Topical pharmaceutical formulations containing kinase inhibitors

Abstract

The present invention relates to a topical pharmaceutical formulation, its use and its manufacturing method, wherein the topical pharmaceutical formulation comprises (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as an active ingredient and an oleaginous base.

Description

[Technical Field]

[0001] The present invention relates to a topical pharmaceutical preparation containing a protein kinase inhibitor as an active ingredient, its uses, and a method for producing the same. [Background technology]

[0002] Janus kinases (JAKs) are enzymes in the intracellular non-receptor tyrosine kinase family that transmit cytokine-mediated signals through the JAK-STAT pathway. These enzymes are comprised of JAK1, JAK2, JAK3, and TYK2. JAK inhibitors are involved in hematopoiesis and immunity, and have been investigated as therapeutic agents for myeloproliferative neoplasms, rheumatoid arthritis, and other immune or inflammatory diseases. Compounds such as tofacitinib, baricitinib, and upadacitinib have been developed.

[0003] JAK inhibitors have attracted attention for their therapeutic efficacy comparable to biologics in the treatment of chronic inflammatory diseases, but concerns remain regarding their long-term safety. Xeljanz (tofacitinib), the world's first oral JAK inhibitor, effectively inhibits JAK1 / 3 and was approved for the treatment of rheumatoid arthritis (RA), adult active psoriatic arthritis (PsA), and adult active ulcerative colitis (UC). However, clinical trials revealed risks of cardiovascular disease, cancer, and blood clots, leading to a FDA warning. JAK3 inhibition has been reported to cause severe combined immune deficiency (SCID) in humans, and JAK2 has been reported to cause anemia as a side effect due to its association with the erythropoietin signaling pathway. To minimize these issues, JAK1 inhibitors that selectively inhibit JAK1 have been developed, which are expected to reduce side effects.

[0004] Meanwhile, efforts are being made to develop topical formulations to further enhance safety in the treatment of inflammatory skin diseases. Ruxolitinib cream and delgocitinib ointment have been approved in the United States and Japan, respectively, as treatments for atopic dermatitis. Topical formulations exert their effects only at the site of the lesion, rather than through the systemic circulation, and are therefore expected to largely eliminate the risk of the aforementioned side effects. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, the present invention provides a new topical pharmaceutical preparation containing a JAK inhibitor as an active ingredient as a protein kinase inhibitor, its use, and a method for producing the same. [Means for solving the problem]

[0006] The topical pharmaceutical formulation of the present invention comprises a therapeutically effective amount of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as an active ingredient, and an oleaginous base.

[0007] In one embodiment, the (S)-N-(4 -(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide may be a compound represented by the following chemical formula I:

[0008] [ka]

[0009] In one example, a topical pharmaceutical formulation may comprise a therapeutically effective amount of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as an active ingredient and an oleaginous base.

[0010] In one example, a topical pharmaceutical formulation may comprise a therapeutically effective amount of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as an active ingredient, an oleaginous base, and one or more pharmaceutically acceptable excipients.

[0011] In some implementations, the dosage form of the pharmaceutical formulation of the present invention may be an ointment, cream, lotion, foam, or suspension. Specifically, the topical dosage form of the present invention may be an ointment, cream, foam, or suspension, and more specifically, the topical dosage form may be an ointment.

[0012] In some implementations, the pharmaceutical formulation may optionally include one or more other pharmaceutically acceptable excipients.

[0013] In some implementations, the oleaginous base may include one or more selected from semi-solid hydrocarbon mixtures, oils, waxes, and fatty acids.

[0014] In some implementations, the semi-solid hydrocarbon mixture may include, but is not limited to, one or more selected from white petrolatum and refined lanolin.

[0015] In some implementations, the oil is selected from the group consisting of liquid paraffin, squalane, medium chain triglycerides, and the like. The oil may include, but is not limited to, one or more selected from the group consisting of glycerides (medium chain triglycerides), olive oil, castor oil, soybean oil, and liquid lanolin.

[0016] In some implementations, the wax may include, but is not limited to, one or more of white wax, paraffin wax, and carnauba wax.

[0017] In some implementations, the fatty acids may include, but are not limited to, one or more of cocoa butter, shea butter, and lanolin acid.

[0018] In one embodiment, the oleaginous base may include white petrolatum, liquid paraffin, white wax, or a combination of two or more selected from these. In one embodiment, the oleaginous base may include white petrolatum and liquid paraffin. In one embodiment, the oleaginous base may include white petrolatum and white wax. In one embodiment, the oleaginous base may include white petrolatum, liquid paraffin, and white wax.

[0019] In some implementations, the oleaginous base may comprise from about 45 to about 99.99% by weight, based on 100% total weight of the pharmaceutical formulation. In some implementations, the content of the oleaginous base may be about 70 to about 99.95% by weight, based on 100% by weight of the total pharmaceutical preparation.

[0020] In the present invention, the term "pharmaceutically acceptable excipient" refers to an excipient other than the oleaginous base, and is defined as not including the oleaginous base. The pharmaceutically acceptable excipient in the present invention may include a skin permeation enhancer, an antioxidant, a preservative, a chelating agent, an emulsifier, a pH adjuster, a stabilizer, a fragrance, a colorant, or a combination of two or more selected from these.

[0021] In some implementations, the excipient may include a skin permeation enhancer, an antioxidant, a preservative, or a combination of two or more selected therefrom.

[0022] In some implementations, the skin permeation enhancer may include, but is not limited to, a combination of two or more of alcohols, amides, fatty acids, esters, surfactants, essential oils, terpenes, and phospholipids.

[0023] In some implementations, the alcohol may include a saturated fatty alcohol having at least 8 carbon atoms, and may include, but is not limited to, caprylic alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, or a combination of two or more selected therefrom.

[0024] In some implementations, the amide may include, but is not limited to, laurocapram.

[0025] In some embodiments, the fatty acid is a saturated or unsaturated fatty acid having 7 or more carbon atoms, specifically 7 to 30 carbon atoms, and may include, but is not limited to, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or a combination of two or more selected from the foregoing.

[0026] In some implementations, the ester is isopropyl decanoate, isopropyl mica, The sucrose may include, but is not limited to, sucrose lactate, isopropyl palmitate, sucrose laurate, or a combination of two or more selected from these.

[0027] In some implementations, the surfactant may include, but is not limited to, sodium lauryl sulfate, vitamin E TPGS, lauryl macrogolglyceride, Span 60, Span 83, or a combination of two or more selected therefrom.

[0028] In some implementations, the essential oil may include, but is not limited to, eucalyptus oil, ylang-ylang oil, chenopodium oil, or a combination of two or more selected therefrom.

[0029] In some implementations, the terpenes may include, but are not limited to, geraniol, linalool, limonene, menthol, eucalyptol, carvone, squalene, or two or more selected from the foregoing.

[0030] In some implementations, the phospholipid may include, but is not limited to, phosphatidylcholine.

[0031] In some implementations, the skin permeation enhancer may be present in an amount of about 0.1 to about 30% by weight, based on 100% total weight of the pharmaceutical formulation. In some embodiments, the content of the skin permeation enhancer may be about 1 to about 15% by weight, specifically about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight, based on 100% by weight of the total pharmaceutical formulation. In some embodiments, the preservative may include, but is not limited to, methylparaben, propylparaben, phenoxyethanol, benzyl alcohol, sodium benzoate, or a combination of two or more selected from these.

[0032] In some implementations, the preservative may be present in an amount of about 0.01 to about 5% by weight, based on 100% of the total weight of the pharmaceutical formulation. In some implementations, the content of the preservative may be about 0.05 to about 3% by weight, based on 100% by weight of the total pharmaceutical formulation, for example, specifically, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3% by weight, based on 100% by weight of the total pharmaceutical formulation.

[0033] In some implementations, the antioxidant may include, but is not limited to, tocopherol, tocopherol acetate, BHT, BHA, ascorbyl palmitate, alpha-lipoic acid, silicon dioxide, zinc oxide, or a combination of two or more selected therefrom.

[0034] In some implementations, the antioxidant may be present in an amount of about 0.05 to about 10% by weight, based on 100% of the total weight of the pharmaceutical formulation. In some embodiments, the content of the antioxidant may be about 0.1 to about 5% by weight, based on 100% by weight of the total pharmaceutical formulation, for example, specifically, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% by weight, based on 100% by weight of the total pharmaceutical formulation.

[0035] In one embodiment, the pharmaceutical formulation of the present invention contains (S)-N-(4-( The composition may contain, together with 1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or its pharmaceutically acceptable and oleaginous base, at least one or more pharmaceutically acceptable excipients different from the oleaginous base selected from the group consisting of (a) skin permeation enhancers, (b) preservatives, and (c) antioxidants.

[0036] The present invention comprises as an active ingredient (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" refers to salts commonly used in the pharmaceutical industry, including, but not limited to, inorganic ion salts prepared from sodium, magnesium, calcium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, etc.; organic acid salts prepared from acetic acid, citric acid, succinic acid, maleic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, benzoic acid, propionic acid, lactic acid, etc.; sulfonate salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, etc.; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, etc.

[0037] In some embodiments, the content of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof in the pharmaceutical formulation may be about 0.01 to 10% by weight of the dosage form on a free base basis, based on 100% by weight of the total pharmaceutical formulation.

[0038] In some embodiments, the topical dosage form contains (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof, in an amount of about 0.05 to 7% by weight of the dosage form on a free base basis, based on 100% by weight of the total pharmaceutical formulation. For example, it may be, specifically, about 0.05% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight, about 5% by weight, about 5.5% by weight, about 6% by weight, about 6.5% by weight, or about 7% by weight, based on 100% by weight of the pharmaceutical formulation.

[0039] In some embodiments, the pharmaceutical formulation may contain, based on a total weight percentage of 100%, (a) about 0.01% to about 10% by weight of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, based on the free base, and (b) about 90% to about 99.99% by weight of an oleaginous base.

[0040] In some implementations, the pharmaceutical formulation may comprise, based on a total weight percentage of 100%, (a) about 0.01% to about 10% by weight of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, based on the free base; (b) about 69% to about 99% by weight of an oleaginous base; and (c) about 0.1% to about 30% by weight of a skin permeation enhancer.

[0041] In some embodiments, the pharmaceutical formulation may comprise (a) about 0.01% to about 10% by weight of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2 ,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, (b) about 45% to about 99.99% by weight of an oleaginous base, (c) optionally about 0.1% to about 30% by weight of a skin permeation enhancer, (d) optionally about 0.01% to about 5% by weight of a preservative, and (e) optionally about 0.05% to about 10% by weight of an antioxidant. When at least one excipient selected from the skin permeation enhancer, preservative, and antioxidant is included together with the active ingredient and the oleaginous base, the content of the excipient can be appropriately adjusted within the above range so that the total weight of the active ingredient and the oleaginous base becomes 100% by weight.

[0042] In some embodiments, the pharmaceutical formulation may contain, based on 100% total weight, (a) about 0.05% to about 7% by weight of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof on a free base basis; (b) about 70% to about 99.9% by weight of an oleaginous base; (c) optionally about 1% to about 15% by weight of a skin permeation enhancer; (d) optionally about 0.05% to about 3% by weight of a preservative; and (e) optionally about 0.1% to about 5% by weight of an antioxidant. When at least one excipient selected from a skin permeation enhancer, a preservative, and an antioxidant is contained together with the active ingredient and the oily base, the content of the excipient may be appropriately adjusted within the above range so that the total weight of the active ingredient and the oily base is 100%.

[0043] The topical pharmaceutical formulation of the present invention may not contain a solvent capable of dissolving the active ingredient. The solvent may be glycerin or propylene glycol. That is, the topical pharmaceutical formulation of the present invention may be a pharmaceutical formulation that does not contain glycerin or propylene glycol.

[0044] In one embodiment, the topical pharmaceutical formulations of the present invention may comprise water. In one embodiment, a topical pharmaceutical formulation according to the present invention may comprise an active ingredient, an oleaginous base, an emulsifier, and water. In one embodiment, the topical pharmaceutical formulations of the present invention may be free of water.

[0045] The active ingredient contained in the pharmaceutical formulation of the present invention is a selective JAK1 inhibitor, and therefore the pharmaceutical formulation of the present invention may be used for the treatment and / or prevention of inflammatory diseases and autoimmune diseases in which JAK1 inhibitors are effective.

[0046] In an embodiment of the present invention, the autoimmune disease may refer to a disease exhibiting a pathological reaction to an autoantigen, and for example, the autoimmune disease may be xeroderma, vitiligo (e.g., non-segmental vitiligo), pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc. In an embodiment of the present invention, the formulation may be applied to anyone, including children, adolescents, adults, and the elderly.

[0047] The pharmaceutical formulations of the present invention can be used for the treatment and / or prevention of skin diseases. Specifically, the pharmaceutical formulation of the present invention can be used to treat and / or prevent at least one of skin diseases including dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin rash, and skin irritation.

[0048] The present invention also provides a method for treating and / or preventing inflammatory and autoimmune diseases, comprising the step of applying the topical pharmaceutical formulation to the skin surface of a patient, wherein the autoimmune diseases may be substantially the same as those described above for the formulation.

[0049] The present invention also provides a method for treating and / or preventing at least one skin disorder selected from the group consisting of xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin rash, and skin irritation, comprising the step of applying the topical pharmaceutical formulation to a skin disorder site of a patient.

[0050] The present invention provides the use of said topical pharmaceutical formulations for treating and / or preventing inflammatory and autoimmune diseases, which may be substantially the same as those previously described for the formulations.

[0051] The present invention also provides a use of the topical pharmaceutical formulation for treating and / or preventing at least one skin disease selected from the group consisting of dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin rash, and skin irritation.

[0052] The present invention provides the use of said topical pharmaceutical formulation for the manufacture of a medicament for treating and / or preventing inflammatory and autoimmune diseases, said autoimmune diseases may be substantially as described above for the formulation.

[0053] The present invention also provides use of the topical pharmaceutical formulation for the manufacture of a medicament for treating and / or preventing at least one skin disease selected from the group consisting of xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin rash, and skin irritation.

[0054] In this specification, the contents described in relation to the formulations can be applied substantially identically to the therapeutic and / or prophylactic methods and uses, unless inconsistent.

[0055] The method for producing a topical pharmaceutical formulation according to the present invention includes the steps of: (Step 1) mixing (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof with an oleaginous base; (Step 2) Cooling the mixture obtained above.

[0056] Specifically, the above (Step 1) is The method may include a step of dispersing the active ingredient, (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, in the oily base.

[0057] The step of dispersing may be synonymous with suspending. The dispersing step comprises: (Step 1a) melting the oleaginous base to obtain a melt; and (Step 1b) adding the active ingredient as is to the melted oily base and mixing.

[0058] Step 1a may include heating an oleaginous base that is solid or semi-solid at room temperature to a temperature higher than room temperature, which may be about 60 to about 85°C, for example, about 65 to about 80°C.

[0059] The term "non-dissolving" the active ingredient means that it is not dissolved in a separate solvent, and the non-dissolved active ingredient is in a solid state, and the active ingredient may be added as is to a melt of an oily base and mixed to disperse it, followed by a cooling step to prepare the topical pharmaceutical formulation according to the present invention.

[0060] In the present invention, the pharmaceutical formulation is prepared by dispersing an active ingredient, including (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, in an oily base, thereby enabling a larger amount of the active ingredient to be stably loaded.

[0061] In one example, (Step 1) may be a step of mixing (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, an oleaginous base, and a pharmaceutically acceptable excipient different from the oleaginous base.

[0062] In one embodiment, in step 1b, a pharmaceutically acceptable excipient different from the oleaginous base may be mixed with the active ingredient in the oleaginous base.

[0063] In one embodiment, step 2 may be performed at a lower temperature than step 1, specifically steps 1a and 1b.

[0064] The inventors of the present invention have confirmed that a formulation prepared by dissolving (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as an active ingredient in a solvent and then mixing it with an oily base discolors over time, and that the degree of discoloration increases as the content of the active ingredient increases. That is, the method of dissolving (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as an active ingredient in a solvent and then mixing it with an oily base does not provide a topical pharmaceutical preparation suitable as a medicine.

[0065] As a result of efforts to solve these problems, the inventors of the present invention have confirmed that a formulation prepared by dispersing (suspending) the active ingredient, (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, in an oily base can be loaded with a high amount of the active ingredient without changing the properties of the topical dosage form, and is stable even under accelerated conditions (40°C, 75% RH, 6 months).

[0066] The topical dosage form according to the present invention can be stably prepared using a simple method while containing a high content of active ingredients, and showed superior therapeutic effects in an atopic dermatitis animal model compared to a placebo dosage form containing no active ingredients.

[0067] It has been confirmed that the topical pharmaceutical formulation according to the present invention has excellent drug content uniformity despite being prepared without a separate solvent.

[0068] In this specification, the contents described above regarding the formulations can be applied to the manufacturing method of the formulations unless there is a contradiction.

[0069] 1) The present invention provides a topical pharmaceutical formulation comprising (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, and an oleaginous base.

[0070] 2) In 1), the pharmaceutical formulation may be an ointment, cream, lotion, foam or suspension.

[0071] 3) In 1) or 2), the pharmaceutical preparation may be an ointment.

[0072] 4) In any one of 1) to 3), the oleaginous base may be one or more selected from a semi-solid hydrocarbon mixture, an oil, a wax, and a fatty acid.

[0073] 5) In 4), the semi-solid hydrocarbon mixture is It may be one or more selected from the group consisting of white petrolatum and purified lanolin.

[0074] 6) In 4) or 5), the oil may be one or more selected from liquid paraffin, squalane, medium-chain triglycerides, olive oil, castor oil, soybean oil, and liquid lanolin.

[0075] 7) In any one of 4) to 6), the wax may be one or more selected from the group consisting of white wax, paraffin wax, and carnauba wax.

[0076] 8) In any one of 4) to 7), the fatty acid may be one or more selected from cocoa butter, shea butter, and lanolin acid.

[0077] 9) In any one of 1) to 8), the pharmaceutical formulation may further include a pharmaceutically acceptable excipient other than the oily base, wherein the excipient may be one or more selected from a skin permeation enhancer, an antioxidant, a preservative, a chelating agent, an emulsifier, a pH adjuster, a stabilizer, a fragrance, and a coloring agent.

[0078] 10) In any one of 1) to 9), the (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.01 to 10% by weight based on the free base, relative to 100% by weight of the total pharmaceutical formulation.

[0079] 11) In any one of 1) to 10), the oily base may be contained in an amount of 45 to 99.99% by weight relative to 100% by weight of the total pharmaceutical preparation.

[0080] 12) In any one of 1) to 11), the pharmaceutical preparation may further comprise a skin permeation enhancer in an amount of 0.1 to 30% by weight relative to 100% by weight of the total pharmaceutical preparation.

[0081] 13) In any one of 1) to 12), the pharmaceutical preparation may further contain a preservative in an amount of 0.01 to 5% by weight relative to 100% by weight of the total pharmaceutical preparation.

[0082] 14) In any one of 1) to 13), the pharmaceutical preparation may further contain 0.05 to 10% by weight of an antioxidant relative to 100% by weight of the total pharmaceutical preparation.

[0083] 15) In any one of 1) to 14), the pharmaceutical preparation may be for the treatment or prevention of inflammation and autoimmune diseases, and for example, the autoimmune disease may be xeroderma, vitiligo (e.g., non-segmental vitiligo), pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc.

[0084] 16) In any one of 1) to 15), the pharmaceutical preparation may be for the treatment or prevention of one or more skin diseases selected from dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash.

[0085] 17) The present invention provides a method for producing a pharmaceutical composition comprising: (Step 1) mixing (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof and an oleaginous base; (Step 2) cooling the mixture obtained above; A method for producing a topical pharmaceutical formulation is provided.

[0086] 18) In 17), the step 1 is The step may be a step of dispersing the active ingredient, (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, in the oily base.

[0087] 19) In 17) or 18), (step 1) is The step may include dispersing the active ingredient, (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, in a melt of the oily base.

[0088] 20) In any one of 17) to 19), (Step 1) may be a step of dispersing a pharmaceutically acceptable excipient different from the oleaginous base in a melt of the oleaginous base.

[0089] 21) In any one of 17) to 20), the pharmaceutical formulation may be a formulation according to any one of 1) to 16).

[0090] 22) The present invention provides a method for treating or preventing inflammation and autoimmune diseases, comprising applying a pharmaceutical preparation according to any one of 1) to 16) to a subject in need thereof. The autoimmune disease may refer to a disease exhibiting a pathological reaction to an autoantigen, for example, xeroderma, vitiligo (e.g., non-segmental vitiligo), scratching, or the like. The symptom may be pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, Pemphigus Vulgaris (PV), Bellous Pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, or the like.

[0091] 23) The present invention provides a method for treating or preventing one or more skin diseases selected from dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash, comprising the step of applying a pharmaceutical preparation according to any one of 1) to 16) to a subject in need thereof.

[0092] 24) The present invention provides a use of a topical pharmaceutical preparation according to any one of 1) to 16) for treating or preventing inflammation and autoimmune diseases. The autoimmune disease may refer to a disease exhibiting a pathological reaction to an autoantigen. For example, the autoimmune disease may be xeroderma, vitiligo (e.g., non-segmental vitiligo), pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc.

[0093] 25) The present invention provides use of a topical pharmaceutical formulation according to any one of 1) to 16) for treating or preventing one or more skin diseases selected from dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash.

[0094] 26) The present invention provides use of a topical pharmaceutical preparation according to any one of 1) to 16) for the manufacture of a medicament for treating or preventing inflammatory diseases and autoimmune diseases. The autoimmune diseases may refer to diseases exhibiting a pathological reaction to an autoantigen. For example, the autoimmune diseases may be xeroderma, vitiligo (e.g., non-segmental vitiligo), pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc.

[0095] 27) The present invention provides use of a topical pharmaceutical formulation according to any one of 1) to 16) for the manufacture of a medicament for treating or preventing one or more skin diseases selected from dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash.

[0096] 28) In any one of 1) to 27), the pharmaceutical formulation may not contain a solvent.

[0097] 29) In any one of 1) to 28), the pharmaceutical formulation may be solvent-free, wherein the solvent may be glycerin, propylene glycol, or a mixture thereof.

[0098] 30) In any one of 1) to 29), the pharmaceutical formulation may be a formulation that is substantially free of or completely free of glycerin, propylene glycol, or mixtures thereof.

[0099] 31) In any one of 1) to 30), the pharmaceutical preparation comprises an active ingredient, (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof; It may contain one or more oleaginous bases selected from the group consisting of white petrolatum, liquid paraffin and white wax.

[0100] 32) In any one of 1) to 31), the pharmaceutically acceptable salt of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide may be a phosphate salt of (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide. [Effects of the Invention]

[0101] The topical pharmaceutical preparation of the present invention, its use, and its manufacturing method exhibit excellent therapeutic effects in animal models of atopic dermatitis, has excellent skin permeability, and has little or no side effects (excellent safety).The topical pharmaceutical preparation of the present invention can be stably manufactured by a simple method while containing a high content of active ingredients.

[0102] The topical pharmaceutical formulation according to the present invention can ensure excellent drug content uniformity despite being prepared without a separate solvent, does not discolor during storage, and generates little or no related substances, exhibiting excellent stability and capable of maintaining excellent stability regardless of the storage container. [Brief explanation of the drawings]

[0103] [Figure 1] 1 is a diagram showing photographs confirming the changes in properties over time of various topical dosage forms prepared in Preparation Example 1. [Figure 2] FIG. 1 shows photographs of lesions in an animal model of atopic dermatitis, comparing lesions in mice to which a placebo, a suspension, or the topical formulation of Example 1 was applied twice daily for 30 days with lesions in mice (normal or DNCB-induced) to which no topical formulation was applied. [Figure 3] 1 is a graph showing atopic dermatitis scores over time for each group in an atopic dermatitis animal model. [Figure 4] 1 is a graph showing the skin thickness over time for each group in an atopic dermatitis animal model. [Figure 5] 1 is a graph showing the amount of main component permeated over time when a topical formulation of the present invention and a comparative formulation were applied to a Franz diffusion cell sandwiched between the skin of a hairless mouse. [Figure 6] 1 is a graph showing atopic dermatitis scores over time for each group in an atopic dermatitis animal model. [Figure 7]1 is a graph showing the skin thickness over time for each group in an atopic dermatitis animal model. DETAILED DESCRIPTION OF THE INVENTION

[0104] The present invention will be described in more detail below with reference to examples. However, these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0105] Manufacturing Example 1. Manufacturing of various topical dosage forms Comparative Examples and Examples were prepared as topical dosage forms of various shapes using various pharmaceutical excipients as shown in Table 1 below, each containing (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide phosphate as an active ingredient.

[0106] [Table 1]

[0107] The topical formulations according to Comparative Examples 1 and 2 are ointments prepared by dissolving the active ingredients. The active ingredients are dissolved in glycerin or propylene glycol as a solvent depending on their concentration, and then heated at high temperature. It was mixed with white petrolatum and / or liquid paraffin melted at (68-78℃) and then cooled to room temperature.

[0108] Example 4 is an oil-in-water cream, which was prepared by dispersing the active ingredient in an oily base melted at high temperature (68-78°C) using a homogenizer as in Examples 1 to 3, adding purified water while dispersing in the homogenizer, and cooling at room temperature. It was also confirmed that this cream did not discolor even after 3 months of storage at room temperature.

[0109] Examples 1 to 3 are ointments prepared without dissolving the active ingredient in order to increase the content of the active ingredient. The active ingredient was dispersed in an oily base melted at high temperature (68-78°C) using a homogenizer, and then cooled to room temperature.

[0110] The properties of the ointments obtained in Examples 1 to 3 and Comparative Examples 1 and 2 were checked on the day of production and after a certain number of days had passed since production, and the results are shown in FIG.

[0111] 1, it was confirmed that the ointments obtained in Comparative Examples 1 and 2 turned yellower after one day of storage at room temperature compared to the dosage form immediately after preparation. In other words, it was confirmed that a topical pharmaceutical preparation suitable for use as a medicine cannot be prepared by dissolving the active ingredient (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide phosphate in a solvent.

[0112] On the other hand, the ointments prepared in Examples 1 to 3 had active ingredient contents more than three times higher than those of Comparative Examples 1 and 2, and it was confirmed that all of them maintained their properties without discoloration even after 3 months of storage at room temperature.

[0113] Evaluation 1. Efficacy confirmation test in an animal model of atopic dermatitis To evaluate the efficacy of a topical formulation containing (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide phosphate, efficacy was confirmed in an atopic dermatitis animal model.

[0114] An atopic dermatitis animal model was created by applying dinitrochlorobenzene (DNCB) to NC / Nga mice. The test groups were divided into four groups: a control group (a group in which no treatment was applied to mice with dermatitis induced with DNCB); a placebo group (prepared as in Example 1 but omitting the active ingredient); a suspension group in which the active ingredient was suspended in 0.5% methyl cellulose solution; and a group treated with the ointment prepared in Example 1. The remaining groups, excluding the control group, were treated with the ointment twice daily for 30 days on the skin with atopic dermatitis lesions, and the degree of improvement of the lesions was assessed. The degree of improvement of the lesions was assessed by measuring the atopic dermatitis (AD) score and skin thickness. The AD score was determined by rating each of the five symptoms of the lesion (erythema, dryness, skin edema and hematoma, erosion, and keratinization) as none (0), mild (1), moderate (2), or severe (3), and then adding up the scores for each of the five symptoms. Skin thickness was measured using a Kellifer. The results are shown in Figures 2 to 4.

[0115] Referring to Figures 2 and 3, it was confirmed that the suspension containing the active ingredient and the ointment according to Example 1 significantly improved the AD score compared to the control group not containing the active ingredient and the placebo group. Referring to FIG. 4, in terms of skin thickness, the ointment of Example 1 was found to be superior to the control group, placebo group, and It was confirmed that both significantly reduced skin thickness when compared with the suspension.

[0116] Evaluation 2. Stability test of topical dosage form The stability test of the dosage form of the ointment obtained in Example 1 of Preparation Example 1 was carried out under two conditions: room temperature / high humidity (25°C, 60% RH) and high temperature / high humidity (40°C, 75% RH), and the results are shown in Table 2 below.

[0117] [Table 2]

[0118] Referring to Table 2, it was confirmed that the ointment obtained in Example 1 was stable even after 6 months under both conditions, and its properties were also maintained at the same level as when it was first used.

[0119] Preparation Example 2: Preparation of topical dosage forms according to Examples 5 to 20 To evaluate the formulation and process characteristics of topical dosage forms, Examples 5 to 20 were prepared according to the experimental design shown in Table 3 below. The active ingredient, (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide phosphate, was fixed at 1.9 wt% based on the total weight of the unit pharmaceutical formulation (100%). The respective contents of liquid paraffin, white wax, and isopropyl myristate were as shown in Table 3, and the total amount was adjusted to 100 wt% with white petrolatum. The dosage forms were prepared as follows: First, all oleaginous bases were melted at high temperature (68-78°C), and then the main ingredients were added using a homogenizer and dispersed at various speeds and for various times. After dispersion, the mixture was stirred at 30°C and cooled.

[0120] [Table 3]

[0121] Evaluation 3. Development of topical dosage forms and evaluation of manufacturing processes and characteristics The properties of the dosage forms prepared in Examples 5 to 22 in Table 3 are shown in Table 4 below. The viscosity was measured immediately after preparation (using a Brookfield viscometer with a 4-spindle), and the total related substances were measured and analyzed after leaving the formulations under high temperature / high humidity conditions for a certain period of time.

[0122] [Table 4]

[0123] As a result, the properties of the dosage forms of Examples 5 to 20 were all non-yellow semi-solid preparations, and the viscosity tended to increase as more white wax was added, and the viscosity tended to decrease as more isopropyl myristate was added. The stability of the dosage form was stable in all formulations. At 40°C and 75% RH, the levels of related substances were similar for all formulations before the test (the difference from the initial level was within the measurement error range), and at 60°C and 80% RH, the levels were slightly higher numerically, but did not increase significantly.

[0124] From the results of the above examples, it can be seen that the dispersion time and dispersion speed using a homogenizer do not significantly affect the properties of the dosage form.

[0125] Evaluation 4. Container screening for topical dosage forms The topical dosage form of Example 8 was used to evaluate stability in various containers, and the results are shown in Table 5 below. The stability of each container was evaluated through purity tests after storing the dosage form for two weeks under two conditions: 40°C, 75% RH and 60°C, 80% RH.

[0126] [Table 5]

[0127] Referring to Table 5, the test results for the topical dosage form of Example 8 were unchanged at 40°C and 75% RH, but at 60°C and 80% RH, due to the low melting point of the excipients used, the dosage form melted and then solidified when taken out at room temperature. For the topical dosage form of Example 8, the related substances were similar to those before the test at 40°C and 75% RH, and although the values ​​were slightly higher at 60°C and 80% RH, they did not increase significantly.

[0128] Evaluation 5. Skin permeability evaluation by topical formulation The skin permeation rate of each topical formulation was evaluated using a Franz-type diffusion cell on hairless mouse skin. The aqueous solution for the Franz diffusion cell was a 6% polyethylene glycol 20 oleyl ether solution, which was stirred at 32°C. Samples were collected at regular intervals and analyzed for drug concentration using LC-MS / MS.

[0129] The experimental groups were selected from Examples 10, 12, 18, and 19 based on the content of white wax and whether or not isopropyl myristate was included, and Corectim ointment (delgocitinib 0.5%) was used as Comparative Example 3. The test results are shown in Figure 5.

[0130] Referring to Figure 5, the amount of active ingredient permeated through the skin was higher in Examples 10 and 19, which contained a high amount of white wax, while Examples 10 and 12, which contained isopropyl myristate, showed a tendency for the amount of permeation to increase with time. (Comparative Example 3 used a different active ingredient from the Examples, so all measurements were taken at 0 ng / mL.)

[0131] Preparation Example 3. Preparation of topical dosage forms according to Examples 21 to 29 The active ingredient is (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine In order to evaluate the characteristics of topical dosage forms depending on the content of (-6-yl)cyclopropanecarboxamido phosphate, the test design shown in Table 6 below was followed and Examples 21 to 29 were prepared. The topical dosage forms were prepared as follows: First, all oily bases were melted at high temperature (68-78°C), and then the main ingredients were added and dispersed using a homogenizer (4,000 rpm, 15 minutes). After dispersion, the mixture was stirred at 30°C and cooled.

[0132] [Table 6]

[0133] Evaluation 6. Manufacturing and Characterization of Topical Dosage Forms by Main Ingredient Content The properties of the Examples in Table 6 are shown in Table 7 below. The viscosity was measured immediately after production (measured using a Brookfield viscometer with a quadruple spindle), and the total related substances were measured and analyzed after leaving the samples under high temperature / high humidity conditions for a certain period of time.

[0134] [Table 7]

[0135] As a result, the viscosity of the formulations according to Examples 21 to 29 tended to increase as the concentrations of the main ingredient and white wax increased. The stability of all formulations was generally stable. The properties during the stability test did not change at 40°C and 75% RH. The related substances were similar to those before the test at 40°C and 75% RH in all formulations, and although the values ​​were slightly higher at 60°C and 80% RH, they did not increase significantly.

[0136] Preparation Example 4. Preparation of topical dosage forms with various active ingredient contents that exhibit similar viscosities In order to prepare topical dosage forms with different main ingredient contents but similar viscosities, the ratio of the main ingredient to white wax was set based on the test results of Preparation Examples 2 and 3, and topical dosage forms according to Examples 30 to 34 were prepared. The topical dosage forms were prepared using substantially the same manufacturing method as described in Preparation Example 3. The detailed formulations and viscosities of the topical dosage forms by main ingredient content are shown in Table 8, and it was confirmed that the viscosities were similar despite the different main ingredient contents.

[0137] [Table 8]

[0138] Evaluation 7. Efficacy confirmation test in an animal model of atopic dermatitis To evaluate the efficacy of topical formulations depending on the active ingredient content, we examined their efficacy in an animal model of atopic dermatitis. The animal model of atopic dermatitis was created by applying dinitrochlorobenzene (DNCB) to NC / Nga mice. The test groups were divided into six groups: a control group (normal), a control group (DNCB-induced), a placebo group (prepared in Example 30 without the active ingredient), and treatment groups (Examples 30, 32, and 33). Except for the two control groups, the remaining groups were treated twice daily with the topical formulation on skin with atopic dermatitis lesions for 28 days, and the degree of improvement in the lesions was assessed. The degree of improvement in the lesions was assessed by measuring the atopic dermatitis (AD) score and skin thickness, using the same experimental methods as described in Evaluation 1. The results are shown in Figures 6 and 7.

[0139] In the AD score results shown in Figure 6, the groups administered with Examples 30, 32, and 33, which are topical formulations containing (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide phosphate, showed improvement effects of 13%, 35%, and 50%, respectively, compared to the placebo group.

[0140] The results of skin thickness in FIG. 7 show that the groups administered with Examples 30, 32 and 33 showed a reduction in skin thickness of 11%, 15% and 20%, respectively, compared to the placebo group.

[0141] While the present invention has been described above with reference to preferred embodiments, it will be understood by those skilled in the art that various modifications and variations of the present invention may be made without departing from the spirit and scope of the present invention as set forth in the following claims.

Claims

1. A topical pharmaceutical formulation comprising (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as an active ingredient, and an oleaginous base.

2. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is in the form of an ointment, a cream, a lotion, a foam, or a suspension.

3. The pharmaceutical formulation of claim 1 , wherein the dosage form of the pharmaceutical formulation is an ointment.

4. 10. The pharmaceutical formulation of claim 1, wherein the oleaginous base comprises one or more selected from the group consisting of semi-solid hydrocarbon mixtures, oils, waxes, and fatty acids.

5. 5. The pharmaceutical formulation of claim 4, wherein the semi-solid hydrocarbon mixture comprises one or more selected from the group consisting of white petrolatum and purified lanolin.

6. 5. The pharmaceutical formulation of claim 4, wherein the oil comprises one or more selected from the group consisting of liquid paraffin, squalane, medium-chain triglycerides, olive oil, castor oil, soybean oil, and liquid lanolin.

7. 5. The pharmaceutical formulation of claim 4, wherein the wax comprises one or more selected from the group consisting of white wax, paraffin wax, and carnauba wax.

8. 5. The pharmaceutical formulation of claim 4, wherein the fatty acids comprise one or more selected from the group consisting of cocoa butter, shea butter, and lanolin acid.

9. The pharmaceutical formulation further comprises a pharmaceutically acceptable excipient different from the oleaginous base; 10. The pharmaceutical formulation of claim 1, wherein the excipient comprises one or more selected from the group consisting of a skin permeation enhancer, an antioxidant, a preservative, a chelating agent, an emulsifier, a pH adjuster, a stabilizer, a fragrance, and a colorant.

10. 2. The pharmaceutical formulation according to claim 1, wherein the (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof is contained in an amount of 0.01 to 10% by weight based on the total weight of the pharmaceutical formulation (100% by weight) on a free base basis.

11. 2. The pharmaceutical preparation according to claim 1, wherein the oleaginous base is contained in an amount of 45 to 99.99% by weight relative to 100% by weight of the total pharmaceutical preparation.

12. The pharmaceutical formulation of claim 1, further comprising a skin permeation enhancer in an amount of 0.1 to 30% by weight relative to 100% by weight of the total pharmaceutical formulation.

13. 2. The pharmaceutical formulation of claim 1, further comprising 0.01 to 5% by weight of a preservative relative to 100% by weight of the total pharmaceutical formulation.

14. 2. The pharmaceutical formulation of claim 1, further comprising 0.05 to 10% by weight of an antioxidant, based on 100% by weight of the total pharmaceutical formulation.

15. 2. The pharmaceutical preparation according to claim 1, which is for the treatment or prevention of inflammation and autoimmune diseases, wherein the autoimmune disease is one or more selected from the group consisting of xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

16. 10. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is for the treatment or prevention of one or more skin diseases selected from the group consisting of dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash.

17. (Step 1) mixing (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof and an oleaginous base; and (Step 2) cooling the mixture obtained above.

18. The above (Step 1) 18. The method for producing the pharmaceutical formulation according to claim 17, comprising a step of dispersing the active ingredient, (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, in the oleaginous base.

19. The above (Step 1) 18. The method for producing the pharmaceutical formulation according to claim 17, which comprises dispersing the active ingredient, (S)—N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, in a melt of the oily base.

20. 20. The method for producing a pharmaceutical formulation according to claim 19, wherein (Step 1) comprises dispersing a pharmaceutically acceptable excipient, different from the oleaginous base, in a melt of the oleaginous base.

21. 10. A method for treating or preventing inflammation and autoimmune diseases, comprising applying the pharmaceutical formulation of claim 1 to a subject in need thereof, The method, wherein the autoimmune disease is one or more selected from the group consisting of xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization, skin irritation, Pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

22. 10. A method for treating or preventing one or more skin disorders selected from the group consisting of dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash, comprising the step of applying the pharmaceutical formulation of claim 1 to a subject in need thereof.

23. 10. Use of the topical pharmaceutical formulation of claim 1 for treating or preventing inflammation and autoimmune diseases, comprising: The autoimmune disease is one or more selected from the group consisting of xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization, skin irritation, Pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

24. 10. Use of the topical pharmaceutical formulation of claim 1 for treating or preventing one or more skin disorders selected from the group consisting of dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash.

25. 10. Use of the topical pharmaceutical formulation of claim 1 for the manufacture of a medicament for treating or preventing inflammatory and autoimmune diseases, comprising: The autoimmune disease is one or more selected from the group consisting of xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, skin rash, skin sensitization, skin irritation, Pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

26. 10. Use of the topical pharmaceutical formulation of claim 1 for the manufacture of a medicament for treating or preventing one or more skin disorders selected from the group consisting of dry skin, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitization, skin irritation, and skin rash.

Images