Pharmaceutical composition for local administration as well as preparation method and application thereof

Abstract

The invention relates to a pharmaceutical composition for topical administration, and a preparation method and application thereof. Specifically, the invention relates to a pharmaceutical composition which comprises the following components: an active ingredient, dimethyl sulfoxide and a penetration enhancer, the active component is (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 the active component is a pharmaceutically acceptable salt thereof. The penetration enhancer is selected from one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate. The pharmaceutical composition has good skin penetration properties, is stable and is easy to administrate.

Description

A local administration pharmaceutical composition, preparation method and application thereof

[0001] This application claims priority to Chinese patent application No. 202310097491.5, filed on February 7, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical preparations, 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 pharmaceutically acceptable salt thereof, and dimethyl sulfoxide. Background Art

[0003] Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dry, scaly skin, erythematous patches, lesions with oozing and crusting, and itchy, excoriation-induced pruritus, which significantly impacts the patient's quality of life. Approximately 3% of adults and 15%-25% of children suffer from atopic dermatitis.

[0004] JAKs (Janus kinases, including JAK1, JAK2, JAK3, and TYK2) are a family of intracellular non-receptor tyrosine kinases. JAK downstream substrates include signal transducer and activator of transcription (STAT) proteins. STAT proteins function both as signaling molecules and transcription factors, ultimately binding to specific DNA sequences within the promoters of cytokine-responsive genes. JAK and STAT signaling are involved in the development of numerous abnormal immune responses, such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, atopic dermatitis, alopecia areata, vitiligo, and various 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 and alopecia areata. Therefore, regulating the activity of SYK and Janus kinases provides a potential approach for treating various inflammatory disorders.

[0006] Given the usefulness of JAK inhibitors in treating skin disorders, there is a need for improved topical formulations of JAK inhibitors. However, (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 with good skin penetration properties.

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present disclosure is that the existing JAK inhibitors have poor skin barrier penetration and solubility, thereby providing a locally administered pharmaceutical composition, a preparation method and application thereof, a JAK inhibitor with good skin penetration properties, and is stable and easy to apply.

[0009] The present disclosure provides a pharmaceutical composition containing the following components: 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 selected from one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate.

[0010] In some embodiments, the dimethyl sulfoxide content is 20%-80%, for example, 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.

[0011] In some embodiments, the content of the active ingredient is 0.3%-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 value therebetween, based on the total mass of the pharmaceutical composition.

[0012] In some embodiments, the water content in the pharmaceutical composition is less than 10% by weight, based on the total weight of the pharmaceutical composition.

[0013] In some embodiments, the pharmaceutical composition contains the following components: 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 selected from one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate; based on the total mass of the pharmaceutical composition, the content of dimethyl sulfoxide is 20%-80%, and the content of the active ingredient is 0.3-2.0%; the water content in the pharmaceutical composition is less than 10%.

[0014] In some embodiments, the active ingredient may be present in an amount of 0.5-2.0%, such as 0.5%, 1%, 1.5%, 1.855%, or 2%, based on the total weight of the pharmaceutical composition. In some embodiments, the active ingredient may be present in an amount of 1%-2%, based on the total weight of the pharmaceutical composition. In some embodiments, the active ingredient may be present in an amount of 0.5%-1%, based on the total weight of the pharmaceutical composition. In some embodiments, the active ingredient is present in a dissolved form in the pharmaceutical composition.

[0015] In some embodiments, the content of dimethyl sulfoxide may be 25%-55% based on the total weight of the pharmaceutical composition. In some embodiments, the content of dimethyl sulfoxide may be 30%-45%, such as 35%, 40% or 45%, based on the total weight of the pharmaceutical composition.

[0016] In some embodiments, the penetration enhancer content may be 1%-10% based on the total weight of the pharmaceutical composition. In some embodiments, the penetration enhancer content may be 5%-10%, such as 5.5%, 7% or 7.5%, based on the total weight of the pharmaceutical composition.

[0017] In some embodiments, the water content may be less than 9% based on the total weight of the pharmaceutical composition. In some embodiments, the water content may be less than 8% based on the total weight of the pharmaceutical composition. In some embodiments, the water content may be less than 7% based on the total weight of the pharmaceutical composition, for example, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%.

[0018] 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, based on the total mass of the pharmaceutical composition, the content of the organic solvent component can be 10% to 80% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or any numerical value therebetween). In some embodiments, based on the total mass of the pharmaceutical composition, the content of the organic solvent component can be 10-60%, for example, 12%, 12.145%, 14%, 21%, 44%, 49.4%, 52%, 52.4%, 52.5%, 53.5% or 54%. In some embodiments, based on the total mass of the pharmaceutical composition, the content of the organic solvent component can be 10%-40%. In some embodiments, the content of the organic solvent component may be 25%-40% based on the total weight of the pharmaceutical composition. In some embodiments, the organic solvent component is independently selected from one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol, and propylene glycol. In some embodiments, the organic solvent component is selected from one or more of 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.

[0019] In some embodiments, the pharmaceutical composition further comprises a matrix, which may be a water-soluble matrix. In some embodiments, the water-soluble matrix is ​​a polyethylene glycol polymer compound. In some embodiments, the average molecular weight of the polyethylene glycol polymer compound may be 100-6000. In an optional embodiment, the average molecular weight of the polyethylene glycol 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, 2800, 2900, 3000, 3100, In some embodiments, the water-soluble matrix is ​​polyethylene glycol 400 or polyethylene glycol 4000. In some embodiments, the water-soluble matrix is ​​polyethylene glycol 400.

[0020] In some embodiments, the matrix is ​​polyethylene glycol 400 and polyethylene glycol 4000, and the mass ratio of polyethylene glycol 400 to polyethylene glycol 4000 is (0.1-10): 1. In some embodiments, the mass ratio of polyethylene glycol 400 to polyethylene glycol 4000 is (0.1-5): 1 (e.g., 0.1:1, 0.3:1, 9:35 (about 0.26:1)) to adjust the ointment to achieve appropriate viscosity and spreadability, and to ensure uniform content of the active ingredient.

[0021] In some embodiments, the matrix content is 30%-80% (e.g., 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any value therebetween) based on the total weight of the pharmaceutical composition. In some embodiments, the matrix content is 40-50%, e.g., 44% or 45.5%, based on the total weight of the pharmaceutical composition. In some embodiments, the matrix content is 1%-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 value therebetween) based on the total weight of the pharmaceutical composition. In some embodiments, the matrix content is 5%-15% based on the total weight of the pharmaceutical composition.

[0022] In some embodiments, the pharmaceutical composition contains an antioxidant, which is known to those skilled in the art. In some embodiments, the antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol. In some embodiments, the antioxidant is butylated hydroxytoluene. In some embodiments, the antioxidant content may be 0.05%-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 numerical value therebetween) based on the total mass of the pharmaceutical composition. In some embodiments, the antioxidant content may be 0.05%-0.2%, for example, 0.05% or 0.1%, based on the total mass of the pharmaceutical composition.

[0023] In some embodiments, the pharmaceutical composition contains a moisturizing agent, which is known to those skilled in the art. In some embodiments, the moisturizing agent is one or more of glycerol, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid, and trehalose. In some embodiments, the moisturizing agent is glycerol. In some embodiments, the moisturizing agent content may be 1%-50% (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any value therebetween) based on the total mass of the pharmaceutical composition. In some embodiments, the moisturizing agent content may be 1%-25%, for example, 5% or 20%, based on the total mass of the pharmaceutical composition. In some embodiments, the moisturizing agent content may be 10%-20% based on the total mass of the pharmaceutical composition. In some embodiments, the moisturizing agent content may be 12%-18% based on the total mass of the pharmaceutical composition.

[0024] In some embodiments, the pharmaceutical composition contains a preservative, which 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 preservative content is 0.05%-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%, based on the total mass of the pharmaceutical composition.

[0025] In some embodiments, the pharmaceutical composition contains a thickener, which is known to those skilled in the art. In some embodiments, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, sodium alginate and poloxamer. In some embodiments, the thickener is hydroxypropyl cellulose. In some embodiments, the thickener can be 0.1%-5% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% or any numerical value therebetween) based on the total mass of the pharmaceutical composition. In some embodiments, the thickener can be 0.5%-3%, such as 1% or 2%, based on the total mass of the pharmaceutical composition. In some embodiments, the thickener can be 2%-3% based on the total mass 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 weight of the pharmaceutical composition. In some embodiments, the thickener may be present in an amount of 5% to 15% based on the total weight of the pharmaceutical composition.

[0026] In some embodiments, the pharmaceutical composition contains a thickener selected from one or more of carbomer and silicones. In some embodiments, the silicones are selected from one or more of cyclomethicone, polydimethylsiloxane, and ST-Elastomer 10.

[0027] In some embodiments, the pH of the pharmaceutical composition is less than 7. In some embodiments, the pH of the pharmaceutical composition is selected from 3-6.5 (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 value therebetween). In some embodiments, the pH of the pharmaceutical composition is selected from 3.5-6.0. In some embodiments, the pH of the pharmaceutical composition is selected from 3.5-4.5. In some embodiments, the reagent used to adjust the pH is selected from one or more of hydrochloric acid, sodium hydroxide, and triethanolamine.

[0028] In some embodiments, the pharmaceutical composition contains a taste masking agent, which is known to those skilled in the art. In some embodiments, the taste masking agent is one or more of strawberry flavor, orange flavor, and cyclodextrin.

[0029] In some embodiments, the pharmaceutical composition contains 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 butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and tocopherol, and the penetration enhancer is selected from one or more of lactic acid, isopropyl myristate, and propylene glycol monocaprylate, wherein the content of each component is as described in any one of the present disclosures. In an optional embodiment, the pharmaceutical composition contains:

[0030] 1) 0.3-2.0% (e.g., 0.5%-2.0%, or 1-2%) by weight of an active ingredient, 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;

[0031] 2) 20%-80% (e.g., 25%-55%, or 30-45%) by mass of dimethyl sulfoxide,

[0032] 3) 10%-80% (e.g. 10-60%) by mass of an organic solvent,

[0033] 4) 0.1%-5% (e.g. 0.5%-3%) by mass of a thickener,

[0034] 5) 0.05% to 0.5% (e.g., 0.05% to 0.2%) by mass of an antioxidant, and

[0035] 6) 1%-10% (e.g. 5-10%) by mass of a penetration enhancer.

[0036] In an optional embodiment, the pharmaceutical composition includes any one of the following groups of components:

[0037] 1) 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, 40% by mass of dimethyl sulfoxide, 49.1% by mass of diethylene glycol monoethyl ether, 0.3% by mass of benzyl alcohol, 2% by mass of hydroxypropylcellulose, 0.1% by mass of dibutylhydroxytoluene, and 7.5% by mass of isopropyl myristate;

[0038] or,

[0039] 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, 40% by mass of dimethyl sulfoxide, 49.1% by mass of diethylene glycol monoethyl ether, 3.3% by mass of oleic acid, 1% by mass of hydroxypropylcellulose, 0.1% by mass of dibutylhydroxytoluene, and 5.5% by mass of isopropyl myristate.

[0040] In some embodiments, the pharmaceutical composition contains 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 polymer compound, and the penetration enhancer is selected from one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate, wherein the content of each component is as described in any one of the present disclosure.

[0041] In an optional embodiment, the pharmaceutical composition contains:

[0042] 1) 0.3-2.0% (e.g., 0.5%-2.0%, or 1-2%) by weight of an active ingredient, 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,

[0043] 2) 20%-80% (e.g., 25%-55%, or 30-45%) by mass of dimethyl sulfoxide,

[0044] 3) 10%-80% (e.g. 10-60%) by mass of an organic solvent,

[0045] 4) 30% to 80% (e.g., 40-50%) by mass of a water-soluble matrix, and

[0046] 5) 1%-10% (e.g. 5-10%) by mass of a penetration enhancer.

[0047] In an optional embodiment, the pharmaceutical composition includes any one of the following groups of components:

[0048] 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;

[0049] 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;

[0050] 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;

[0051] 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;

[0052] or,

[0053] 5) 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.

[0054] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, and a penetration enhancer, wherein the penetration enhancer is selected from one or more of lactic acid, isopropyl myristate, and propylene glycol monocaprylate, and comprises:

[0055] 1) 0.3-2.0% (e.g., 0.5-2.0%) by weight of an active ingredient, 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,

[0056] 2) 20%-80% (e.g., 25%-55%, and also 30-45%) by mass of dimethyl sulfoxide, and

[0057] 3) 1%-10% (e.g. 5-10%) by mass of a penetration enhancer.

[0058] In some embodiments, the pharmaceutical composition comprises an active ingredient, dimethyl sulfoxide, a penetration enhancer, and an organic solvent, wherein the penetration enhancer is selected from one or more of 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 an optional embodiment, the pharmaceutical composition comprises:

[0059] 1) 0.3-2.0% (e.g., 0.5-2.0%) by weight of an active ingredient, 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,

[0060] 2) 20%-80% (e.g., 25%-55%, or 30-45%) by mass of dimethyl sulfoxide,

[0061] 3) 1%-10% (e.g., 5-10%) by mass of a penetration enhancer, and

[0062] 4) 10%-80% (e.g., 10-60%) by mass of an organic solvent.

[0063] In an optional embodiment, the pharmaceutical composition comprises the following components:

[0064] 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.

[0065] In some embodiments, the pharmaceutical composition contains an active ingredient, dimethyl sulfoxide, a penetration enhancer, an organic solvent, a thickener, and a water-soluble matrix, wherein the penetration enhancer is selected from one or more of 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, methyl cellulose, and poloxamer, and the water-soluble matrix is ​​a polyethylene glycol polymer compound. In an optional embodiment, the pharmaceutical composition contains:

[0066] 1) 0.3-2.0% (e.g., 0.5-2.0%) by weight of an active ingredient, 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,

[0067] 2) 20%-80% (e.g., 25%-55%, or 30-45%) by mass of dimethyl sulfoxide,

[0068] 3) 1%-10% (e.g. 5-10%) by mass of a penetration enhancer,

[0069] 4) 10%-80% (e.g. 10-60%) by mass of an organic solvent,

[0070] 5) 0.1% to 15% (e.g., 1% to 15%) by mass of a thickener, and

[0071] 6) 1%-20% (eg, 5%-15%) or 30%-80% (eg, 40-50%) by mass of a water-soluble matrix.

[0072] In some embodiments, the pharmaceutical composition contains 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 selected from one or more of 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 selected from one or more of carbomer and silicone substances, the water-soluble matrix is ​​a polyethylene glycol polymer compound, and the antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and tocopherol. In an optional embodiment, the pharmaceutical composition contains:

[0073] 1) 0.3-2.0% (e.g., 0.5-2.0%) by weight of an active ingredient, 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,

[0074] 2) 20%-80% (e.g., 25%-55%, or 30-45%) by mass of dimethyl sulfoxide,

[0075] 3) 1%-10% (e.g. 5-10%) by mass of a penetration enhancer,

[0076] 4) 10%-80% (e.g. 10-60%) by mass of an organic solvent,

[0077] 5) 0.1%-15% (e.g. 1%-15%) by mass of a thickener,

[0078] 6) 1% to 20% (e.g., 5% to 15%) by mass of a water-soluble matrix, and

[0079] 7) 0.05%-0.5% (e.g., 0.05%-0.2%) by mass of an antioxidant.

[0080] In an optional embodiment, the pharmaceutical composition comprises the following components:

[0081] 0.37% 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, 0.05% by mass of butylated hydroxytoluene, 2% by mass of benzyl alcohol, 9.63% by mass of propylene glycol, 7% by mass of lactic acid, 12.5% ​​by mass of polyethylene glycol 400, 2.3% by mass of carbomer, 7% by mass of cyclomethicone, 1% by mass of polydimethylsiloxane, and 2% by mass of ST-Elastomer 10.

[0082] In some embodiments, the pharmaceutical composition contains 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 selected from one or more of lactic acid, isopropyl myristate, and propylene glycol monocaprylate, the water-soluble matrix is ​​a polyethylene glycol polymer compound, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, sodium alginate, and poloxamer, the moisturizer is one or more of glycerol, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid, and trehalose, and the antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and tocopherol. In an optional embodiment, the pharmaceutical composition contains:

[0083] 1) 0.3-2.0% (e.g., 0.5%-2.0%) by weight of an active ingredient, 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,

[0084] 2) 20%-80% (e.g., 25%-55%, or 30-45%) by mass of dimethyl sulfoxide,

[0085] 3) 10%-80% (e.g. 10-60%) by mass of an organic solvent,

[0086] 4) 1%-10% (e.g. 5-10%) by mass of a penetration enhancer,

[0087] 5) 1%-20% (e.g. 5%-15%) by weight of a water-soluble matrix,

[0088] 6) 0.1%-5% (e.g. 0.5%-3%) by mass of a thickener,

[0089] 7) 0.05% to 0.5% (e.g., 0.05% to 0.2%) by mass of an antioxidant, and

[0090] 8) 1%-50% (e.g. 10%-20%) by mass of a moisturizing agent.

[0091] In an optional embodiment, the pharmaceutical composition comprises any one of the following groups of components:

[0092] (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 butylated hydroxytoluene, 10% by mass of diethylene glycol monoethyl ether, 12%-18% by mass of glycerol, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, 15%-23% by mass of propylene glycol, and 2%-3% of hydroxypropyl cellulose.

[0093] (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%-18% by mass of glycerol, 7% by mass of lactic acid, 9% by mass of polyethylene glycol 400, 15%-23% by mass of propylene glycol, and 2%-3% of hydroxypropyl cellulose.

[0094] In some embodiments, the pharmaceutical composition is a topical pharmaceutical composition. In some embodiments, the pharmaceutical composition is selected from a gel, a cream, or an ointment. In some embodiments, the pharmaceutical composition is selected from a gel.

[0095] The present disclosure also provides a method for preparing the aforementioned pharmaceutical composition, comprising: mixing the components. In some embodiments, the active ingredient, dimethyl sulfoxide, and a penetration enhancer are mixed, and further mixed with at least one selected from an organic solvent, a matrix, and an antioxidant.

[0096] In some embodiments, the method comprises mixing the active ingredient, dimethyl sulfoxide, and further mixing with at least one of an optional self-penetration enhancer, an organic solvent, a matrix, an antioxidant, a moisturizer, a thickener, and a preservative.

[0097] In some embodiments, the active ingredient is mixed with dimethyl sulfoxide and an antioxidant to obtain a mixture I. In some embodiments, the mixture I is mixed with at least one of a penetration enhancer, an organic solvent, a matrix, a moisturizer, and a preservative to obtain a mixture II. In some embodiments, the mixture II is mixed with a thickener.

[0098] In some embodiments, the method further comprises a pH adjustment step, wherein the pH is adjusted to <7 (e.g., 3.0-6.5, 3.5-6.0, or 3.5-4.5). In some embodiments, the pH of the mixture II is adjusted to <7 (e.g., 3.0-6.5, 3.5-6.0, or 3.5-4.5).

[0099] In some embodiments, the active ingredient is mixed with dimethyl sulfoxide and an antioxidant to obtain a mixture I, and then the mixture I is mixed with at least one of a penetration enhancer, an organic solvent, a matrix, a moisturizer and a preservative to obtain a mixture II. The pH is adjusted to <7 (e.g., 3.0-6.5, 3.5-6.0 or 3.5-4.5), and further mixed with a thickener.

[0100] In some embodiments, the method comprises mixing the active substance with dimethyl sulfoxide, and further mixing with at least one selected from an organic solvent, a base, an antioxidant, a moisturizer, a thickener, and a preservative. In some embodiments, the thickener is previously mixed with the organic solvent.

[0101] The present disclosure also provides a use of the aforementioned pharmaceutical composition in preparing a medicament for treating or preventing immune system disorders or diseases.

[0102] In some embodiments, the immune system disorder or disease can be selected from diseases of the immune system, including, for example, organ transplant rejection (such as allogeneic transplant rejection and graft-versus-host disease); autoimmune diseases, including, for example, lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, enterocolitis, Crohn's disease, autoimmune thyroid disease, etc.; skin diseases, including, for example, psoriasis, rash, atopic dermatitis, etc.; allergic disorders, including, for example, asthma, rhinitis, etc.; viral diseases, Including, for example, hepatitis B, hepatitis C, varicella, herpes zoster virus, etc.; type 1 diabetes and diabetic complications; Alzheimer's disease, dry eye disease, myelofibrosis, thrombocytosis, polycythemia vera or leukemia; cancer, including, for example, solid tumors (such as prostate cancer, kidney cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, etc.), blood cancer (such as lymphoma, leukemia, etc.), skin cancer (such as cutaneous T-cell lymphoma, cutaneous B-cell lymphoma), etc.

[0103] In an optional embodiment, the aforementioned pharmaceutical composition is used in the preparation of a drug for treating skin diseases.

[0104] In some embodiments, the immune system disorder or disease is selected from organ transplant rejection (such as allogeneic transplant rejection and graft-versus-host disease), ankylosing spondylitis, active radiographically 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.

[0105] The present disclosure also provides a use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease selected from organ transplant rejection (such as allogeneic transplant rejection and graft-versus-host disease), ankylosing spondylitis, active radiographically 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.

[0106] 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)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide disclosed herein is one or more of a hydrochloride, a maleate, a hydrobromide, a p-toluenesulfonate, a methanesulfonate, a sulfate, a bisulfate, and an ethanesulfonate. In some embodiments, the pharmaceutically acceptable salt is a bisulfate salt.

[0107] In each pharmaceutical composition disclosed herein, no additional water is added except for the trace amount of water that may be contained in each component.

[0108] The “penetration enhancer” in the present disclosure may be selected from, in addition to one or more of the above-mentioned lactic acid, isopropyl myristate and propylene glycol monocaprylate, other excipients that can promote the percutaneous absorption of the active ingredient.

[0109] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present disclosure.

[0110] The reagents and raw materials used in the present disclosure are commercially available.

[0111] The positive advances of the present disclosure are: a pharmaceutical composition, a JAK inhibitor with good skin penetration properties, stable and easy to administer. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] FIG1 is a PLM diagram of the blank PEG4000+DMSO dissolving ointment of Example 5.7.

[0113] Figure 2 shows the PLM diagram of API.

[0114] FIG3 is a PLM diagram of Example 5.5 dissolving ointment 1% API+PEG4000+DMSO+LA.

[0115] FIG4 is a PLM diagram of Example 5.6 ointment 1% API+PEG4000+DMSO.

[0116] FIG5 is a PLM diagram of the 1% suspension ointment of Example 7.2. DETAILED DESCRIPTION

[0117] The present disclosure is further illustrated by way of examples below, but the present disclosure is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0118] Example 1 Synthesis of active ingredients

[0119] The preparation was carried out with reference to Example 1 in patent CN108884100B.

[0120] Example 2 Preparation of bisulfate

[0121] The preparation was carried out with reference to the example of patent CN105980390B.

[0122] Example 3 Solution Preparation

[0123] According to the formulation in Table 1, a certain amount of active ingredient was dissolved in the prescribed dimethyl sulfoxide until a clear solution was obtained. The prescribed amount of other non-aqueous solvents, benzyl alcohol, oleyl alcohol, or oleic acid, was then added. Hydroxypropyl cellulose was uniformly swollen in diethylene glycol monoethyl ether. The dimethyl sulfoxide solvent and diethylene glycol monoethyl ether were mixed to obtain a clear and highly viscous solution.

[0124] As shown in Table 2, at a 1% active ingredient concentration, replacing DMSO with other organic solvents, such as ethanol, propylene glycol, polyethylene glycol 400, and dimethylformamide, resulted in suspensions. Furthermore, as shown in Table 3, even at high DMSO concentrations, the addition of trace amounts of water failed to produce a clear solution above 1% active ingredient concentration.

[0125] Table 1 Note: The ones with * in the table indicate the HPC-L model is used, and those without * indicate the HPC-H model is used.

[0126] Table 2

[0127] Table 3

[0128] Example 4 Solution Stability Results

[0129] The solution of Example 3 was placed under 25°C / 60% RH and 40°C / 75% RH conditions for stability testing. The appearance was visually observed, and the content and related substances were determined by HPLC. The results are shown in Tables 4-5, indicating that the anhydrous solution exhibited good physical and chemical stability.

[0130] HPLC content determination method:

[0131] HPLC related substance detection method:

[0132] Table 4

[0133] Table 5 Stability data of Example 3.3 Note: “RRT” in the table indicates relative retention time, and “--” indicates not detected.

[0134] Example 5 Dissolving Ointment

[0135] 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 (free base) or its applicable salt is dissolved in the 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, are added to the dimethyl sulfoxide solution and heated to 60°C. The solution becomes clear and transparent. The solution is stirred continuously and cooled to room temperature. After solid precipitation, the sample is homogenized at 4000 rpm for 10 minutes to form a semisolid ointment formulation. As shown in PLM Figures 1-4, the formulation containing a high proportion of DMSO solvent only exhibits polarization of the PEG matrix, and the API is primarily present in a dissolved form.

[0136] Table 6

[0137] Example 6 Ointment Stability Results

[0138] The solution of Example 5 was placed under 25°C / 60% RH conditions for stability testing. The appearance was visually observed and the content and related substances were detected by HPLC. The dissolving ointment had good physical and chemical stability.

[0139] Table 7

[0140] Example 7 Preparation of Suspension Ointment

[0141] A certain amount of micronized (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, glycerol, polyethylene glycol 400, butylated hydroxytoluene, and ethyl hydroxybenzoate were heated to 70°C and homogenized with stirring. Polyethylene glycol 4000 was then added until melted, and the mixture was cooled by continuous homogenization and stirring to 40-50°C. As the ointment was continuously stirred and homogenized at this temperature, a white or off-white semisolid ointment gradually formed. The ointment was then kept warm for later use. The PLM diagram of Example 7.2 is shown in Figure 5.

[0142] Table 8

[0143] Example 8

[0144] Freshly excised Bama miniature pig skin samples were mounted in Franz diffusion cells to investigate the permeability of APIs in topical formulations. Fresh Bama miniature pig skin was depilated and stored at -20°C until ready for use. On the morning of the experiment, the skin was removed and revived, and the transepidermal water loss value was tested to be less than 30 before use. Pig skin samples, cut to a size suitable for placement between the donor and receptor chambers, were then placed between the donor and receptor chambers of the Franz diffusion cell. The Franz cell opening was 1 cm. 2 Approximately 200 mg of sample was evenly applied to pig skin. 8.0 mL of the receptor solution was used. At 0.5, 2, 4, 8, 12, and 24 hours, 1.5 mL of sample was removed and replaced with fresh receptor solution. At 24 hours, the skin was removed. Skin retention and permeated drug concentration were determined by HPLC.

[0145] IVPT experimental parameters: Note: Skin retention amount = epidermal drug amount + dermal drug amount.

[0146] For solutions containing dimethyl sulfoxide, increasing the concentration from 0.5% to 1.0% showed a general trend of increasing skin retention and permeation, whereas this trend was not observed for suspension ointments. Furthermore, the skin retention and permeation of the solution were several times greater than those of the suspension ointment.

[0147] Example 9 Emulsion

[0148] 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 is dissolved in dimethyl sulfoxide, butylated hydroxytoluene, propylene glycol, benzyl alcohol, lactic acid, polyethylene glycol 400, carbomer 980, and water, and heated to 50°C with stirring until clear. Cyclomethicone, polydimethylsiloxane, ST-Elastomer 10, and carbomer are then uniformly stirred and heated to 50°C, then added to the drug-containing phase and stirred until a gel-bound semisolid is formed. The pH is adjusted to a specified value, and then stirred continuously and naturally cooled to room temperature.

[0149] Table 9

[0150] Example 10

[0151] Freshly excised Bama miniature pig skin samples were installed in a Franz diffusion cell to study the permeability of the API in topical formulations. Fresh Bama miniature pig skin was depilated and stored at -20°C until ready for use. On the morning of the experiment, the skin was removed and revived, and the transepidermal water loss value of the skin was tested to be less than 30 before 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, and approximately 60 mg of the sample was evenly applied to the pig skin. The opening of the Franz cell is 3.14 cm. 2 8.0 mL of receptor fluid was used. At 2, 6, and 20 hours, 1.0 mL samples were removed and replaced with fresh receptor fluid. At 20 hours, the skin was removed. Pig skin was processed, the epidermis and dermis separated, and extracted with the skin extract. Drug concentrations in the epidermis and dermis were determined by HPLC.

[0152] IVPT experimental parameters:

[0153] Example 11

[0154] The active ingredient is dissolved in the prescribed amount of dimethyl sulfoxide until a clear solution is obtained, and then the prescribed amounts of other non-aqueous solvents, propylene glycol and ethanol, and a penetration enhancer are added to obtain a clear solution.

[0155] Table 10

[0156] Example 12

[0157] Freshly excised Bama miniature pig skin samples were installed in a Franz diffusion cell to study the permeability of the API in topical formulations. Fresh Bama miniature pig skin was depilated and stored at -20°C until ready for use. On the morning of the experiment, the skin was removed and revived, and the transepidermal water loss value of the skin was tested to be less than 30 before 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, and approximately 60 mg of the sample was evenly applied to the pig skin. The opening of the Franz cell is 3.14 cm. 2 8.0 mL of receptor fluid was used. 1.0 mL samples were removed and replaced with fresh receptor fluid at 0.5, 2, 4, 8, and 24 hours. At 24 hours, the skin was removed. Pig skin was processed, the epidermis and dermis separated, and extracted with the skin extract. The remaining drug, epidermal, dermal, and permeated drug concentrations were determined by HPLC.

[0158] IVPT experimental parameters:

[0159] Compared with the blank solution, lactic acid showed better skin penetration promoting effect, while propylene glycol monocaprylate also showed a certain skin penetration promoting effect.

[0160] Example 13

[0161] Dissolve the active ingredient in the prescribed amount of dimethyl sulfoxide until it becomes a clear solution and set aside. Evenly swell the prescribed amount of hydroxypropyl cellulose in the prescribed amount of diethylene glycol monoethyl ether. Add the prescribed amount of other non-aqueous solvents such as propylene glycol and ethanol and stir evenly. Mix the dimethyl sulfoxide solvent and diethylene glycol monoethyl ether. The specific ingredients are as follows:

[0162] Table 11

[0163] Example 14

[0164] Freshly excised Bama miniature pig skin samples were installed in a Franz diffusion cell to study the permeability of API in topical preparations. Fresh Bama miniature pig skin was depilated and stored at -20°C. On the morning of the experiment, the skin was removed and revived, and the skin transepidermal water loss value was tested to be less than 30 before 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, and approximately 15 mg of sample was evenly applied to the pig skin. The opening of the Franz cell is 1 cm 28.0 mL of receptor fluid was used. 1.5 mL samples were removed and replaced with fresh receptor fluid at 0.5, 2, 4, 8, and 24 hours. At 24 hours, the skin was removed. Pig skin was processed, the epidermis and dermis separated, and extracted with the skin extract. The remaining drug, epidermal, dermal, and permeated drug concentrations were determined by HPLC.

[0165] IVPT experimental parameters:

[0166] Example 15

[0167] Dissolve the active ingredient and butylated hydroxytoluene in the prescribed amount of dimethyl sulfoxide until a clear solution is formed. Add the prescribed amount of lactic acid and the remaining liquid excipients, such as propylene glycol and glycerol. Stir and mix thoroughly, then adjust the pH to 3.5-4.5. Add the prescribed amount of hydroxypropyl cellulose and allow it to swell evenly in the drug-containing solution. The specific ingredients are shown in the following table:

[0168] Table 12

[0169] Example 16

[0170] Freshly excised Bama miniature pig skin samples were installed in a Franz diffusion cell to study the permeability of API in topical preparations. Fresh Bama miniature pig skin was depilated and stored at -20°C. On the morning of the experiment, the skin was removed and revived, and the skin transepidermal water loss value was tested to be less than 30 before 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, and approximately 15 mg of sample was evenly applied to the pig skin. The opening of the Franz cell is 1 cm 2 8.0 mL of receptor fluid was used. 1.5 mL samples were removed and replaced with fresh receptor fluid at 0.5, 2, 4, 8, and 24 hours. At 24 hours, the skin was removed. Pig skin was processed, the epidermis and dermis separated, and extracted with the skin extract. The remaining drug, epidermal, dermal, and permeated drug concentrations were determined by HPLC.

[0171] IVPT experimental parameters:

Claims

1. A pharmaceutical composition comprising the following components: 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 selected from one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate.

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

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

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

5. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition satisfies one or more of the following conditions: (1) Based on the total weight of the pharmaceutical composition, the content of the penetration enhancer is 1%-10%, preferably 5%-10%; (2) Based on the total weight of the pharmaceutical composition, the water content is less than 9%, preferably less than 8%, and more preferably less than 7%.

6. The pharmaceutical composition according to claim 1 or 2, further comprising one or more of the following components: (1) Organic solvent components other than dimethyl sulfoxide; (2) Matrix; (3) Antioxidants; (4) Moisturizer; (5) Preservatives; (6) thickeners; and (7) Odor-masking agents.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition satisfies one or more of the following conditions: (1) the organic solvent component is independently selected from one or more of benzyl alcohol, oleic acid, oleyl alcohol, diethylene glycol monoethyl ether, ethanol and propylene glycol; (2) The matrix is ​​a water-soluble matrix, the water-soluble matrix is ​​a polyethylene glycol polymer compound, and the average molecular weight of the polyethylene glycol polymer compound is preferably 100-6000; (3) The antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol; (4) The moisturizing agent is one or more of glycerol, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid and trehalose; (5) The preservative is methylparaben, ethylparaben, benzoic acid, sorbic acid, phenoxyethanol, chlorobutanol, phenylmercuric acetate, One or more of 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 flavor masking agent is one or more of strawberry flavor, orange flavor, and cyclodextrin.

8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition satisfies one or more of the following conditions: (1) Based on the total weight of the pharmaceutical composition, the content of the organic solvent component is 10% to 80%, preferably 10-60%; (2) Based on the total weight of the pharmaceutical composition, the matrix content is 30%-80%, preferably 40-50%, or the matrix content is 1%-20%, preferably 5%-15%; (3) The antioxidant content is 0.05%-0.5%, preferably 0.05%-0.2%, based on the total weight of the pharmaceutical composition; (4) The content of the moisturizer is 1%-50%, preferably 1%-25%, based on the total weight of the pharmaceutical composition; (5) the content of the preservative is 0.05% to 0.5% based on the total weight of the pharmaceutical composition; and (6) The thickener is present in an amount of 0.1% to 5%, preferably 0.5% to 3%, based on the total weight of the pharmaceutical composition.

9. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is any of the following: Scheme 1: The pharmaceutical composition contains 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 butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol, and the penetration enhancer is one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate; Scheme 2: The pharmaceutical composition contains 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 polymer compound, and the penetration enhancer is one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate; Scheme 3: The pharmaceutical composition contains an active ingredient, dimethyl sulfoxide, a penetration enhancer and an organic solvent, wherein the penetration enhancer is selected from one or more of 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; Scheme 4: The pharmaceutical composition contains an active ingredient, dimethyl sulfoxide, a penetration enhancer, an organic solvent, a thickener and a water-soluble matrix, the penetration enhancer is selected from one or more of 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, methyl cellulose and poloxamer, and the water-soluble matrix is ​​a polyethylene glycol polymer compound; Scheme 5: The pharmaceutical composition contains 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 selected from one or more of 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 selected from one or more of carbomer and silicone substances, the water-soluble matrix is ​​a polyethylene glycol polymer compound, and the antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol; Solution 6: The pharmaceutical composition contains an active ingredient, dimethyl sulfoxide, an organic solvent, a penetration enhancer, a water-soluble matrix, a thickener, The invention relates to a humectant 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 of lactic acid, isopropyl myristate and propylene glycol monocaprylate, the water-soluble matrix is ​​a polyethylene glycol polymer compound, the thickener is one or more of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, sodium alginate and poloxamer, the humectant is one or more of glycerol, propylene glycol, 1,3-butylene glycol, sorbitol, xylitol, hyaluronic acid and trehalose, and the antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is any of the following: Scheme 1: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, 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, 20%-80% by weight of dimethyl sulfoxide, 10%-80% by weight of an organic solvent, 0.1%-5% by weight of a thickener, and 0.0 5%-0.5% by weight of an antioxidant, and 1%-10% by weight of 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 butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol, and the penetration enhancer is one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate; Scheme 2: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, 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, 20%-80% by weight of dimethyl sulfoxide, 10%-80% by weight of an organic solvent, 30%-80% by weight of a water-soluble matrix, and 1%-10% by weight of 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 polymer compound, and the penetration enhancer is selected from one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate; Scheme 3: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, 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, 20%-80% by weight of dimethyl sulfoxide, and 1%-10% by weight of a penetration enhancer, wherein the penetration enhancer is selected from one or more of lactic acid, isopropyl myristate and propylene glycol monocaprylate; Scheme 4: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, 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, 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 selected from one or more of 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; Scheme 5: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, 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, 20%-80% by weight of dimethyl sulfoxide, 1%-10% by weight of a penetration enhancer, and 1 0%-80% by weight of an organic solvent, 0.1%-15% by weight of a thickener, 1%-20% or 30%-80% by weight of a water-soluble matrix, the penetration enhancer is selected from one or more of 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 of xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and poloxamer or more, the water-soluble matrix is ​​a polyethylene glycol polymer compound; Scheme 6: The pharmaceutical composition contains 0.3-2.0% by mass of an active ingredient, 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, 20%-80% by mass of dimethyl sulfoxide, 1%-10% by mass of a penetration enhancer, 10%-80% by mass of an organic solvent, and 0.1%-15% by mass of a thickener , 1%-20% by weight of a water-soluble matrix, 0.05%-0.5% by weight of an antioxidant, the penetration enhancer is selected from one or more of 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 selected from one or more of carbomer and silicone substances, the water-soluble matrix is ​​a polyethylene glycol polymer compound, and the antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol; Scheme 7: The pharmaceutical composition contains 0.3-2.0% by weight of an active ingredient, 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, 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 base, 0.1%-5% by weight of a thickener, 0.05%-0.5% by weight of an antioxidant and 1%-50% by weight of a The present invention relates to a composition comprising the following steps: the composition comprises a humectant in an amount of 1,2-diethylene glycol monoethyl ether, ...

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition comprises components of any of the following groups: (1) 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, 40% by mass of dimethyl sulfoxide, 49.1% by mass of diethylene glycol monoethyl ether, 0.3% by mass of benzyl alcohol, 2% by mass of hydroxypropyl cellulose, 0.1% by mass of dibutylhydroxytoluene, and 7.5% by mass of isopropyl myristate; (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, 40% by mass of dimethyl sulfoxide, 49.1% by mass of diethylene glycol monoethyl ether, 3.3% by mass of oleic acid, 1% by mass of hydroxypropylcellulose, 0.1% by mass of dibutylhydroxytoluene, and 5.5% by mass 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 mass of hydrogen sulfate 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, 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; (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 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, 0.05% by mass of butylated hydroxytoluene, 2% by mass of benzyl alcohol, 9.63% by mass of propylene glycol, 7% by mass of lactic acid, 12.5% ​​by mass of polyethylene glycol 400, 2.3% by mass of carbomer, 7% by mass of cyclomethicone, 1% by mass of polydimethylsiloxane, and 2% by mass of ST-Elastomer 10.

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

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

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

15. Use of a pharmaceutical composition as described in any one of claims 1 to 13 in the preparation of a medicament for treating or preventing an immune system disorder or disease; preferably, the immune system disorder or disease is selected from organ transplant rejection, ankylosing spondylitis, active radiologically negative 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 vitiligo.

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