Topical Compositions Comprising Janus Kinase Inhibitors

Abstract

The present invention describes a topical veterinary solution composition comprising a JAK inhibitor, preferably oclacitinib, or a pharmaceutically acceptable salt thereof, for use in animals, preferably dogs, for the treatment of skin disorders, such as allergic dermatitis, atopic dermatitis, pruritus, and / or hot spot(s).

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., maleate salt). [Background technology]

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified as tyrosine and serine / threonine kinases. Inappropriate kinase activity resulting from mutation, overexpression, or improper regulation, dysregulation, or deregulation, as well as excessive or underproduction of growth factors or cytokines, is involved in many diseases, including, but not limited to, cancer, allergies, asthma and other respiratory diseases, autoimmune diseases, and inflammatory diseases. Inappropriate kinase activity triggers various biological cellular responses related to cell proliferation, cell differentiation, survival, apoptosis, mitosis, cell cycle control, and cell motility, which are involved in the aforementioned and related diseases.

[0003] Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, 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). Upon binding to their receptors, cytokines activate JAKs, which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, particularly members of the signal transducer and activator of transcription (STAT) family, which ultimately result in gene expression. Numerous cytokines are known to activate the JAK family.

[0004] Patent applications have recently been published describing topical compositions for other JAK inhibitors (e.g., WO2021 / 014453, WO2022 / 013708, and WO2022 / 027041). WO2021 / 014453 describes an emulsion-based topical cream containing tofacitinib, a retinoid, menthol, oil, and alcohol. WO2022 / 013708 describes an oil-in-water emulsion containing a JAK inhibitor, white petrolatum (10%), and an antibacterial 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 penetration of this particular JAK inhibitor. Additionally, U.S. Patent Application No. 2020 / 0352965 describes a topical ointment containing 70% white petrolatum containing tofacitinin and chrysoborole. U.S. Patent Application No. 2020 / 0276109 describes an ointment composition containing the 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 with diethylene glycol monoethyl ether (DEGMEE). Unlike these oil-in-emulsion, cream, and ointment-based compositions, the present invention describes a solution-based composition that can be easily sprayed onto the skin of an animal in need thereof.

[0005] Current dosage forms containing oclacitinib include orally administered film-coated tablets and flavored chewable tablets.Instead of these oral doses, oclacitinib also needs to be administered topically to control site-specific areas of dermatitis (such as hot spots).Previous patent application publication WO2006 / 069080 merely describes the topical administration of a JAK inhibitor from a broad genus of JAK inhibitors, but the cited document does not describe any specific compound or composition that can actually be prepared and / or administered topically.Therefore, a topical spray solution composition has been developed for use in animals, particularly dogs. 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 [ka] The 7H-pyrrolo[2,3-d]pyrimidine compound of formula A is N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methanesulfonamide (oclacitinib) as the free base, or a veterinarily acceptable salt thereof. A preferred salt form of formula A is the maleate salt.

[0007] In another embodiment is a topical composition comprising a JAKi compound of Formula (B), Formula (C), or Formula (D), either as the free base or a pharmaceutically acceptable salt thereof. [ka]

[0008] In another embodiment, 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 drug, i.e., does not include the total weight of the compound when combined with a pharmaceutically acceptable salt. For example, 10 mg / mL of a compound of Formula (A) is based on the amount of the free base of the compound. In another embodiment, the topical composition comprises a JAKi compound of Formula (A), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient. In another embodiment, the topical composition comprises a JAKi compound of Formula (B), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient. In another embodiment, the topical composition comprises a JAKi compound of Formula (C), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient. In another embodiment, a topical composition comprises a JAKi compound of formula (D), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient. In one embodiment, the pharmaceutically acceptable excipient comprises a solvent or a mixture of solvents. In another embodiment, the pharmaceutically acceptable excipient comprises a solvent or a mixture of solvents, and optionally, a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the composition comprises a mixture of solvents selected from glycols, glycol ethers, alcohols, dimethyl sulfoxide, and water, and optionally, a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the composition comprises a mixture of solvents selected from glycols, glycol ethers, dimethyl sulfoxide, and water, and optionally, a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the composition comprises a mixture of a glycol ether selected from the group consisting of propylene glycol, dipropylene glycol monomethyl ether (DPGMME), diethylene glycol monoethyl ether (DEGMEE), and diethylene glycol monobutyl ether (DEGMBE), dimethyl sulfoxide, alcohol, water, and optionally a solvent selected from a surfactant, an antioxidant, and a pH adjuster.In another embodiment, the composition comprises a mixture of solvents selected from propylene glycol, a glycol ether selected from DPGMME, DEGMEE, or DEGMBE, dimethyl sulfoxide, water, and optionally a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the solvent mixture comprises propylene glycol, a glycol ether selected from DPGMME, DEGMEE, or DEGMBE, dimethyl sulfoxide, ethanol, and water, and optionally a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the solvent mixture comprises propylene glycol, a glycol ether selected from DPGMME, DEGMEE, or DEGMBE, dimethyl sulfoxide, and water, and optionally a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the solvent mixture comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, and water, and optionally a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the solvent mixture comprises propylene glycol, DEGMEE, dimethyl sulfoxide, and water, and optionally a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, a surfactant, and optionally an antioxidant and a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, a surfactant, and optionally an antioxidant and a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, a surfactant, and an antioxidant, and optionally a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, a surfactant, and an antioxidant, and optionally a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, a surfactant, and an antioxidant, and optionally a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, a surfactant, and an antioxidant, and optionally a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, a surfactant, an antioxidant, and a pH adjuster.In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, an antioxidant, and a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, an antioxidant, and a pH adjuster. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, ethanol, water, and an antioxidant. In another embodiment, the composition comprises propylene glycol, DEGMEE, dimethyl sulfoxide, water, and an antioxidant. In another embodiment, the antioxidant is BHT or BHA, and the pH adjuster is sodium hydroxide. In another embodiment, the composition comprises about 1-15 mg / mL of a compound of Formula (A), Formula (B), Formula (C), or Formula (D), or a pharmaceutically acceptable salt thereof, about 0-15 w / v% glycol, about 10-40 w / v% glycol ether, about 0-15 w / v% alcohol, about 25-50 w / v% DMSO, and water, and optionally, a surfactant, an antioxidant, and a pH adjuster. In another embodiment, 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% glycol, about 10 w / v% to about 40 w / v% glycol ether, about 0 w / v% to about 15 w / v% alcohol, about 25 w / v% to about 50 w / v% DMSO, and water, and optionally, a surfactant, an antioxidant, and a pH adjuster. In another embodiment, 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.% glycol, about 20 v / v.% to about 35 w / v.% glycol ether, about 0 w / v.% to about 10 w / v.% alcohol, about 30 w / v.% to about 50 w / v.% DMSO, and water, and optionally, a surfactant, an antioxidant, and a pH adjuster.In another embodiment, 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 propylene glycol, about 20% 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 alcohol, about 30% w / v to about 45% w / v of DMSO, and water, and optionally, a surfactant, an antioxidant, and a pH adjuster. In another embodiment, the composition comprises about 1 mg / mL to about 10 mg / mL of the compound of formula (A), or a pharmaceutically acceptable salt thereof, about 2% to about 8% w / v propylene glycol, about 25% to about 35% w / v of a glycol ether selected from DPGMME, DEGMEE, and DEGMBE, about 0% to about 10% w / v ethanol, about 30% to about 45% w / v DMSO, and water, and optionally, about 0% to about 6% w / v Labrasol®, and the antioxidants BHA or BHT and pH adjusters. In another embodiment, the composition comprises about 1 mg / mL to about 10 mg / mL of the compound of formula (A), or a pharmaceutically acceptable salt thereof, about 2% to about 8% w / v propylene glycol, about 25% to about 35% w / v DEGMEE, about 0% to about 10% w / v ethanol, about 30% to about 45% w / v DMSO, and water, and optionally, BHA or BHT and a pH adjuster. In another embodiment, the composition comprises about 1 mg / mL to about 10 mg / mL of the compound of formula (A), or a pharmaceutically acceptable salt thereof, about 2% to about 8% w / v propylene glycol, about 25% to about 35% w / v DEGMEE, about 0% to about 10% w / v ethanol, about 30% to about 45% w / v DMSO, water, and BHA or BHT, and optionally a pH adjuster. In another embodiment, the composition comprises about 1 mg / mL to about 10 mg / mL of the 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 adjuster.In all embodiments of the present invention, about 0 w / v% can be zero w / v% (i.e., not included in the composition). In another embodiment, the composition contains about 1 mg / mL to about 5 mg / mL of the 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 30 w / v% to about 45 w / v% DMSO, water, BHA or BHT, and a pH adjuster that is sodium hydroxide, and the pH is in the range of about 4.8 to 6.0. In another embodiment, the composition comprises about 1 mg / mL to about 5 mg / mL of the 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 that is sodium hydroxide, and the pH ranges from about 4.8 to 6.0. In another embodiment, the composition comprises about 1 mg / mL to about 5 mg / mL of the 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 that is sodium hydroxide, and the pH ranges from about 4.8 to 6.0. In another embodiment, the composition comprises about 1 mg / mL to about 5 mg / mL of the 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 / v% to about 5 w / v% ethanol, water, BHA or BHT, and a pH adjuster that is sodium hydroxide, and the pH is in the range of about 4.8 to 6.0. In another embodiment, the composition comprises about 1 mg / mL to about 5 mg / mL of the 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 / v% to about 5 w / v% ethanol, water, BHA or BHT, and a pH adjuster that is sodium hydroxide, and the pH is in the range of about 4.8 to 6.0. In another embodiment, the compositions of the present invention are administered topically to an animal in need thereof to treat or prevent a skin disease or disorder, hi another embodiment, the skin disease or disorder is atopic dermatitis, allergic dermatitis, pruritus, or hot spots.In another embodiment, the compositions of the present invention are topically administered to an animal in need thereof to treat or prevent atopic dermatitis, allergic dermatitis, or hot spots. In another embodiment, the compositions of the present invention are topically administered to an animal in need thereof to treat or prevent atopic dermatitis or allergic dermatitis. In another embodiment, the compositions of the present invention are topically administered to an animal in need thereof to treat or prevent atopic dermatitis. In another embodiment, the compositions of the present invention are topically administered to an animal in need thereof to treat or prevent allergic dermatitis. In another embodiment, the compositions of the present invention are topically administered to an animal in need thereof to treat hot spots. In another embodiment, the animal is a horse, dog, or cat. In another embodiment, the animal is a dog. is.

[0009] In another aspect, the compositions of the present invention are used to prepare a medicament for topical administration to an animal in need thereof to treat or prevent atopic dermatitis, allergic dermatitis, or hot spots.

[0010] In another embodiment, the composition of the present invention can be co-administered with other drugs administered orally, topically, or by injection, and / or with cleansing agent(s).Non-exclusive examples of other drugs include nutritional supplements, antiparasitic agents, antibacterial agents, antifungal agents, anti-inflammatory agents, and dermatological drugs (e.g., JAK inhibitors, cyclosporine, prednisone, dexamethasone, betamethasone, etc.).Non-limiting examples of cleansing agents include, for example, hydrogen peroxide, medicated shampoo, chlorhexidine gluconate, benzoyl peroxide, etc. DETAILED DESCRIPTION OF THE INVENTION

[0011] definition For purposes of the present invention, as described and claimed herein, the following terms and phrases are defined below.

[0012] "About," when used in connection with a measurable, numerical variable, refers to the stated value of the variable and all values ​​of the variable that are within experimental error of the stated value (e.g., within a 95% confidence interval of the mean) or within 10 percent of the stated value, whichever is greater. In some jurisdictions, this term is considered vague, and therefore, the term can be readily deleted from a claim, thereby ensuring the scope of the claim.

[0013] As used herein, "active pharmaceutical ingredient" (API) or "active agent" are used interchangeably, unless otherwise indicated, and mean that the ingredient is a pharmaceutical agent that is biologically active, e.g., a JAK inhibitor.

[0014] As used herein, "animal" refers to an individual animal, and said individual animal is a mammal, unless otherwise indicated. Specifically, mammals refer to human and non-human vertebrates, and are taxonomic members of the class Mammalia. Non-exclusive examples of non-human animals include companion animals and livestock. Non-exclusive examples of companion animals include dogs (Canidae), cats (Felidae), and horses (Equidae). A preferred companion animal is a dog. Non-exclusive examples of livestock include pigs (Porcine), rabbits (Leporidae), goats (Caprine), sheep (Ovis), and cattle (Bovidae).

[0015] As used herein, "clinical signs" refers to observable or measurable conditions or behaviors in animals that indicate a disease, condition, or symptom, unless otherwise indicated.Clinical signs can be symptoms, conditions, or behaviors that are measured by known or established diagnostic evaluations.For example, diagnostic evaluations for determining allergic dermatitis or atopic dermatitis can be performed by visual analog scale (VAS) scores or clinical evaluation of the condition, or established scoring systems such as the Canine Atopic Dermatitis Severity and Severity Index (CADESI) score. Non-limiting examples of some clinical signs of atopic dermatitis, allergic dermatitis, or hot spot(s) that may sometimes be used in such evaluation or scoring systems include: itching ranging from very severe (in the case of companion animals such as dogs, indicated by scratching, chewing, and nearly continuous licking regardless of what else is happening), to severe (indicated by itching while awake and prolonged episodes of itching at night and / or during eating, playing, or exercise), to moderate (indicated by frequent episodes of itching), to very mild (occasional episodes of itching); the presence of pustules or epidermal ringlets; the presence of skin lesions; pruritus; erythema; erosions, excoriations, and / or self-induced alopecia; the presence of papules and / or crusts; lichenification and / or hyperpigmentation.

[0016] As used herein, unless otherwise indicated, "composition(s) of the invention" refers to a composition that is a solution comprising 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 glycol, glycol ether, DMSO, and water, and optionally further comprising an alcohol, a surfactant, an antioxidant, and a pH adjuster.

[0017] As used herein, unless otherwise indicated, "hot spot" refers to an inflammatory skin lesion or skin irritation on an animal, which can be aggravated by scratching and licking, and is also known as suppurative traumatic dermatitis or acute moist dermatitis. Hot spots are red, inflamed skin lesions.

[0018] As used herein, unless otherwise indicated, "pharmaceutically acceptable" refers to a substance or composition that must be chemically and / or toxicologically compatible with other ingredients comprising the composition and / or with the animal being treated therewith. The term "pharmaceutically" encompasses "veterinarily acceptable."

[0019] As used herein, unless otherwise indicated, a "pharmaceutically acceptable salt" means any salt that is suitable for pharmaceutical use in animals, preferably acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, etoglutarate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glycerophosphate, hexafluoro ... The term "oclacitinib" refers to phosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodine, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, or trifluoroacetate salt.Preferably, the pharmaceutically acceptable salt of oclacitinib is maleate (or maleic acid) salt.

[0020] As used herein, "quantity" or "qs," unless otherwise indicated, refers to an amount that is sufficient, or in other words, the amount of solvent (e.g., water) needed to bring the final w / v % of the solution to 100%.

[0021] As used herein, unless otherwise indicated, a "therapeutically effective amount" refers to an amount of a JAK inhibitor, preferably oclacitinib (free base), to treat or prevent a JAK-related disease, condition, or disorder in an animal, i.e., a disease or condition caused by or associated with immune system dysfunction or immune system dysregulation, and includes topically administering to the animal an effective amount of a JAK inhibitor as described herein.

[0022] As used herein, "treating" or "treatment," unless otherwise indicated, means controlling, treating, or preventing the progression of the indicated condition or disease. The terms "controlling," "treating," or "treatment" of a condition or disease include (1) preventing the condition or disease, i.e., not causing clinical symptoms or signs of the disease to develop in a mammal that may be exposed to or afflicted with the disease, provided that the symptoms / signs of the disease are not yet experienced or exhibited; (2) inhibiting the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms or signs; or (3) palliating the disease, i.e., causing regression of the disease or its clinical symptoms or signs.

[0023] A "symptom" of a disease or condition is any of those symptoms known to those skilled in the art as being associated with a disease or condition. 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, the "symptom" of a disease or condition, such as atopic dermatitis or allergic dermatitis, is also a "clinical sign." In the case of allergic dermatitis, the allergic dermatitis can be flea allergy dermatitis, i.e., "FAD" (also known as "flea allergy dermatitis," "flea bite dermatitis" ("FBD"), or "flea-associated dermatitis"), food allergy dermatitis, contact dermatitis, or allergic dermatitis associated with Sarcoptes scabiei (i.e., scabies). Other indications and conditions that can be treated by the methods including the dosing regimens described herein include any indications or conditions that can be treated by administering a JAK inhibitor, including 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 desirable.

[0024] As used herein, the percentage of a component of a composition refers to the weight / volume percentage of the total weight of the composition, and is referred to as "w / v%" and is expressed by the formula m i / m tot defines the mass fraction of a compositional component expressed as a percentage, determined according to the formula m × 100, i is the mass of the substance of interest present in the composition, and m tot is the total mass of the composition.

[0025] The pharmacokinetics and pharmacodynamics (PK / PD) of orally administered oclacitinib (0.4-0.6 mg / kg) are well understood. Plasma concentrations above 12 ng / mL have been shown to be effective in reducing IL-31-induced pruritus. 14A C-oclacitinib study determined that a single 0.4 mg / kg dose achieved a mean skin concentration of 212 ng equivalents / gram of tissue. The house dust model (HDM) was used to evaluate the efficacy of the compositions described herein. Topical HDM challenge results in exfoliative lesions and erythema at the challenge site. In one study, placebo (saline, T01), triamcinolone acetonide 0.15 mg / mL (T02), oclacitinib maleate 7.5 mg / mL (T03), and oclacitinib maleate 10 mg / mL (T04) were administered topically to beagle dogs (8 dogs / group). Drug weights in T02–T04 were the free base amount. Animals received approximately 1 mL of each solution according to the following treatment / dosing regimen, as shown in Table 1: [Table 1]

[0026] Daily assessments were conducted through Day 41. Colorimeter measurements provided quantified erythema scores. Both concentrations of oclacitinib achieved significant erythema reduction compared to saline after approximately one month of administration. Triamcinolone spray had significantly less erythema reduction compared to saline as early as Day 12, consistent with a gradual reduction in administration frequency and continued multiple time-point comparisons throughout the observation period. Triamcinolone-treated animals had significantly less erythema reduction compared to saline-treated animals on Days 12, 14, 19, 24-26, 28-33, and 35-41 (P ≤ 0.0912). Animals administered 7.5 mg / mL oclacitinib showed significantly greater erythema reduction compared to saline-treated animals on Day 36 (P = 0.0993). Animals administered 10 mg / mL oclacitinib showed significantly greater reductions than animals administered saline on days 27, 28, and 36 (p≦0.0948). Lesions were observed and scored based on the severity of erythema, papule, and excoriation at the challenge site. Total lesion scores after challenge were significantly higher in the triamcinolone and oclacitinib-treated groups compared with the saline group. Triamcinolone-treated animals had significantly greater reductions in lesion scores on days 4, 8, 10, and 11, but significantly less on day 35, compared with saline-treated animals. Animals treated with 7.5 mg / mL oclacitinib spray had significantly greater reductions in lesion scores than saline-treated animals on days 4, 7, 11, 26, 27, 30, and 39. Animals treated with 10 mg / mL oclacitinib spray had significantly greater lesion score reductions than saline-treated animals on days 7-11, 26, 30, and 32-34. The oclacitinib-treated group continued to show significant reductions in lesion scores after the treatment period compared with the other treatment groups. Animals treated with 10 mg / mL oclacitinib had a significantly lower area under the curve (AUC) for total lesion score compared with saline-treated animals (p<0.08).For similar AUC lesion scores, no other treatment tested was significantly different from the saline control.

[0027] In a subsequent study, animals received 2.5–10 mg / mL of oclacitinib in two to three sprays of a total of approximately 0.25–0.5 mL of topical solution applied to the skin area. This study also provided acceptable skin concentrations of oclacitinib.

[0028] Topical administration includes the treatment of skin that is easily accessible by topical application to produce a local and / or systemic effect. The term "topically" is used herein in its conventional sense to refer to a route of administration in which an active substance is delivered over a portion of the surface of the skin so that the active substance is delivered to one or more of the subcutaneous tissue, dermis, and epidermis, including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Thus, topical compositions containing APIs are formulated for application to any location on an animal. In some embodiments, the skin is intact, healthy skin. In other embodiments, the skin may be skin in which one or more layers (e.g., the stratum corneum, stratum germinativum, stratum spinosum, stratum basale, etc.) may be diseased or inflamed. In certain embodiments, the API is delivered locally to the site of administration. The term "topically" is used herein in its conventional sense to mean that the API is delivered within the vicinity of or beneath the site of application. Based on the size of the spray head, the volume dispensed 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. Furthermore, depending on the distance from the skin when pumped (e.g., 3, 4, 5, 6 inches), the composition may be dispensed (e.g., 1x, 2x, 3x, etc.) from about 10 cm. 2 ~Approx. 125cm 2 For example, a 0.2 mL volume spray can cover an area of ​​skin approximately 3 to 6 inches wide, or approximately 25 cm. 2 , or 4 to 7 inches, or about 40 cm 2 , or 5 to 8 inches, or approximately 55 cm 2Similarly, a 0.4 mL (2x) volume spray will cover approximately 4-6 inches and approximately 50 cm 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 about 1 mg of API and the sprayed area will be about 25 cm 2 If the amount of API administered to the site is about 1 mg / 25 cm 2 or 0.04 mg / cm 2 Overall, the drug concentration administered to the skin depends on the composition API concentration (mg / mL), pump volume (mL), number of pumps, distance from the skin (inches), and area of ​​skin treated (cm 2 ) will vary depending on the composition. In some embodiments, the API diffuses from the application site by as much as 12 cm or less, 10 cm or less, 8 cm or less, 6 cm or less, 4 cm or less, 2 cm or less, or 1 cm or less from the application site. In other words, in these embodiments, the topical composition is administered with the intention of delivering the API to the administration site or a location within a short distance from the administration site. The penetration depth of an API administered topically to the skin at the application site can also vary depending on the components of the composition. In some cases, topical administration of the API can also result in systemic absorption of the API.

[0029] Whenever a numerical range is given herein, it is meant to include any recited numbers (fractional or integer) within the stated range. Comprises, comprising, includes, including means "including but not limited to." As used herein, "a" and "an" mean at least one or one or more, unless the context clearly dictates otherwise.

[0030] Clinical signs of allergic and atopic dermatitis on the skin include, for example, erythema (redness) and alopecia (hair loss). Skin lesions associated with allergic and atopic dermatitis can vary significantly in clinical settings. The most common locations of localized skin lesions are the ears, abdomen, groin, and / or feet. In addition, secondary superficial bacterial and / or yeast infections may occur, resulting in the development of suppurative traumatic dermatitis, colloquially known as hot spots. Unlike systemically acting oral Apoquel® (oclacitinib maleate), the purpose of topical therapy is to provide treatment to very specific areas associated with atopic and / or allergic dermatitis and hot spots. Topical therapy provides higher skin concentrations in targeted areas, thereby increasing efficacy. Therefore, topical oclacitinib compositions must penetrate the skin and achieve sufficient skin concentrations.

[0031] Systemic plasma and skin concentrations 24 hours after dosing have been evaluated for multiple compositions of the invention in several PK studies, including compositions with oclacitinib or oclacitinib maleate having API concentrations ranging from 1 to 10 mg / mL oclacitinib. The compositions tested to date have demonstrated prolonged absorption lasting at least 72 hours after a single dose, and rapid absorption after a single oral dose. 14 demonstrated low local bioavailability of less than 10% with single-dose skin concentrations at least 20-80 times those observed in the C study. 14 C-oclacitinib studies determined that an oral dose of 0.4 mg / kg of oclacitinib achieved a mean skin concentration of 212 ng equivalents / gram. Penetration and permeation studies with compositions containing glycol, glycol ether, and DMSO, as described above, achieved higher single-dose skin concentrations (28.4-54.5 μg / g) than those achieved after oral administration, and demonstrated the reported oclacitinib IC for pro-inflammatory and pruritic cytokines. 50 far exceeded.

[0032] Comparisons across studies demonstrated that skin concentrations 24 hours after administration were at least five times higher after repeated dosing. Systemic plasma concentrations in single-dose and multiple-dose studies indicated prolonged absorption with no apparent end-point 10 days after dosing. The rate and amount of topical absorption may be a nonlinear function of the API concentration of the composition. The topical compositions of the present invention minimized systemic plasma oclacitinib concentrations while maintaining high skin concentrations. PK after topical administration of oclacitinib maleate and oclacitinib free base formulations was comparable. Studies to date and the formulations described herein have shown that the compositions result in higher skin concentrations than those observed with oral administration. An oclacitinib formulation with an oclacitinib concentration of 7.5 mg / mL exhibited prolonged absorption, lasting more than 7 days after a single dose. Topical single-dose bioavailability was low, less than 5% when administered to areas that limit oral exposure from licking. However, low bioavailability does not equate to low exposure. Accumulation in the skin and plasma was observed after multiple daily doses. Systemic levels after multiple daily doses were at concentrations that demonstrated efficacy in reducing IL-31-induced itch. Formulations with lower oclacitinib concentrations had lower systemic exposure.

[0033] The resulting composition of the present invention is a solution, which can be administered as an aerosol (containing a propellant such as carbon dioxide, hydrofluoroalkane, etc.) or spray. Preferred topical compositions are solutions that can be sprayed.

[0034] Depending on the application site and physiology of the subject, as well as the surface area on the skin to which the topical composition is applied, the amount of active agent in the composition can vary, and in some examples, the amount of active agent ranges from about 0.5 mg / mL to about 15 mg / mL, or from about 1 mg / mL to about 15 mg / mL, or from about 1 mg / mL to about 10 mg / mL, such as about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, and about 10 mg / mL. On a weight / volume basis, the amount of active agent is from about 0.05 w / v % to about 1.5 w / v % of the total weight of the topical composition.

[0035] The compositions are stable for a period of time, for example, 1 month or more, 3 months or more, 6 months or more, or 12 months or more, under standard VICH storage conditions, for example, under packaged sterile conditions at room temperature.

[0036] The topical compositions of the present invention involve the use of a JAKi in combination with one or more pharmaceutically acceptable excipients that provide a means for solubilizing and stabilizing the JAKi compound and for increasing the permeability of the JAKi across and through the skin of an animal being treated with the topical composition.

[0037] The topical compositions of the present invention comprise a JAK inhibitor. In another embodiment, 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) (irnocitinib; 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)-2H-pyran-3-yl)-2H-pyrazole-1-yl), formula (D) (1-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((2-fluoro-6-methoxypyridin-4-yl)-2H-pyrazole-1-yl)-2H-pyrazole-1-yl), formula (E) (1-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((2-fluoro-6-methoxypyridin-4-yl)-2H-pyrazole-1-yl)-2H-pyrazole-1-yl), formula (F) (1-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((2-fluoro-6-methoxypyridin-4-yl)-2H-pyrazole-1-yl)-2H-pyrazole-1-yl), formula (G) (1-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((2-fluoro-6-methoxypyridin-4-yl)-2H-pyrazole-1-yl)-2H-pyrazole- The JAK inhibitor is selected from the group consisting of formula (D) (1-[(3R,4S)-(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. A preferred topical composition of the present invention comprises oclacitinib (Formula A) or a pharmaceutically acceptable salt thereof, and in particular oclacitinib maleate. The chemical structures of the JAK inhibitors of formulas (A-D) are shown below. Chemical structure: [ka]

[0038] 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 facilitate processing of the API into a preparation that can be used for topical administration. Pharmaceutically acceptable excipients are generally known to those skilled in the art and are therefore included in the present invention. Such excipients can be found, for example, in "Remington's Pharmaceutical Sciences" 1999. th Edition, Mack Pub. Co., New Jersey (1995).

[0039] As described above, exemplary dosages of the JAKi in the topical composition can range from about 0.5 mg / mL to about 15 mg / mL, or from about 1 mg / mL to about 15 mg / mL, or from about 1 mg / mL to about 10 mg / mL. Topical compositions can include 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.

[0040] Pharmaceutically acceptable excipients useful in the compositions include at least one solvent or mixture of solvents. Solvents useful in preparing the compositions of the present invention may be selected from the group consisting of glycols, glycol ethers, glycerides, alcohols, dimethyl sulfoxide, water, and mixtures thereof. Glycols and glycol ethers, as well as other solvents described herein, can also assist in enhancing API skin penetration. Non-limiting examples of glycols include glycerol (glycerin), ethylene glycol, propylene glycol, butylene glycol, and low molecular weight polyethylene glycols (PEGs), such as PEG 200, PEG 300, and PEG 400. Preferred glycols are propylene glycol or glycerol. More preferred glycols are propylene glycol. The amount of glycol in the composition may range from 0% to about 15% w / v, or from about 1% to about 10% w / v, or from about 2% to about 8% w / v of the total weight of the composition. Non-limiting examples of glycol ethers include monoglycol ethers, diglycol ethers, and triglycol ethers. 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-t-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 (Transcutol®)), dipropylene glycol methyl ether (DPGMME or DPGME), diethylene glycol monobutyl ether (DEGMBE or DEGBE (butyl digol)), dipropylene glycol monomethyl ether (DPGMME or DPGME), diethylene glycol dimethyl ether (DEGDME), and the like. Non-exclusive examples of triglycols include 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), and the like. Glycol ethers also include acetylated glycol ethers, such as diethylene monoethyl ether acetate and diethylene monobutyl ether acetate. Preferred glycol ethers are selected from the group consisting of DEGMME, DEGMEE, DEGMBE, and DPGMME, and mixtures thereof. More preferred glycol ethers are DPGMME, DEGMEE, and DEGMME. Even more preferred glycol ethers are DPGMME and DEGMEE. The most preferred glycol ether is DEGMEE. The amount of glycol ether in the composition can 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% of the total weight of the composition.

[0041] Alcohols are C1-C 18The term "alcohol" refers to aliphatic alcohols as well as C4-C6 cyclic and aromatic alcohols. Alcohol also includes fatty alcohols. Non-limiting examples of aliphatic alcohols include ethanol, propanol, isopropanol, butanol, pentanol, hexanol, decanol, dodecanol, myristyl, cetyl, stearyl, oleic acid, octyldecyl, and the like. Non-limiting examples of cyclic 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 may range from about 0% to about 15% w / v, or from about 0% to about 10% w / v, or from about 1% to about 10% w / v, of the total weight of the composition. When used, the preferred alcohol is ethanol. In one embodiment, the composition of the present invention does not contain ethanol. In another embodiment, the amount of ethanol in the composition is about 5% w / v, hi another embodiment, the amount of ethanol in the composition is about 10% w / v.

[0042] The amount of DMSO in the composition may 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 the "qs" amount. The qs amount refers to the amount of water added to the composition to bring the total weight of the composition to 100%. The amount of water may 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.

[0043] Additional pharmaceutically acceptable solvents that can be used in the compositions include terpene alkaloids (e.g., limonene, eucalyptol, menthol), pyrrolidones (e.g., 2-pyrrolidone, N-methylpyrrolidone, and azone), glycerol formal, tetraglycol (glycoflurol), tetrahydrofurfuryl alcohol, solketal, dimethyl isosorbide, citrate buffer, macrogolglycerol hydroxystearate (PEG-40 castor oil; Kolliphor EH40®), and dimethylacetamide (DMA).

[0044] In the present invention, the composition may further comprise a pharmaceutically acceptable excipient, such as an anionic, cationic, or 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., Span® 20), polyoxyethylated sorbitan esters (e.g., Polysorbate 80), polyoxyethylated alkyl ethers, polyethylene glycol stearates, polyoxyethylated castor oil derivatives (e.g., Cremaphor® EL), polyglycerol esters, caprylocaproyl macrogol-8 glycerides (Labrasol®), Kolliphor® HS15 (macrogol 15 hydroxystearate or polyoxyl 15 hydroxystearate), etc. 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% of the total weight of the composition.

[0045] In another embodiment of the present invention, the composition may further comprise a spreading agent (e.g., siloxane, indapole, etc.), an antioxidant (e.g., ascorbic acid, tocopherol, butylated hydroxanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, thioglycerol, citric acid, etc.), or a pH adjuster (e.g., sodium hydroxide (NaOH), potassium hydroxide (KOH), triethanolamine, ethanolamine, hydrochloric acid (HCl), etc.). The antioxidant is preferably present in an amount of about 0.1 w / v% to about 0.3 w / v%, or about 0.1 w / v% to about 0.2 w / v%, or about 0.1 w / v% to about 0.15 w / v% of the total weight of the composition. The pH of the topical composition of the present invention may range from about 4.5 to 7.5. The preferred pH of the topical composition is about 5 to 6.5.

[0046] In another embodiment, the composition of the present invention can further comprise a fragrance. Non-limiting examples of fragrances include jasmine, lavender, rose, orchid, lotus, lilac, peony, honeysuckle, hibiscus, citrus fruits, sandalwood, vetiver, vanilla, cinnamon, and burberry. In another embodiment, the composition further comprises a fragrance. The amount of fragrance in the composition can be about 0 w / v % to about 0.2 w / v % of the total weight of the composition.

[0047] Non-limiting examples of topical compositions of the present invention are shown in Table 2. [Table 2]

[0048] In another aspect, the topical compositions of the present invention can be administered alone or in conjunction with other pharmaceutical agents, whether administered orally, parenterally, or topically, which may be administered to animals to aid in the healing of skin disorders or other diseases. 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, sulconazole, miconazole, amphotericin, fluconazole, nystatin, etc.), anti-inflammatory agents (e.g., hydrocortisone, diamino-diphenylsulfone, triamcinolone acetonide, menthol, nonsteroidal anti-inflammatory drugs (NSAIDs (e.g., meloxicam, flunixin meglumine, carprofen, aspirin, ketoprofen, naproxen, diclofenac, etc.)), and the like. Antiseptics (e.g., chlorhexidine, povidone-iodine, chloroxylenol, hexachlorophene, isopropyl alcohol, benzalkonium chloride, hydrogen peroxide, etc.), steroids (e.g., clobetasol propionate, flurandrenolide, betamethasone diproprionate, diflorasone diacetate, desoximetasone, halobetasol propionate, fluocinonide, halcinonide, flurandrenolide, dexamethasone, betamethasone valerate, etc.), analgesics (e.g., capsaicin, camphor, menthol, gingerol, lidocaine, bupivacaine, NSAIDs, ibuprofen, etc.).

[0049] The topical compositions of the present invention as described herein can be prepared by conventional methods for preparing solutions. First, the solvent, dimethyl sulfoxide, ethanol, glycol ether (DEGMEE, DEGMME, or DEGMBE), propylene glycol, and, optionally, Labrasol®, are mixed together. An antioxidant (e.g., BHA or BHT) and a JAKi are then added sequentially to the solvent mixture and mixed until dissolved. Alternatively, the active agent can be dissolved in DMSO before mixing with other solvents, and then, optionally, a surfactant and antioxidant can be added. The mixture is adjusted to approximately pH 5.4, if necessary. The final weight of the composition is adjusted to 100% with water (qs). The final solution is filtered and filled into spray bottles. Each bottle can contain approximately 30-240 mL of the present composition. For example, the bottle can contain approximately 30 mL, 45 mL, 60 mL, 90 mL, 100 mL, 120 mL, 150 mL, 175 mL, 190 mL, 200 mL, 225 mL, or 240 mL of the composition of the present invention. Bottle cans also include volumes ranging from 30 to 240 mL, such as 40 mL, 80 mL, 140 mL, and 170 mL.

[0050] Oclacitinib (7.5 mg / mL) stability during one month of accelerated stability (40°C / 75% relative humidity) ranged from approximately 97.2 to 99.3% for compositions containing 0.15 to 0.2 w / v% BHT.

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; 【Chemistry 1】 b) a pharmaceutically acceptable solvent mixture comprising glycol, glycol ether, dimethyl sulfoxide, and water; c) optionally, an antioxidant and a pH adjuster.

2. 2. The composition of claim 1, wherein the JAK inhibitor is Compound A, or a pharmaceutically acceptable salt thereof, 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. 10. The composition of any one of the preceding claims, wherein the composition further comprises an antioxidant and a pH adjuster.

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

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

7. 7. The composition of claim 6, wherein the JAK inhibitor is in an amount of 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. 10. The composition of any one of the preceding claims, further comprising ethanol in an amount of about 1% w / v to about 5% w / v of the total weight of the composition.

10. 1. 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% to about 8% w / v, DEGMEE in an amount of about 20% to about 35% w / v, DMSO in an amount of about 30% to about 45% w / v, and water, and optionally, an antioxidant and a pH adjuster, wherein the w / v % are percentages based on the total weight of the composition.

11. 11. The composition of claim 10, further comprising an antioxidant and a pH adjuster.

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

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

0.

14. 10. Use of the topical solution composition of any one of the preceding claims for the manufacture of a medicament for the treatment and prevention of skin disorders selected from allergic dermatitis, atopic dermatitis, hot spots, pruritus, and symptoms thereof, in a non-human animal in need thereof.

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

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