Topical pharmaceutical formulation comprising kinase inhibitor

Abstract

The present invention relates to a topical pharmaceutical preparation 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 oily matrix, the use thereof, and a process for the preparation thereof, wherein the topical pharmaceutical preparation 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.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480018746.7 (22) Application Date 2024.03.14 (30) Priority Data 10-2023-0034196 2023.03.15 KR (85) PCT International Application Entering National Phase Date 2025.09.12 (86) PCT International Application Application Data PCT / KR2024 / 095547 2024.03.14 (87) PCT International Application Publication Data WO2024 / 191266 KO 2024.09.19 (71) Applicant: Inoan Co., Ltd. Address: Chungcheongbuk-do, South Korea (72) Inventors: Park Mi-ran, Oh Taek-yun, Lee Joo-hyun, Lee Chung-ki, Jeon Eun-kyung, Jung Jin-woo, Hwang Do-seok (74) Patent Agency: Yongxin Patent & Trademark Agency Co., Ltd. 72002 Patent Attorneys: Liu Honglin, Zhang Xiaowei (51) Int.Cl. A61K 9 / 00 (2006.01) A61K 47 / 06 (2006.01) A61K 47 / 44 (2017.01) A61K 47 / 14 (2017.01) A61K 9 / 06 (2006.01) A61K 31 / 444 (2006.01) A61P 29 / 00 (2006.01) A61P 37 / 00 (2006.01) A61P 17 / 00(2006.01) A61P 17 / 06(2006.01) (54) Invention Title: Topical Pharmaceutical Product Including Kinase Inhibitor (57) Abstract: This invention relates to a topical pharmaceutical product, its use and method of preparation thereof, wherein the topical pharmaceutical product comprises: (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient, and an oily matrix. Claims (2 pages), Description (17 pages), Drawings (4 pages), CN 121013710 A 2025.11.25 CN 1 21 01 37 10 A 1. A pharmaceutical article for topical use, 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 oily base. 2. The pharmaceutical article of claim 1, wherein the formulation of the pharmaceutical article is any one of an ointment, cream, lotion, foam, and suspension. 3. The pharmaceutical article of claim 1, wherein the formulation of the pharmaceutical article is an ointment.4. The pharmaceutical product of claim 1, wherein the oily matrix comprises at least one selected from a mixture of semi-solid hydrocarbons, oils, waxes, and fatty acids. 5. The pharmaceutical product of claim 4, wherein the semi-solid hydrocarbon mixture comprises at least one selected from white mineral oil and purified lanolin. 6. The pharmaceutical product of claim 4, wherein the oil comprises at least one selected from liquid paraffin, squalane, medium-chain triglycerides, olive oil, castor oil, soybean oil, and liquid lanolin. 7. The pharmaceutical product of claim 4, wherein the wax comprises at least one selected from beeswax, paraffin wax, and carnauba wax. 8. The pharmaceutical product of claim 4, wherein the fatty acid comprises at least one selected from cocoa butter, shea butter, and lanolinic acid. 9. The pharmaceutical product of claim 1, wherein the pharmaceutical product further comprises a pharmaceutically acceptable excipient other than the oily matrix, wherein the excipient comprises at least one selected from: skin penetration enhancers, antioxidants, preservatives, chelating agents, emulsifiers, pH adjusters, stabilizers, fragrances, and colorants. 10. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, 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 is 0.01 to 10% by weight, calculated as free base. 11. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, the content of the oily matrix is ​​45 to 99.99% by weight. 12. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, the pharmaceutical product further comprises 0.1 to 30% by weight of a skin penetration enhancer. 13. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, the pharmaceutical product further comprises 0.01 to 5% by weight of a preservative. 14. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, the pharmaceutical product further comprises 0.05 to 10% by weight of an antioxidant. 15. The pharmaceutical product of claim 1, wherein the pharmaceutical product is for the treatment or prevention of inflammatory diseases and autoimmune diseases, wherein the autoimmune disease is at least one selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.16. The pharmaceutical product according to claim 1, wherein the pharmaceutical product is for the treatment or prevention of at least one skin disease selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergy, skin irritation, and rash. Claims 1 / 2 page 2 CN 121013710 A 17. A method for preparing a pharmaceutical product for topical application, the method 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof with an oily matrix; and (step 2) cooling the mixture obtained as described above. 18. The method of claim 17, wherein step (1) comprises: dispersing (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as the active ingredient in the oily matrix. 19. The method of claim 17, wherein step (1) comprises: dispersing (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as the active ingredient in a melt of the oily matrix. 20. The method of claim 19, wherein step (1) comprises dispersing a pharmaceutically acceptable excipient, different from the oily matrix, in the melt of the oily matrix. 21. A method for treating or preventing inflammatory diseases and autoimmune diseases, the method comprising administering the pharmaceutical product of claim 1 to an individual in need, wherein the autoimmune disease is at least one selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergies, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus. 22. A method for treating or preventing at least one skin disease selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, skin irritation, and rash, the method comprising administering the pharmaceutical product of claim 1 to an individual in need.23. The use of the pharmaceutical product for topical application as claimed in claim 1 for the treatment or prevention of inflammatory diseases and autoimmune diseases, wherein the autoimmune disease is at least one selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus. 24. The use of the pharmaceutical product for topical application as claimed in claim 1 for the treatment or prevention of at least one skin disease, wherein the at least one skin disease is selected from xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergy, skin irritation, and rash. 25. Use of the pharmaceutical product for topical application as claimed in claim 1 in the preparation of a medicament for treating or preventing inflammatory diseases and autoimmune diseases, wherein the autoimmune disease is at least one selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus. 26. Use of the pharmaceutical product for topical application as claimed in claim 1 in the preparation of a medicament for treating or preventing at least one skin disease, wherein the at least one skin disease is selected from xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergy, skin irritation, and rash. Claims 2 / 2 Page 3 CN 121013710 A Topical pharmaceutical product including a protein kinase inhibitor [Technical Field]

[0001] This invention relates to a pharmaceutical product for topical application comprising a protein kinase inhibitor as an active ingredient; its use; and a method for its preparation.

Background Art

[0002] Janus kinase (JAK) is an enzyme in the intracellular non-receptor tyrosine kinase family. It delivers cytokine-mediated signals through the JAK-STAT pathway and is composed of JAK1, JAK2, JAK3, and TYK2. JAK inhibitors are involved in hematopoiesis and immunity, and have therefore been studied as therapeutic agents for myeloproliferative neoplasms, rheumatoid arthritis, and other immune and inflammatory diseases. Compounds such as tofacitinib, baricitinib, and upadacitinib have been developed.

[0003] JAK inhibitors have attracted attention because of their therapeutic efficacy in treating chronic inflammatory diseases, which is comparable to that of biologics, but concerns have been raised about their long-term safety.Xeljanz (component name: tofacitinib) is the world's first oral JAK inhibitor. It effectively inhibits JAK1 / 3 and has been approved as a therapeutic agent for rheumatoid arthritis (RA), active psoriatic arthritis (PsA) in adults, and active ulcerative colitis (UC) in adults. However, as a result of clinical trials, it has been found to have the risk of causing cardiovascular disease, cancer, and thrombosis, thus prompting the FDA to issue a warning about this risk. It has been reported that inhibiting JAK3 can lead to severe combined immunodeficiency (SCID) in humans, and JAK2 has been reported to have anemia as a side effect related to the erythropoietin (EPO) signaling pathway. In order to minimize such problems, JAK1 inhibitors that selectively inhibit JAK1 have been developed, and it is expected that they can reduce side effects in terms of safety.

[0004] At the same time, in terms of therapeutic agents for inflammatory skin diseases, in order to further improve safety, topical formulations are also being developed. The United States and Japan have approved ruxolitinib cream and delgocitinib ointment, respectively, as treatments for atopic dermatitis. Topical formulations show efficacy only at the site of lesion, rather than in systemic circulation, and are therefore expected to greatly reduce concerns about the aforementioned side effects. [Summary of the Invention]

[0005] Technical Problem

[0006] Therefore, the present invention provides a pharmaceutical product for topical use comprising a JAK inhibitor as an active ingredient, said JAK inhibitor being a protein kinase inhibitor; its use, and its preparation method.

[0007] Technical Solution

[0008] The pharmaceutical product for topical use according to the present invention 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient; and an oily matrix.

[0009] In one example, the above-mentioned (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide, which is included as an active ingredient in a pharmaceutical article for topical use, may be a compound represented by the following Formula I.

[0010] [Formula I] Specification 1 / 17 page 4 CN 121013710 A

[0011]

[0012] In one example, a pharmaceutical article for topical use may include a theoretically 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient, and an oily matrix.

[0013] In one example, a pharmaceutical product for topical application may include 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 oily matrix; and at least one pharmaceutically acceptable excipient.

[0014] In some embodiments, the formulation of the pharmaceutical product according to the invention may be an ointment, cream, lotion, foam, or suspension. Specifically, the topical formulation of the invention may be an ointment, cream, foam, or suspension, and more specifically, the topical formulation may be an ointment.

[0015] In some embodiments, the pharmaceutical product may optionally include one or more other pharmaceutically acceptable excipients.

[0016] In some embodiments, the oily matrix may include at least one selected from mixtures of semi-solid hydrocarbons, oils, waxes, and fatty acids.

[0017] In some embodiments, the semi-solid hydrocarbon mixture may include, but is not limited to, at least one selected from white mineral oil and purified lanolin.

[0018] In some embodiments, the oil may include, but is not limited to, at least one selected from: liquid paraffin, squalane, medium-chain triglycerides, olive oil, castor oil, soybean oil, and liquid lanolin.

[0019] In some embodiments, the wax may include, but is not limited to, at least one selected from beeswax, paraffin, and carnauba wax.

[0020] In some embodiments, the fatty acid may include, but is not limited to, at least one selected from cocoa butter, shea butter, and lanolinic acid.

[0021] In one example, the oily matrix may include white mineral oil, liquid paraffin, beeswax, or a combination of two or more of these.

[0022] In one example, the oily matrix may include white mineral oil and liquid paraffin.

[0023] In one example, the oily matrix may include white mineral oil and beeswax.

[0024] In one example, the oily matrix may include white petrolatum, liquid paraffin, and beeswax.

[0025] In some embodiments, the content of the oily matrix may be from about 45% by weight to about 99.99% by weight relative to a total of 100% by weight of the pharmaceutical article.

[0026] In some embodiments, the content of the oily matrix may be from about 70% by weight to about 99.95% by weight relative to a total of 100% by weight of the pharmaceutical article.

[0027] In this invention, "pharmaceuticalally acceptable excipient" may refer to excipients other than the oily matrix and may be defined as those that do not include the oily matrix.In this invention, the pharmaceutically acceptable excipients may include skin penetration enhancers, antioxidants, preservatives, chelating agents, emulsifiers, pH adjusters, stabilizers, fragrances, colorants, or combinations thereof.

[0028] In some embodiments, the excipients may include skin penetration enhancers, antioxidants, preservatives, or combinations thereof.

[0029] In some embodiments, skin penetration enhancers may include, but are not limited to, combinations of, alcohols, amides, fatty acids, esters, surfactants, essential oils, terpenes, and phospholipids.

[0030] In some embodiments, alcohols may include saturated fatty alcohols having at least eight carbon atoms. Alcohols may include, but are not limited to, decanol, lauryl alcohol, myristol, cetyl alcohol, stearyl alcohol, or combinations thereof.

[0031] In some embodiments, amides may include, but are not limited to, laurocapram.

[0032] In some embodiments, the fatty acid, which is a saturated or unsaturated fatty acid having seven or more carbon atoms, particularly seven or more and 30 or fewer carbon atoms, may include, but is not limited to, hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or combinations of two or more thereof.

[0033] In some embodiments, the ester may include isopropyl decanoate, isopropyl myristate, isopropyl palmitate, sucrose laurate, or combinations of two or more thereof.

[0034] In some embodiments, the surfactant may include sodium lauryl sulfate, vitamin E TPGS, lauryl polyethylene glycol glyceride, Span 60, Span 83, or combinations of two or more thereof.

[0035] In some embodiments, the essential oil may include eucalyptus oil, ylang-ylang oil, chenopodium oil, or combinations of two or more thereof.

[0036] In some embodiments, the terpene may include geraniol, linalool, limonene, menthol, eucalyptol, carvone, squalene, or a combination of two or more of these, but is not limited thereto.

[0037] In some embodiments, the phospholipid may include phosphatidylcholine, but is not limited thereto.

[0038] In some embodiments, the content of the skin penetration enhancer may be from about 0.1% by weight to about 30% by weight relative to a total of 100% by weight of the pharmaceutical product.

[0039] In some embodiments, the content of the skin penetration enhancer may be from about 1% to about 15% by weight relative to a total of 100% by weight of the pharmaceutical article, specifically, it may be about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, or about 15% by weight relative to a total of 100% by weight of the pharmaceutical article.

[0040] In some embodiments, the preservative may include methylparaben, propylparaben, phenoxyethanol, benzyl alcohol, sodium benzoate, or combinations of two or more of these, but is not limited thereto.

[0041] In some embodiments, the content of the preservative may be from about 0.01% by weight to about 5% by weight relative to a total of 100% by weight of the pharmaceutical article.

[0042] In some embodiments, the preservative content may be from about 0.05% by weight to about 3% by weight relative to a total of 100% by weight of the pharmaceutical article, specifically, it may be, for example, 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, or about 3% by weight relative to a total of 100% by weight of the pharmaceutical article. (Specification 3 / 17 page 6 CN 121013710 A)

[0043] In some embodiments, the antioxidant may include, but is not limited to, tocopherol, tocopheryl acetate, BHT, BHA, ascorbyl palmitate, α-lipoic acid, silica, zinc oxide, or combinations of two or more of these.

[0044] In some embodiments, the antioxidant content may be from about 0.05% by weight to about 10% by weight relative to a total of 100% by weight of the pharmaceutical article.

[0045] In some embodiments, the antioxidant content may be from about 0.1% by weight to about 5% by weight relative to a total of 100% by weight of the pharmaceutical article, specifically, it may be, for example, 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, or about 5% by weight relative to a total of 100% by weight of the pharmaceutical article.

[0046] In one example, the pharmaceutical product according to the invention may include at least one selected from the group consisting of a pharmaceutically acceptable excipient other than an oily matrix: (a) a skin penetration enhancer, (b) a preservative, and (c) an antioxidant, and (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient; and an oily matrix.

[0047] The pharmaceutical product according to the invention may include (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient. "Medically acceptable salts" can refer to salts commonly used in the pharmaceutical industry, such as inorganic ionic 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.; sulfonates 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., but are not limited to those listed.

[0048] In some embodiments, the 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)cyclopropaneformamide or a pharmaceutically acceptable salt in the pharmaceutical product, based on free base, may be from about 0.01 to 10% by weight of the formulation, relative to a total of 100% by weight of the pharmaceutical product.

[0049] In some embodiments, relative to a total of 100% by weight of the pharmaceutical product, 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 topical formulation, calculated as free base, may be from about 0.05 to about 7% by weight of the formulation. Specifically, relative to a total of 100% by weight of the pharmaceutical product, it may be, for example, 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, or about 5.5% by weight. % by weight, about 6% by weight, about 6.5% by weight, or about 7% by weight.

[0050] In some embodiments, the pharmaceutical article according to the invention may comprise (a) from 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, based on free base, and (b) from about 90% to about 99.99% by weight of an oily matrix.

[0051] In some embodiments, the pharmaceutical product may include (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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, based on free base; (b) about 69% to about 99% by weight of an oily matrix; and (c) about 0.1% to about 30% by weight of a skin penetration enhancer. Specification 4 / 17 pages 7 CN 121013710 A

[0052] In some embodiments, relative to a total of 100% by weight of the pharmaceutical product, the pharmaceutical product may include (a) about 0.01% by weight 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, based on free base; (b) about 45% by weight to about 99.99% by weight of an oily matrix; (c) optionally about 0.1% by weight to about 30% by weight of a skin penetration enhancer; (d) optionally about 0.01% by weight to about 5% by weight of a preservative; and (e) optionally about 0.05% by weight to about 10% by weight of an antioxidant. When at least one excipient selected from skin penetration enhancers, preservatives and antioxidants is included together with the active ingredient and the oily matrix, the content of the excipient may be appropriately controlled within the above range so as to achieve 100% by weight together with the active ingredient and the oily matrix.

[0053] In some embodiments, relative to a total of 100% by weight of the pharmaceutical product, the pharmaceutical product may include (a) from about 0.05% by weight 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, based on free base; (b) from about 70% by weight to about 99.99% by weight of an oily matrix; (c) optionally present from about 1% by weight to about 15% by weight of a skin penetration enhancer; (d) optionally present from about 0.05% by weight to about 3% by weight of a preservative; and (e) optionally present from about 0.1% by weight to about 5% by weight of an antioxidant. When at least one excipient selected from skin penetration enhancers, preservatives, and antioxidants is included together with the active ingredient and the oily matrix, the content of the excipient can be appropriately controlled within the above-mentioned range so as to achieve 100% by weight together with the active ingredient and the oily matrix.

[0054] The pharmaceutical product for topical use according to the present invention may not include a solvent capable of dissolving the active ingredient. The solvent may be glycerol or propylene glycol. In other words, the pharmaceutical product for topical use according to the present invention may be a pharmaceutical product that does not contain glycerol and propylene glycol.

[0055] In one example, the pharmaceutical product for topical use according to the present invention may include water.

[0056] In one example, the pharmaceutical product for topical use according to the present invention may include the active ingredient, the oily matrix, the emulsifier, and water.

[0057] In one example, the pharmaceutical product for topical use according to the present invention may not include water.

[0058] The active ingredient included in the pharmaceutical product of the present invention may be a selective JAK1 inhibitor. Therefore, the pharmaceutical product of the present invention can be used to treat and / or prevent inflammatory diseases and autoimmune diseases in which JAK1 inhibitors show efficacy.

[0059] In an example of the present invention, an autoimmune disease may refer to a disease in which a pathological reaction to an autoantigen is observed; for example, an autoimmune disease may be xeroderma, vitiligo (e.g., non-segmental vitiligo), pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, rash, skin allergies (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 example of the present invention, the product can be applied to all children, adolescents, adults, or the elderly.

[0060] The pharmaceutical products of the present invention can be used to treat and / or prevent skin diseases.

[0061] Specifically, the pharmaceutical products of the present invention can be used to treat and / or prevent at least one of the following skin diseases: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, rash, and skin irritation.

[0062] The present invention may also provide a method for treating and / or preventing inflammatory diseases and autoimmune diseases, comprising applying a topical pharmaceutical preparation to the skin surface of a patient, wherein the autoimmune disease may be substantially the same as described above regarding the product.

[0063] The present invention may also provide a method for treating and / or preventing at least one skin disease selected from xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, rashes, and skin irritation, comprising applying the topical pharmaceutical product to the affected skin site of a patient. Specification 5 / 17 pages 8 CN 121013710 A

[0064] The present invention may provide the use of the topical pharmaceutical product for treating and / or preventing inflammatory diseases and autoimmune diseases, wherein the autoimmune disease may be substantially the same as described above regarding the product.

[0065] Additionally, the present invention can provide the use of the pharmaceutical product for topical application in the treatment and / or prevention of at least one skin disease selected from xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, rashes, and skin irritation.

[0066] The present invention can provide the use of the pharmaceutical product for topical application in the preparation of medicaments for the treatment and / or prevention of inflammatory diseases and autoimmune diseases, wherein the autoimmune diseases may be substantially the same as those described above regarding the product.

[0067] Additionally, the present invention can provide the use of the pharmaceutical product for topical application in the preparation of medicaments for the treatment and / or prevention of at least one skin disease selected from: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, rashes, and skin irritation.

[0068] In this specification, the contents described in the above-described product are substantially equally applicable to the treatment and / or prevention methods and uses (if not contradictory).

[0069] A method for preparing a pharmaceutical article for topical use according to the present invention may include

[0070] (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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof with an oily matrix; and

[0071] (step 2) cooling the mixture obtained above.

[0072] Specifically, step (1) above may include

[0073] dispersing (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient in the oily matrix.

[0074] The dispersion may have the same meaning as suspension.

[0075] The dispersion may include:

[0076] (step 1a) melting the oily matrix to obtain a melt; and

[0077] (step 1b) adding the active ingredient itself to the melt of the oily matrix and mixing it therewith.

[0078] Step (1a) may include heating the oily matrix, which is in a solid or semi-solid phase at a temperature from room temperature to above room temperature. The heating may be performed at about 60 to about 85°C, for example, about 65 to about 80°C.

[0079] The insolubility of the active ingredient may refer to its insolubility in individual solvents. The insolubility of the active ingredient may be in a solid phase and the dispersion process may be performed by adding the active ingredient itself and mixing it into the melt of the oily matrix. A cooling process may then be performed to prepare a pharmaceutical article for topical use according to the present invention.

[0080] In this invention, the pharmaceutical article can be prepared by dispersing an active ingredient comprising (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof in the oily matrix to stably load a greater amount of the active ingredient.

[0081] In one example, step (1) above 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, an oily matrix, and a pharmaceutically acceptable excipient different from the oily matrix.

[0082] In one example, in step (1b) above, a pharmaceutically acceptable excipient different from the oily matrix may be mixed together with the active ingredient into the oily matrix.

[0083] In one example, step (2) above may be performed at a temperature lower than that of step (1) above (specifically, step (1a) and step (1b) above).

[0084] The inventors of the present invention have demonstrated that when the article is 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient in a solvent and then mixing the resulting solution with the oily matrix, the formulation changes color over time, and the degree of color change increases with the increase of the content of the active ingredient.In other words, 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 the active ingredient in a solvent and then mixing the resulting solution with the oily matrix may not yield a pharmaceutical product suitable for topical application as a drug.

[0085] The inventors of this application have attempted to solve the above-mentioned problems, thereby demonstrating that when the article is provided by dispersing (suspending) (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as the active ingredient in the oily matrix, the appearance of the topical formulation remains unchanged even when the active ingredient is loaded at high concentrations, and it is stable even under accelerated conditions (40°C, 75% RH, six months).

[0086] According to the invention, the topical formulation can be stably prepared by a simple method, while containing a high concentration of the active ingredient, and showing superior therapeutic efficacy in animal models of atopic dermatitis compared to placebo formulations without the main ingredient.

[0087] It has been demonstrated that the pharmaceutical articles for topical use according to the invention, although not prepared using individual solvents, exhibit excellent uniformity of drug content.

[0088] In this specification, unless otherwise specified, the contents described in the article are applicable to the method of preparing the article.

[0089] 1) The present invention can provide a pharmaceutical article for topical use, comprising (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, and an oily matrix.

[0090] 2) In 1), the pharmaceutical article may be an ointment, cream, lotion, foam or suspension.

[0091] 3) In 1) or 2), the pharmaceutical article may be an ointment.

[0092] 4) In any of 1) to 3), the oily matrix may be at least one selected from mixtures of semi-solid hydrocarbons, oils, waxes and fatty acids.

[0093] 5) In 4), the semi-solid hydrocarbon mixture may be selected from at least one of white petrolatum and purified lanolin.

[0094] 6) In 4) or 5), the oil may be selected from at least one of the following: liquid paraffin, squalane, medium-chain triglycerides, olive oil, castor oil, soybean oil, and liquid lanolin.

[0095] 7) In any of 4) to 6), the wax may be selected from at least one of white wax, paraffin wax, and carnauba wax.

[0096] 8) In any of 4) to 7), the fatty acid may be selected from at least one of cocoa butter, shea butter, and lanolinic acid.

[0097] 9) In any of 1) to 8), the pharmaceutical product may further comprise a pharmaceutically acceptable excipient different from the oily matrix, wherein the excipient may be selected from at least one of: skin penetration enhancers, antioxidants, preservatives, chelating agents, emulsifiers, pH adjusters, stabilizers, fragrances, and colorants.

[0098] 10) In any of 1) to 9), the content of the above (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof may be 0.01 to 10% by weight, based on free base, relative to a total of 100% by weight of the pharmaceutical product.

[0099] 11) In any of 1) to 10), the content of the oily base may be 45 to 99.99% by weight relative to a total of 100% by weight of the pharmaceutical product.

[0100] 12) In any of 1) to 11), the pharmaceutical product may further comprise 0.1 to 30% by weight of a skin penetration enhancer relative to a total of 100% by weight of the pharmaceutical product.

[0101] 13) In any of 1) to 12), the pharmaceutical product may further comprise 0.01 to 5% by weight of a preservative relative to a total of 100% by weight of the pharmaceutical product.

[0102] 14) In any of 1) to 13), the pharmaceutical product may further comprise 0.05 to 10% by weight of an antioxidant relative to a total of 100% by weight of the pharmaceutical product.

[0103] 15) In any one of 1) to 14), the pharmaceutical product may be used to treat or prevent inflammatory diseases and autoimmune diseases; 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, rash, skin allergies (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc.

[0104] 16) In any one of 1) to 15), the pharmaceutical product may be used to treat or prevent at least one skin disease selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin sensitivity, skin irritation, and rash.

[0105] 17) The present invention may provide a method for preparing a pharmaceutical article for topical use, the method comprising:

[0106] (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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof with an oily matrix; and

[0107] (Step 2) cooling the mixture obtained above.

[0108] 18) In 17), step (1) above may be a step of dispersing (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient in the oily matrix.

[0109] 19) In 17) or 18), step (1) above may be a step of dispersing (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient in the melt of the oily matrix.

[0110] 20) In any of 17) to 19), step (1) above may be a step of dispersing a pharmaceutically acceptable excipient, different from the oily matrix, in the melt of the oily matrix.

[0111] 21) In any of 17) to 20), the pharmaceutical article may be an article according to any of 1) to 16).

[0112] 22) The present invention may provide a method for treating or preventing inflammatory diseases and autoimmune diseases, the method comprising administering a pharmaceutical product according to any one of 1) to 16) to an individual in need, wherein the autoimmune disease may refer to a disease that shows 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, rash, skin allergy (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc.

[0113] 23) The present invention may provide a method for treating or preventing at least one skin disease selected from the following: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergy, skin irritation and rash, said method comprising applying a pharmaceutical product according to any one of 1) to 16) to an individual in need.

[0114] 24) The present invention can provide a pharmaceutical product for topical use according to any one of 1) to 16) for the treatment of inflammatory diseases and autoimmune diseases, wherein the autoimmune disease can refer to a disease that shows a pathological reaction to self-antigens; for example, autoimmune diseases can be xeroderma, vitiligo (e.g., non-segmental vitiligo), pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc.

[0115] 25) The present invention provides the use of any of the pharmaceutical products according to 1) to 16) for topical application in the treatment or prevention of at least one skin disease selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, skin irritation, and rashes.

[0116] 26) The present invention provides the use of any of the pharmaceutical products according to 1) to 16) for topical application in the preparation of medicaments for the treatment or prevention of inflammatory diseases and autoimmune diseases, wherein the autoimmune disease may refer to a disease that shows a pathological reaction to self-antigens; for example, autoimmune diseases may be xeroderma, vitiligo (e.g., non-segmental vitiligo), pruritus, eczema (e.g., chronic hand eczema), alopecia areata, psoriasis, atopic dermatitis, rashes, skin allergies (e.g., contact dermatitis or allergic contact dermatitis), skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, discoid lupus erythematosus, etc.

[0117] 27) The present invention can provide the use of any of 1) to 16) of a pharmaceutical product for topical application in the preparation of a medicament for treating or preventing at least one skin disease selected from: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, skin irritation, and rash.

[0118] 28) In any of 1) to 27), the pharmaceutical product may not contain a solvent.

[0119] 29) In any of 1) to 28), the pharmaceutical product may not contain a solvent, wherein the solvent may be glycerol, propylene glycol, or a mixture thereof.

[0120] 30) In any of 1) to 29), the pharmaceutical product may be a product substantially free of, or free of, glycerol, propylene glycol, or a mixture thereof.

[0121] 31) In any of 1) to 30), the pharmaceutical product may include (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof as an active ingredient; and

[0122] at least one oily matrix selected from white petrolatum, liquid paraffin and beeswax.

[0123] 32) In any of 1) to 31), a 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)cyclopropaneformamide may be a phosphate of (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide.

[0124] Beneficial Effects

[0125] In the pharmaceutical products for topical use according to the present invention, their uses and preparation methods thereof, the pharmaceutical products for topical use of the present invention have excellent therapeutic efficacy in animal models of atopic dermatitis, excellent skin penetration and minimal or no side effects (excellent safety). The pharmaceutical products for topical use according to the present invention can be stably prepared by a simple method and contain a high content of active ingredients.

[0126] The pharmaceutical products for topical use according to the present invention ensure excellent uniformity of drug content even when prepared without the use of individual solvents, exhibit excellent stability during storage due to no discoloration and minimal or no impurities, and maintain excellent stability regardless of the storage container.

[0127] Brief Description of the Drawings 9 / 17 pages of the specification 12 CN 121013710 A

[0128] FIG1 is a view showing photographs demonstrating the changes in the appearance of various topical preparations prepared according to Preparation Example 1 over time.

[0129] Figure 2 is a view showing photographs of lesions in an animal model of atopic dermatitis, used to compare lesions in mice treated twice daily for 30 days with placebo, suspension, and the topical formulation of Example 1 with lesions in mice not treated with the topical formulation (normal or DNCB-induced).

[0130] Figure 3 is a view showing the changes in atopic dermatitis scores over time in each group of the animal model of atopic dermatitis.

[0131] Figure 4 is a view showing the changes in skin thickness over time in each group of the animal model of atopic dermatitis.

[0132] Figure 5 is a view showing the changes in the amount of the main component permeated over time when the topical formulation of the present invention and the comparative formulation were applied to the Franz diffusion cell inserted into the skin of hairless mice.

[0133] Figure 6 is a view showing the change of atopic dermatitis scores over time in each group in an animal model of atopic dermatitis.

[0134] Figure 7 is a view showing the change of skin thickness over time in each group in an animal model of atopic dermatitis.

Detailed Description

[0135] The invention will be described in more detail below by way of exemplary embodiments. However, these exemplary embodiments are provided only for the purpose of illustrating the invention, and therefore the scope of the invention is not limited thereto.

[0136] Preparation Example 1. Preparation of various topical formulations

[0137] Topical formulations according to the comparative examples and embodiments were prepared using various pharmaceutically acceptable excipients according to Table 1 below, said topical formulations being various forms of topical formulations having (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide phosphate as the active ingredient.

[0138] [Table 1] Specification 10 / 17 pages 13 CN 121013710 A

[0139]

[0140] *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)cyclopropaneformamide phosphate

[0141] The topical formulations (ointment preparations prepared by dissolving the active ingredient) according to Comparative Examples 1 and 2 were prepared as follows: The active ingredient was dissolved in glycerol or propylene glycol as a solvent according to various concentrations of the active ingredient, mixed with white petrolatum and / or liquid paraffin melted at high temperature (68-78°C), and then cooled at room temperature.

[0142] Example 4, as an oil-in-water cream, was prepared as follows: As in Examples 1 to 3, the active ingredient was dispersed in an oily matrix molten at a high temperature (68-78°C) using a homogenizer. Purified water was added during the dispersion process, and the resulting mixture was cooled at room temperature. It was confirmed that no discoloration occurred even after storage at room temperature for three months.

[0143] Examples 1 to 3 (ointments prepared without dissolving the active ingredient to increase its content) were prepared as follows: The active ingredient was dispersed in an oily matrix molten at a high temperature (68-78°C) using a homogenizer, and then the resulting mixture was cooled at room temperature.

[0144] The appearance of the ointments obtained according to Examples 1 to 3 and Comparative Examples 1 and 2 was confirmed at the preparation date and at predetermined time points after preparation, and the results are shown in Figure 1.

[0145] Referring to Figure 1, it was confirmed that the ointments obtained according to Comparative Examples 1 and 2 changed color after being stored at room temperature for one day after preparation, becoming a more concentrated yellow than the formulation immediately after preparation.In other words, it has been confirmed that pharmaceutical products suitable for topical use as medicines cannot be 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)cyclopropaneformamide phosphate as the active ingredient in a solvent.

[0146] On the contrary, it has been confirmed that the active ingredient content in the ointments prepared according to Examples 1 to 3 is at least three times higher than that in Comparative Examples 1 and 2, but they do not change color and maintain their appearance even after being stored at room temperature for three months.

[0147] Evaluation 1. Tests to confirm efficacy in animal models of atopic dermatitis

[0148] To evaluate the efficacy of a topical 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)cyclopropaneformamide phosphate, efficacy was confirmed in animal models of atopic dermatitis.

[0149] An animal model of atopic dermatitis was prepared by administering dinitrochlorobenzene (DNCB) to NC / Nga mice. The test group was divided into four groups: a control group (a non-treatment group in which no agent was administered to mice with DNCB-induced dermatitis); a placebo group, which was prepared in the same manner as in Example 1 except for the active ingredient; a suspension group in which the active ingredient was suspended in a 0.5% methylcellulose solution; and a group that received the ointment obtained according to Example 1. All groups except the control group were applied to skin showing atopic dermatitis lesions twice daily for 30 days, and the degree of improvement in the lesions was then confirmed. The degree of improvement in the lesions was confirmed by atopic dermatitis (AD) scores and skin thickness measurements. AD scores were determined as follows: each of the five symptoms of the lesions (erythema, dryness, skin edema and hematoma, erosion and keratinization) was rated according to no (0), mild (1), moderate (2) and severe (3), and all scores for each of the five symptoms were summed, and skin thickness was measured using calipers. The results are shown in Figures 2 to 4.

[0150] Referring to Figures 2 and 3, it has been demonstrated that the suspension containing the active ingredient and the ointment according to Example 1 significantly improved AD scores compared to the control group and the placebo group, which did not contain the main ingredient.

[0151] Referring to Figure 4, in terms of skin thickness, it has been demonstrated that the ointment according to Example 1 significantly reduced skin thickness compared to the control or placebo and suspension.

[0152] Evaluation 2. Stability Test of Topical Formulation

[0153] The stability of the ointment formulation obtained according to Example 1 of Preparation Example 1 was tested under both room temperature / high humidity (25°C, 60% RH) and high temperature / high humidity (40°C, 75% RH) conditions, and the results are shown in Table 2 below.

[0154] [Table 2]

[0155]

[0156] Referring to Table 2, it has been confirmed that the ointment obtained according to Example 1 is stable even after being kept under both conditions for six months, and its appearance remains the same as that at the initial stage. Preparation Example 2: Preparation of Topical Formulations according to Examples 5 to 20

[0157] In order to evaluate the composition of excipients in the topical formulation and the characteristics of the formulation prepared according to this method, the tests shown in Table 3 below were designed, and Examples 5 to 20 were prepared. Relative to a total of 100% by weight of a unit pharmaceutical product, (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide phosphate, as the active ingredient, was fixed at 1.9% by weight, and the contents of each of liquid paraffin, beeswax, and isopropyl myristate were as shown in Table 3, and the total amount was adjusted to 100% by weight using white petrolatum. The formulation was prepared as follows. First, all oily matrices were melted at a high temperature (68-78°C), and then the main components were added under homogenization to disperse them at different ratios and times. After dispersion, the resulting mixture was stirred and cooled at 30°C. Instructions for Use, Pages 12 / 17, 15 CN 121013710 A

[0158] [Table 3]

[0159]

[0160] Evaluation 3. Evaluation of the composition, preparation and characteristics of the topical formulations for each method

[0161] The characteristics of the formulations prepared according to Examples 5 to 20 of Table 3 above are shown in Table 4 below. Viscosity was measured immediately after preparation (using a Brookfield viscometer with a No. 4 rotor), and total impurities were analyzed after standing for a period of time under various high temperature / high humidity conditions.

[0162] [Table 4] Instructions for Use, Pages 13 / 17, 16 CN 121013710 A

[0163]

[0164] As a result, the formulations according to Examples 5 to 20 above all showed a light yellow semi-solid appearance, which tended to increase in viscosity with increasing paraffin content and decrease in viscosity with the addition of isopropyl myristate.

[0165] The stability of the formulations was stable under all compositions.

[0166] The impurities in all formulations were similar to those before testing at 40°C and 75% RH (the difference from the initial values ​​was within the measurement error range), and even at 60°C and 80% RH, the values ​​were slightly higher, but not significantly increased.

[0167] Based on the results of the above embodiments, it can be confirmed that the dispersion time and dispersion rate achieved by using a homogenizer have no significant effect on the characteristics of the formulation.

[0168] Evaluation 4. Container screening of the topical formulation

[0169] The stability of the topical formulation in various containers was evaluated using the topical formulation of Example 8, and the results are shown in Table 5 below. After storing the formulation for two weeks under two conditions, 40°C, 75% RH and 60°C, 80% RH, the stability of the formulation in various containers was evaluated by purity testing.

[0170] [Table 5]

[0171]

[0172] Referring to Table 5, as the test results of the topical formulation of Example 8, no change in appearance was observed at 40°C and 75% RH, and the formulation melted at 60°C and 80% RH. This is because the melting point of the excipient is lower than that of CN 121013710 A on pages 14 / 17 of the specification due to the characteristics of the excipient used, and then solidified again when removed from the container and placed at room temperature. The impurities in the topical formulation of Example 8 were similar to those before testing at 40°C and 75% RH, and the values ​​were slightly higher at 60°C and 80% RH, but without a significant increase.

[0173] Evaluation 5. Evaluation of skin penetration for various components of the topical formulation

[0174] For various components of the topical formulation, skin penetration in a Franz diffusion cell was evaluated using hairless mouse skin. The aqueous solution in the Franz diffusion cell was a 6% polyethylene glycol 20 oleyl ether solution, and after stirring the sample at 32°C, the concentration of the drug was analyzed by LC-MS / MS and the concentration was recorded over time.

[0175] For the experimental group, Examples 10, 12, 18 and 19 were selected based on the content of paraffin wax and the presence of isopropyl myristate, and Corectim ointment (0.5% digotinib) was used as Comparative Example 3. The test results are shown in Figure 5.

[0176] Referring to Figure 5, the skin penetration of the active ingredients in Examples 10 and 19, which have higher beeswax content, is higher, and the penetration of the active ingredients in Examples 10 and 12, which include isopropyl myristate, tends to increase over time. (In Comparative Example 3, which includes an active ingredient different from the active ingredients in the examples, 0 ng / mL was measured at each measurement time point).

[0177] Preparation Example 3. Preparation of topical formulations according to Examples 21 to 29

[0178] In order to evaluate the characteristics of the topical formulations based on 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)cyclopropaneformamide phosphate as the active ingredient, tests were designed to prepare Examples 21 to 29 as shown in Table 6 below. The topical formulations were prepared as follows.First, all oily matrices were melted at a high temperature (68-78°C), and then the main component was added under homogenization to disperse (4,000 rpm, 15 minutes). After dispersion, the resulting mixture was stirred and cooled at 30°C.

[0179] [Table 6]

[0180] Evaluation 6. Preparation of topical formulations according to various contents of the main component and evaluation of properties

[0181] The properties of the embodiments in Table 6 above are shown in Table 7 below. Viscosity was measured immediately after preparation (using a Brookfield viscometer with a No. 4 rotor), and total impurities were analyzed after standing for a period of time under various high temperature / high humidity conditions.

[0182] [Table 7] Specification 15 / 17 pages 18 CN 121013710 A

[0183]

[0184] As a result, the viscosity of the formulations according to Examples 21 to 29 above tended to increase with increasing concentration of the main component and paraffin. The stability of the formulations was generally stable under all components. During the stability test period, the appearance remained unchanged at 40°C and 75% RH. Impurities in all formulations were similar to those prior to the 40°C, 75% RH test, and the values ​​were slightly higher at 60°C, 80% RH, but without a significant increase.

[0185] Preparation Example 4. Preparation of Topical Formulations with Different Main Component Contents and Similar Viscosities

[0186] In order to prepare topical formulations with different main component contents but similar viscosities, the ratio of main components and beeswax was set based on the test results of Preparation Examples 2 and 3 in order to prepare topical formulations according to Examples 30 to 34. The topical formulations were prepared by substantially the same preparation method as described in Preparation Example 3. The detailed composition and viscosity of the topical formulations with various main component contents are shown in Table 8, and it has been confirmed that the main component contents are different, but the viscosities are similar.

[0187] [Table 8]

[0188] Evaluation 7. Tests to confirm efficacy in an animal model of atopic dermatitis

[0189] To evaluate the efficacy of the topical formulation based on the content of the active ingredient, efficacy in an animal model of atopic dermatitis was confirmed. An animal model of atopic dermatitis was prepared by administering dinitrochlorobenzene (DNCB) to NC / Nga mice. The test group was divided into six groups: control group (normal); control group (DNCB induced); placebo group, which was prepared as in Example 30 except for the active ingredient; group treated with Example 30; group treated with Example 32; and group treated with Example 33. The remaining groups, except for the two control groups, were applied to skin showing atopic dermatitis lesions twice daily for 28 days to examine the degree of improvement of the lesions. The degree of improvement of the lesions was confirmed by the atopic dermatitis (AD) score, and the skin thickness was measured by the same experimental method as described in Evaluation 1. The results are shown in Figures 6 and 7.

[0190] The AD score results in Figure 6 show that, compared with the placebo group, the groups treated with Examples 30, 32, and 33 (which are topical formulations containing A(S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide phosphate) showed improvement of 13%, 35%, and 50%, respectively.

[0191] The skin thickness results in Figure 7 show that, compared with the placebo group, the groups treated with Examples 30, 32, and 33 showed reductions in skin thickness of 11%, 15%, and 20%, respectively.

[0192] The present invention has been described with reference to preferred exemplary embodiments herein, but those skilled in the art will understand that various changes and modifications can be made to the invention without departing from the spirit and scope of the invention, as set forth in the following claims. Specification 17 / 17 pages 20 CN 121013710 A Figure 1 Figure 2 Specification Drawings 1 / 4 pages 21 CN 121013710 A Figure 3 Figure 4 Specification Drawings 2 / 4 pages 22 CN 121013710 A Figure 5 Figure 6 Specification Drawings 3 / 4 pages 23 CN 121013710 A Figure 7 Specification Drawings 4 / 4 pages 24 CN 121013710 A.

Claims

1. Pharmaceutical products for topical application, including: The active ingredient is (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, and an oily matrix.

2. The pharmaceutical product according to claim 1, wherein the formulation of the pharmaceutical product is any one of ointment, cream, lotion, foam and suspension.

3. The pharmaceutical product according to claim 1, wherein the formulation of the pharmaceutical product is an ointment.

4. The pharmaceutical product according to claim 1, wherein the oily matrix comprises at least one selected from semi-solid hydrocarbon mixtures, oils, waxes and fatty acids.

5. The pharmaceutical product according to claim 4, wherein the semi-solid hydrocarbon mixture comprises at least one selected from white mineral oil and purified lanolin.

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

7. The pharmaceutical product according to claim 4, wherein the wax comprises at least one selected from beeswax, paraffin wax and carnauba wax.

8. The pharmaceutical product according to claim 4, wherein the fatty acid comprises at least one selected from cocoa butter, shea butter and lanolinic acid.

9. The pharmaceutical product of claim 1, wherein the pharmaceutical product further comprises a pharmaceutically acceptable excipient different from the oily matrix. The excipients therein include at least one of the following: skin penetration enhancers, antioxidants, preservatives, chelating agents, emulsifiers, pH adjusters, stabilizers, fragrances, and colorants.

10. The pharmaceutical product according to claim 1, wherein, relative to a total of 100% by weight of the pharmaceutical product, 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 is 0.01 to 10% by weight, based on free base.

11. The pharmaceutical product of claim 1, wherein the content of the oily matrix is ​​45 to 99.99% by weight relative to a total of 100% by weight of the pharmaceutical product.

12. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, the pharmaceutical product further comprises 0.1 to 30% by weight of a skin penetration enhancer.

13. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, the pharmaceutical product further comprises 0.01 to 5% by weight of a preservative.

14. The pharmaceutical product of claim 1, wherein, relative to a total of 100% by weight, the pharmaceutical product further comprises 0.05 to 10% by weight of an antioxidant.

15. The pharmaceutical product of claim 1, wherein the pharmaceutical product is used for the treatment or prevention of inflammatory diseases and autoimmune diseases. The autoimmune diseases mentioned therein are selected from at least one of the following groups: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

16. The pharmaceutical product of claim 1, wherein the pharmaceutical product is for the treatment or prevention of at least one skin disease selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergy, skin irritation, and rash.

17. A method for preparing a pharmaceutical article for topical application, the method comprising: (Step 1) Mix (S)-N-(4-(1-(2-cyanoacetyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropaneformamide or a pharmaceutically acceptable salt thereof with an oily matrix; and (Step 2) Cool the mixture obtained as described above.

18. The method of claim 17, wherein step (1) comprises: 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, is dispersed in the oily matrix.

19. The method of claim 17, wherein step (1) comprises: 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)cyclopropaneformamide or a pharmaceutically acceptable salt thereof, is dispersed in the melt of the oily matrix.

20. The method of claim 19, wherein step (1) comprises dispersing a pharmaceutically acceptable excipient, different from the oily matrix, in the melt of the oily matrix.

21. A method for treating or preventing inflammatory diseases and autoimmune diseases, said method comprising administering the pharmaceutical product of claim 1 to an individual in need. The autoimmune diseases mentioned therein are selected from at least one of the following groups: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

22. A method for treating or preventing at least one skin condition selected from the group consisting of: xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, skin irritation, and rashes, said method comprising applying the pharmaceutical product of claim 1 to an individual in need.

23. The use of the pharmaceutical product for topical application as claimed in claim 1 for the treatment or prevention of inflammatory diseases and autoimmune diseases. The autoimmune diseases mentioned therein are selected from at least one of the following groups: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

24. The use of the pharmaceutical product for topical application as claimed in claim 1 for the treatment or prevention of at least one skin disease, wherein the at least one skin disease is selected from xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergy, skin irritation, and rash.

25. Use of the pharmaceutical product for topical application as claimed in claim 1 in the preparation of a medicament for the treatment or prevention of inflammatory diseases and autoimmune diseases. The autoimmune diseases mentioned therein are selected from at least one of the following groups: xeroderma, vitiligo, pruritus, eczema, alopecia areata, psoriasis, atopic dermatitis, rash, skin allergy, skin irritation, pemphigus vulgaris (PV), bullous pemphigoid (BP), hidradenitis suppurativa, scleroderma, and discoid lupus erythematosus.

26. Use of the pharmaceutical product for topical application as claimed in claim 1 in the preparation of a medicament for treating or preventing at least one skin disease, wherein the at least one skin disease is selected from xeroderma, vitiligo, pruritus, eczema, alopecia areata, atopic dermatitis, psoriasis, skin allergies, skin irritation, and rashes.

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