex mixer at high speed for 15 minutes, followed by centrifugation of the contents at 10,000 g for 10 minutes. The concentration of GA was measured in the supernatant using the described HPLC method. Table 1 summarizes the concentration of GA measured in the tape strips. Table 1. Patch formulation Skin Exposure Time Measured GA (mins) (n / cm2)ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Liveo™ MG7-9850 with 2% GA and 6 180 728.8 µM TEOA and 0.05% oleic acidER SKIN.

[0524] The amount of 18-β-Glycyrrhetinic acid (GA) absorbed in the stratum corneum, epidermis, and dermis layer and permeated into the receptor medium at each time point (2, 8, and 24-hr) were analyzed and reported using a dermatomed human cadaver skin model.

[0525] The vertical Franz diffusion cell apparatus in a high-throughput screening (HTS) station was used. Each cell in the station had a diffusion area of 0.503 cm2(8 mm in diameter). The receptor chamber in each cell was filled with 3.0 mL of 4% BSA (Bovine Serum Albumin) in water supplemented with 0.02% gentamicin sulfate, which was vigorously and continuously mixed. The temperature of recirculating water was set at 32 ± 0.2oC.

[0526] One lot of dermatomed human cadaver skin (male, age 43 years, race Caucasian, site abdomen and average thickness: 511.7 µm) was used in the study. The tissues were received in dry ice packaging and stored at −20°C until use. Prior to use, the barrier integrity of the skin samples was tested by a transepidermal electrical resistance measurement (TEER measurement, Z value). Skin samples with no visual defects and with Z values of 7.0 KOhms and above were selected.

[0527] Three topical patch formulations with 2% GA were taken from Examples 6, 7 and 8. Patch circles with size of 8-mm in diameter were punched out, the release liner gently removed and the patch circles were applied to the skin tissues carefully and pressed gently with a glass rod to make sure that the patch circles had good and intimate contact with the skin tissues. Each patch was run in triplicate (N=3). The skin section was placed on each cell with the patch end up and the dermis in contact with the receptor medium.

[0528] At 2, 8, and 24-hr, the Franz Cells were removed from the HTS station. The patch circles were carefully removed from the skin tissues using a tweezer. The tissue surface was wiped with Q-tip wetted with 1x PBS solution and then with a dry Q-tip for three wet-dry cycles to remove the “unabsorbed and unpenetrated” GA. Then, the skin tissues were removed from the Franz Cells. The standard tape-stripping method (Scotch tape type from 3M) was used to remove layers of the stratum corneum (SC). The first two tape strips remove the remaining “unabsorbed and unpenetrated” API. The collected q-tips and first two tape strips were discarded.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0529] The tape-stripping cycle was continued for additional 15 times for each skin sample to remove SC layer completely. For each stripping cycle, all applied tapes / tissues were lined up on a Teflon plate. Then a hard rubber-lined roller was pressed against the tapes / tissues to apply equal pressure across all samples to ensure uniformity for each cycle and entire procedure. Then, the tape strip was removed in a quick motion from each tape / tissue pair. A total of 15-tape-strips were collected, combined, and extracted with 3.0 mL of DMSO / Ethanol / D.I.water 40 / 40 / 20 (v / v / v) - overnight at room temperature using an orbit shaker. The supernatants were collected and were ready for analysis.

[0530] After removal of the SC layer, epidermis and dermis layer were separated using a surgical scalpel. The epidermis / dermis surface was first wetted with distilled water to aid the separation. The surgical blade was used to scrape off epidermis from dermis. The scraped- off epidermis was collected from the surgical blade by wiping with damp paper towels (about 1.5x1.5 cm in size). The paper towels were collected, combined, and extracted with 3.0 mL of DMSO / Ethanol / D.I. water 40 / 40 / 20 (v / v / v) for overnight at room temperature using an orbit shaker. The remaining dermis layer was cut into small pieces and extracted with 3.0 mL of DMSO / Ethanol / D.I. water 40 / 40 / 20 (v / v / v) overnight at room temperature using an orbit shaker. The supernatants were collected and ready for analysis.

[0531] The receptor medium at all time points was also collected and ready for analysis.

[0532] The supernatants and receptor medium were assayed for GA concentration using a triple quad HPLC-MS / MS method.

[0533] The amount of GA (ng) in the receptor medium and in each layer of the human cadaver skin for each time point (2, 8, and 24-hr) is summarized in Table 2 below. Without wishing to be bound by a particular theory, the data suggest that addition of excipients to the patch formulations allow for increased delivery of drug to the skin’s stratum corneum, epidermis and dermis. Table 2. Average GA levels (ng) ± SDFormulation 1 Formulation 2 .4Table 2, continued.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Average GA levels (ng) ± SDFormulation 3 (example 8) 1 EXAMPLE 15: EFFICAMOUSE.

[0534] The objective of the study was to evaluate the efficacy of the 18-β-Glycyrrhetinic acid (GA) topical patches in the MC903 (calcipotriol) induced atopic dermatitis (AD) model in mice.

[0535] Female BALB / c mice were used in the study. They were 6-8 weeks old and weighing 17-19 g. The mice were grouped in 5 animals per group group based on similar mean body weights and back skin thickness. Before the initiation of the study, the thickness and erythema of the back skin and body weights of the animals were measured and recorded.

[0536] Challenge: The MC903 challenge was conducted in two cycles, from days 1-4 and from days 6-9. MC903 solution was dropped on the mouse’s backs after anesthetizing them with isoflurane (2%-3%, inhalation). The mice were given 75 μl of MC903 solution on the dorsal skin and in the center of the 2×3 cm shaven areas.

[0537] Treatment: The placebo and GA patches (2x3 cm in dimensions) were applied 30 min after the MC903 stimulation, once daily, for a total of 9 times (coverage period from Day 1 to Day 10) as shown in FIG.8. Each 2×3 cm patch was placed on the MC903 treated site on the animal’s back to cover the entire 2×3 cm area. After patch application, all the mice were wrapped with self-adherent bandage for patch fixation.

[0538] Measurements: To score the severity of inflammation, the clinical scores (erythema, thickness and scab) are measured on days 1-10, using the scoring system in Table 3 below. Table 3. Score Erythema Thickness Scab 0 N rm l N rm l<25% N rm l

[0539] FIG.9 shows the clinical scores for each treatment over time. Results suggest a significant dose dependent improvement in inflammation for each GA patch concentration overATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) that of the placebo patch. EXAMPLE 16: IN-VIVO RELEASE OF 18β-GLYCYRRHETINIC ACID FROM PATCH – MOUSE AND PIG SKIN.

[0540] The objective of the study was to evaluate the amount of the 18-β-Glycyrrhetinic acid (GA) present in mouse and minipig skin following repeated administration of GA patches at concentrations of 2, 4 and 6%.

[0541] The female BALB / c mice from Example 15 were used in this part of the study. They were distributed into 5 animals per group based on similar mean body weights and back skin thickness. They were 6-8 weeks old and weighing 17-19 g. Placebo and GA patches (2×3 cm in dimensions) were applied once daily, from Day 0 to Day 10 as shown in FIG.8. Each 2×3 cm patch was placed over the MC903 treated site on the animal’s back to cover the entire 2×3 cm area. Following termination of the study, the 2×3 sections of the whole dorsal skin were excised, pulverized and homogenized. The homogenate was extracted and the extract was assayed for GA concentration using a triple quad HPLC-MS / MS method.

[0542] Male and female Sinclair nano pigs, 3 to 6 months in age and weighing between 4 and 10 kg, were used in the study. The dose site on the dorsum was carefully clipped and shaved to remove the hair on the day prior to dose administration. Care was taken to avoid abrasion and damage of the skin. Prior to daily patch application, the dose sites on the dorsum were wiped clean with water moistened gauze or paper towels and wiped dry with dry gauze or paper towels. The placebo and GA patches were applied daily side by side to the dorsal surface to cover 10% Body Surface Area (BSA) for 28 days i.e. approximately a 6 x 8-inch area. The patches were covered with film dressing that extends and covers around the perimeter of the dose site and then wrapped in vet wrap. A designated biopsy area (medial on dose site A, approximately 2-3 cm laterally from the spine) was wiped with water-moistened gauze, dried with dry gauze, then tape stripped up to 5 times to remove the upper layer of the stratum corneum containing undissolved test materials. Punch whole skin biopsy samples (12 mm) were taken on day 29 from each pig and placed into prelabeled containers, flash frozen in liquid nitrogen and stored in a freezer set to maintain -80 °C. The punch biopsy skin whole skin was pulverized and homogenized. The homogenate was extracted and the extract was assayed for GA concentration using a triple quad HPLC-MS / MS method.

[0543] The concentration of GA in mouse and nano pig whole skin was calculated and reported in ng / g of tissue (FIG.10). EXAMPLE 17: FORMULATION OF A TOPICAL PATCH OF CURCUMIN IN SILICONE ELASTOMERS.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02)

[0544] Liveo™ MG7-9850 soft skin adhesive (part B) (4.95 gm, 1 eq.) was weighed into a 250 mL beaker. Curcumin (0.10 g, 1 % by weight) was added, and mixed and blended for 3 minutes with a clean spatula to attain a smooth mix. The MG7-9850 soft skin adhesive (part A) (4.95 gm, 1 eq.) was added into a 250 mL beaker and the mixing was continued for another 3 minutes until a smooth consistent free-flowing mixture was formed. The patch was made on PE backing as described in the previous example. The drug matrix was cured at 55°C for 2 h in a solvent-safe oven. The release of LDPE liner from the matrix produced no tack or matrix residue. EXAMPLE 18: PROSPECTIVE CLINICAL STUDY TO EVALUATE SAFETY AND EFFICACY OF A DISCLOSED 18β-GLYCYRRHETINIC ACID FROM PATCH.

[0545] Title: A Phase 1b Placebo-Controlled, Parallel Group Study Assessing Pharmacokinetics, Safety, Tolerability and Efficacy of Daily KP-77 Patch Application in the Treatment of Atopic Dermatitis.

[0546] Rationale: This study is being conducted to evaluate the safety, tolerability, efficacy and pharmacokinetics (PK) of KP-77 patch for targeted occlusive treatment of atopic dermatitis (AD) in adults. Results of this study will inform subsequent clinical study designs.

[0547] Target Population: Males and females, 18 years to 65 years of age, with localized AD lesions at Baseline. Approximately 20 subjects randomized.

[0548] Study Design: This is a Phase 1b single-center, randomized, double-blind, placebo- controlled, parallel group study to be conducted in approximately 20 subjects with mild to moderate AD. After obtaining informed consent, subjects who satisfy entry criteria will be randomized 3:1 (active:placebo). Subjects receiving current treatment for AD at the time of the Screening Visit may enter a wash out period prior to randomization. In the event no wash out period is required, Screening and Baseline visit activities may be combined into a single visit.

[0549] Subjects will apply KP-77 patch 6% or placebo patch once daily for 4 weeks to all target lesions identified at Baseline. New lesions that arise during the course of the study will not be treated if they are outside of the patch treatment areas. Subjects or their caregivers will continue to treat the area for 3 weeks even if the lesion(s) clear. Subjects will visit the clinic at Screening / Baseline (Day 1), Day 8, Day 15, Day 22 and Day 29. Subjects will also visit the clinic at Day 43 as a follow up. Subjects who discontinue the study prior to the Day 29 visit due to adverse events or other reasons, will be asked to complete the Day 29 visit assessments; this will be recorded as an Early Termination (ET) visit. The PK profile of GA after repeated patch application of KP-77 will be assessed as data allows. Approximately 10 subjects will also participate in the PK sub-study. Blood will be collected on Day 1 and DayATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 29 for PK sampling at pre-dose, 1 h, 3h, 5h and 8h post-dose, processed and analyzed for GA plasma concentration.

[0550] Dosing Regimen: Subjects will apply 3 patches once daily to target lesions identified at Baseline for 3 weeks continuously. Th placebo patch will contain no GA, and the active patch will contain between 4 and 6% GA. The patch size is 4” x 5.5” in dimensions and will be cut into a maximum of 2 pieces to incorporate as many AD lesions as possible. The two pieces may be different sizes and shapes. All 3 patch sheets must be used, possibly including non-lesional skin, and the lesions outside of the patches will not be treated. All patches must be applied on the skin for approximately 24 hours and removed daily. Face lesions will be excluded from the target treatment.

[0551] Inclusion criteria: 1. Male or female, 18 years to 65 years of age at the time of informed consent, and in good general health; 2. Have a written informed consent form signed by subject or a parent or legal guardian and an assent form as required; 3. Have diagnosis of AD fulfilling the criteria developed by Hannifin and Rajka [Hannifin 1980]; 4. Have Validate Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) of 2 (mild) or 3 (moderate) 5. Have AD lesions covering at least 3% Body Surface Area (BSA); 6. Have localized AD lesions that are suitable for patch treatment at Baseline; a. Subjects will receive target area treatment, which will be comprised of 420 cm2for 28 days. The target treatment area(s) should include as many AD lesions as possible. The 3 patch sheets (4” x 5.5” each and can be cut into a maximum of 2 pieces) applied to the designated areas by the subject or caregiver. The two pieces may be different sizes and shapes. All 3 patch sheets must be used, possibly including non-lesional skin, and the lesions outside of the patches will not be treated. 7. At least 1 target lesion that measures at least 5 cm2at Baseline for clinical photography. Must be representative of the subject’s disease state, but not located on the face, hands, feet, or genitalia; 8. Female subjects with reproductive potential must have a negative urine pregnancy test (UPT) at Baseline; 9. Female subjects with reproductive potential must agree to practice a medically acceptable form of birth control during the study and for 30 days after their final study visit; 10. Be willing and able to follow study instructions and likely to complete all study requirements.

[0552] Exclusion criteria:ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Have unstable course of AD (spontaneously improving or rapidly deteriorating) as determined by the investigator over the previous 4 weeks prior to Baseline; Concurrent conditions and history of other diseases: a. Are immunosuppressed, have immunodeficiency disorder, or are on immunosuppressive treatment; b. Have chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks before the baseline visit; c. Have active acute bacterial, fungal, or viral skin infection within 1 week before the baseline visit; d. Any other concomitant skin disorder (eg, generalized erythroderma such as Netherton’s syndrome, or psoriasis), pigmentation, or extensive scarring that in the opinion of the investigator may interfere with the evaluation of targeted AD lesions or compromise subject safety; e. Presence of AD lesions outside of the defined target lesions that need treatment other than nonmedicated emollients and / or moisturizers during the 21-day treatment period; f. Other types of eczema. Have unstable course of AD (spontaneously improving or rapidly deteriorating) as determined by the investigator over the previous 4 weeks prior to Baseline; Concurrent conditions and history of other diseases: a. Are immunosuppressed, have immunodeficiency disorder, or are on immunosuppressive treatment; b. Have chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks before the baseline visit; c. Have active acute bacterial, fungal, or viral skin infection within 1 week before the baseline visit; d. Any other concomitant skin disorder (eg, generalized erythroderma such as Netherton’s syndrome, or psoriasis), pigmentation, or extensive scarring that in the opinion of the investigator may interfere with the evaluation of targeted AD lesions or compromise subject safety; e. Presence of AD lesions outside of the defined target lesions that need treatment other than nonmedicated emollients and / or moisturizers during the 28-day treatment period; f. Other types of eczema. Have AD lesions only in the unsuitable area such as face, hands, feet, or genitalia for patch treatment; Have ultraviolet (UV) light therapy of prolonged exposure to natural or artificial source of UV radiation (eg, sunlight or tanning booth) within 4 weeks prior to the Baseline and / orATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) intention to have such exposure during the study, which is thought by the investigator to potentially impact the subject’s AD condition; 7. Have used any of the following treatments within the indicated washout period before the baseline visit. a. 24 weeks – dupilumab, tralokinumab or other biologics agents; b. 4 weeks – JAK inhibitors, PDE4 inhibitors, cyclosporin, methotrexate, azathioprine, or other systemic immunosuppressive or immunomodulating agents, systemic corticosteroids or adrenocorticotropic hormone analogs; c. 4 weeks – retinoids, hydroxycarbamide (hydroxyurea); d. 2 weeks – topical treatments: corticosteroids, calcineurin inhibitors, JAK inhibitors, PDE4 inhibitors, AhR agonists, tars; e. 2 weeks – immunizations, sedating antihistamines (nonsedating antihistamines are permitted) f. 1 week – topical antibiotics, antibacterial cleansing body wash / soap or diluted sodium hypochlorite “bleach” baths. Note: Stable doses of inhaled corticosteroids ≤1000 ug daily dose, corticosteroid eye / nasal / ear drops, and non-sedating oral antihistamines such as cetirizine or loratadine are allowed during the study. 8. Have known hypersensitivity to the KP-77 patch ingredients, excipients or adhesives; 9. Female subjects who are pregnant, planning a pregnancy or breastfeeding; 10. Have participated in any other trial of an interventional investigational drug or device within 30 days or 5 half-lives (whichever is longer) or concurrent participation in another interventional research study; 11. Has a history of malignant disease within 5 years before the Baseline visit (3 years for successfully treated squamous-cell carcinoma of the skin, or cervical carcinoma in situ); 12. Had a major surgery within 8 weeks of Baseline or has a major surgery planned during the study; 13. Has a known history of clinically significant drug or alcohol abuse in the last year prior to Baseline; 14. Have a history or ongoing serious illness or medical, physical, or psychiatric condition(s) that, in the investigator’s opinion, may interfere with the subject’s completion of the study.

[0553] Primary Endpoint: Safety and Tolerability.

[0554] The safety parameters include monitoring and reporting of AEs, clinical laboratory test results (hematology including coagulation parameters, serum chemistry, and urinalysis), 12- lead ECG results, vital sign measurements, and physical examination findings. Local skin reactions (LSRs) assessment will also be conducted and reported (see Table 4 below). Table 4.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Score Erythema Flaking / Crusting Swelling Vesiculation / Erosion / Scaling Pustulation Ulceration al e e r n

[0555] Primary Endpoint: Efficacy.

[0556] Proportion of subjects who have an Investigator Global Assessment (IGA) score of clear or almost clear (0 or 1) for the target lesions (average) at Day 29 and a minimum 2-grade improvement in IGA score from Baseline to Day 29 (see Table 5 below). Table 5. Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-AD) n g .ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 4: Severe Marked erythema (deep or bright red), marked induration / papulation, and / or marked lichenification. Disease is widespread in extent Oozing or crusting may be present

[0557]

[0558] The primary assessment will be the PK profile of GA after patch application of KP-77 to 420 cm2once daily. Plasma concentrations of GA will be determined. The following standard PK parameters will be calculated for Day 1 and Day 29, as data allows, for GA using non-compartmental analysis: • Cmax: maximum observed plasma concentration value • Tmax: actual plasma sampling time (relative to dose administration) associated with Cmax• AUC0-8: area under the plasma concentration-time curve from time = 0 to the end of the last measurable concentration • Exposure ratios of Day 29 / Day1 for Cmaxand AUC0-8

[0559] Secondary Endpoints:

[0560] Briefly, secondary endpoints to be assessed comprise: • The percent change from Baseline in Itch numerical rating score (NRS) at every visit through Day 29. • NRS-11 for peak itch over past 24 hours, 0 for no itch and 10 for worst itch imaginable • Change from Baseline in the total Patient-Oriented Eczema Measure (POEM) score at every visit through Day 29. • Change from Baseline in the IGA score for target lesions (average) at every visit through Day 29. • Proportion of subjects who have IGA score of clear or almost clear (0 or 1) for target lesions (average) at Day 43. • Proportion of subjects with Itch NRS reduction of 3 or greater from Baseline at each visit; • For subjects in Itch NRS score ≥ 3 at Baseline only • Change from Baseline in microbiome results from treatment lesional skin versusATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) placebo lesional skin, with non-lesional skin as a control for normal microbiome change at Day 29.

[0561] Photography: Lesion photography – medical photographs of up to 3 target AD lesions will be taken to illustrate any visible clinical change.

[0562] Statistics: If sufficient quantifiable samples are observed, analysis of population PK will be considered.

[0563] Safety and efficacy endpoints will be displayed using descriptive statistics and graphical displays. For categorical variables, frequencies, and percentages will be presented. The denominators for percentages will be based on the number of subjects appropriate for the purpose of analysis. Continuous variables will be summarized using descriptive statistics (number of subjects, mean, median, standard deviation [SD], minimum, and maximum).

[0564] The analysis populations include the following: • The intent-to-treat (ITT) population will consist of all subjects who are randomized. All efficacy analyses using the ITT population will be based on the subjects’ randomly assigned treatments. • The safety (SAF) population will include all randomized subjects who applied at least one dose of study medication. All safety and tolerability analyses will be performed on the SAF population based on the treatments the subjects actually applied. • The per protocol (PP) population will include randomized subjects who completed the Week 12 visit (or whose lesions were clear at an earlier visit) and did not have study protocol deviations that would confound the evaluation of treatment efficacy. • The Pharmacokinetic population will consist of all subjects in the SAF who have one post-application blood draw for GA analysis.

[0565] All AEs that occur during the study will be recorded and coded using Medical Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-emergent AEs (TEAEs) are defined as AEs that occurred any time on or after the first in-clinic application of study drug and within 2 days of the last application of study drug.

[0566] Treatment-emergent AEs will be summarized by treatment group, the number of subjects reporting a TEAE, SOC, preferred term, severity, relationship to study drug (causality), and seriousness.

[0567] Serious adverse events (SAEs) will be summarized by treatment group, severity, and relationship to study drug, and individual SAEs will be listed by subject. In addition, a list ofATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) subjects who prematurely discontinue from the study due to an AE will be provided. EXAMPLE 18: REPRESENTATIVE DISCLOSED FORMULATIONS.

[0568] Exemplary formulations of the present disclosure are shown in Table 6. Table 6. Excipient Range Active Drug (18β-glycyrrhetinic acid or 0.1 to 10.0 % w / w Gl c rrhizin)

[0569] Additional exemplary formulations of the present disclosure are shown in Table 7. Table 7. Excipient Range Active Drug (18β-glycyrrhetinic acid or 0.5 to 8.0 % w / w w w

[0570] Additional exemplary formulations of the present disclosure are shown in Table 8. Table 8. Excipient Range A tiv Dr (18 l rrh tini id r 10 to 60 % w / wATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Propylene glycol 0.05 to 0.25% Glycerin 0.05 to 0.25% Diethylene glycol monoethyl ether 0.05 to 0.25% EXAMPLE

[0571] Table 9 below shows patch formulations containing different amounts of 18β- glycyrrhetinic acid, their specifications and their stability at room temperature, refrigerator and at elevated temperatures. Table 9. Product Storage Condition Time Test Coat Adhesion Release Points Description Weight of Liner NTable 9, continued.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) Product Storage Time Test Description Microbial Limits Condition Points (m nth )A earance UniformitAerobic Yeast Pathogens

[0572] It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the disclosure. Other aspects of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) CLAIMS What is claimed is:

1. An article comprising a backing material layer, a matrix layer, and a liner layer; wherein the matrix layer comprises a polymer adhesive system and therapeutic agent mixture in contact with a substrate; and wherein the polymer adhesive system is a self-adhesive, a pressure adhesive, or a combination thereof.

2. The article of claim 1, wherein the polymer adhesive system is an adhesive water insoluble polymer.

3. The article of claim 2, wherein the therapeutic agent is in solution or suspended or emulsified in the matrix.

4. The article of claim 2 or claim 3, wherein the therapeutic agent is micronized or size reduced.

5. The article of any of claims 2-4, wherein the therapeutic agent is mixed with an excipient or solvent.

6. The article of claim 1, wherein the polymer adhesive system is an elastomeric silicone adhesive.

7. The article of claim 6, wherein the elastomeric silicone adhesive is selected from a one- part elastomeric silicone adhesive and a two-part silicone adhesive.

8. The article of any preceding claim, wherein the therapeutic agent is in a salt form or counter-ion complex.

9. The article of any preceding claim, wherein the therapeutic agent is incorporated in a liposome or lipid nanoparticle vesicle prior to mixing with the polymer adhesive system.

10. The article of any preceding claim, wherein the therapeutic agent is emulsified with an oil, aqueous-polyol and surfactant prior to mixing with the matrix layer.

11. The article of any preceding claim, wherein the therapeutic agent comprises glycyrrhizic acid, enoxolone, a derivative thereof, or any combination thereof.

12. The article of claim 11, wherein the therapeutic agent comprises 18β-glycyrrhetinic acid.

13. The article of any preceding claim, wherein the therapeutic agent is selected from glycyrrhizic acid, 18β-glycyrrhetinic acid, enoxolone, curcumin, adapalene, cannabinoids, and methylnissolin.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 14. The article of claim 13, wherein the therapeutic agent is glycyrrhizic acid.

15. The article of claim 13, wherein the therapeutic agent is 18β-glycyrrhetinic acid.

16. The article of claim 13, wherein the therapeutic agent is enoxolone.

17. The article of claim 13, wherein the therapeutic agent is adapalene.

18. The article of claim 13, wherein the therapeutic agent is a cannabinoid; and wherein the cannabinoid is selected from cannabidiol, cannabigerol, cannabichromene, cannabinol, tetrahydrocannabinol, cannabidiolic acid, cannabigerolic acid, cannabichromenic acid, cannabinolic acid, tetrahydrocannabinolic acid, cannabidivarin, cannabigerovarin, cannabichromevarin, cannabinolivarin, tetrahydrocannabivarinol, cannabicyclol, cannabielsoin, cannabitriol, and combinations thereof.

19. The article of claim 18, wherein the cannabinoid is selected from cannabidiol and cannabigerol.

20. The article of claim 18, wherein the cannabinoid is selected from cannabidiol.

21. The article of claim 18, wherein the cannabinoid is cannabigerol.

22. The article of claim 13, wherein the therapeutic agent is methylnissolin or curcumin.

23. The article of any of claims 11-22, wherein the therapeutic agent is present in an amount from 0.1 to 20.0% w / w.

24. The article of claim 23, wherein the therapeutic agent is present in an amount from 0.5 to 8.0% w / w.

25. The article of claim 24, wherein the therapeutic agent is present in an amount from 1.0 to 6.0% w / w.

26. The article of claim 25, wherein the therapeutic agent is present in an amount from 2.0 to 5.0% w / w.

27. The article of claim 26, wherein the therapeutic agent is present in an amount from 2.5 to 4.5% w / w.

28. The article of any preceding claim, wherein the polymer adhesive system and therapeutic agent mixture further comprises a penetration enhancer.

29. The article of any preceding claim, wherein the polymer adhesive system is an elastomeric polymer adhesive system.

30. The article of claim 29, wherein the elastomeric polymer adhesive system is derived from a two-part catalyzed system comprising a component A and a component B, wherein component A, component B or both comprise a catalyst.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 31. The article of claim 30, wherein the catalyst is a platinum catalyst.

32. The article of any one of claims 29-31, wherein the elastomeric polymer adhesive system is cured.

33. The article of claim 32, wherein the elastomeric polymer adhesive system is cured via catalysis of a component A and component B, thereby forming the elastomeric polymer adhesive system.

34. The article of any preceding claim, wherein the polymer adhesive system is present in an amount from 90.0 to 99.9% w / w.

35. The article of claim 34, wherein the polymer adhesive system is present in an amount from 92.0 to 99.5% w / w.

36. The article of claim 35, wherein the polymer adhesive system is present in an amount from 94.0 to 99.0% w / w.

37. The article of claim 36, wherein the polymer adhesive system is present in an amount from 95.0 to 98.5% w / w.

38. The article of claim 37, wherein the polymer adhesive system is present in an amount from 96.0 to 98.0% w / w.

39. The article of any preceding claim, wherein the polymer adhesive system comprises Liveo MG7-9850 or MG7-9900.

40. The article of any preceding claim, wherein the matrix layer further comprises a weak base selected from triethanolamine or TRIS.

41. The article of claim 40, wherein the weak base is present in an amount from 0 to 200 mM.

42. The article of claim 41, wherein the weak base is present in an amount from 6 to 190 mM.

43. The article of claim 42, wherein the weak base is present in an amount from 30 to 90 mM.

44. The article of claim 43, wherein the weak base is present in an amount from 40 to 80 mM.

45. The article of claim 44, wherein the weak base is present in an amount from 50 to 70 mM.

46. The article of any preceding claim, wherein the matrix layer further comprises a fatty acid.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 47. The article of claim 46, wherein the fatty acid is selected from oleic acid, linoleic acid, palmitic acid, stearic acid, myristic acid, lauric acid, capric acid, caprylic acid, caproic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and combinations thereof.

48. The article of claim 47, wherein the fatty acid is oleic acid.

49. The article of claim 47, wherein the fatty acid is linoleic acid.

50. The article of claim 47, wherein the fatty acid is palmitic acid.

51. The article of claim 47, wherein the fatty acid is stearic acid.

52. The article of claim 47, wherein the fatty acid is myristic acid.

53. The article of claim 47, wherein the fatty acid is lauric acid.

54. The article of claim 47, wherein the fatty acid is capric acid.

55. The article of claim 47, wherein the fatty acid is caprylic acid.

56. The article of claim 47, wherein the fatty acid is caproic acid.

57. The article of claim 47, wherein the fatty acid is arachidonic acid.

58. The article of claim 47, wherein the fatty acid is eicosapentaenoic acid.

59. The article of claim 47, wherein the fatty acid is docosahexaenoic acid.

60. The article of any of claims 46-59, wherein the fatty acid is present in an amount from 0 to 1.0% w / w.

61. The article of claim 60, wherein the fatty acid is present in an amount from 0.05 to 0.5% w / w.

62. The article of claim 61, wherein the fatty acid is present in an amount from 0.05 to 0.25% w / w.

63. The article of claim 62, wherein the fatty acid is present in an amount from 0.08 to 0.20% w / w.

64. The article of claim 63, wherein the fatty acid is present in an amount from 0.10 to 0.15% w / w.

65. The article of any preceding claim, wherein the matrix layer further comprises a fatty alcohol.

66. The article of claim 65, wherein the fatty alcohol is selected from oleyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, behenyl alcohol, arachidyl alcohol, lignoceryl alcohol, ceryl alcohol, montanyl alcohol, melissyl alcohol, and combinations thereof.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 67. The article of claim 66, wherein the fatty alcohol is oleyl alcohol.

68. The article of claim 66, wherein the fatty alcohol is cetyl alcohol.

69. The article of claim 66, wherein the fatty alcohol is stearyl alcohol.

70. The article of claim 66, wherein the fatty alcohol is cetostearyl alcohol.

71. The article of claim 66, wherein the fatty alcohol is lauryl alcohol.

72. The article of claim 66, wherein the fatty alcohol is myristyl alcohol.

73. The article of claim 66, wherein the fatty alcohol is palmityl alcohol.

74. The article of claim 66, wherein the fatty alcohol is behenyl alcohol.

75. The article of claim 66, wherein the fatty alcohol is arachidyl alcohol.

76. The article of claim 66, wherein the fatty alcohol is lignoceryl alcohol.

77. The article of claim 66, wherein the fatty alcohol is ceryl alcohol.

78. The article of claim 66, wherein the fatty alcohol is montanyl alcohol.

79. The article of claim 66, wherein the fatty alcohol is melissyl alcohol.

80. The article of any of claims 65-79, wherein the fatty alcohol is present in an amount from 0 to 1.0% w / w.

81. The article of claim 80, wherein the fatty alcohol is present in an amount from 0.05 to 0.5% w / w.

82. The article of claim 81, wherein the fatty alcohol is present in an amount from 0.05 to 0.25% w / w.

83. The article of claim 82, wherein the fatty alcohol is present in an amount from 0.08 to 0.20% w / w.

84. The article of claim 83, wherein the fatty alcohol is present in an amount from 0.10 to 0.15% w / w.

85. The article of any preceding claim, wherein the matrix layer further comprises a fatty acid ester.

86. The article of claim 85, wherein the fatty acid ester is selected from isopropyl myristate, ethyl oleate, methyl palmitate, propyl stearate, butyl laurate, isopropyl palmitate, ethyl stearate, methyl oleate, propyl myristate, butyl palmitate, isopropyl stearate, ethyl myristate, methyl stearate, propyl oleate, butyl myristate, isopropyl oleate, ethyl palmitate, methyl myristate, propyl palmitate, butyl stearate, isopropyl laurate, ethyl laurate, methyl laurate, propyl laurate, butyl oleate, and combinations thereof.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 87. The article of claim 86, wherein the fatty acid ester is isopropyl myristate.

88. The article of claim 86, wherein the fatty acid ester is ethyl oleate.

89. The article of claim 86, wherein the fatty acid ester is methyl palmitate.

90. The article of claim 86, wherein the fatty acid ester is propyl stearate.

91. The article of claim 86, wherein the fatty acid ester is butyl laurate.

92. The article of claim 86, wherein the fatty acid ester is isopropyl palmitate.

93. The article of claim 86, wherein the fatty acid ester is ethyl stearate.

94. The article of claim 86, wherein the fatty acid ester is methyl oleate.

95. The article of claim 86, wherein the fatty acid ester is propyl myristate.

96. The article of claim 86, wherein the fatty acid ester is butyl palmitate.

97. The article of claim 86, wherein the fatty acid ester is isopropyl stearate.

98. The article of claim 86, wherein the fatty acid ester is ethyl myristate.

99. The article of claim 86, wherein the fatty acid ester is methyl stearate.

100. The article of claim 86, wherein the fatty acid ester is propyl oleate.

101. The article of claim 86, wherein the fatty acid ester is butyl myristate.

102. The article of claim 86, wherein the fatty acid ester is isopropyl oleate.

103. The article of claim 86, wherein the fatty acid ester is ethyl palmitate.

104. The article of claim 86, wherein the fatty acid ester is methyl myristate.

105. The article of claim 86, wherein the fatty acid ester is propyl palmitate.

106. The article of claim 86, wherein the fatty acid ester is butyl stearate.

107. The article of claim 86, wherein the fatty acid ester is isopropyl laurate.

108. The article of claim 86, wherein the fatty acid ester is ethyl laurate.

109. The article of claim 86, wherein the fatty acid ester is methyl laurate.

110. The article of claim 86, wherein the fatty acid ester is propyl laurate.

111. The article of claim 86, wherein the fatty acid ester is butyl oleate.

112. The article of any of claims 85-111, wherein the fatty acid ester is present in an amount from 0 to 1.0% w / w.

113. The article of claim 112, wherein the fatty acid ester is present in an amount from 0.05ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) to 0.5% w / w.

114. The article of claim 113, wherein the fatty acid ester is present in an amount from 0.05 to 0.25% w / w.

115. The article of claim 114, wherein the fatty acid ester is present in an amount from 0.08 to 0.20% w / w.

116. The article of claim 115, wherein the fatty acid ester is present in an amount from 0.10 to 0.15% w / w.

117. The article of any preceding claim, wherein the matrix layer further comprises a glycol.

118. The article of claim 117, wherein the glycol is selected from propylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, neopentyl glycol, 2-methyl-1,3-propanediol, 3-methyl-1,5-pentanediol, 2-ethyl-2-methyl-1,3- propanediol, and combinations thereof.

119. The article of claim 118, wherein the glycol is propylene glycol.

120. The article of claim 118, wherein the glycol is ethylene glycol.

121. The article of claim 118, wherein the glycol is diethylene glycol.

122. The article of claim 118, wherein the glycol is triethylene glycol.

123. The article of claim 118, wherein the glycol is tetraethylene glycol.

124. The article of claim 118, wherein the glycol is polyethylene glycol.

125. The article of claim 118, wherein the glycol is dipropylene glycol.

126. The article of claim 118, wherein the glycol is tripropylene glycol.

127. The article of claim 118, wherein the glycol is polypropylene glycol.

128. The article of claim 118, wherein the glycol is 1,3-propanediol.

129. The article of claim 118, wherein the glycol is 1,4-butanediol.

130. The article of claim 118, wherein the glycol is 1,5-pentanediol.

131. The article of claim 118, wherein the glycol is 1,6-hexanediol.

132. The article of claim 118, wherein the glycol is 1,2-butanediol.

133. The article of claim 118, wherein the glycol is 1,3-butanediol.

134. The article of claim 118, wherein the glycol is 2,3-butanediol.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 135. The article of claim 118, wherein the glycol is neopentyl glycol.

136. The article of claim 118, wherein the glycol is 2-methyl-1,3-propanediol.

137. The article of claim 118, wherein the glycol is 3-methyl-1,5-pentanediol.

138. The article of claim 118, wherein the glycol is 2-ethyl-2-methyl-1,3-propanediol.

139. The article of claim 118, wherein the glycol is selected from propylene glycol, ethylene glycol, diethylene glycol, and polyethylene glycol.

140. The article of claim 118, wherein the glycol is selected from propylene glycol, dipropylene glycol, and polypropylene glycol.

141. The article of claim 118, wherein the glycol is selected from 1,3-propanediol, 1,4- butanediol, 1,5-pentanediol, and 1,6-hexanediol.

142. The article of any of claims 117-141, wherein the propylene glycol is present in an amount from 0 to 1.0% w / w.

143. The article of claim 142, wherein the propylene glycol is present in an amount from 0.05 to 0.5% w / w.

144. The article of claim 143, wherein the propylene glycol is present in an amount from 0.05 to 0.25% w / w.

145. The article of claim 144, wherein the propylene glycol is present in an amount from 0.08 to 0.20% w / w.

146. The article of claim 145, wherein the propylene glycol is present in an amount from 0.10 to 0.15% w / w.

147. The article of any preceding claim, wherein the matrix layer further comprises glycerin.

148. The article of claim 147, wherein the glycerin is present in an amount from 0 to 1.0% w / w.

149. The article of claim 148, wherein the glycerin is present in an amount from 0.05 to 0.5% w / w.

150. The article of claim 149, wherein the glycerin is present in an amount from 0.05 to 0.25% w / w.

151. The article of claim 150, wherein the glycerin is present in an amount from 0.08 to 0.20% w / w.

152. The article of claim 151, wherein the glycerin is present in an amount from 0.10 to 0.15% w / w.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 153. The article of any preceding claim, wherein the matrix layer further comprises diethylene glycol monoethyl ether.

154. The article of claim 153, wherein the diethylene glycol monoethyl ether is present in an amount from 0 to 1.0% w / w.

155. The article of claim 154, wherein the diethylene glycol monoethyl ether is present in an amount from 0.05 to 0.5% w / w.

156. The article of claim 155, wherein the diethylene glycol monoethyl ether is present in an amount from 0.05 to 0.25% w / w.

157. The article of claim 156, wherein the diethylene glycol monoethyl ether is present in an amount from 0.08 to 0.20% w / w.

158. The article of claim 157, wherein the diethylene glycol monoethyl ether is present in an amount from 0.10 to 0.15% w / w.

159. The article of any preceding claim, wherein the matrix layer further comprises purified water.

160. The article of claim 159, wherein the purified water is present in an amount from 0 to 1.0% w / w.

161. The article of claim 160, wherein the purified water is present in an amount from 0.005 to 0.25% w / w.

162. The article of claim 161, wherein the purified water is present in an amount from 0.01 to 0.10% w / w.

163. The article of claim 162, wherein the purified water is present in an amount from 0.02 to 0.08% w / w.

164. The article of any preceding claim, wherein the matrix layer further comprises a second therapeutic agent.

165. The article of claim 164, wherein the second therapeutic agent is selected from a therapeutic agent.

166. The article of claim 165, wherein the second therapeutic agent is selected from an antibiotic, an antifungal, an antimicrobial, an NSAID, and a corticosteroid, or combinations thereof.

167. The article of claim 166, wherein the second therapeutic agent is an antibiotic or an antimicrobial agent.

168. The article of claim 166, wherein the second therapeutic agent is an NSAID.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 169. The article of claim 166, wherein the second therapeutic agent is a corticosteroid.

170. A method of treating or providing prophylaxis of a clinical condition by administering to a subject an article of any one of claims 1-169.

171. The method of claim 170, wherein the clinical condition is selected from a wound, radiation-induced skin damage, and inflammation.

172. The method of claim 170, wherein the clinical condition is atopic dermatitis.

173. The method of claim 172, wherein the atopic dermatitis is mild to moderate atopic dermatitis.

174. The method of claim 172, wherein the atopic dermatitis is severe atopic dermatitis.

175. The method of claim 172, wherein the atopic dermatitis is localized atopic dermatitis.

176. The method of claim 172, wherein the atopic dermatitis is generalized atopic dermatitis.

177. The method of claim 170, wherein the clinical condition is psoriasis.

178. The method of claim 177, wherein the psoriasis is plaque psoriasis.

179. The method of claim 177, wherein the psoriasis is mild to moderate psoriasis.

180. The method of claim 177, wherein the psoriasis is severe psoriasis.

181. The method of claim 177, wherein the psoriasis is localized psoriasis.

182. The method of claim 177, wherein the psoriasis is guttate psoriasis.

183. The method of claim 177, wherein the psoriasis is inverse psoriasis.

184. The method of claim 170, wherein the clinical condition is alopecia areata.

185. The method of claim 184, wherein the alopecia areata is patchy alopecia areata.

186. The method of claim 184, wherein the alopecia areata is alopecia totalis.

187. The method of claim 184, wherein the alopecia areata is alopecia universalis.

188. The method of claim 184, wherein the alopecia areata is ophiasis alopecia areata.

189. The method of claim 170, wherein the clinical condition is acne.

190. The method of claim 189, wherein the acne is mild to moderate acne.

191. The method of claim 189, wherein the acne is severe acne.

192. The method of claim 189, wherein the acne is inflammatory acne.

193. The method of claim 189, wherein the acne is comedonal acne.

194. The method of claim 189, wherein the acne is cystic acne.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 195. The method of claim 189, wherein the acne is nodular acne.

196. The method of claim 170, wherein the clinical condition is hyperpigmentation.

197. The method of claim 196, wherein the hyperpigmentation is melasma.

198. The method of claim 196, wherein the hyperpigmentation is post-inflammatory hyperpigmentation.

199. The method of claim 196, wherein the hyperpigmentation is solar lentigines.

200. The method of claim 196, wherein the hyperpigmentation is age spots.

201. The method of claim 196, wherein the hyperpigmentation is café-au-lait macules.

202. The method of claim 170, wherein the clinical condition is dermatitis.

203. The method of claim 202, wherein the dermatitis is contact dermatitis.

204. The method of claim 202, wherein the dermatitis is seborrheic dermatitis.

205. The method of claim 202, wherein the dermatitis is allergic dermatitis.

206. The method of claim 202, wherein the dermatitis is irritant dermatitis.

207. The method of any of claims 172-206, wherein the article is applied topically to the affected skin area.

208. The method of any of claims 172-207, wherein the article provides sustained release of the therapeutic agent over a period of 12 to 72 hours.

209. The method of any of claims 172-208, wherein the article is applied once daily.

210. The method of any of claims 172-209, wherein the treatment reduces inflammation in the affected skin area.

211. The method of any of claims 172-210, wherein the treatment improves skin barrier function.

212. The method of any of claims 172-211, wherein the treatment reduces pruritus associated with the clinical condition.

213. The method of any of claims 184-188, wherein the treatment promotes hair regrowth.

214. The method of any of claims 189-195, wherein the treatment reduces sebum production.

215. The method of any of claims 189-195, wherein the treatment reduces comedone formation.

216. The method of any of claims 196-201, wherein the treatment reduces melaninATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) production.

217. The method of any of claims 196-201, wherein the treatment lightens existing hyperpigmented areas.

218. The article of any of claims 1-169 for use in a method for the treatment of a wound, radiation-induced skin damage, and inflammation.

219. The article of any of claims 1-169 for use in a method for the treatment of atopic dermatitis.

220. The article of claim 219, wherein the atopic dermatitis is mild to moderate atopic dermatitis.

221. The article of claim 219, wherein the atopic dermatitis is severe atopic dermatitis.

222. The article of claim 219, wherein the atopic dermatitis is localized atopic dermatitis.

223. The article of claim 219, wherein the atopic dermatitis is generalized atopic dermatitis.

224. The article of any of claims 1-169 for use in a method for the treatment of psoriasis.

225. The article of claim 224, wherein the psoriasis is plaque psoriasis.

226. The article of claim 224, wherein the psoriasis is mild to moderate psoriasis.

227. The article of claim 224, wherein the psoriasis is severe psoriasis.

228. The article of claim 224, wherein the psoriasis is localized psoriasis.

229. The article of claim 224, wherein the psoriasis is guttate psoriasis.

230. The article of claim 224, wherein the psoriasis is inverse psoriasis.

231. The article of any of claims 1-169 for use in a method for the treatment of alopecia areata.

232. The article of claim 231, wherein the alopecia areata is patchy alopecia areata.

233. The article of claim 231, wherein the alopecia areata is alopecia totalis.

234. The article of claim 231, wherein the alopecia areata is alopecia universalis.

235. The article of claim 231, wherein the alopecia areata is ophiasis alopecia areata.

236. The article of any of claims 1-169 for use in a method for the treatment of acne.

237. The article of claim 236, wherein the acne is mild to moderate acne.

238. The article of claim 236, wherein the acne is severe acne.

239. The article of claim 236, wherein the acne is inflammatory acne.ATTORNEY DOCKET NO.330304-8010 (KALM-00001-U-USPRV-02) 240. The article of claim 236, wherein the acne is comedonal acne.

241. The article of claim 236, wherein the acne is cystic acne.

242. The article of claim 236, wherein the acne is nodular acne.

243. The article of any of claims 1-169 for use in a method for the treatment of hyperpigmentation.

244. The article of claim 243, wherein the hyperpigmentation is melasma.

245. The article of claim 243, wherein the hyperpigmentation is post-inflammatory hyperpigmentation.

246. The article of claim 243, wherein the hyperpigmentation is solar lentigines.

247. The article of claim 243, wherein the hyperpigmentation is age spots.

248. The article of claim 243, wherein the hyperpigmentation is café-au-lait macules.

249. The article of any of claims 1-169 for use in a method for the treatment of dermatitis.

250. The article of claim 249, wherein the dermatitis is contact dermatitis.

251. The article of claim 249, wherein the dermatitis is seborrheic dermatitis.

252. The article of claim 249, wherein the dermatitis is allergic dermatitis.

253. The article of claim 249, wherein the dermatitis is irritant dermatitis.

254. The article of any of claims 218-253, wherein the polymer adhesive system is an adhesive water insoluble polymer.

255. The article of any of claims 218-254, wherein the therapeutic agent comprises glycyrrhizic acid, 18β-glycyrrhetinic acid, curcumin, enoxolone, adapalene, cannabinoids, and methylnissolin.

256. The article of any of claims 218-255, wherein the polymer adhesive system is an elastomeric silicone adhesive.

257. The article of any of claims 218-256, wherein the therapeutic agent is present in an amount from 0.1 to 10.0% w / w.

258. The article of any of claims 218-257, wherein the matrix layer further comprises a second therapeutic agent selected from an antibiotic, an antifungal, an antimicrobial, an NSAID, a corticosteroid, or combinations thereof.

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