Pharmaceutical composition of JAK kinase inhibitor

Abstract

The present disclosure relates to a pharmaceutical composition of a JAK kinase inhibitor. Specifically, the invention provides a pharmaceutical composition, which comprises an active component (3aR, 5s, 6aS)-N-(3-methoxy-1, 2, 4-thiadiazole-5-yl)-5-(methyl (7H-pyrrolo [2, 3-d] pyrimidine-4-yl) amino) hexahydrocyclopenta [c] pyrrol-2 (1H)-formamide or a pharmaceutically acceptable salt thereof, and an anionic surfactant, and the active component (3aR, 5s, 6aS)-N-(3-methoxy-1, 2, 4-thiadiazole-5-yl)-5-(methyl (7H-pyrrolo [2, 3-d] pyrimidine-4-yl) amino) hexahydrocyclopenta [c] pyrrol-2 (1H)-formamide or a pharmaceutically acceptable salt thereof, the anionic surfactant is selected from at least one of lauryl sodium sulfate and sodium deoxycholate. The pharmaceutical composition can improve the solubility of the active ingredients, the content of impurities in the finished product is low, and the pharmaceutical composition has good stability and meets the quality requirements of oral preparations.

Description

Technical Field

[0001] This disclosure pertains to the field of pharmaceutical formulations, specifically relating to a pharmaceutical composition comprising (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof. Background Technology

[0002] Numerous protein kinases constitute a large family of kinases, which control various intracellular signal transductions through catalytic activity. Many diseases are associated with abnormal intracellular responses induced by protein kinase regulation, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, and cardiovascular diseases.

[0003] Janus kinases (JAKs) are a class of tyrosine kinases, including four members: JAK1, JAK2, JAK3, and TYK2. JAKs play important roles in the signaling of various cytokines. JAK1, JAK2, and TYK2 are widely distributed in various tissues and cells, while JAK3 is mainly distributed in lymphocytes. JAK3 specifically and non-covalently binds to the γ chain (Fcγ) shared by cytokine receptors, while JAK1 binds to the beta chain; both are activated by cytokines IL-2, IL-4, IL-7, IL-9, and IL-15. JAK2 plays an important role in the erythropoietin (EPO) signaling pathway, including promoting erythrocyte differentiation and activating STAT5.

[0004] Signal transducer and activator of transcription (STAT) is a group of cytoplasmic proteins that can bind to the DNA of the regulatory regions of target genes. As downstream substrates of JAKs, STATs can be activated by tyrosine phosphorylation in response to external signals, and then translocate into the cell nucleus to regulate gene transcription.

[0005] Cytokines bind to their receptors, causing receptor molecule dimerization. These dimerized molecules then approach receptor-coupled JAKs and are activated through interactive tyrosine residue phosphorylation. Activated JAKs catalyze the phosphorylation of tyrosine residues on the receptor itself, forming "docking sites" for the corresponding STATs to bind to the receptor complex. STATs bind to phosphotyrosine residues on the receptor molecule through their SH2 domains, and under the influence of JAKs, their C-terminal tyrosine residues are phosphorylated. The two phosphorylated STAT molecules interact to form homo / heterodimers, leaving the receptor molecule and entering the cell nucleus. There, they bind to the promoter region of the target gene, regulating gene transcription and expression.

[0006] Many abnormal immune responses, such as allergies, asthma, (allogeneic) transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, as well as myeloproliferative disorders, hematologic malignancies such as leukemia and lymphoma, are regulated by the JAK / STAT signaling pathway.

[0007] (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide is a class of highly absorbed JAK kinase inhibitor compounds with in vivo and in vitro activity; however, there are no reports on oral solution formulations of this molecule. Summary of the Invention

[0008] This disclosure provides a pharmaceutical composition comprising the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, and an anionic surfactant selected from at least one of sodium dodecyl sulfate and sodium deoxycholate.

[0009] In some embodiments, the anionic surfactant is selected from sodium dodecyl sulfate.

[0010] In some embodiments, the concentration of the active ingredient in the pharmaceutical composition, based on the free state of the active ingredient, is 0.01–20.0 mg / ml, including but not limited to 0.01 mg / ml, 0.02 mg / ml, 0.03 mg / ml, 0.04 mg / ml, 0.05 mg / ml, 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, etc. The dosage can be g / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, 9.5 mg / ml, 10.0 mg / ml, 10.5 mg / ml, 11.0 mg / ml, 11.5 mg / ml, 12.0 mg / ml, 12.5 mg / ml, 13.0 mg / ml, 13.5 mg / ml, 14.0 mg / ml, 14.5 mg / ml, 15.0 mg / ml, 15.5 mg / ml, 16.0 mg / ml, 16.5 mg / ml, 17.0 mg / ml, 17.5 mg / ml, 18.0 mg / ml, 18.5 mg / ml, 19.0 mg / ml, 19.5 mg / ml, 20.0 mg / ml, or any value between any two of these values. In some embodiments, the concentration of the active ingredient in the pharmaceutical composition is 0.01 to 10.0 mg / ml, based on the free state of the active ingredient. In some embodiments, the concentration of the active ingredient in the pharmaceutical composition is 0.1 to 10.0 mg / ml, based on the free state of the active ingredient.

[0011] In some embodiments, the concentration of the anionic surfactant is 0.01–10.0 mg / ml, including but not limited to 0.01 mg / ml, 0.05 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, 9.5 mg / ml, 10.0 mg / ml, or any value between any two of these values. In some embodiments, the concentration of the anionic surfactant is 0.01–5.0 mg / ml. In some embodiments, the concentration of the anionic surfactant is 0.1–5.0 mg / ml.

[0012] In some embodiments, the concentration of sodium lauryl sulfate in the pharmaceutical composition is 0.01 to 10.0 mg / ml, including but not limited to 0.01 mg / ml, 0.05 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, 9.5 mg / ml, 10.0 mg / ml, or any value between any two of these values. In some embodiments, the concentration of sodium lauryl sulfate in the pharmaceutical composition is 0.01 to 5.0 mg / ml. In some embodiments, the concentration of sodium dodecyl sulfate in the pharmaceutical composition is 0.1 to 5.0 mg / ml.

[0013] In some embodiments, the pH of the pharmaceutical composition is 2.5 to 6.0, including but not limited to 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, or any value between any two of these values. In some embodiments, the pH of the pharmaceutical composition is 3.0 to 5.0.

[0014] In some embodiments, the pH is adjusted by a pH adjuster. In some embodiments, the pH adjuster is selected from, but is not limited to, at least one of glycine, hydrochloric acid, sodium hydroxide, tartaric acid, tartrate, malic acid, citric acid, citric acid, acetic acid, acetate, phosphoric acid, and phosphate. In some embodiments, the pH adjuster is selected from at least one of glycine, hydrochloric acid, sodium hydroxide, malic acid, tartaric acid, and sodium tartrate. In some embodiments, the pH adjuster is selected from tartaric acid and / or tartaric acid-sodium tartrate.

[0015] In some embodiments, there is no particular limitation on the amount of the pH adjuster, as long as it is adjusted to the appropriate pH range. In some embodiments, the concentration of the pH adjuster in the pharmaceutical composition is 0.01–20.0 mg / ml, including but not limited to 0.01 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, etc. 9.5 mg / ml, 10.0 mg / ml, 10.5 mg / ml, 11.0 mg / ml, 11.5 mg / ml, 12.0 mg / ml, 12.5 mg / ml, 13.0 mg / ml, 13.5 mg / ml, 14.0 mg / ml, 14.5 mg / ml, 15.0 mg / ml, 15.5 mg / ml, 16.0 mg / ml, 16.5 mg / ml, 17.0 mg / ml, 17.5 mg / ml, 18.0 mg / ml, 18.5 mg / ml, 19.0 mg / ml, 19.5 mg / ml, 20.0 mg / ml, or any value between any two values.

[0016] In some embodiments, the concentration of the pH adjuster is from 0.01 mol / L to 20 mol / L, including but not limited to 0.01 mol / L, 0.1 mol / L, 0.5 mol / L, 1.0 mol / L, 1.5 mol / L, 2.0 mol / L, 2.5 mol / L, 3.0 mol / L, 3.5 mol / L, 4.0 mol / L, 4.5 mol / L, 5.0 mol / L, 5.5 mol / L, 6.0 mol / L, 6.5 mol / L, 7.0 mol / L, 7.5 mol / L, 8.0 mol / L, 8.5 mol / L. 9.0 mol / L, 9.5 mol / L, 10.0 mol / L, 10.5 mol / L, 11.0 mol / L, 11.5 mol / L, 12.0 mol / L, 12.5 mol / L, 13.0 mol / L, 13.5 mol / L, 14.0 mol / L, 15.5 mol / L, 16.0 mol / L, 16.5 mol / L, 17.0 mol / L, 17.5 mol / L, 18.0 mol / L, 18.5 mol / L, 19.0 mol / L, 19.5 mol / L, 20.0 mol / L, or any value between two of these.

[0017] In some embodiments, the pharmaceutical composition further includes a preservative. In some embodiments, the preservative is selected from, but is not limited to, at least one of benzoic acid, sodium benzoate, potassium benzoate, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, parabens, benzalkonium bromide, benzalkonium chloride, and sodium metabisulfite. In some embodiments, the preservative is selected from sodium benzoate.

[0018] In some embodiments, the concentration of the preservative in the pharmaceutical composition is from 0.01 to 10.0 mg / ml, including but not limited to 0.01 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, 9.5 mg / ml, 10.0 mg / ml, or any value between any two of these values. In some embodiments, the concentration of the preservative in the pharmaceutical composition is from 0.01 to 5.0 mg / ml.

[0019] In some embodiments, the pharmaceutical composition further includes a flavoring agent. In some embodiments, the flavoring agent is selected from, but is not limited to, at least one selected from sucrose, glycerol, sorbitol, steviol glycosides, mannitol, sucralose, sodium saccharin, and aspartame. In some embodiments, the flavoring agent is selected from sucralose.

[0020] In some embodiments, the concentration of the flavoring agent in the pharmaceutical composition is from 0.01 to 500.0 mg / ml, including but not limited to 0.01 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, 9.5 mg / ml, and 10.0 mg / ml. l, 10.5mg / ml, 11.0mg / ml, 11.5mg / ml, 12.0mg / ml, 12.5mg / ml, 13.0mg / ml, 13.5mg / ml, 14.0mg / ml, 14.5mg / ml, 15.0mg / ml, 15.5mg / ml, 16.0mg / ml, 16.5mg / ml, 17.0mg / ml, 17.5mg / ml, 18.0mg / ml, 18.5mg / ml, 19.0mg / ml, 19.5mg / ml, 20.0mg / ml, 30.0mg / ml, 40.0mg / ml, 50.0mg / ml, 60.0mg / ml, 70 .0mg / ml, 80.0mg / ml, 90.0mg / ml, 100.0mg / ml, 110.0mg / ml, 120.0mg / ml, 130.0mg / ml, 140.0mg / ml, 150.0mg / ml, 160.0mg / ml, 170.0mg / ml, 180.0m g / ml, 190.0mg / ml, 200.0mg / ml, 210.0mg / ml, 220.0mg / ml, 230.0mg / ml, 240.0mg / ml, 250.0mg / ml, 260.0mg / ml, 270.0mg / ml, 280.0mg / ml, 290.0mg / ml, 300.0mg / ml, 310.0mg / ml, 320.0mg / ml, 330.0mg / ml, 340.0mg / ml, 350.0mg / ml, 360.0mg / ml, 370.0mg / ml, 380.0mg / ml, 390.0mg / ml, 400.0mg / ml, 410.0mg / ml, 420.0mg / ml, 430.0mg / ml, 440.0mg / ml, 450.0mg / ml, 460.0mg / ml, 470.0mg / ml, 480.0mg / ml, 490.0mg / ml, 500.0mg / ml, or any value between any two values.In some embodiments, the concentration of the flavoring agent in the pharmaceutical composition is 0.01–50.0 mg / ml. In some embodiments, the concentration of the flavoring agent in the pharmaceutical composition is 0.1–10.0 mg / ml.

[0021] In some embodiments, the pharmaceutical composition further includes an antioxidant. In some embodiments, the antioxidant is selected from, but not limited to, vitamin C, butylated hydroxyethyl ether, butylated hydroxytoluene, sodium sulfite, or sodium metabisulfite.

[0022] In some embodiments, the concentration of the antioxidant in the pharmaceutical composition is from 0.01 to 20.0 mg / ml, including but not limited to 0.01 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, 9... 0.5 mg / ml, 10.0 mg / ml, 10.5 mg / ml, 11.0 mg / ml, 11.5 mg / ml, 12.0 mg / ml, 12.5 mg / ml, 13.0 mg / ml, 13.5 mg / ml, 14.0 mg / ml, 14.5 mg / ml, 15.0 mg / ml, 15.5 mg / ml, 16.0 mg / ml, 16.5 mg / ml, 17.0 mg / ml, 17.5 mg / ml, 18.0 mg / ml, 18.5 mg / ml, 19.0 mg / ml, 19.5 mg / ml, 20.0 mg / ml, or any value between any two values.

[0023] In some embodiments, the pharmaceutical composition further includes a fragrance. In some embodiments, the fragrance may be a fragrance conventionally used in the art. In some embodiments, the amount of the fragrance may be a conventional amount used in the art.

[0024] In some embodiments, the pharmaceutical composition comprises the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof and sodium dodecyl sulfate, wherein the pH of the pharmaceutical composition is 3.0 to 5.0.

[0025] In some embodiments, the pharmaceutical composition comprises the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof and sodium dodecyl sulfate, wherein the pH of the pharmaceutical composition is 3.0 to 5.0, and the pH is adjusted by a pH adjuster.

[0026] In some embodiments, the pharmaceutical composition comprises the following components:

[0027] 1) On a free basis, 0.01–20.0 mg / ml of the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or its pharmaceutically acceptable salt;

[0028] 2) Sodium dodecyl sulfate at concentrations of 0.01–10.0 mg / ml.

[0029] In some embodiments, the pharmaceutical composition comprises the following components:

[0030] 1) On a free basis, 0.01–20.0 mg / ml of the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or its pharmaceutically acceptable salt;

[0031] 2) Sodium dodecyl sulfate at concentrations of 0.01–10.0 mg / ml;

[0032] The pH of the pharmaceutical composition is 3.0 to 5.0.

[0033] In some embodiments, the pharmaceutical composition comprises the following components:

[0034] 1) On a free basis, 0.01–20.0 mg / ml of the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or its pharmaceutically acceptable salt;

[0035] 2) Sodium dodecyl sulfate at concentrations of 0.01–10.0 mg / ml;

[0036] 3) Choose at least one of the following: preservatives, flavoring agents, antioxidants, and fragrances.

[0037] The pH of the pharmaceutical composition is 3.0 to 5.0, and the pH is adjusted by a pH adjuster.

[0038] In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is a solution. In some embodiments, the solvent in the solution is an organic solvent or water. In some embodiments, the solvent in the solution is water, including but not limited to water for injection, purified water, etc. In some embodiments, the liquid formulation is administered orally.

[0039] In some embodiments, the total impurity content of the pharmaceutical composition does not exceed 2.0% after being stored at 25–60°C (e.g., 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C or any value between any two values) for 5 days, 10 days, 30 days, 2 months, 3 months or longer (including but not limited to 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0% or any value between any two values). In some embodiments, the total impurity content of the pharmaceutical composition does not exceed 2.0% after being stored at 25–40°C (e.g., 25°C, 30°C, 35°C, 40°C, or any two of these values) for 5 days, 10 days, 30 days, 2 months, 3 months, or longer. In some embodiments, the total impurity content of the pharmaceutical composition does not exceed 2.0% after being stored at 60°C for 5 days, 10 days, or 30 days.

[0040] In some embodiments, the humidity of the pharmaceutical composition during storage is 10% to 80% (including but not limited to 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any value between any two values).

[0041] This disclosure also provides a method for preparing the aforementioned pharmaceutical composition, comprising the step of mixing the active ingredient and an anionic surfactant, optionally using a pH adjuster to adjust the pH.

[0042] In some embodiments, the pH adjuster is selected from, but not limited to, at least one of glycine, hydrochloric acid, sodium hydroxide, tartaric acid, tartrate, malic acid, citric acid, citric acid, acetic acid, acetate, phosphoric acid, and phosphate. In some embodiments, the pH adjuster is selected from at least one of glycine, hydrochloric acid, sodium hydroxide, malic acid, tartaric acid, and sodium tartrate. In some embodiments, the pH adjuster is selected from tartaric acid and / or tartaric acid-sodium tartrate.

[0043] This disclosure provides a pharmaceutical composition containing the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is maintained at 25–60°C (e.g., 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C or any other temperature). The total impurity content does not exceed 2.0% after being stored for 5 days, 10 days, 30 days, 2 months, 3 months or longer (including but not limited to 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0% or any value between any two values).

[0044] In some embodiments, the pharmaceutical composition includes an anionic surfactant selected from at least one of sodium dodecyl sulfate and sodium deoxycholate. In some embodiments, the anionic surfactant is selected from sodium dodecyl sulfate.

[0045] In some embodiments, the total impurity content of the pharmaceutical composition does not exceed 2.0% after being stored at 25–40°C (e.g., 25°C, 30°C, 35°C, 40°C, or any value between any two values) for 5 days, 10 days, 30 days, 2 months, 3 months, or longer (including but not limited to 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, or any value between any two values).

[0046] In some embodiments, the total impurity content of the pharmaceutical composition after being stored at 25°C for 5 days, 30 days, 2 months, 3 months or longer does not exceed 2.0% (including but not limited to 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0% or any value between any two values).

[0047] In some embodiments, the total impurity content of the pharmaceutical composition after being stored at 40°C for 5 days, 10 days, 30 days, 2 months, 3 months or longer does not exceed 2.0% (including but not limited to 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0% or any value between any two values).

[0048] In some embodiments, the total impurity content of the pharmaceutical composition after being placed at 60°C for 5 days, 10 days, and 30 days does not exceed 2.0% (including but not limited to 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, or any value between any two values).

[0049] In some embodiments, the humidity of the pharmaceutical composition during storage is 10% to 80% (including but not limited to 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any value between any two values).

[0050] In this disclosure, the pharmaceutically acceptable salt of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentano[c]pyrrolo-2(1H)-formyl is selected from hydrogen sulfate salts.

[0051] This disclosure provides a lyophilized composition prepared by lyophilizing the aforementioned pharmaceutical composition.

[0052] This disclosure also provides a method for preparing the aforementioned lyophilized composition, which includes the step of lyophilizing the aforementioned pharmaceutical composition.

[0053] This disclosure also provides a reconstituted solution prepared by reconstitution of the aforementioned lyophilized composition. In some embodiments, the liquid medium used for reconstitution is selected from water for injection.

[0054] This disclosure also provides a method for preparing the aforementioned reconstituted solution, which includes the step of reconstituted the aforementioned lyophilized composition. In some embodiments, the liquid medium used for reconstitution is selected from water for injection.

[0055] This disclosure also provides the use of the aforementioned pharmaceutical compositions, the aforementioned lyophilized compositions, or the aforementioned reconstituted solutions in the preparation of medicaments for the prevention and / or treatment of diseases related to JAK kinase. In some embodiments, the JAK kinase-related diseases are selected from immune system disorders or diseases. In some embodiments, the immune system disorders or diseases are selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. In some embodiments, the immune system disorders or diseases are selected from graft-versus-host disease.

[0056] This disclosure also provides the use of the aforementioned pharmaceutical compositions, the aforementioned lyophilized compositions, or the aforementioned reconstituted solutions in the preparation of medicaments for the prevention and / or treatment of immune system disorders or diseases. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease.

[0057] This disclosure also provides a method for treating a JAK kinase-related disease, comprising administering to a subject a therapeutically effective amount of the aforementioned pharmaceutical composition, the aforementioned lyophilized composition, or the aforementioned reconstituted solution. In some embodiments, the JAK kinase-related disease is selected from immune system disorders or diseases. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease.

[0058] This disclosure also provides a method for treating an immune system disorder or disease, comprising administering to a subject a therapeutically effective amount of the aforementioned pharmaceutical composition, the aforementioned lyophilized composition, or the aforementioned reconstituted solution. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease.

[0059] This disclosure also provides a pharmaceutical composition, the aforementioned lyophilized composition, or the aforementioned reconstituted solution for the prevention and / or treatment of diseases related to JAK kinase, as described above. In some embodiments, the JAK kinase-related disease is selected from immune system disorders or diseases. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease.

[0060] This disclosure also provides a pharmaceutical composition, the aforementioned lyophilized composition, or the aforementioned reconstituted solution for the prevention and / or treatment of immune system disorders or diseases, as described above. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. In some embodiments, the immune system disorder or disease is selected from graft-versus-host disease.

[0061] Terminology Definition

[0062] In this disclosure, "pH adjuster" refers to a component with the ability to regulate acidity and alkalinity, enabling the drug to be in a suitable pH state, including acids, bases, and buffers. Acids include inorganic or organic acids; examples of inorganic acids include hydrochloric acid and phosphoric acid, and examples of organic acids include citric acid and tartaric acid. Bases include inorganic or organic bases; examples of inorganic bases include sodium hydroxide and sodium carbonate, and examples of organic bases include sodium citrate and sodium tartrate. Buffers are buffer pairs formed by two or more substances, including but not limited to tartrate salts and phosphates; examples of buffers include tartaric acid-sodium tartrate, disodium hydrogen phosphate-sodium dihydrogen phosphate, and glycine-hydrochloric acid.

[0063] In this disclosure, "composition" refers to a mixture containing one or more of the active ingredients described herein, along with other chemical components, including but not limited to physiologically / pharmaceutically applicable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. In this document, "composition" and "formulation" are not mutually exclusive.

[0064] In this disclosure, "lyophilized composition" refers to a pharmaceutical composition or solution preparation obtained after a vacuum freeze-drying step.

[0065] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which these values ​​are used must be considered, including but not limited to the statement that the error variation after measurement does not exceed ±10%, which can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0066] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of this disclosure.

[0067] Unless otherwise specified, all reagents and raw materials used in this disclosure are commercially available.

[0068] The pharmaceutical composition disclosed herein can improve the solubility of the active ingredient, has low impurity content in the finished product, good stability, meets the quality requirements of oral preparations, and the total impurity content does not exceed 2.0%. Detailed Implementation

[0069] This disclosure is further described in detail through the following examples and experimental cases. These examples and experimental cases are for illustrative purposes only and are not intended to limit the scope of this disclosure. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions favorable to production or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0070] In the following examples, compound A is used instead of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentano[c]pyrrolo-2(1H)-carboxamide hydrogen sulfate.

[0071] The contents of impurities and active ingredients involved in the following examples were determined by HPLC. The detection conditions were as follows: the chromatographic column was a Waters Xselect HSST3 column (4.6 mm × 150 mm, 3.5 μm) or a YMC-Triart C18 column (4.6 × 150 mm, 3 μm), the column temperature was 30 °C, the mobile phase A was 0.01 mol / L potassium dihydrogen phosphate buffer solution, the mobile phase B was acetonitrile, the flow rate was 1.0 ml / min, the detection wavelength was 218 nm, and the injection volume was 10 μl.

[0072] In the examples, the content of the active ingredient is calculated based on the free state of compound A and should be 90.0% to 110.0% of the labeled amount.

[0073] In the following examples, “appropriate amount” refers to the mass used when adjusting the pH of the final solution with hydrochloric acid, malic acid, or tartaric acid solution.

[0074] Example 1

[0075] Mix the components according to the formulation proportions in Table 1, stir to dissolve, adjust the pH with 1 mol / L hydrochloric acid solution, and use the clear and transparent solution as the experimental endpoint. Formulations 1-4 all produce colorless and transparent solutions, meeting the quality requirements for oral solutions. The formulation strength is 0.5 mg / ml (based on the free state of compound A).

[0076] Table 1

[0077] Element Prescription 1 Prescription 2 Prescription 3 Prescription 4 Compound A 61.83mg 61.83mg 61.83mg 61.83mg glycine 375mg 375mg 375mg 375mg Twain 80 6.40g - - 6.40g Sodium dodecyl sulfate - 0.208g - - Polosham 188 - - 1.50g 0.5g hydrochloric acid Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Add to 100ml Add to 100ml Add to 100ml Add to 100ml Final solution pH 3.87 3.20 3.02 3.03

[0078] Stability studies were conducted on prescriptions 1–4, and the results are shown in Tables 2 and 3.

[0079] Table 2

[0080] prescription Start 25℃ / 10 days 40℃ / 5 days 40℃ / 10 days Total impurities (%) Total impurities (%) Total impurities (%) Total impurities (%) Prescription 1 2.84 - 10.95 - Prescription 2 0.08 0.12 0.19 0.22 Prescription 3 0.19 0.76 1.98 5.17 Prescription 4 0.21 0.40 2.38 7.20

[0081] Table 3

[0082]

[0083] As can be seen from the above, sodium dodecyl sulfate provides better stability in the finished product compared to Tween 80 and poloxamer 188.

[0084] Example 2

[0085] The components were mixed and dissolved according to the formulation ratios in Table 4. The pH was adjusted using 1 mol / L hydrochloric acid solution, and the final experimental endpoint was achieved when the solution became clear and transparent. Both formulations 5 and 6 produced colorless and transparent solutions, meeting the quality requirements for oral solutions. The formulation strength of formulation 5 is 0.4 mg / ml, and that of formulation 6 is 0.5 mg / ml (both based on the free state of compound A).

[0086] Table 4

[0087] Element Prescription 5 Prescription 6 Compound A 49.46mg 61.83mg glycine 375mg 375mg Sodium dodecyl sulfate 0.2g 0.28g Sodium benzoate 0.3g 0.3g sucrose 30g 30g hydrochloric acid Appropriate amount Appropriate amount Purified water Add to 100ml Add to 100ml Final solution pH 4.26 2.47

[0088] Stability studies were conducted on prescription 5, and the results are shown in Table 5.

[0089] Table 5

[0090]

[0091]

[0092] As can be seen from the above, the initial products of formulations 5 and 6 were clear and transparent, with low total impurity content, and the content of active ingredients met the requirements. After being placed at 30°C for 5 days, the content of active ingredients and total impurities in formulation 5 showed no significant change.

[0093] Example 3

[0094] The components were mixed and dissolved according to the formulation ratios in Table 6. The pH was adjusted using 1 mol / L hydrochloric acid solution, and the final experimental endpoint was achieved when the solution became clear and transparent. The final product of Formulation 7 was a colorless and transparent solution with low total impurity content, meeting the quality requirements for oral solutions.

[0095] Table 6

[0096] Element Prescription 7 Compound A 49.46mg glycine 375mg Sodium dodecyl sulfate 0.2g Sodium benzoate 0.3g Sorbitol 28g Steviosides 0.07g hydrochloric acid Appropriate amount Purified water Add to 100ml Final solution pH 4.15

[0097] Stability studies were conducted on prescription 7, and the results are shown in Table 7.

[0098] Table 7

[0099]

[0100]

[0101] Example 4

[0102] Mix the components according to the formulation ratios in Table 8, stir to dissolve, and adjust the pH using 1 mol / L hydrochloric acid solution and / or 1 mol / L sodium hydroxide solution. The final experimental endpoint is when the solution becomes clear and transparent. The finished products of formulations 8-10 are colorless and transparent solutions with low total impurity content, meeting the quality requirements for oral solutions.

[0103] Table 8

[0104] Element Prescription 8 Prescription 9 Prescription 10 Compound A 49.46mg 49.46mg 49.46mg Sodium dodecyl sulfate 0.2g 0.2g 0.2g hydrochloric acid Appropriate amount Appropriate amount Appropriate amount Sodium hydroxide - - Appropriate amount Sodium benzoate 0.3g 0.3g 0.3g Sucralose 0.05g 0.1g 0.15g Purified water Add to 100ml Add to 100ml Add to 100ml Final solution pH 4.23 5.00 6.03

[0105] Stability studies were conducted on prescriptions 8-10, and the results are shown in Table 9.

[0106] Table 9

[0107]

[0108] Example 5

[0109] The components were mixed and dissolved according to the formulation ratios in Table 10. The pH was adjusted using 1 mol / L hydrochloric acid and 1 mol / L malic acid solutions, respectively, until the solution became clear and transparent, which was taken as the experimental endpoint. The finished products of formulations 11 and 12 were colorless and transparent solutions with low total impurity content, meeting the quality requirements for oral solutions.

[0110] Table 10

[0111] Element Prescription 11 Prescription 12 Prescription 13 Compound A 49.46mg 49.46mg 49.46mg Sodium dodecyl sulfate 0.2g 0.2g 0.2g tartaric acid Appropriate amount Appropriate amount - malic acid - - Appropriate amount Sodium benzoate 0.3g 0.3g 0.3g Sucralose 0.05g 0.05g 0.05g Purified water Add to 100ml Add to 100ml Add to 100ml Final solution pH 3.16 4.49 4.85

[0112] Stability studies were conducted on prescriptions 11 and 12, and the results are shown in Table 11.

[0113] Table 11

[0114]

[0115] Example 6

[0116] The components were mixed and dissolved according to the proportions in Table 12. The pH was adjusted using 1 mol / L tartaric acid solution, and the final experimental endpoint was achieved when the solution became clear and transparent. Formulas 14 and 15 produced colorless and transparent solutions with low total impurity content, meeting the quality requirements for oral solutions.

[0117] Table 12

[0118]

[0119]

[0120] Stability studies were conducted on prescriptions 14 and 15, and the results are shown in Table 13.

[0121] Table 13

[0122]

[0123] Example 7

[0124] The components were mixed and dissolved according to the formulation ratios in Table 14. The pH was adjusted using 1 mol / L tartaric acid solution, and the final experimental endpoint was achieved when the solution became clear and transparent. Formulations 16 and 17 produced colorless and transparent solutions with low total impurity content, meeting the quality requirements for oral solutions, and their antibacterial efficacy met the requirements of the Chinese Pharmacopoeia.

[0125] Table 14

[0126] Element Prescription 16 Prescription 17 Compound A 49.46mg 49.46mg Sodium dodecyl sulfate 0.2g 0.2g tartaric acid Appropriate amount Appropriate amount Sodium tartrate 0.24g 0.24g Sodium benzoate 0.01g 0.01g Sucralose 0.05g 0.05g Purified water Add to 100ml Add to 100ml Final solution pH 3.05 4.94

[0127] Stability studies were conducted on prescriptions 16 and 17, and the results are shown in Table 15.

[0128] Table 15

[0129]

[0130] Example 8

[0131] Using the formulation proportions in Table 16, mix all components, stir to dissolve, adjust the pH with 1 mol / L tartaric acid solution, and use a clear and transparent solution as the experimental endpoint. Formulation 18 produces a colorless and transparent solution with low total impurity content, meeting the quality requirements for oral solutions, and its antibacterial efficacy meets the requirements of the Chinese Pharmacopoeia.

[0132] Table 16

[0133] Element Prescription 18 Compound A 49.46mg Sodium dodecyl sulfate 0.2g tartaric acid Appropriate amount Sodium tartrate 0.24g Potassium sorbate 0.02g Sucralose 0.05g Purified water Add to 100ml Final solution pH 3.96

[0134] Stability studies were conducted on formulation 18, and the results are shown in Table 17.

[0135] Table 17

[0136]

[0137] Example 9

[0138] Using the formulation proportions in Table 18, mix all components, stir to dissolve, adjust the pH with 1 mol / L tartaric acid solution, and use a clear and transparent solution as the experimental endpoint. Formulation 19 produces a colorless and transparent solution with low total impurity content, meeting the quality requirements for oral solutions, and its antibacterial efficacy meets the requirements of the Chinese Pharmacopoeia.

[0139] Table 18

[0140]

[0141]

[0142] Stability studies were conducted on formulation 19, and the results are shown in Table 19. After being placed at 40℃ / 75% RH for 1, 2, 3, and 6 months, and at 25℃ / 60% RH for 3 and 6 months, the solutions were all colorless and transparent, and the microbial limits all met the requirements.

[0143] Table 19

[0144]

[0145] Example 10

[0146] The components were mixed and dissolved according to the formulation proportions in Table 20. The pH was adjusted using 1 mol / L tartaric acid solution, and the final experimental endpoint was achieved when the solution became clear and transparent. The finished product of Formulation 20 was a colorless and transparent solution with low total impurity content, meeting the quality requirements for oral solutions, and its antibacterial efficacy met the requirements of the Chinese Pharmacopoeia.

[0147] Table 20

[0148]

[0149]

[0150] Stability studies were conducted on formulation 20, and the results are shown in Table 21. After being placed at 40℃ / 75% RH for 1, 2, and 3 months, and at 25℃ / 60% RH for 3 months, all solutions were colorless and transparent, and the microbial limits all met the requirements.

[0151] Table 21

[0152]

Claims

1. A pharmaceutical composition comprising an active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof and an anionic surfactant, said anionic surfactant being selected from at least one of sodium dodecyl sulfate and sodium deoxycholate.

2. The pharmaceutical composition according to claim 1, wherein the anionic surfactant is sodium dodecyl sulfate.

3. The pharmaceutical composition according to claim 1 or 2, wherein, Based on the free state of the active ingredient, the concentration of the active ingredient in the pharmaceutical composition is 0.01–20.0 mg / ml, preferably 0.01–10.0 mg / ml, and more preferably 0.1–10.0 mg / ml; And / or, the concentration of the anionic surfactant is 0.01 to 10.0 mg / ml, preferably 0.01 to 5.0 mg / ml.

4. The pharmaceutical composition according to claims 1-3, wherein, The pH of the pharmaceutical composition is 2.5 to 6.0, preferably 3.0 to 5.

0.

5. The pharmaceutical composition according to claim 4, wherein, The pH is adjusted by a pH adjuster selected from at least one of glycine, hydrochloric acid, sodium hydroxide, tartaric acid, tartrate, malic acid, citric acid, citric acid, acetic acid, acetate, phosphoric acid, and phosphate, preferably at least one of glycine, hydrochloric acid, sodium hydroxide, malic acid, tartaric acid, and sodium tartrate, more preferably tartaric acid and / or tartaric acid-sodium tartrate.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The pharmaceutical composition further includes at least one of a preservative, a flavoring agent, an antioxidant, and a fragrance.

7. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition is any of the following formulations: Option 1: The pharmaceutical composition comprises the following components: 1) On a free basis, 0.01–20.0 mg / ml of the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or its pharmaceutically acceptable salt; 2) Sodium dodecyl sulfate at concentrations of 0.01–10.0 mg / ml; The pH of the pharmaceutical composition is 3.0–5.0; Option 2: The pharmaceutical composition comprises the following components: 1) On a free basis, 0.01–20.0 mg / ml of the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or its pharmaceutically acceptable salt; 2) Sodium dodecyl sulfate at concentrations of 0.01–10.0 mg / ml; 3) Choose at least one of the following: preservatives, flavoring agents, antioxidants, and fragrances. The pH of the pharmaceutical composition is 3.0 to 5.0, and the pH is adjusted by a pH adjuster.

8. A pharmaceutical composition comprising the active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, wherein the total impurity content of the pharmaceutical composition does not exceed 2.0% after being stored at 25–60°C for 5 days, 10 days, 30 days, 2 months, 3 months or longer.

9. Use of a pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for the prevention and / or treatment of diseases related to JAK kinase; Preferably, the diseases associated with JAK kinase are selected from immune system disorders or diseases; More preferably, the immune system disorder or disease is selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. More preferably, the immune system disorder or disease is selected from graft-versus-host disease.

10. Use of a pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for the prevention and / or treatment of disorders or diseases of the immune system; Preferably, the immune system disorder or disease is selected from graft-versus-host disease, ankylosing spondylitis, active radionegative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma; More preferably, the immune system disorder or disease is selected from graft-versus-host disease.

Images