Pharmaceutical compositions for topical administration, methods for their preparation and use

Abstract

The present disclosure relates to a pharmaceutical composition for topical administration, its preparation method, and use. Specifically, the present disclosure relates to a pharmaceutical composition containing an active ingredient, dimethyl sulfoxide, and a penetration enhancer, where the active ingredient is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, and the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate. The pharmaceutical composition has good skin penetration properties, is stable, and is easily administered.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 202310097491.5, filed on February 7, 2023. The entire contents of the above Chinese patent application are incorporated herein by reference.

[0002] The present disclosure belongs to the field of drug formulations, and specifically relates to a pharmaceutical composition of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicament salt thereof, and dimethyl sulfoxide. [Background technology]

[0003] Atopic dermatitis (AD) is a chronic inflammatory skin disease. It is characterized by dry, scaly skin, erythema, oozing, crusting, and itchy lesions, excoriation, and lichenification. The skin disease is accompanied by severe itching and severely impacts the patient's quality of life. Approximately 3% of adults and 15%-25% of children in the general population suffer from atopic dermatitis.

[0004] JAKs (Janus kinases, including JAK1, JAK2, JAK3, and TYK2) are a family of intracellular non-receptor tyrosine kinases. Downstream substrates of JAKs include signal transducers and activators of transcription (STAT) proteins. STAT proteins function both as signaling molecules and transcription factors, ultimately binding to specific DNA sequences present in cytokine-responsive gene promoters. JAK and STAT signaling are involved in mediating many abnormal immune responses, including autoimmune diseases such as allergies, asthma, and transplant rejection, as well as rheumatoid arthritis, amyotrophic lateral sclerosis, atopic dermatitis, alopecia areata, vitiligo, and various types of hematologic and solid tumors.

[0005] Spleen tyrosine kinase (SYK) and JANUS kinase (JAK) are tyrosine kinases that play important roles in the pathogenesis of various autoimmune and inflammatory diseases, including atopic dermatitis, alopecia areata, etc. Therefore, inhibiting SYK and JANUS kinase activity provides a possible method for treating various inflammatory disorders.

[0006] Given the utility of JAK inhibitors in the treatment of skin diseases, there is a need for improved topical formulations of JAK inhibitors. (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide and its pharmaceutically acceptable salts do not penetrate the skin barrier well. In particular, there is a need for stable and easily administered formulations of JAK inhibitors that have good targeted skin penetration. Summary of the Invention [Problem to be solved by the invention]

[0007] The technical problem to be solved by the present disclosure is that existing JAK inhibitors have poor ability to penetrate the skin barrier and poor dissolution ability. Therefore, the present disclosure provides a pharmaceutical composition for topical administration that contains a JAK inhibitor with good skin permeability, is stable, and is easily administered, as well as a preparation method and use thereof. [Means for solving the problem]

[0008] The present disclosure provides a pharmaceutical composition comprising an active ingredient, dimethyl sulfoxide, and a penetration enhancer, wherein the active ingredient is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, and the penetration enhancer is one or more selected from the group consisting of lactic acid, isopropyl myristate, and propylene glycol monocaprylate.

[0009] In some embodiments, the content of dimethyl sulfoxide is 20% to 80% based on the total mass of the pharmaceutical composition, for example, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any value therebetween.

[0010] In some embodiments, the content of the active ingredient is 0.3% to 2.0%, for example, 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 number therebetween, based on the total mass of the pharmaceutical composition.

[0011] In some embodiments, the water content in the pharmaceutical composition is less than 10%, based on the total weight of the pharmaceutical composition.

[0012] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, and a penetration enhancer; the active ingredient is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof; the penetration enhancer is one or more selected from the group consisting of lactic acid, isopropyl myristate, and propylene glycol monocaprylate; and the content of dimethyl sulfoxide is 20% to 80%, the content of the active ingredient is 0.3 to 2.0%, and the content of water in the pharmaceutical composition is less than 10%, based on the total mass of the pharmaceutical composition.

[0013] In some embodiments, the content of the active ingredient may be 0.5 to 2.0%, for example, 0.5%, 1%, 1.5%, 1.855%, or 2%, based on the total mass of the pharmaceutical composition. In some embodiments, the content of the active ingredient may be 1% to 2%, based on the total mass of the pharmaceutical composition. In some embodiments, the content of the active ingredient may be 0.5% to 1%, based on the total mass of the pharmaceutical composition. In some embodiments, the active ingredient is present in a dissolved form in the pharmaceutical composition.

[0014] In some embodiments, the content of dimethyl sulfoxide may be 25% to 55% by weight of the total pharmaceutical composition, or 30% to 45%, for example, 35%, 40%, or 45%, by weight of the total pharmaceutical composition.

[0015] In some embodiments, the content of the penetration enhancer may be 1% to 10% by weight of the total pharmaceutical composition, or 5% to 10%, for example, 5.5%, 7%, or 7.5%, by weight of the total pharmaceutical composition.

[0016] In some embodiments, the water content may be less than 9% by weight of the pharmaceutical composition. In some embodiments, the water content may be less than 8% by weight of the pharmaceutical composition. In some embodiments, the water content may be less than 7%, e.g., less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the pharmaceutical composition.

[0017] In some embodiments, the pharmaceutical composition further comprises an organic solvent component other than dimethyl sulfoxide, and the organic solvent is known to those skilled in the art. In some embodiments, the content of the organic solvent component may be 10% to 80% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any value therebetween) based on the total mass of the pharmaceutical composition. In some embodiments, the content of the organic solvent component may be 10% to 60%, e.g., 12%, 12.145%, 14%, 21%, 44%, 49.4%, 52%, 52.4%, 52.5%, 53.5%, or 54%, based on the total mass of the pharmaceutical composition. In some embodiments, the content of the organic solvent component may be 10% to 40% based on the total mass of the pharmaceutical composition. In some embodiments, the content of the organic solvent component may be 25% to 40% based on the total mass of the pharmaceutical composition. In some embodiments, the organic solvent component is independently one or more selected from benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol. In some embodiments, the organic solvent component is one or more selected from benzyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol. In some embodiments, the organic solvent component is selected from diethylene glycol monoethyl ether and / or propylene glycol.

[0018] In some embodiments, the pharmaceutical composition further comprises a matrix, and the matrix may be a water-soluble matrix. In some embodiments, the water-soluble matrix is ​​a polyethylene glycol-based polymer compound. In some embodiments, the polyethylene glycol-based polymer compound may have an average molecular weight of 100 to 6000. In alternative embodiments, the average molecular weight of the polyethylene glycol-based polymer compound may be 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 280 The water soluble matrix may be 0, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, or 6000. In some embodiments, the water soluble matrix is ​​polyethylene glycol 400 and polyethylene glycol 4000. In some embodiments, the water soluble matrix is ​​polyethylene glycol 400.

[0019] In some embodiments, the matrix is ​​polyethylene glycol 400 and polyethylene glycol 4000, and the mass ratio of the polyethylene glycol 400 to the polyethylene glycol 4000 is (0.1 to 10): 1. In some embodiments, the mass ratio of the polyethylene glycol 400 to the polyethylene glycol 4000 is (0.1 to 5): 1 (e.g., 0.1:1, 0.3:1, 9:35 (approximately 0.26:1)) to adjust the ointment to have appropriate viscosity and spreadability and to ensure a uniform content of the active ingredient.

[0020] In some embodiments, the content of the matrix may be 30% to 80% (e.g., 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any one value therebetween) based on the total mass of the pharmaceutical composition. In some embodiments, the content of the matrix may be 40% to 50%, e.g., 44% or 45.5%, based on the total mass of the pharmaceutical composition. In some embodiments, the content of the matrix is ​​1% to 20% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or any one value therebetween) based on the total mass of the pharmaceutical composition. In some embodiments, the content of the matrix is ​​5% to 15% based on the total mass of the pharmaceutical composition.

[0021] In some embodiments, the pharmaceutical composition contains an antioxidant, and the antioxidant is known to those skilled in the art. In some embodiments, the antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol. In some embodiments, the antioxidant is dibutylhydroxytoluene. In some embodiments, the content of the antioxidant, based on the total mass of the pharmaceutical composition, may be 0.05% to 0.5% (e.g., 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, or any value therebetween). In some embodiments, the content of the antioxidant, based on the total mass of the pharmaceutical composition, may be 0.05% to 0.2%, for example, 0.05% or 0.1%.

[0022] In some embodiments, the pharmaceutical composition contains a humectant, and the humectant is known to those skilled in the art. In some embodiments, the humectant is one or more of glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid, and trehalose. In some embodiments, the humectant is glycerin. In some embodiments, the content of the humectant may be 1% to 50% (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or any value therebetween) based on the total weight of the pharmaceutical composition. In some embodiments, the content of the humectant may be 1% to 25%, for example, 5% or 20%, based on the total weight of the pharmaceutical composition. In some embodiments, the content of the humectant may be 10% to 20% based on the total weight of the pharmaceutical composition. In some embodiments, the content of the humectant may be 12% to 18% based on the total mass of the pharmaceutical composition.

[0023] In some embodiments, the pharmaceutical composition contains a preservative, and the preservative is known to those skilled in the art. In some embodiments, the preservative is one or more of methylparaben, ethylparaben, benzoic acid, sorbic acid, phenoxyethanol, chlorobutanol, phenylmercuric acetate, phenol, cresol, and benzalkonium chloride. In some embodiments, the preservative is ethylparaben. In some embodiments, the content of the preservative, based on the total mass of the pharmaceutical composition, is 0.05% to 0.5% (e.g., 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, or any value therebetween), for example, 0.2%.

[0024] In some embodiments, the pharmaceutical composition contains a thickening agent, and the thickening agent is known to those skilled in the art. In some embodiments, the thickening agent is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, sodium alginate, and poloxamer. Furthermore, in some embodiments, the thickening agent is hydroxypropyl cellulose. In some embodiments, the thickening agent may be present in an amount of 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or any value therebetween) based on the total weight of the pharmaceutical composition. In some embodiments, the thickening agent may be present in an amount of 0.5% to 3%, e.g., 1% or 2%, based on the total weight of the pharmaceutical composition. In some embodiments, the thickening agent may be present in an amount of 2% to 3% based on the total weight of the pharmaceutical composition. In some embodiments, the thickener may be present in an amount of 0.1% to 15% (e.g., 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or any value therebetween) based on the total mass of the pharmaceutical composition, or 5% to 15% based on the total mass of the pharmaceutical composition.

[0025] In some embodiments, the pharmaceutical composition includes a thickening agent, and the thickening agent is one or more selected from carbomer and siloxane-based materials. In some embodiments, the siloxane-based materials are one or more selected from cyclodimethylsiloxane, polydimethylsiloxane, and ST-Elastomer 10.

[0026] In some embodiments, the pH of the pharmaceutical composition is <7. In some embodiments, the pH of the pharmaceutical composition is selected from the range of 3 to 6.5 (e.g., 3.0, 3.1, 3.2, 3.3, 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, 6.1, 6.2, 6.3, 6.4, 6.5, or any one value therebetween). In some embodiments, the pH of the pharmaceutical composition is selected from the range of 3.5 to 6.0. In some embodiments, the pH of the pharmaceutical composition is selected from the range of 3.5 to 4.5. In some embodiments, the reagent used to adjust the pH is one or more selected from hydrochloric acid, sodium hydroxide, and triethanolamine.

[0027] In some embodiments, the pharmaceutical composition includes a taste-masking agent, wherein the taste-masking agent is one or more of a strawberry flavor, an orange flavor, and a cyclodextrin, known to those skilled in the art.

[0028] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, an organic solvent, a thickener, an antioxidant, and a penetration enhancer, wherein the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, and poloxamer, the antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol, and the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate, wherein the content of each component is as described in any one of the present disclosure. In alternative embodiments, the pharmaceutical composition comprises: 1) 0.3 to 2.0% by weight (e.g., 0.5 to 2.0% by weight, also e.g., 1 to 2% by weight) of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicament salt thereof; 2) 20 to 80% by mass (for example, 25 to 55% by mass, or for example, 30 to 45% by mass) of dimethyl sulfoxide; 3) 10 to 80% by mass (e.g., 10 to 60% by mass) of an organic solvent; 4) 0.1 to 5% by mass (e.g., 0.5 to 3% by mass) of a thickener, 5) 0.05 to 0.5% by weight (e.g., 0.05 to 0.2% by weight) of an antioxidant, and 6) 1 to 10% by weight (e.g., 5 to 10% by weight) of a penetration enhancer.

[0029] In alternative embodiments, the pharmaceutical composition comprises any one of the following ingredients: 1) 1% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 40% by weight of dimethyl sulfoxide, 49.1% by weight of diethylene glycol monoethyl ether, 0.3% by weight of benzyl alcohol, 2% by weight of hydroxypropyl cellulose, 0.1% by weight of dibutylhydroxytoluene, and 7.5% by weight of isopropyl myristate; Or, 2) 1% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 40% by weight of dimethyl sulfoxide, 49.1% by weight of diethylene glycol monoethyl ether, 3.3% by weight of oleic acid, 1% by weight of hydroxypropyl cellulose, 0.1% by weight of dibutylhydroxytoluene, and 5.5% by weight of isopropyl myristate.

[0030] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, an organic solvent, a water-soluble matrix, and a penetration enhancer, wherein the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol, the water-soluble matrix is ​​a polyethylene glycol-based polymer compound, and the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate, wherein the content of each component is as described in any one of the present disclosure.

[0031] In an alternative embodiment, the pharmaceutical composition contains: 1) 0.3 to 2.0% by weight (e.g., 0.5 to 2.0% by weight, also e.g., 1 to 2% by weight) of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicament salt thereof; 2) 20 to 80% by mass (for example, 25 to 55% by mass, or for example, 30 to 45% by mass) of dimethyl sulfoxide; 3) 10 to 80% by mass (e.g., 10 to 60% by mass) of an organic solvent; 4) 30 to 80% by weight (e.g., 40 to 50% by weight) of a water-soluble matrix, and 5) 1 to 10% by weight (e.g., 5 to 10% by weight) of a penetration enhancer.

[0032] In alternative embodiments, the pharmaceutical composition comprises any one of the following ingredients: 1) 0.5% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 5% by mass of diethylene glycol monoethyl ether, 5% by mass of propylene glycol, 2% by mass of benzyl alcohol, 7% by mass of lactic acid, 10.5% by mass of polyethylene glycol 400, and 35% by mass of polyethylene glycol 4000; 2) 1% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 4% by mass of propylene glycol, 7% by mass of lactic acid, 4% by mass of polyethylene glycol 400, and 40% by mass of polyethylene glycol 4000; 3) 1.5% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 4% by mass of propylene glycol, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, and 35% by mass of polyethylene glycol 4000; 4) 1.855% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 2.145% by mass of propylene glycol, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, and 35% by mass of polyethylene glycol 4000; Or, 5) 1% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by weight of dimethyl sulfoxide, 10% by weight of diethylene glycol monoethyl ether, 4% by weight of propylene glycol, 7% by weight of lactic acid, 9% by weight of polyethylene glycol 400, and 35% by weight of polyethylene glycol 4000.

[0033] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, and a penetration enhancer, wherein the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate, and comprises: 1) 0.3 to 2.0% by weight (e.g., 0.5 to 2.0% by weight) of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicamentable salt thereof; 2) 20 to 80% by mass (e.g., 25 to 55% by mass, or, for example, 30 to 45% by mass) of dimethyl sulfoxide, and 3) 1 to 10% by weight (e.g., 5 to 10% by weight) of a penetration enhancer.

[0034] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, a penetration enhancer, and an organic solvent, wherein the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate, and the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol. In alternative embodiments, the pharmaceutical composition comprises: 1) 0.3 to 2.0% by weight (e.g., 0.5 to 2.0% by weight) of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicamentable salt thereof; 2) 20 to 80% by mass (for example, 25 to 55% by mass, or for example, 30 to 45% by mass) of dimethyl sulfoxide; 3) 1 to 10% by weight (e.g., 5 to 10% by weight) of a penetration enhancer, and 4) 10 to 80% by mass (for example, 10 to 60% by mass) of an organic solvent.

[0035] In an alternative embodiment, the pharmaceutical composition comprises the following ingredients: 1% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 12.5% ​​by mass of propylene glycol, 10% by mass of ethanol, and 7% by mass of lactic acid.

[0036] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, a penetration enhancer, an organic solvent, a thickener, and a water-soluble matrix, wherein the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate, the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, and poloxamer, and the water-soluble matrix is ​​a polyethylene glycol-based polymer compound. In alternative embodiments, the pharmaceutical composition comprises: 1) 0.3 to 2.0% by weight (e.g., 0.5 to 2.0% by weight) of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicamentable salt thereof; 2) 20 to 80% by mass (for example, 25 to 55% by mass, or for example, 30 to 45% by mass) of dimethyl sulfoxide; 3) 1 to 10% by weight (e.g., 5 to 10% by weight) of a penetration enhancer; 4) 10 to 80% by mass (e.g., 10 to 60% by mass) of an organic solvent; 5) 0.1 to 15% by weight (e.g., 1 to 15% by weight) of a thickener, and 6) 1 to 20% by mass (for example, 5 to 15% by mass) or 30 to 80% by mass (for example, 40 to 50% by mass) of a water-soluble matrix.

[0037] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, a penetration enhancer, an organic solvent, a thickener, a water-soluble matrix, and an antioxidant; the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate; the organic solvent is one or more selected from benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; the thickener is one or more selected from carbomer or siloxane-based materials; the water-soluble matrix is ​​a polyethylene glycol-based polymer; and the antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol. In alternative embodiments, the pharmaceutical composition comprises: 1) 0.3 to 2.0% by weight (e.g., 0.5 to 2.0% by weight) of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicamentable salt thereof; 2) 20 to 80% by mass (for example, 25 to 55% by mass, or for example, 30 to 45% by mass) of dimethyl sulfoxide; 3) 1 to 10% by weight (e.g., 5 to 10% by weight) of a penetration enhancer; 4) 10 to 80% by mass (e.g., 10 to 60% by mass) of an organic solvent; 5) 0.1 to 15% by mass (e.g., 1 to 15% by mass) of a thickener, 6) 1 to 20% by weight (e.g., 5 to 15% by weight) of a water-soluble matrix, and 7) 0.05 to 0.5% by weight (e.g., 0.05 to 0.2% by weight) of an antioxidant.

[0038] In an alternative embodiment, the pharmaceutical composition comprises the following ingredients: 0.37% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate, 35% by weight of dimethyl sulfoxide, 0.05% by weight of dibutylhydroxytoluene, 2% by weight of benzyl alcohol, 9.63% by weight of propylene glycol, 7% by weight of lactic acid, 12.5% ​​by weight of polyethylene glycol 400, 2.3% by weight of carbomer, 7% by weight of cyclodimethylsiloxane, 1% by weight of polydimethylsiloxane, and 2% by weight of ST-Elastomer 10.

[0039] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, an organic solvent, a penetration enhancer, a water-soluble matrix, a thickener, a humectant, and an antioxidant; the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; the penetration enhancer is one or more of lactic acid, isopropyl myristate, and propylene glycol monocaprylate; the water-soluble matrix is ​​a polyethylene glycol-based polymer; the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, sodium alginate, and poloxamer; the humectant is one or more of glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid, and trehalose; and the antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol. In an alternative embodiment, the pharmaceutical composition contains: 1) 0.3 to 2.0% by weight (e.g., 0.5 to 2.0% by weight) of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicamentable salt thereof; 2) 20 to 80% by mass (for example, 25 to 55% by mass, or for example, 30 to 45% by mass) of dimethyl sulfoxide; 3) 10 to 80% by mass (e.g., 10 to 60% by mass) of an organic solvent; 4) 1 to 10% by weight (e.g., 5 to 10% by weight) of a penetration enhancer; 5) 1 to 20% by weight (e.g., 5 to 15% by weight) of a water-soluble matrix; 6) 0.1 to 5% by weight (e.g., 0.5 to 3% by weight) of a thickener, 7) 0.05 to 0.5% by weight (e.g., 0.05 to 0.2% by weight) of an antioxidant, and 8) 1 to 50% by weight (e.g., 10 to 20% by weight) of a humectant.

[0040] In alternative embodiments, the pharmaceutical composition comprises any one of the following ingredients: (1) 0.5% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 0.2% by mass of dibutylhydroxytoluene, 10% by mass of diethylene glycol monoethyl ether, 12 to 18% by mass of glycerin, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, 15 to 23% by mass of propylene glycol, 2% to 3% by mass of hydroxypropyl cellulose.

[0041] (2) 1.0% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 0.2% by mass of dibutylhydroxytoluene, 10% by mass of diethylene glycol monoethyl ether, 12 to 18% by mass of glycerin, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, 15 to 23% by mass of propylene glycol, 2% to 3% by mass of hydroxypropyl cellulose.

[0042] In some embodiments, the pharmaceutical composition is for topical use. In some embodiments, the pharmaceutical composition is selected from a gel, an emulsion, or an ointment. In some embodiments, the pharmaceutical composition is selected from a gel.

[0043] The present disclosure further provides a method for preparing the pharmaceutical composition, the method comprising mixing the components. In some embodiments, the active ingredient, dimethyl sulfoxide, and a penetration enhancer are mixed, and optionally, at least one selected from an organic solvent, a matrix, and an antioxidant.

[0044] In some embodiments, the method includes combining the active ingredient with dimethyl sulfoxide and, optionally, at least one selected from a penetration enhancer, an organic solvent, a matrix, an antioxidant, a humectant, a thickener, and a preservative.

[0045] In some embodiments, the active ingredient is mixed with dimethyl sulfoxide and an antioxidant to obtain Mixture I. In some embodiments, Mixture I is mixed with at least one of a penetration enhancer, an organic solvent, a matrix, a humectant, and a preservative to obtain Mixture II. In some embodiments, Mixture II may be mixed with a thickener.

[0046] In some embodiments, the method further comprises a pH adjustment step of adjusting the pH to <7 (e.g., 3.0 to 6.5, 3.5 to 6.0, or 3.5 to 4.5). In some embodiments, the pH of mixture II is adjusted to <7 (e.g., 3.0 to 6.5, 3.5 to 6.0, or 3.5 to 4.5).

[0047] In some embodiments, the active ingredient is mixed with dimethyl sulfoxide and an antioxidant to obtain Mixture I, and Mixture I is mixed with at least one of a penetration enhancer, an organic solvent, a matrix, a humectant, and a preservative to obtain Mixture II, which is then adjusted to a pH of <7 (e.g., 3.0 to 6.5, 3.5 to 6.0, or 3.5 to 4.5), and further mixed with a thickener.

[0048] In some embodiments, the method includes combining an active agent and dimethyl sulfoxide, and optionally further combining with at least one selected from an organic solvent, a matrix, an antioxidant, a humectant, a thickener, and a preservative. In some embodiments, the thickener is premixed with the organic solvent.

[0049] The present disclosure further provides the use of the pharmaceutical composition in the preparation of a medicament for treating or preventing a disorder or disease of the immune system.

[0050] In some embodiments, the immune system disorder or disease is a disease of the immune system, including, for example, organ transplant rejection (e.g., allograft rejection and graft-versus-host disease); an autoimmune disease, including, for example, lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, autoimmune thyroid disease, and the like; a skin disease, including, for example, psoriasis, rash, atopic dermatitis, and the like; an allergic disease, including, for example, asthma, rhinitis, and the like; or an immune system disorder or disease, including, for example, hepatitis B, hepatitis C, chickenpox, and the like. , varicella-zoster virus, and the like; type I diabetes and diabetic complications; Alzheimer's disease, xerophthalmia, bone marrow fibrosis, thrombocytosis, erythrocytosis, or leukemia; cancer, including, for example, solid tumors (e.g., prostate cancer, kidney cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, and the like), blood cancers (e.g., lymphoma, leukemia, and the like), skin cancers (e.g., cutaneous T-cell lymphoma, cutaneous B-cell lymphoma), and the like.

[0051] In an alternative embodiment, the pharmaceutical composition is used in the preparation of a medicament for treating a skin disorder.

[0052] In some embodiments, the immune system disorder or disease is selected from organ transplant rejection (e.g., allograft rejection and graft-versus-host disease), ankylosing spondylitis, active radiation-negative 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 vitiligo.

[0053] The present disclosure further provides use of the pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is selected from organ transplant rejection (e.g., allograft rejection and graft-versus-host disease), ankylosing spondylitis, active radiation-negative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease, and lymphoma. In some embodiments, the disease is selected from vitiligo.

[0054] Pharmaceutically acceptable salts of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide described herein are one or more of the following salts: hydrochloride, maleate, hydrobromide, p-toluenesulfonate, mesylate, sulfate, hydrogensulfate, and ethanesulfonate. In some embodiments, the pharmaceutically acceptable salt is the hydrogensulfate salt.

[0055] In each pharmaceutical composition of the present disclosure, no additional water is added other than the trace amounts of water that may be contained in each component.

[0056] The "penetration enhancer" in the present disclosure may be selected from one or more of the above-mentioned lactic acid, isopropyl myristate, and propylene glycol monocaprylate, as well as other additives that can promote percutaneous absorption of the active ingredient.

[0057] Any combination of the above-described preferred conditions can be used to obtain each preferred embodiment of the present disclosure without violating common knowledge in this field.

[0058] All reagents and materials used in this disclosure are commercially available.

[0059] A positive improvement of the present disclosure is the provision of a stable and easily administered pharmaceutical composition containing a JAK inhibitor with good skin penetration. [Brief explanation of the drawings]

[0060] [Figure 1] This is a PLM diagram of blank PEG4000+DMSO of the dissolving ointment of Example 5.7. [Figure 2] PLM diagram of API. [Figure 3] FIG. 5 is a PLM diagram of the dissolving ointment 1% API+PEG4000+DMSO+LA of Example 5.5. [Figure 4]FIG. 5 is a PLM diagram of the ointment 1% API+PEG4000+DMSO of Example 5.6. [Figure 5] FIG. 7 is a PLM diagram of 1% suspension ointment of Example 7.2. DETAILED DESCRIPTION OF THE INVENTION

[0061] The present disclosure will be further described below with reference to examples, but the present disclosure is not limited to the scope of the examples described. In the following examples, experimental methods without specific conditions are selected according to conventional methods and conditions or according to product instructions.

[0062] Example 1 Synthesis of the active ingredient [ka]

[0063] The preparation was carried out with reference to Example 1 of Patent CN108884100B.

[0064] Example 2 Preparation of hydrogen sulfate salt The preparation was carried out with reference to the examples in patent CN105980390B.

[0065] Example 3 Preparation of a Solution According to the formulation in Table 1, a certain amount of active ingredient was dissolved in the prescribed amount of dimethyl sulfoxide until a clear solution was obtained, and then the prescribed amount of other non-aqueous solvents, i.e., benzyl alcohol, oleyl alcohol, or oleic acid, was added, and the hydroxypropyl cellulose was uniformly swollen in diethylene glycol monoethyl ether. The dimethyl sulfoxide solvent and diethylene glycol monoethyl ether phases were mixed to obtain a clear, highly viscous solution.

[0066] As shown in Table 2, when dimethyl sulfoxide was replaced with other organic solvents such as ethanol, propylene glycol, polyethylene glycol 400, and dimethylformamide at a 1% active ingredient concentration, the resulting solutions were all suspensions. At the same time, as shown in Table 3, even when a high concentration of dimethyl sulfoxide was used, adding a small amount of water did not result in a clear solution exceeding 1%.

[0067] [Table 1]

[0068] [Table 2]

[0069] [Table 3]

[0070] Example 4 Solution Stability Results The solution of Example 3 was left to stand under conditions of 25°C / 60% RH and 40°C / 75% RH to examine its stability. The appearance was visually observed, and the content and related substances were detected by HPLC. The results are shown in Tables 4 and 5. The anhydrous solution has good physical and chemical stability.

[0071] HPLC content determination method:

[0072] [Table 4]

[0073] HPLC Related Substance Detection Methods:

[0074] [Table 5]

[0075] [Table 6]

[0076] [Table 7]

[0077] Example 5: Dissolving ointment A fixed amount of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide (free base) or its available salt was dissolved in a prescribed amount of dimethyl sulfoxide. The remaining solvents (diethylene glycol monoethyl ether, propylene glycol, benzyl alcohol, polyethylene glycol 400, lactic acid, and polyethylene glycol 4000) were added to the dimethyl sulfoxide solution and heated to 60 °C until the solution became clear and transparent. The solution was then cooled to room temperature with constant stirring. After solids precipitated, the sample was homogenized at 4000 rpm for 10 min to form a semisolid ointment formulation. As shown in Figures 1-4, formulations containing a high percentage of DMSO solvent only exhibited polarization of the PEG matrix, with the API remaining primarily in dissolved form.

[0078] [Table 8]

[0079] Example 6 Ointment Stability Results The solution of Example 5 was left to stand under conditions of 25°C / 60%RH to examine its stability, and its appearance was visually observed, while the content and related substances were detected by HPLC. The dissolving ointment has good physical and chemical stability.

[0080] [Table 9]

[0081] Example 7 Preparation of suspension ointment A quantity of finely divided (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide (free base), diethylene glycol monoethyl ether, propylene glycol, glycerin, polyethylene glycol 400, dibutylhydroxytoluene, and ethylparaben was heated to 70°C and dispersed with constant stirring. The polyethylene glycol 4000 was then added to the molten mixture, and the mixture was cooled to 40-50°C with constant stirring. As the mixture was stirred and homogenized at this temperature, a white or off-white semi-solid ointment gradually formed, which was then kept warm and ready for use. The PLM diagram for Example 7.2 is shown in Figure 5.

[0082] [Table 10]

[0083] Example 8 Freshly excised Bama minipig skin samples placed in Franz diffusion cells were used to study the permeability of APIs in topical formulations. Fresh Bama minipig skin was depilated and stored at -20°C for use. On the morning of the experiment, the skin was removed and resuscitated. After detecting a transepidermal water loss value of less than 30, the skin was prepared for use. Pig skin samples cut to a size suitable for placement between the donor and receptor chambers were placed between the donor and receptor chambers of the Franz diffusion cell. The Franz cell opening was 1 cm. 2 Approximately 200 mg of the sample was evenly applied to pig skin. 8.0 mL was used as the receptor solution, and 1.5 mL of the sample was removed and replaced with fresh receptor solution at 0.5, 2, 4, 8, 12, and 24 hours. The skin was then removed at 24 hours. The skin retention and permeation drug concentrations were measured by HPLC.

[0084] IVPT experimental parameters:

[0085] [Table 11]

[0086] [Table 12]

[0087] In the case of dimethyl sulfoxide-containing solutions, there is a general tendency for the skin retention and penetration amounts to increase as the concentration increases from 0.5% to 1.0%, but this tendency was not observed in the suspension-type ointment, and both the skin retention and penetration amounts of the solution were several times higher than those of the suspension-type ointment.

[0088] Example 9 Emulsion A certain amount of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide available salt was dissolved in dimethyl sulfoxide, dibutylhydroxytoluene, propylene glycol, benzyl alcohol, lactic acid, polyethylene glycol 400, carbomer 980, and water, heated to 50°C, and stirred until clear. Then, cyclodimethylsiloxane, polydimethylsiloxane, ST-Elastomer 10, and carbomer were added to the drug-containing phase and stirred until a gel-like semi-solid was formed. The pH value was adjusted to the specified value, and the solution was allowed to cool to room temperature while constantly stirring.

[0089] [Table 13]

[0090] Example 10 Freshly excised Bama minipig skin samples placed in a Franz diffusion cell were used to study the permeability of APIs in topical formulations. Fresh Bama minipig skin was depilated and stored at -20°C for use. On the morning of the experiment, the skin was removed and resuscitated. After detecting a transepidermal water loss value of less than 30, the skin was prepared for use. A pig skin sample cut to a size suitable for placement between the donor and receptor chambers was placed between the donor and receptor chambers of the Franz diffusion cell, and approximately 60 mg of the sample was evenly applied to the pig skin. The Franz cell opening was 3.14 cm. 2 8.0 mL was used as the receptor solution, and 1.0 mL samples were removed at 2, 6, and 20 hours and replaced with fresh receptor solution. At 20 hours, the skin was removed. The pig skin was processed, and the epidermis and dermis layers were separated and extracted with skin extract. The drug concentrations in the epidermis and dermis were measured by HPLC.

[0091] IVPT experimental parameters:

[0092] [Table 14]

[0093] [Table 15]

[0094] Example 11 The active ingredient was dissolved in the prescribed amount of dimethyl sulfoxide until a clear solution was obtained, and then the prescribed amounts of other non-aqueous solvents, propylene glycol and ethanol, and a penetration enhancer were added to obtain a clear solution.

[0095] [Table 16]

[0096] Example 12 Freshly excised Bama minipig skin samples placed in a Franz diffusion cell were used to study the permeability of APIs in topical formulations. Fresh Bama minipig skin was depilated and stored at -20°C for use. On the morning of the experiment, the skin was removed and resuscitated. After detecting a transepidermal water loss value of less than 30, the skin was prepared for use. A pig skin sample cut to a size suitable for placement between the donor and receptor chambers was placed between the donor and receptor chambers of the Franz diffusion cell, and approximately 60 mg of the sample was evenly applied to the pig skin. The Franz cell opening was 3.14 cm. 2 8.0 mL was used as the receptor solution, and 1.0 mL samples were removed at 0.5, 2, 4, 8, and 24 hours and replaced with fresh receptor solution. At 24 hours, the skin was removed. The pig skin was processed, and the epidermis and dermis layers were separated and extracted with skin extract. The excess drug amount, epidermal layer, dermal layer, and permeated drug concentration were measured by HPLC.

[0097] IVPT experimental parameters:

[0098] [Table 17]

[0099] [Table 18]

[0100] Compared with the solution of the blank group, lactic acid exhibits a relatively good skin permeation enhancing effect, and at the same time, propylene glycol monocaprylate also exhibits a certain skin permeation enhancing effect.

[0101] Example 13 The active ingredient is dissolved in the prescribed amount of dimethyl sulfoxide until a clear solution is obtained. In preparation for use, the prescribed amount of hydroxypropyl cellulose is uniformly swollen in the prescribed amount of diethylene glycol monoethyl ether, and the prescribed amounts of other non-aqueous solvents such as propylene glycol and ethanol are added and stirred uniformly to mix the dimethyl sulfoxide solvent and diethylene glycol monoethyl ether phases. The specific ingredients are as follows:

[0102] [Table 19]

[0103] Example 14 Freshly excised Bama minipig skin samples placed in a Franz diffusion cell were used to study the permeability of APIs in topical formulations. Fresh Bama minipig skin was depilated and stored at -20°C for use. On the morning of the experiment, the skin was removed and resuscitated. After detecting a transepidermal water loss value of less than 30, the skin was prepared for use. A pig skin sample cut to a size suitable for placement between the donor and receptor chambers was placed between the donor and receptor chambers of the Franz diffusion cell, and approximately 15 mg of the sample was evenly applied to the pig skin. The Franz cell opening was 1 cm. 2 8.0 mL was used as the receptor solution, and 1.5 mL samples were removed at 0.5, 2, 4, 8, and 24 hours and replaced with fresh receptor solution. At 24 hours, the skin was removed. The pig skin was processed, and the epidermis and dermis layers were separated and extracted with skin extract. The excess drug amount, epidermis layer, dermis layer, and permeated drug concentration were measured by HPLC.

[0104] IVPT experimental parameters:

[0105] [Table 20]

[0106] [Table 21]

[0107] Example 15 The active ingredient, dibutylhydroxytoluene, is dissolved in the prescribed amount of dimethyl sulfoxide until a clear solution is obtained, and then the prescribed amount of lactic acid and other liquid additives, such as propylene glycol and glycerin, are added. After stirring to mix uniformly, the pH is adjusted to 3.5-4.5, and the prescribed amount of hydroxypropyl cellulose is added to uniformly swell the drug-containing solution. The specific ingredients are as shown in the table below:

[0108] [Table 22]

[0109] Example 16 Freshly excised Bama minipig skin samples placed in a Franz diffusion cell were used to study the permeability of APIs in topical formulations. Fresh Bama minipig skin was depilated and stored at -20°C for use. On the morning of the experiment, the skin was removed and resuscitated. After detecting a transepidermal water loss value of less than 30, the skin was prepared for use. A pig skin sample cut to a size suitable for placement between the donor and receptor chambers was placed between the donor and receptor chambers of the Franz diffusion cell, and approximately 15 mg of the sample was evenly applied to the pig skin. The Franz cell opening was 1 cm. 2 8.0 mL was used as the receptor solution, and 1.5 mL samples were removed at 0.5, 2, 4, 8, and 24 hours and replaced with fresh receptor solution. At 24 hours, the skin was removed. The pig skin was processed, and the epidermis and dermis layers were separated and extracted with skin extract. The excess drug amount, epidermis layer, dermis layer, and permeated drug concentration were measured by HPLC.

[0110] IVPT experimental parameters:

[0111] [Table 23]

[0112] Table 24

Claims

1. A pharmaceutical composition comprising an active ingredient, dimethyl sulfoxide, and a penetration enhancer, wherein the active ingredient is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicament salt thereof, and the penetration enhancer is one or more selected from the group consisting of lactic acid, isopropyl myristate, and propylene glycol monocaprylate; Pharmaceutical compositions.

2. Based on the total mass of the pharmaceutical composition, the content of the dimethyl sulfoxide is 20% to 80%, the content of the active ingredient is 0.3 to 2.0%, and the content of water in the pharmaceutical composition is less than 10%. The pharmaceutical composition of claim 1.

3. Based on the total mass of the pharmaceutical composition, the content of the active ingredient is 0.5-2.0%, and the active ingredient is preferably present in the pharmaceutical composition in a dissolved form. The pharmaceutical composition according to claim 1 or 2.

4. Based on the total mass of the pharmaceutical composition, the content of dimethyl sulfoxide is 25% to 55%, preferably 30% to 45%. The pharmaceutical composition according to claim 1 or 2.

5. The pharmaceutical composition is prepared under the following conditions: (1) Based on the total mass of the pharmaceutical composition, the content of the penetration enhancer is 1% to 10%, preferably 5% to 10%; (2) Based on the total mass of the pharmaceutical composition, the water content is less than 9%, preferably less than 8%, and more preferably less than 7%. One or more of the following is satisfied: The pharmaceutical composition according to claim 1 or 2.

6. The following ingredients: (1) Organic solvent components other than dimethyl sulfoxide, (2) matrix, (3) antioxidants, (4) moisturizer, (5) preservatives, (6) a thickener, and (7) taste masking agents, further comprising one or more of: The pharmaceutical composition according to claim 1 or 2.

7. The pharmaceutical composition is prepared under the following conditions: (1) The organic solvent component is independently one or more selected from the group consisting of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; (2) The matrix is ​​a water-soluble matrix, and the water-soluble matrix is ​​a polyethylene glycol-based polymer compound, and the average molecular weight of the polyethylene glycol-based polymer compound is preferably 100 to 6000; (3) The antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol; (4) The moisturizing agent is one or more of glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid, and trehalose; (5) The preservative is one or more of methylparaben, ethylparaben, benzoic acid, sorbic acid, phenoxyethanol, chlorobutanol, phenylmercuric acetate, phenol, cresol, and benzalkonium chloride; (6) The thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, sodium alginate, and poloxamer; and (7) The taste masking agent is one or more of strawberry flavor, orange flavor, and cyclodextrin. One or more of the following is satisfied: The pharmaceutical composition according to claim 6.

8. The pharmaceutical composition is prepared under the following conditions: (1) The content of the organic solvent component is 10% to 80%, preferably 10 to 60%, based on the total mass of the pharmaceutical composition; (2) Based on the total mass of the pharmaceutical composition, the content of the matrix is ​​30% to 80%, preferably 40 to 50%, or the content of the matrix is ​​1% to 20%, preferably 5% to 15%; (3) Based on the total mass of the pharmaceutical composition, the content of the antioxidant is 0.05% to 0.5%, preferably 0.05% to 0.2%; (4) Based on the total mass of the pharmaceutical composition, the content of the humectant is 1% to 50%, preferably 1% to 25%; (5) Based on the total mass of the pharmaceutical composition, the content of the preservative is 0.05% to 0.5%; and (6) Based on the total mass of the pharmaceutical composition, the viscosity enhancer is 0.1% to 5%, preferably 0.5% to 3%. One or more of the following is satisfied: The pharmaceutical composition according to claim 6.

9. The pharmaceutical composition comprises: Remedy 1: The pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, an organic solvent, a thickener, an antioxidant, and a penetration enhancer, wherein the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and poloxamer, the antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol, and the penetration enhancer is one or more of lactic acid, isopropyl myristate, and propylene glycol monocaprylate; Method 2: The pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, an organic solvent, a water-soluble matrix, and a penetration enhancer, wherein the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol, the water-soluble matrix is ​​a polyethylene glycol-based polymer compound, and the penetration enhancer is one or more of lactic acid, isopropyl myristate, and propylene glycol monocaprylate; Method 3: The pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, a penetration enhancer, and an organic solvent, wherein the penetration enhancer is one or more selected from the group consisting of lactic acid, isopropyl myristate, and propylene glycol monocaprylate, and the organic solvent is one or more selected from the group consisting of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; Remedy 4: The pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, a penetration enhancer, an organic solvent, a thickener, and a water-soluble matrix, wherein the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate; the organic solvent is one or more selected from benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; the thickener is one or more selected from xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, and poloxamer; and the water-soluble matrix is ​​a polyethylene glycol-based polymer compound; Remedy 5: The pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, a penetration enhancer, an organic solvent, a thickener, a water-soluble matrix, and an antioxidant, wherein the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate; the organic solvent is one or more selected from benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; the thickener is one or more selected from carbomer and siloxane-based substances; the water-soluble matrix is ​​a polyethylene glycol-based polymer compound; and the antioxidant is one or more selected from butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol; Remedy 6: The pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, an organic solvent, a penetration enhancer, a water-soluble matrix, a thickener, a moisturizer, and an antioxidant, wherein the organic solvent is one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol, the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate, the water-soluble matrix is ​​a polyethylene glycol-based polymer compound, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, sodium alginate, and poloxamer, the moisturizer is one or more of glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid, and trehalose, and the antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol. It is one of the following methods: The pharmaceutical composition according to claim 1 or 2.

10. The pharmaceutical composition comprises: Remedy 1: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 20-80% by weight of dimethyl sulfoxide, 10-80% by weight of an organic solvent, 0.1-5% by weight of a thickener, 0.05-0.5% by weight of an antioxidant, and 1-10% by weight of a penetration enhancer, wherein the organic solvent is benzyl alcohol, olein, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and poloxamer; the antioxidant is one or more of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol; and the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate; Method 2: The pharmaceutical composition comprises 0.3-2.0% by weight of an active ingredient, which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 20-80% by weight of dimethyl sulfoxide, 10-80% by weight of an organic solvent, and 30-80% by weight of a water-soluble matrix. and 1 to 10% by mass of a penetration enhancer, the organic solvent being one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol, the water-soluble matrix being a polyethylene glycol-based polymer compound, and the penetration enhancer being one or more of lactic acid, isopropyl myristate, and propylene glycol monocaprylate, Method 3: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicament salt thereof, 20-80% by weight of dimethyl sulfoxide, and 1-10% by weight of a penetration enhancer, wherein the penetration enhancer is one or more selected from the group consisting of lactic acid, isopropyl myristate, and propylene glycol monocaprylate; Remedy 4: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a medicament salt thereof, 20-80% by weight of dimethyl sulfoxide, 1-10% by weight of a penetration enhancer, and 10-80% by weight of an organic solvent, wherein the penetration enhancer is one or more selected from the group consisting of lactic acid, isopropyl myristate, and propylene glycol monocaprylate, and the organic solvent is one or more selected from the group consisting of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; Method 5: The pharmaceutical composition comprises 0.3-2.0% by weight of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 20-80% by weight of dimethyl sulfoxide, 1-10% by weight of a penetration enhancer, 10-80% by weight of an organic solvent, 0.1-15% by weight of a thickener, and 1-20% by weight or 30-80% by weight of a water-soluble matrix, the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate; the organic solvent is one or more selected from benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; the thickener is one or more selected from xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and poloxamer; and the water-soluble matrix is ​​a polyethylene glycol-based polymer compound. Remedy 6: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 20-80% by weight of dimethyl sulfoxide, 1-10% by weight of a penetration enhancer, 10-80% by weight of an organic solvent, 0.1-15% by weight of a thickener, 1-20% by weight of a water-soluble matrix, and 0.05-0.5% by weight of an antioxidant, and the penetration enhancer is selected from the group consisting of lactic acid, myrisol, methylparaben ... the organic solvent is one or more selected from benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol; the thickener is one or more selected from carbomer and siloxane-based substances; the water-soluble matrix is ​​a polyethylene glycol-based polymer compound; the antioxidant is one or more selected from butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol; Remedy 7: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient which is (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 20-80% by weight of dimethyl sulfoxide, 10-80% by weight of an organic solvent, 1-10% by weight of a penetration enhancer, 1-20% by weight of a water-soluble matrix, 0.1-5% by weight of a thickener, 0.05-0.5% by weight of an antioxidant, and 1-50% by weight of a humectant, wherein the organic solvent is benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, or propylene glycol. the penetration enhancer is one or more selected from lactic acid, isopropyl myristate, and propylene glycol monocaprylate; the water-soluble matrix is ​​a polyethylene glycol-based polymer compound; the thickener is one or more selected from xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, sodium alginate, and poloxamer; the moisturizer is one or more selected from glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid, and trehalose; and the antioxidant is one or more selected from butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, and tocopherol. It is one of the following methods: The pharmaceutical composition of claim 9.

11. The pharmaceutical composition comprises: (1) 1% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 40% by weight of dimethyl sulfoxide, 49.1% by weight of diethylene glycol monoethyl ether, 0.3% by weight of benzyl alcohol, 2% by weight of hydroxypropyl cellulose, 0.1% by weight of dibutylhydroxytoluene, and 7.5% by weight of isopropyl myristate; (2) 1% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 40% by weight of dimethyl sulfoxide, 49.1% by weight of diethylene glycol monoethyl ether, 3.3% by weight of oleic acid, 1% by weight of hydroxypropyl cellulose, 0.1% by weight of dibutylhydroxytoluene, and 5.5% by weight of isopropyl myristate; (3) 0.5% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 5% by mass of diethylene glycol monoethyl ether, 5% by mass of propylene glycol, 2% by mass of benzyl alcohol, 7% by mass of lactic acid, 10.5% by mass of polyethylene glycol 400, and 35% by mass of polyethylene glycol 4000; (4) 1% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 4% by mass of propylene glycol, 7% by mass of lactic acid, 4% by mass of polyethylene glycol 400, and 40% by mass of polyethylene glycol 4000; (5) 1.5% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 4% by mass of propylene glycol, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, and 35% by mass of polyethylene glycol 4000; (6) 1.855% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate, 35% by weight of dimethyl sulfoxide, 10% by weight of diethylene glycol monoethyl ether, 2.145% by weight of propylene glycol, 7% by weight of lactic acid, 9% by weight of polyethylene glycol 400, and 35% by weight of polyethylene glycol 4000; (7) 1% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 4% by mass of propylene glycol, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, and 35% by mass of polyethylene glycol 4000; (8) 1% by mass of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate, 35% by mass of dimethyl sulfoxide, 10% by mass of diethylene glycol monoethyl ether, 12.5% ​​by mass of propylene glycol, 10% by mass of ethanol, and 7% by mass of lactic acid. (9) 0.37% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate, 35% by weight of dimethyl sulfoxide, 0.05% by weight of dibutylhydroxytoluene, 2% by weight of benzyl alcohol, 9.63% by weight of propylene glycol, 7% by weight of lactic acid, 12.5% ​​by weight of polyethylene glycol 400, 2.3% by weight of carbomer, 7% by weight of cyclodimethylsiloxane, 1% by weight of polydimethylsiloxane, 2% by weight of ST-Elastomer 10, Contains any one of the following groups of ingredients: The pharmaceutical composition of claim 10.

12. The pharmaceutically acceptable salt is one or more of the hydrochloride, maleate, hydrobromide, p-toluenesulfonate, mesylate, sulfate, hydrogen sulfate and ethanesulfonate salts, and the pharmaceutically acceptable salt is preferably hydrogen sulfate; The pharmaceutical composition according to any one of claims 1 to 11.

13. The pharmaceutical composition is a pharmaceutical composition for topical use, and the pharmaceutical composition is preferably a gel, emulsion or ointment, more preferably a gel. The pharmaceutical composition according to any one of claims 1 to 12.

14. A method for preparing the pharmaceutical composition according to any one of claims 1 to 13, characterized in that the method comprises mixing each component, preferably mixing the active ingredient, dimethyl sulfoxide and a penetration enhancer, and optionally further mixing with at least one selected from an organic solvent, a matrix and an antioxidant. Preparation method.

15. Use of the pharmaceutical composition according to any one of claims 1 to 13 in the preparation of a medicament for treating or preventing a disorder or disease of the immune system, preferably wherein said disorder or disease of the immune system is selected from organ transplant rejection, ankylosing spondylitis, active radiation-negative axial spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, vitiligo, alopecia areata, atopic dermatitis, Crohn's disease and lymphoma, more preferably wherein said disorder or disease of the immune system is selected from vitiligo. use.

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