Topical composition containing JANUS kinase inhibitor

Abstract

The present invention describes a topical veterinary solution composition comprising a JAK inhibitor, preferably olatinib or a pharmaceutically acceptable salt thereof, for use in an animal, preferably a canine, for the treatment of skin conditions such as allergic dermatitis, atopic dermatitis, pruritus and / or hot spots.

Description

Technical Field

[0001] Described herein are topical compositions comprising a Janus kinase (JAK) inhibitor (JAKi); and in particular, N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methanesulfonamide (oclacitinib) or a pharmaceutically acceptable salt thereof (e.g., the maleate salt). Background Art

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine kinases and serine / threonine kinases. Inappropriate kinase activity, caused by mutation, overexpression or inappropriate regulation, dysregulation or deregulation, and overproduction or underproduction of growth factors or cytokines, is associated with numerous diseases, including but not limited to cancer, allergies, asthma and other respiratory diseases, autoimmune diseases, and inflammatory diseases. Inappropriate kinase activity triggers a variety of biological cellular responses related to cell growth, cell differentiation, survival, apoptosis, mitosis, cell cycle control, and cell motility, which are associated with the above-mentioned and related diseases.

[0003] Therefore, protein kinases have become an important class of enzymes as targets for therapeutic intervention. Specifically, the JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3 and Tyk-2) plays a central role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253). After binding to its receptor, cytokines activate JAK, which then phosphorylates the cytokine receptor, thereby creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription (STAT) family that ultimately causes gene expression. It is known that a variety of cytokines activate the JAK family.

[0004] Patent applications for topical compositions for other JAK inhibitors have recently been published (e.g., WO2021 / 014453, WO2022 / 013708, and WO2022 / 027041). WO2021 / 014453 describes an emulsion-based topical cream containing tofacitinib, retinoids, menthol, oils, and alcohols. WO2022 / 013708 describes an oil-in-water emulsion containing a JAK inhibitor, white petrolatum (10%), and an antimicrobial agent. WO2022 / 027041 describes a topical oil-in-water emulsion composition containing a JAK inhibitor (SHR0302), laureth-4, and a solvent. Thus, laureth-4 (a synthetic polymer composed of lauryl alcohol and polyethylene glycol) has been shown to enhance the skin permeability of this particular JAK inhibitor. In addition, U.S. patent application US2020-0352965 describes a topical ointment containing 70% white petrolatum as well as tofacitinib and crisaborole. U.S. patent application US2020-0276109 describes an ointment composition containing a JAK inhibitor (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide and diethylene glycol monoethyl ether (DEGMEE). Unlike these compositions based on oil-in-emulsions, creams, and ointments, the present invention describes a solution-based composition that can be easily sprayed on the skin of animals in need.

[0005] Current dosage forms containing oclacitinib include film-coated tablets for oral administration and flavored chewable tablets. In addition to oral administration, oclacitinib needs to be applied externally to control site-specific areas of dermatitis (e.g., hot spots). An earlier patent application publication WO2006 / 069080 only describes the external administration of JAK inhibitors from the large genus of JAK inhibitors; however, the citation does not describe any specific compounds or compositions that can actually be prepared and / or applied externally. Therefore, a topical spray solution composition for animals (particularly canines) has been developed. Summary of the Invention

[0006] The present invention provides a topical solution spray composition comprising a JAK inhibitor. In one aspect, the JAK inhibitor (JAKi) is a 7H-pyrrolo[2,3-d]pyrimidine compound of formula A, i.e.

[0007]

[0008] N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methanesulfonamide (oclacitinib), as a free base or a veterinarily acceptable salt thereof. The preferred salt form of Formula A is the maleate salt.

[0009] In another aspect, a topical composition is provided, comprising a JAKi compound of Formula (B), Formula (C), or Formula (D) as a free base or a pharmaceutically acceptable salt thereof.

[0010]

[0011] On the other hand, the topical composition comprises a JAKi compound of formula (A), formula (B), formula (C) or formula (D) or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient. The amount of API as described herein is the weight of the free base of the medicament, that is, excluding the total weight of the compound when associated with a pharmaceutically acceptable salt. For example, 10 mg / mL of formula (A) compound is based on the amount of the free base of the compound. On the other hand, the topical composition comprises a JAKi compound of formula (A) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. On the other hand, the topical composition comprises a JAKi compound of formula (B) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. On the other hand, the topical composition comprises a JAKi compound of formula (C) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. On the other hand, the topical composition comprises a JAKi compound of formula (D) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In one aspect, pharmaceutically acceptable excipients include a mixture of solvents or solvents. On the other hand, pharmaceutically acceptable excipients include a mixture of solvents or solvents, and optional surfactants, antioxidants and pH adjusting agents. On the other hand, said composition includes a mixture of solvents selected from glycols, glycol ethers, alcohols, dimethyl sulfoxide and water; and optional surfactants, antioxidants and pH adjusting agents. On the other hand, said composition includes a mixture of solvents selected from glycols, glycol ethers, dimethyl sulfoxide and water; and optional surfactants, antioxidants and pH adjusting agents. On the other hand, said composition includes a mixture of solvents selected from the following: propylene glycol; glycol ethers selected from the group consisting of dipropylene glycol monomethyl ether (DPGMME), diethylene glycol monoethyl ether (DEGMEE) and diethylene glycol monobutyl ether (DEGMBE); dimethyl sulfoxide; alcohol; water; and optional surfactants, antioxidants and pH adjusting agents. On the other hand, said composition comprises a mixture of solvents selected from the following: propylene glycol; a glycol ether selected from DPGMME, DEGMEE or DEGMBE; dimethyl sulfoxide; water; and optional surfactants, antioxidants and pH regulators. On the other hand, said solvent mixture comprises propylene glycol; a glycol ether selected from DPGMME, DEGMEE or DEGMBE; dimethyl sulfoxide; ethanol and water; and optional surfactants, antioxidants and pH regulators. On the other hand, said solvent mixture comprises propylene glycol; a glycol ether selected from DPGMME, DEGMEE or DEGMBE; dimethyl sulfoxide and water; and optional surfactants, antioxidants and pH regulators. On the other hand, said solvent mixture comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol and water; and optional surfactants, antioxidants and pH regulators.On the other hand, the solvent mixture comprises propylene glycol, DEGMEE, dimethyl sulfoxide and water; and optionally a surfactant, an antioxidant and a pH adjuster. On the other hand, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, a surfactant; and optionally an antioxidant and a pH adjuster. On the other hand, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, a surfactant; and optionally an antioxidant and a pH adjuster. On the other hand, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, a surfactant and an antioxidant, and optionally a pH adjuster. On the other hand, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, a surfactant and an antioxidant, and optionally a pH adjuster. On the other hand, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, a surfactant, an antioxidant and a pH adjuster. On the other hand, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, a surfactant, an antioxidant and a pH adjuster. On the other hand, said composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, antioxidant and pH adjusting agent. On the other hand, said composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, antioxidant and pH adjusting agent. On the other hand, said composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water and antioxidant. On the other hand, said composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water and antioxidant. On the other hand, the antioxidant is BHT or BHA and the pH adjusting agent is sodium hydroxide. On the other hand, said composition comprises about 1-15mg / mL of formula (A), formula (B), formula (C) or formula (D) compound or its pharmaceutically acceptable salt; about 0-15w / v% ethylene glycol; about 10-40w / v% glycol ether; about 0-15w / v% alcohol; about 25-50w / v% DMSO; and water; and optional surfactant, antioxidant and pH adjusting agent. On the other hand, the composition comprises about 1 mg / mL to about 10 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 0 w / v% to about 15 w / v% of a glycol; about 10 w / v% to about 40 w / v% of a glycol ether; about 0 w / v% to about 15 w / v% of an alcohol; about 25 w / v% to about 50 w / v% of DMSO; and water; and optionally a surfactant, an antioxidant, and a pH adjuster. On the other hand, the composition comprises about 1 mg / mL to about 10 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 1 w.v% to about 10 w / v% of a glycol; about 20 v / v% to about 35 w / v% of a glycol ether; about 0 w / v% to about 10 w / v% of an alcohol; about 30 w / v% to about 50 w / v% of DMSO; and water; and optionally a surfactant, an antioxidant, and a pH adjuster.In another aspect, the composition comprises from about 1 mg / mL to about 10 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; from about 1 w / v% to about 10 w / v% of propylene glycol; from about 20 w / v% to about 35 w / v% of a glycol ether selected from DPGMME, DEGMEE, and DEGMBE; from about 0 w / v% to about 10 w / v% of an alcohol; from about 30 w / v% to about 45 w / v% of DMSO; and water; and optionally, a surfactant, an antioxidant, and a pH adjuster. On the other hand, the composition comprises about 1 mg / mL to about 10 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 2 w / v% to about 8 w / v% of propylene glycol; about 25 w / v% to about 35 w / v% of a glycol ether selected from DPGMME, DEGMEE and DEGMBE; about 0 w / v% to about 10 w / v% of ethanol; about 30 w / v% to about 45 w / v% of DMSO; and water; and optionally, about 0 w / v% to about 6 w / v% of. and antioxidants BHA or BHT and a pH adjuster. In another aspect, the composition comprises about 1 mg / mL to about 10 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 2 w / v% to about 8 w / v% of propylene glycol; about 25 w / v% to about 35 w / v% of DEGMEE; about 0 w / v% to about 10 w / v% of ethanol; about 30 w / v% to about 45 w / v% of DMSO; and water; and optionally BHA or BHT and a pH adjuster. On the other hand, the composition comprises about 1 mg / mL to about 10 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 2 w / v% to about 8 w / v% propylene glycol; about 25 w / v% to about 35 w / v% DEGMEE; about 0 w / v% to about 10 w / v% ethanol; about 30 w / v% to about 45 w / v% DMSO; water; and BHA or BHT; and an optional pH adjusting agent. On the other hand, the composition comprises about 1 mg / mL to about 10 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 2 w / v% to about 8 w / v% propylene glycol; about 25 w / v% to about 35 w / v% DEGMEE; about 0 w / v% to about 10 w / v% ethanol; about 30 w / v% to about 45 w / v% DMSO; water; BHA or BHT; and a pH adjusting agent. In all aspects of the invention; about 0 w / v% can be zero w / v% (i.e., not included in the composition). On the other hand, the composition comprises about 1 mg / mL to about 5 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 2 w / v% to about 8 w / v% of propylene glycol; about 25 w / v% to about 35 w / v% of DEGMEE; about 30 w / v% to about 45 w / v% of DMSO; water; BHA or BHT; and a pH adjuster, which is sodium hydroxide, and wherein the pH range is about 4.8 to 6.0. On the other hand, the composition comprises about 1 mg / mL to about 5 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 2 w / v% to about 8 w / v% propylene glycol; about 25 w / v% to about 35 w / v% DEGMEE; about 40 w / v% DMSO; water; BHA or BHT; and a pH adjuster, which is sodium hydroxide, and wherein the pH range is about 4.8 to 6.0. On the other hand, the composition comprises about 1 mg / mL to about 5 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 5 w / v% propylene glycol; about 30 w / v% DEGMEE; about 40 w / v% DMSO; water; BHA or BHT; and a pH adjuster, which is sodium hydroxide, and wherein the pH range is about 4.8 to 6.0.On the other hand, the composition comprises about 1 mg / mL to about 5 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 5 w / v% propylene glycol; about 30 w / v% DEGMEE; about 35 w / v% DMSO; about 1 w / % to about 5 w / v% ethanol, water; BHA or BHT; and a pH adjuster, which is sodium hydroxide, and wherein the pH range is about 4.8 to 6.0. On the other hand, the composition comprises about 1 mg / mL to about 5 mg / mL of a compound of formula (A) or a pharmaceutically acceptable salt thereof; about 5 w / v% propylene glycol; about 30 w / v% DEGMEE; about 40 w / v% DMSO; about 1 w / % to about 5 w / v% ethanol, water; BHA or BHT; and a pH adjuster, which is sodium hydroxide, and wherein the pH range is about 4.8 to 6.0. On the other hand, the composition of the present invention is externally applied to an animal in need thereof to treat or prevent a skin disease or condition. In another aspect, the skin disease or condition is atopic dermatitis, allergic dermatitis, pruritus, or hot spots. In another aspect, the composition of the present invention is applied externally to an animal in need thereof to treat or prevent atopic dermatitis, allergic dermatitis, or hot spots. In another aspect, the composition of the present invention is applied externally to an animal in need thereof to treat or prevent atopic dermatitis or allergic dermatitis. In another aspect, the composition of the present invention is applied externally to an animal in need thereof to treat or prevent atopic dermatitis. In another aspect, the composition of the present invention is applied externally to an animal in need thereof to treat or prevent allergic dermatitis. In another aspect, the composition of the present invention is applied externally to an animal in need thereof to treat hot spots. In another aspect, the animal is an equine, canine, or feline. In another aspect, the animal is a canine.

[0012] In another aspect, the composition of the invention is used in the preparation of a medicament for external administration to an animal in need thereof for the treatment or prevention of atopic dermatitis, allergic dermatitis, or hot spots.

[0013] In another aspect, the compositions of the present invention can be co-administered with another pharmaceutical agent administered orally, topically, or by injection; and / or co-administered with a cleaning agent. Non-limiting examples of other pharmaceutical agents include nutritional supplements, antiparasitics, antibacterials, antifungals, anti-inflammatory drugs, and dermatological drugs (e.g., JAK inhibitors, cyclosporine, prednisone, dexamethasone, betamethasone, etc.). Non-limiting examples of cleaning agents include, for example: hydrogen peroxide, medicated shampoo, chlorhexidine gluconate, benzoyl peroxide, etc. DETAILED DESCRIPTION

[0014] definition

[0015] For purposes of the present invention, as described and claimed herein, the following terms and phrases are defined below:

[0016] When used in conjunction with a measurable numerical variable, "about" refers to the indicated value of the variable and all values ​​of the variable that are within the experimental error range of the indicated value (e.g., within a 95% confidence interval about the mean) or within 10% of the indicated value, whichever is greater. In some jurisdictions, this term is considered vague and, therefore, can be readily deleted from a claim to ensure the claimed scope.

[0017] As used herein, unless otherwise indicated, "active pharmaceutical ingredient" (API) or "active agent" are interchangeable and mean that the ingredient is a biologically active drug, such as a JAK inhibitor.

[0018] Unless otherwise indicated, "animal" as used herein refers to an individual animal, and the individual animal is a mammal. Specifically, mammal refers to humans and non-human vertebrates that are taxonomically classified as belonging to the class Mammalia. Non-exclusive examples of non-human animals include companion animals and livestock. Non-limiting examples of companion animals include: dogs (canines), cats (felines), and horses (equines). A preferred companion animal is a dog. Non-exclusive examples of livestock include: pigs (suicides), rabbits (leporids), goats (ovines), sheep (ovines), and cattle (bovines).

[0019] Unless otherwise indicated, as used herein, "clinical signs" refers to observable or measurable conditions or behaviors in an animal that indicate a disease, condition, or symptom. Clinical signs may be those symptoms, conditions, or behaviors measured in a known or established diagnostic assessment. For example, a diagnostic assessment for determining allergic dermatitis or atopic dermatitis may be performed by a visual analog scale (VAS) score or clinical assessment of the condition, or by an established scoring system such as the Canine Atopic Dermatitis Extent and Severity Index (CADESI) score. Non-limiting examples of some clinical signs of atopic dermatitis, allergic dermatitis, or hot spots that can sometimes be used in such an assessment or scoring system include: pruritus, ranging from extremely severe (as exhibited in companion animals such as dogs by almost continuous scratching, chewing, licking, regardless of what is happening) to severe (as exhibited by prolonged episodes of pruritus during waking hours, as well as episodes of pruritus at night and / or when eating, playing, or exercising) to moderate (as exhibited by frequent episodes of pruritus) to very mild (occasional episodes of pruritus); presence of pustules or skin wrinkles; presence of skin lesions; pruritus; erythema; erosions, excoriations, and / or spontaneous alopecia; presence of papules and / or crusts; lichenification and / or hyperpigmentation.

[0020] Unless otherwise indicated, as used herein, "the composition of the present invention" refers to a composition as a solution, which comprises a JAK inhibitor of formula (A), formula (B), formula (C) or formula (D) or a pharmaceutically acceptable salt thereof; preferably formula (A), and at least one pharmaceutically acceptable excipient selected from the group consisting of glycols, glycol ethers, DMSO and water, and optionally further comprises an alcohol, a surfactant, an antioxidant and a pH adjuster.

[0021] Unless otherwise indicated, as used herein, "hot spot" refers to an inflammatory skin lesion or skin irritation in an animal that may be aggravated by scratching and licking and is also known as suppurative wound dermatitis or acute moist dermatitis. A hot spot is a red, inflamed skin lesion.

[0022] Unless otherwise indicated, "pharmaceutically acceptable" as used herein means that the substance or composition must be compatible chemically and / or toxicologically with the other ingredients that make up the composition and / or the animal to be treated therewith. The term "pharmaceutically" encompasses "veterinarily acceptable".

[0023] As used herein, "pharmaceutically acceptable salt" refers to any salt suitable for pharmaceutical use in animals, preferably acetate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edetate, estoglutarate, essulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, glycerophosphate, hexafluorophosphate, hydroxybenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylsulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, sucrose salt, stearate, succinate, tartrate, toluenesulfonate, or trifluoroacetate, unless otherwise indicated. Preferably, the pharmaceutically acceptable salt of oclacitinib is maleate (or maleate salt).

[0024] As used herein, unless otherwise indicated, "amount sufficient" or "qs" refers to a sufficient amount; or in other words, the amount of solvent (eg, water) required to bring the final w / v % of the solution to 100%.

[0025] Unless otherwise indicated, as used herein, "therapeutically effective amount" refers to an amount of a JAK inhibitor, preferably oclacitinib (free base), useful for treating or preventing a JAK-associated disease, condition or disorder, i.e., a disease or condition caused by or associated with immune system dysfunction or immune system dysregulation, in an animal; including externally administering to the animal an effective amount of a JAK inhibitor described herein.

[0026] As used herein, "treating" or "treatment" means controlling, curing, or preventing the progression of the indicated condition or disease, unless otherwise indicated. The terms "controlling," "curing," or "treating" a condition or disease include: (1) preventing the condition or disease, i.e., causing clinical symptoms or signs of the disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or exhibit symptoms / signs of the disease; (2) inhibiting the disease, i.e., arresting or slowing the progression of the disease or its clinical symptoms or signs; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms or signs.

[0027] "Symptoms" of a disease or condition are any of those symptoms associated with the disease or condition known to those of ordinary skill in the art. In the case of atopic dermatitis, allergic dermatitis, flea allergy dermatitis and scabies, symptoms include, for example: pruritus, itching and skin lesions. In many cases, "symptoms" of a disease or condition, such as atopic dermatitis or allergic dermatitis, are also "clinical signs." In the case of allergic dermatitis, allergic dermatitis can be flea allergy dermatitis, i.e., "FAD" (also referred to as "flea allergy dermatitis," "flea bite dermatitis" ("FBD") or "flea-associated dermatitis"), food allergy dermatitis, contact dermatitis, or allergic dermatitis associated with scabies (Sarcoptes scabiei) (i.e., scabies (sarcoptic mange)). Other indications and conditions that can be treated by the method comprising the dosage regimen described herein include any indication or condition that can be treated by administering a JAK inhibitor, including those related to JAK-1, JAK-2 or JAK-3. Such indications and conditions include cancer, asthma, atopic dermatitis, allergic dermatitis, autoimmune thyroid disorders, pruritus, chronic respiratory diseases and other indications where immunosuppression or immunomodulation is desired.

[0028] As used herein, percentages of components of a composition refer to weight / volume percentages of the total weight of the composition and are referred to as "w / v %", which defines the weight expressed as a percentage according to the formula m i / m tot x 100 determines the mass fraction of the composition component, where m i is the mass of the substance of interest present in the composition, and m tot is the total mass of the composition.

[0029] The pharmacokinetics and pharmacodynamics (PK / PD) of orally administered oclacitinib (0.4-0.6 mg / kg) are well understood. Plasma concentrations greater than 12 ng / mL have been shown to be effective in reducing IL-31-induced itch.14 C-Oclacitinib studies determined that a single 0.4 mg / kg dose can achieve an average skin concentration of 212 ng equivalents / gram of tissue. The efficacy of the compositions described herein was evaluated using the house dust model (HDM). External HDM challenge resulted in exfoliative lesions and erythema at the challenge site. In one study, beagle dogs (8 / group) were externally administered placebo (normal saline, T01), 0.15 mg / mL triamcinolone acetonide (T02), 7.5 mg / mL oclacitinib maleate (T03), and 10 mg / mL oclacitinib maleate (T04). The weight of the drug in T02-T04 is the amount of the free base. Animals received approximately 1 mL of each solution according to the treatment / dosing regimen shown in Table 1 below.

[0030] Table 1. Treatment options

[0031]

[0032] aCommercially available dosing regimen

[0033] b 0.03 mg / kg daily for 7 days, then 0.015 mg / kg daily

[0034] Assessments were observed daily until day 41. Colorimeter measurements provided quantitative erythema scores. After approximately 1 month of dosing, both concentrations of oclacitinib achieved significant reductions in erythema compared to saline. As early as day 12, triamcinolone acetonide spray had significantly less erythema reduction compared to saline, which was consistent with the gradual reduction in dosing frequency and continued to be compared at multiple time points throughout the observation period. On days 12, 14, 19, 24-26, 28-33, and 35-41, triamcinolone acetonide-treated animals had significantly less erythema reduction compared to those treated with saline (P≤0.0912). On day 36, animals administered 7.5 mg / mL of oclacitinib had significantly greater erythema reduction compared to those administered saline (P=0.0993). On days 27, 28, and 36, animals dosed with 10 mg / mL of oclacitinib had significantly greater reductions than animals dosed with saline (p≤0.0948). Lesions were observed and scored based on the severity of erythema, papules, and excoriations at the challenge site. The total lesion score after challenge was significantly higher for the triamcinolone acetonide and oclacitinib treated groups compared to the saline group. On days 4, 8, 10, and 11, triamcinolone acetonide treated animals had significantly greater reductions in lesion scores compared to saline treated animals, but had significantly less reductions on day 35. On days 4, 7, 11, 26, 27, 30, and 39, animals treated with 7.5 mg / mL of oclacitinib spray had significantly greater reductions in lesion scores compared to animals treated with saline. Animals treated with 10 mg / mL oclacitinib spray had significantly greater reductions in lesion scores than saline-treated animals on days 7-11, 26, 30, and 32-34. After the dosing period, the oclacitinib-treated group continued to demonstrate a significant reduction in lesion scores compared to the other treatment groups. Animals treated with 10 mg / mL oclacitinib had a significantly lower area under the curve (AUC) for total lesion scores compared to animals treated with saline (p < 0.08). For similar AUC lesion scores, no other treatments tested were significantly different from the saline control.

[0035] In a subsequent study, animals received 2.5-10 mg / mL oclacitinib by applying a total of approximately 0.25 to 0.5 mL of topical solution 2-3 times to an area of ​​the skin. This study also provided acceptable skin concentrations of oclacitinib.

[0036] External application includes the skin treatment that is easily reached by topical application, to produce local and / or systemic effect.Term " externally " is used with its conventional meaning in this article, refers to the route of administration that wherein active substance is sent across a part of the surface of skin, such as being delivered to one or more in subcutaneous tissue, dermis and epidermis, including stratum corneum, stratum germinativum, stratum spinosum and stratum basale.Therefore, the topical composition with API is formulated as any position applied to animal.In some respects, skin is healthy and complete skin.In other aspects, skin can be wherein one or more layers (for example, stratum corneum, stratum germinativum, stratum spinosum, stratum basale etc.) may be sick or inflamed skin.In some aspects, API is delivered topically to application site.Term " topically " is used with its conventional meaning in this article, means that API is delivered near application site or near below. Based on the size of the applicator, the volume applied per pump (stroke) can range from about 0.05 to about 0.3 mL; or about 0.08 to about 0.25 mL; or about 0.1 to about 0.25 mL; or about 0.15 to about 0.25 mL; or about 0.1 to about 0.2 mL. In addition, depending on the distance (e.g., 3, 4, 5, 6 inches) from the skin when pumping (e.g., 1x, 2x, 3x, etc.), the composition can cover an area of ​​about 10 cm 2 to about 125cm 2 For example, a 0.2 mL volume spray can cover approximately 25 cm at approximately 3-6 inches. 2 ; or cover about 40cm at about 4-7 inches 2 ; or cover about 55cm at about 5-8 inches 2 Similarly, a 0.4 mL (2x) volume spray can cover approximately 50 cm at approximately 4-6 inches. 2 If the composition contains an API at a concentration of 5 mg / mL, a single 0.2 mL pump will spray an amount of approximately 1 mg of API, and if the area of ​​spraying is approximately 25 cm 2 , the amount of API applied to the site will be about 1 mg / 25 cm 2 or 0.04 mg / cm 2 In general, the drug concentration applied to the skin will depend on the composition API concentration (mg / mL), pump volume (mL), number of pumps, distance from the skin (inches), and skin area to be treated (cm 2) and change. In some aspects, API diffuses up to 12cm or shorter from the application site; 10cm or shorter; 8cm or shorter; 6cm or shorter; 4cm or shorter; 2cm or shorter; or diffuses 1cm or shorter from the application site. In other words, in these aspects, the purpose of topical composition application is to deliver API to a position at the application site or within a very small distance from the application site. The penetration depth of the API topically applied to the skin at the application site can also vary according to the components of the composition. In some cases, the external application of API may also cause systemic absorption of API.

[0037] Whenever a numerical range is indicated herein, it is intended to include any cited numeral (fractional or integral) within the indicated range. The terms "comprises" and "comprising" and "includes" and "including" mean "including but not limited to." As used herein, the indefinite articles "a" and "an" mean at least one or one or more, unless the context clearly indicates otherwise.

[0038] Clinical signs of allergic and atopic dermatitis in the skin include, for example, erythema (redness) and alopecia (hair loss). The skin lesions associated with allergic and atopic dermatitis can vary significantly in clinical settings. The most common locations for localized skin lesions are the ears, abdomen, inguinal area, and / or feet. In addition, there may be secondary superficial bacterial and / or yeast infections, leading to the development of suppurative traumatic dermatitis (commonly known as hot spots). Oral administration of a systemic agent may be associated with Unlike oclacitinib maleate, topical therapies aim to provide treatment to very specific areas associated with atopic and / or allergic dermatitis and hot spots. Topical treatments will provide higher skin concentrations in the targeted area, resulting in improved efficacy. Therefore, topical oclacitinib compositions must penetrate the skin and achieve adequate skin concentrations.

[0039] In numerous PK studies, systemic plasma and skin concentrations of various compositions of the invention were evaluated 24 hours after administration; including compositions containing oclacitinib or oclacitinib maleate with API concentrations ranging from 1-10 mg / mL oclacitinib. Compositions tested to date have demonstrated prolonged absorption for at least 72 hours after a single dose and low topical bioavailability of less than 10%, with single-dose skin concentrations being approximately 10% of that observed after a single oral dose. 14 At least 20-80 times the level observed in the C study. 14The oclacitinib study determined that a 0.4 mg / kg oral dose of oclacitinib achieved a mean skin concentration of 212 ng equivalents / gram. As described above, permeation and permeation studies with compositions comprising glycols, glycol ethers, and DMSO achieved single-dose skin concentrations (28.4-54.5 μg / g) that were higher than those achieved following oral administration and were well above the reported oclacitinib IC values ​​for pro-inflammatory and pruritic cytokines. 50 .

[0040] Comparisons across studies showed that skin concentrations 24 hours after dosing were at least five-fold higher than after repeated dosing. Systemic plasma concentrations in single-dose and repeat-dose studies demonstrated prolonged absorption, with a terminal phase not evident 10 days after dosing. The rate and amount of topical absorption can be a nonlinear function of the composition's API concentration. The topical compositions of the present invention minimize systemic plasma concentrations of oclacitinib while maintaining high skin concentrations. PK following topical administration of oclacitinib maleate and oclacitinib free base formulations was comparable. Studies to date and the formulations described herein demonstrate that the composition delivers skin concentrations greater than those observed with oral administration. Following a single dose, oclacitinib formulations with an oclacitinib concentration of 7.5 mg / mL exhibited prolonged absorption, with a duration greater than 7 days. Topical single-dose bioavailability was low, less than 5% when administered to areas limiting oral exposure from licking. However, low bioavailability does not equate to low exposure. Accumulation in the skin and plasma was observed after multiple daily applications. Systemic levels after multiple daily dosing were at concentrations shown to be effective in reducing IL-31-induced itch. Formulations with lower oclacitinib concentrations had lower systemic exposure.

[0041] The resulting composition of the present invention is a solution. It can be applied as an aerosol (containing a propellant (e.g., carbon dioxide, hydrofluoroalkanes, etc.)) or a spray. Preferred topical compositions are solutions that can be sprayed.

[0042] According to the physiology of application site and experimenter and the skin surface area of ​​applying topical composition, the amount of active agent in composition can change, and in some cases, the amount range of active agent is about 0.5mg / mL to about 15mg / mL, or about 1mg / mL to about 15mg / mL, or about 1mg / mL to about 10mg / mL; Such as, for example, about 1mg / mL, about 1.5mg / mL, about 2mg / mL, about 2.5mg / mL, about 3mg / mL, about 3.5mg / mL, about 4mg / mL, about 4.5mg / mL, about 5mg / mL, about 5.5mg / mL, about 6mg / mL, about 6.5mg / mL, about 7mg / mL, about 7.5mg / mL, about 8mg / mL, about 8.5mg / mL, about 9mg / mL, about 9.5mg / mL and about 10mg / mL.Based on weight / volume, the amount of active agent is about 0.05w / v% to about 1.5w / v% of the gross weight of topical composition.

[0043] The composition is storage stable under standard VICH storage conditions, eg, packaged sterile conditions at room temperature, for a period of time, eg, 1 month or longer, 3 months or longer, 6 months or longer, or 12 months or longer.

[0044] The topical compositions of the present invention comprise the use of a JAKi in combination with one or more pharmaceutically acceptable excipients. The excipients provide a means for solubilizing and stabilizing the JAKi compound and for increasing the permeability of the JAKi across and through the skin of the animal being treated with the topical composition.

[0045] The topical composition of the present invention comprises a JAK inhibitor. In another aspect, the JAK inhibitor is selected from the group consisting of: Formula (A) (oclacitinib; N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methanesulfonamide); Formula (B) (ibrutinib; 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)-azetidin-3-yl) acetonitrile); Formula (C) (1-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((2-fluoro-6-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide) and its stereoisomers; or Formula (D) (1-[(3R,4S)-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((2-fluoro-6-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide); or a pharmaceutically acceptable salt thereof. Preferred topical compositions of the present invention comprise oclacitinib (Formula A) or a pharmaceutically acceptable salt thereof, and in particular oclacitinib maleate. The chemical structure of the JAK inhibitor of Formula (AD) is shown below:

[0046] Chemical structure:

[0047]

[0048] The compositions of the present invention comprising a JAK inhibitor can be formulated in a conventional manner using one or more pharmaceutically acceptable excipients that aid in processing the API into a formulation that can be used for external administration. Pharmaceutically acceptable excipients are generally known to those skilled in the art and are therefore encompassed by the present invention. Such excipients are described, for example, in "Remingtons Pharmaceutical Sciences," 19th edition, Mack Pub. Co., New Jersey (1995).

[0049] As described above, exemplary dosages of JAKi in topical compositions can be in the range of about 0.5 mg / mL to about 15 mg / mL; or about 1 mg / mL to about 15 mg / mL; or about 1 mg / mL to about 10 mg / mL. Topical compositions can contain about 1 mg / mL, about 2.5 mg / mL, about 5 mg / mL, about 7.5 mg / mL, or about 10 mg / mL. Typical administration frequencies of the composition can be once daily, twice daily, or as needed, depending on the size and condition of the animal.

[0050] The pharmaceutically acceptable excipient that can be used for said composition comprises at least one solvent or a mixture of solvents. The solvent that can be used for preparing the composition of the present invention can be selected from the group consisting of the following: glycol, glycol ether, glyceride, alcohol, dimethyl sulfoxide, water and mixtures thereof. Glycol and glycol ether and other solvents as described herein can also contribute to enhancing API skin penetration. Non-limiting examples of glycol include glycerol (glycerine), ethylene glycol, propylene glycol, butylene glycol and low molecular weight polyethylene glycol (PEG), such as PEG200, PEG300 and PEG400. Preferred glycol is propylene glycol or glycerine. More preferred glycol is propylene glycol. The amount range of glycol in the composition can be 0w / v% to about 15w / v%, or about 1w / v% to about 10w / v%, or about 2w / v% to about 8w / v% of the total weight of the composition. Non-limiting examples of glycol ether include: monoglycol ether, diglycol ether and triglycol ether. Non-exclusive examples of monoglycol ethers include: ethylene glycol monomethyl ether (EGMME (EGME)), ethylene glycol monoethyl ether (EGMEE or EGEE), ethylene glycol monopropyl ether (EGMPE or EGPE), ethylene glycol monoisopropyl ether (EGMIE or EGIE), propylene glycol mono-tert-butyl ether (PGMBE or PGBE), propylene glycol propyl ether (PGMPE or PGPE), propylene glycol monomethyl ether (PGMME or PGME), propylene glycol monoethyl ether (PGMEE or PGEE), etc. Non-exclusive examples of diglycol ethers include: diethylene glycol monomethyl ether (DEGMME or DEGME), diethylene glycol monoethyl ether (DEGMEE or DEGEE ), dipropylene glycol methyl ether (DPGMME or DPGME), diethylene glycol monobutyl ether (DEGMBE or DEGBE (butyl diethylene glycol)), dipropylene glycol monomethyl ether (DPGMME or DPGME), diethylene glycol dimethyl ether (DEGDME) etc. The non-exclusive example of triglycol includes: tripropylene glycol monomethyl ether (TPGMME or TPGME), tripropylene glycol monoethyl ether (TPGMEE or TBGEE), triethylene glycol monoethyl ether (TEGMEE or TEGEE), triethylene glycol monomethyl ether (TEGMME or TEGME) etc. Glycol ether also includes acetylated glycol ether, such as diethylene glycol monoethyl ether acetate and diethylene glycol monobutyl ether acetate. Preferred glycol ether is selected from the group consisting of the following: DEGMME, DEGMEE, DEGMBE and DPGMME and mixtures thereof. Preferred glycol ether is DPGMME, DEGMEE and DEGMME. Preferred glycol ether is DPGMME and DEGMEE. The most preferred glycol ether is DEGMEE.The amount of glycol ether in the composition may range from about 10 w / v% to about 40 w / v%, or from about 20 w / v% to about 35 w / v%, or from about 25 w / v% to about 35 w / v%, based on the total weight of the composition.

[0051] Alcohol refers to C1-C18 Aliphatic alcohols also refer to C4-C6 cyclic alcohols and aromatic alcohols. Alcohols also include fatty alcohols. Non-limiting examples of aliphatic alcohols include ethanol, propanol, isopropanol, butanol, pentanol, hexanol, decanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, octyldecyl alcohol, and the like. Non-limiting examples of cyclic alcohols and aromatic alcohols include cyclobutanol, cyclopentanol, cyclohexanol, benzyl alcohol, and the like. Preferred alcohols are ethanol, butanol, isopropanol, and benzyl alcohol. A more preferred alcohol is ethanol. The amount of alcohol in the composition can range from about 0 w / v% to about 15 w / v%, or from about 0 w / v% to about 10 w / v%; or from about 1 w / v% to about 10 w / v%. If used, the preferred alcohol is ethanol. In one aspect, the composition of the present invention does not contain ethanol. In another aspect, the amount of ethanol in the composition is 5 w / v%. In another aspect, the amount of ethanol in the composition is 10 w / v%.

[0052] The amount of DMSO in the composition can range from about 25 w / v% to about 50 w / v%, or from about 30 w / v% to about 50 w / v%, or from about 30 w / v% to about 45 w / v%, or from about 35 w / v% to about 45 w / v%, of the total weight of the composition. The amount of water added to the composition is a "sufficient amount". A sufficient amount refers to the amount of water added to the composition so that the total weight of the composition reaches 100%. The amount of water can range from about 10 w / v% to about 35 w / v%, or from about 15 w / v% to about 30 w / v%; or from about 15 w / v% to about 25 w / v%, of the total weight of the composition.

[0053] Additional pharmaceutically acceptable solvents that can be used in the composition include: terpene alkaloids (e.g., limonene, eucalyptol, menthol); pyrrolidones (e.g., 2-pyrrolidone, N-methylpyrrolidone, and azone), glycerol formal, tetraethylene glycol (glycofurol), tetrahydrofurfuryl alcohol, glycerol acetone, dimethyl isosorbide, citrate buffer, polyethylene glycol hydroxyglyceryl stearate (PEG-40 castor oil; Kolliphor ) and dimethylacetamide (DMA).

[0054] In the present invention, the composition may further comprise a pharmaceutically acceptable excipient, which is an anionic surfactant, a cationic surfactant or a nonionic surfactant, or a mixture thereof. Non-limiting examples of these surfactants include: alkaline stearates (e.g., sodium stearate, potassium stearate or ammonium stearate, calcium stearate and triethanolamine stearate), alkyl sulfates (e.g., sodium lauryl sulfate, sodium dodecyl sulfate, sodium cetyl sulfate), fatty acid sorbitan esters (e.g., 20), polyoxyethylated sorbitan esters (e.g. polysorbate 80), polyoxyethylated alkyl ethers, polyethylene glycol stearate, polyoxyethylated derivatives of castor oil (e.g. EL), polyglyceryl esters, caprylocaproyl macrogol-8 glyceryl HS15 (polyethylene glycol 15 hydroxystearate or polyoxyethylene 15 hydroxystearate) and the like. A preferred surfactant is caprylocaproyl macrogol-8 glyceride. The amount of surfactant in the composition can range from about 0 w / v% to about 6 w / v%, or from about 0 w / v% to about 5 w / v%, or from about 0 w / v% to about 2 w / v%, based on the total weight of the composition.

[0055] In another aspect of the present invention, the composition can further include a spreading agent (e.g., silicone, indapamide, etc.); an antioxidant (e.g., ascorbic acid, tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, thioglycerol, citric acid, etc.); a pH regulator (e.g., sodium hydroxide (NaOH), potassium hydroxide (KOH), triethanolamine, ethanolamine, hydrochloric acid (HCl), etc.). The antioxidant is preferably present in an amount of about 0.1w / v% to about 0.3w / v% or about 0.1w / v% to about 0.2w / v% or about 0.1w / v% to about 0.15w / v% of the total weight of the composition. The pH range of the topical composition of the present invention can be about 4.5 to 7.5. The preferred pH range of the topical composition is about 5 to 6.5.

[0056] In another aspect, the composition of the present invention may further comprise a fragrance. Non-limiting examples of fragrances include jasmine, lavender, rose, orchid, lotus, clove, peony, honeysuckle, hibiscus, citrus, sandalwood, vetiver, vanilla, cinnamon, and Burberry. In another aspect, the composition further comprises a fragrance. The amount of the fragrance in the composition may be from about 0 w / v% to about 0.2 w / v% of the total weight of the composition.

[0057] Non-limiting examples of the topical compositions of the present invention are shown in Table 2.

[0058] Table 2. Examples of external use compositions

[0059]

[0060] Each composition optionally comprises an antioxidant (0.1-0.3 w / v%) and the pH is adjusted as needed. The sufficient amount of water ranges from about 10-35 w / v%.

[0061] In another aspect, the topical compositions of the present invention can be administered alone or in combination with other pharmaceutical agents, whether orally, parenterally, or externally, which can be administered to animals to aid in the healing of skin disorders or other disorders. For example, other known pharmaceutical agents include, for example, antibiotics (e.g., neosporin, fusidic acid, amikacin, thiostrepton, metronidazole, clindamycin, cephalosporins, fluoroquinolones, tetracyclines, etc.); antifungals (e.g., ketoconazole, sulfonconazole, miconazole, amphotericin, fluconazole, nystatin, etc.); anti-inflammatory drugs (e.g., hydrocortisone, diaminodiphenyl sulfone, triamcinolone acetonide, menthol, nonsteroidal anti-inflammatory drugs (NSAIDS (e.g., meloxicam, flunixin meglumine, carprofen, aspirin, ketoprofen, naproxen, diclofenac, etc.); antiseptic drugs (e.g., chlorhexidine, povidone iodine, chloroxylenol, hexachlorophene, isopropyl alcohol, benzalkonium chloride, hydrogen peroxide, etc.); steroids (e.g., clobetasol propionate, fludrocortisone, betamethasone dipropionate, diflorasone diacetate, desoxymethasone, halobetasol propionate, fluocinolone acetonide, halcinonide, fludrocortisone, dexamethasone, betamethasone valerate, etc.); analgesics (e.g., capsaicin, camphor, menthol, gingerol, lidocaine, bupivacaine, NSAIDS, ibuprofen, etc.).

[0062] As described herein, the topical composition of the present invention can be prepared by conventional means for preparing solutions. First, solvents dimethyl sulfoxide, ethanol, glycol ether (DEGMEE, DEGMME or DEGMBE), propylene glycol and optional Distribute and mix together. Then antioxidant (such as BHA or BHT) and JAKi are added to the solvent mixture in sequence and mixed until dissolved. Alternatively, the activating agent can be dissolved in DMSO before mixing with other solvents, and then optionally add surfactant and antioxidant. As needed, the mixture is pH-adjusted to a pH of about 5.4. The final weight of the composition is adjusted to 100% with water (qs). The final solution is filtered and filled into a spray-type bottle. Each bottle can hold about 30-240mL of the composition of the present invention. For example, the bottle can hold about 30mL, 45mL, 60mL, 90mL, 100mL, 120mL, 150mL, 175mL, 190mL, 200ml, 225mL or 240mL of the composition of the present invention. The bottle can also be held between 30-240mL, such as a volume of 40mL, 80mL, 140mL, 170mL, etc.

[0063] For compositions containing 0.15-0.2 w / v % BHT, the stability of oclacitinib (7.5 mg / mL) at 1 month accelerated stability (40° C. / 75% relative humidity) ranged from about 97.2 to 99.3%.

Claims

1. A topical solution composition comprising a) a JAK inhibitor selected from the group consisting of Compound A, Compound B, Compound C, and Compound D; or a pharmaceutically acceptable salt thereof; b) a pharmaceutically acceptable solvent mixture comprising glycols, glycol ethers, dimethyl sulfoxide, and water; and c) Optional antioxidants and pH adjusters.

2. The composition of claim 1, wherein the JAK inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the glycol is propylene glycol, and the glycol ether is DEGMEE, DPGMME or DEGMBE.

3. The composition of claim 2, wherein the glycol ether is DEGMEE.

4. The composition according to any one of the preceding claims, wherein the composition further comprises an antioxidant and a pH adjuster.

5. The composition of claim 11, wherein the antioxidant is BHA, BHT, or a mixture thereof; and the pH adjuster is NaOH or KOH.

6. The composition of any one of the preceding claims, wherein the amount of the glycol is about 2-8 w / v%; the amount of the glycol ether is about 25 w / v% to about 35 w / v%; and the amount of dimethyl sulfoxide is about 30 w / v% to about 45 w / v% of the total weight of the composition.

7. The composition of claim 6, wherein the amount of the JAK inhibitor is from about 1 mg / mL to about 10 mg / mL.

8. The composition of claim 2, wherein the pharmaceutically acceptable salt is a maleate salt.

9. The composition of any preceding claim, further comprising ethanol in an amount of about 1 w / v % to about 5 w / v % of the total weight of the composition.

10. A topical solution composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof in an amount of about 1 mg / mL to about 5 mg / mL, propylene glycol in an amount of about 2 w / v% to about 8 w / v%, DEGMEE in an amount of about 20 w / v% to about 35 w / v%, DMSO in an amount of about 30 w / v% to about 45 w / v% and water; and optionally an antioxidant and a pH adjuster; and wherein the w / v% is a percentage of the total weight of the composition. The composition according to claim 10 , further comprising an antioxidant and a pH adjuster.

12. The composition of claim 11, wherein the antioxidant is BHA, BHT, or a mixture thereof.

13. The composition of claim 12, wherein the amount of propylene glycol is about 5 w / v%, the amount of DEGMEE is about 30 w / v%, the amount of DMSO is about 40 w / v%, and the antioxidant is BHT; and wherein the pH range of the composition is about 4.8 to 6.

0.

14. Use of the topical solution composition according to any one of the preceding claims in the preparation of a medicament for treating and preventing a skin disorder selected from atopic dermatitis, atopic dermatitis, hot spots, itching and symptoms thereof in a non-human animal in need thereof.

15. A method of treating a skin condition selected from the group consisting of allergic dermatitis, atopic dermatitis, hot spots, pruritus, and symptoms thereof in a non-human animal by administering the composition according to any one of claims 1 to 13.

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