WO2022022434A1

WO2022022434A1 - Pharmaceutical composition and preparation containing pharmaceutically acceptable salt of tofacitinib and use thereof

Info

Publication number: WO2022022434A1
Application number: PCT/CN2021/108320
Authority: WO
Inventors: 周星露; 钟诗春; 朱建荣; 胡苗; 罗文华
Original assignee: 杭州和正医药有限公司
Priority date: 2020-07-27
Filing date: 2021-07-26
Publication date: 2022-02-03
Also published as: CN113975280A; CN113975280B

Abstract

A pharmaceutical composition, comprising a pharmaceutically acceptable salt of tofacitinib and a penetration enhancer, and the use thereof in the preparation of a drug for treating and/or preventing autoimmune diseases. The penetration enhancer can be chosen to be diethylene glycol monoethyl ether, and the autoimmune diseases comprise vitiligo, alopecia areata, scleroderma, psoriasis, atopic dermatitis etc.

Description

含托法替尼药学上可接受的盐的药物组合物、制剂及应用Pharmaceutical composition, formulation and use containing pharmaceutically acceptable salt of tofacitinib

技术领域technical field

本发明属于药物组合物研发技术领域，具体是涉及一种含托法替尼药学上可接受的盐的药物组合物、制剂及应用。The invention belongs to the technical field of research and development of pharmaceutical compositions, in particular to a pharmaceutical composition, preparation and application containing a pharmaceutically acceptable salt of tofacitinib.

背景技术Background technique

托法替尼(Tofacitinib)，化学名为3-{(3R,4R)-4-甲基-3-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]哌啶-1-基}-3-氧代丙腈：

Tofacitinib, chemical name is 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] Piperidin-1-yl}-3-oxopropionitrile:

托法替尼是一种JAK抑制剂，可用于器官移植，异种移植，狼疮，多发性硬化症，类风湿性关节炎，牛皮癣，银屑病关节炎，1型糖尿病以及其他类型糖尿病，癌症，哮喘，特应性皮炎(Atopic Dermatitis，又称特异性皮炎)，自身免疫性甲状腺疾病，溃疡性结肠炎，克罗恩氏病，阿尔茨海默氏病，白血病和其他需要免疫抑制的适应症的疗法的免疫抑制剂。Tofacitinib is a JAK inhibitor indicated for organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, type 1 diabetes and other types of diabetes, cancer, Asthma, Atopic Dermatitis (also known as atopic dermatitis), autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications requiring immunosuppression of immunosuppressive therapy.

目前枸橼酸托法替尼已经在美国获批。以片剂形式销售，每片含8mg枸橼酸托法替尼，每日两次，用以治疗类风湿关节炎等。目前研究证明，口服枸橼酸托法替尼有较多副作用。例如上呼吸道感染、感冒、头痛等症状。目前学界已有提出使用局部制剂来避免口服所造成的副作用。例如专利文献CN103459394B公开了游离态托法替尼制作的油膏用于治疗牛皮癣。专利文献TW201940174A公开了枸橼酸托法替尼制作的局部配方用于治疗白癜风与特应性皮炎。专利文献CN103459394B中提出以游离态托法替尼制作油膏，在实施例15中，游离态托法替尼的稳定性较差，在40℃储存4周，纯度仅为97.3％。Tofacitinib citrate is currently approved in the United States. Sold in tablet form, each tablet contains 8 mg of tofacitinib citrate twice daily for the treatment of rheumatoid arthritis, among others. Current studies have shown that oral tofacitinib citrate has many side effects. Such as upper respiratory tract infection, cold, headache and other symptoms. At present, the academic community has proposed to use topical preparations to avoid the side effects caused by oral administration. For example, patent document CN103459394B discloses that an ointment made from free state tofacitinib is used for the treatment of psoriasis. Patent document TW201940174A discloses a topical formulation made of tofacitinib citrate for the treatment of vitiligo and atopic dermatitis. Patent document CN103459394B proposes to use free state tofacitinib to make ointment. In Example 15, free state tofacitinib has poor stability, and the purity is only 97.3% when stored at 40° C. for 4 weeks.

专利文献TW201940174A中，以二甲基亚砜作为其原料药的溶剂使用，使用量在45％，用量较大。二甲基亚砜作为一种常见的万能溶剂，有局部毒性作用和低的全身毒性。二甲基亚砜主要刺激皮肤，产生红肿、灼烧、瘙痒、结垢、引起荨麻疹等(R.C.罗，P.J.舍斯基，P.J.韦勒.药物辅料手册[M].北京：化学工业出版社，2005：256)。In the patent document TW201940174A, dimethyl sulfoxide is used as the solvent of its bulk drug, and the usage amount is 45%, which is relatively large. As a common universal solvent, dimethyl sulfoxide has local toxicity and low systemic toxicity. Dimethyl sulfoxide mainly stimulates the skin, causing redness, burning, itching, scaling, urticaria, etc. (RC Luo, PJ Shesky, PJ Weller. Handbook of Pharmaceutical Excipients [M]. Beijing: Chemical Industry Press , 2005: 256).

考虑专利文献CN103459394B与TW201940174A的局限性，在本领域中需要具有更高保留率、低刺激性、高稳定性的托法替尼外用制剂以治疗自身免疫性疾病。Considering the limitations of patent documents CN103459394B and TW201940174A, topical tofacitinib formulations with higher retention rate, low irritation and high stability are needed in the art to treat autoimmune diseases.

发明内容SUMMARY OF THE INVENTION

本发明提供了一种含托法替尼药学上可接受的盐的药物组合物，，该组合物稳定性高，安全性好，溶解性佳，且具有显著的抗炎效果。一种药物组合物，包括托法替尼药学上可接受的盐和一种或多种促渗剂，所述促渗剂包含二乙二醇单乙基醚、聚甘油脂肪酸酯、月桂氮酮、油酸、油醇、聚乙二醇中的一种或多种或者多种。The present invention provides a pharmaceutical composition containing a pharmaceutically acceptable salt of tofacitinib. The composition has high stability, good safety, good solubility and significant anti-inflammatory effect. A pharmaceutical composition comprising a pharmaceutically acceptable salt of tofacitinib and one or more penetration enhancers comprising diethylene glycol monoethyl ether, polyglycerol fatty acid ester, lauryl nitrogen One or more or more of ketone, oleic acid, oleyl alcohol, and polyethylene glycol.

作为优选，所述药物组合物中不含二甲基亚砜。Preferably, the pharmaceutical composition does not contain dimethyl sulfoxide.

作为一种实施方案，在所述组合物中，所述促渗剂的重量百分比含量为1％至80％。作为优选，药物组合物中，所述促渗剂的重量百分比含量低于40％。作为进一步优选，药物组合物中，所述促渗剂的重量百分比含量为1～39％；作为更进一步优选，药物组合物中，所述促渗剂的重量百分比含量为1～35％；作为更为具体的实施方案，药物组合物中，所述促渗剂的重量百分比含量为5～30％；作为最优的技术方案，药物组合物中，所述促渗剂的重量百分比含量为5～20％；作为具体的优选方案，药物组合物中，所述促渗剂的重量百分比含量为5～15％。As an embodiment, in the composition, the content of the penetration enhancer is 1% to 80% by weight. Preferably, in the pharmaceutical composition, the weight percentage of the penetration enhancer is less than 40%. As a further preference, in the pharmaceutical composition, the weight percentage of the penetration enhancer is 1-39%; as a further preference, in the pharmaceutical composition, the weight percentage of the penetration enhancer is 1-35%; A more specific embodiment, in the pharmaceutical composition, the weight percent content of the penetration enhancer is 5-30%; as an optimal technical solution, in the pharmaceutical composition, the weight percent content of the penetration enhancer is 5%. ～20%; as a specific preferred solution, in the pharmaceutical composition, the content of the penetration enhancer is 5-15% by weight.

作为一种实施方案，所述促渗剂为二乙二醇单乙基醚(Transcutol)。即作为优选，所述的药物组合物包括托法替尼药学上可接受的盐和二乙二醇单乙基醚。As an embodiment, the penetration enhancer is diethylene glycol monoethyl ether (Transcutol). That is, preferably, the pharmaceutical composition includes a pharmaceutically acceptable salt of tofacitinib and diethylene glycol monoethyl ether.

作为另一种实施方案，所述促渗剂为二乙二醇单乙基醚与月桂氮酮、聚甘油脂肪酸酯、油酸、油醇、聚乙二醇中一种或多种的组合。即所述组合物包括托法替尼药学上可接受的盐以及二乙二醇单乙基醚和其他促渗剂(即月桂氮酮、聚甘油脂肪酸酯、油酸、油醇、聚乙二醇中的一种或多种)的组合。As another embodiment, the penetration enhancer is a combination of diethylene glycol monoethyl ether and one or more of lauryl azone, polyglycerol fatty acid ester, oleic acid, oleyl alcohol, and polyethylene glycol . That is, the composition includes a pharmaceutically acceptable salt of tofacitinib as well as diethylene glycol monoethyl ether and other penetration enhancers (i.e., lauryl azone, polyglycerol fatty acid esters, oleic acid, oleyl alcohol, polyethylene glycol one or more of the diols) in combination.

作为一种实施方案，所述托法替尼药学上可接受的盐选自酒石酸盐托法替尼、硫酸托法替尼、磷酸托法替尼。As an embodiment, the pharmaceutically acceptable salt of tofacitinib is selected from tofacitinib tartrate, tofacitinib sulfate, and tofacitinib phosphate.

作为一种实施方案，包括托法替尼药学上可接受的盐为酒石酸盐托法替尼。作为优选，所述的药物组合物包括酒石酸托法替尼和二乙二醇单乙基醚；或者包括酒石酸托法替尼以及二乙二醇单乙基醚和其他促渗剂(即月桂氮酮、聚甘油脂肪酸酯、油酸、油醇、聚乙二醇中的一种或多种)的组合。As one embodiment, the pharmaceutically acceptable salt including tofacitinib is tofacitinib tartrate. Preferably, the pharmaceutical composition includes tofacitinib tartrate and diethylene glycol monoethyl ether; or includes tofacitinib tartrate and diethylene glycol monoethyl ether and other penetration enhancers (ie lauryl nitrogen ketone, polyglycerol fatty acid ester, oleic acid, oleyl alcohol, one or more of polyethylene glycol).

作为优选，在所述组合物中，所述托法替尼药学上可接受的盐的重量百分比含量为0.1％～10％。作为优选，所述的药物组合物，按照重量百分比计，包括，0.1％～10％的托法替尼药学上可接受的盐和1％～80％的二乙二醇单乙基醚。Preferably, in the composition, the weight percentage of the pharmaceutically acceptable salt of tofacitinib is 0.1% to 10%. Preferably, the pharmaceutical composition, in terms of weight percentage, comprises 0.1%-10% of a pharmaceutically acceptable salt of tofacitinib and 1%-80% of diethylene glycol monoethyl ether.

作为优选，所述的药物组合物，按照重量百分比计，包括，0.1％～10％的托法替尼药学上可接受的盐和1％～35％的二乙二醇单乙基醚。Preferably, the pharmaceutical composition, in terms of weight percentage, comprises 0.1%-10% of a pharmaceutically acceptable salt of tofacitinib and 1%-35% of diethylene glycol monoethyl ether.

作为进一步优选，在所述组合物中，所述托法替尼药学上可接受的盐的重量百分比含量为0.5％～5％。作为优选，所述的药物组合物，按照重量百分比计，包括，0.5％～5％酒石酸托法替尼和1％～80％二乙二醇单乙基醚。作为优选，所述的药物组合物，按照重量百分比计，包括，0.5％～5％的酒石酸托法替尼和1％～35％的二乙二醇单乙基醚。作为进一步优选，所述的药物组合物，按照重量百分比计，包括，0.5％～5％的酒石酸托法替尼和5％～30％的二乙二醇单乙基醚。As a further preference, in the composition, the weight percent content of the pharmaceutically acceptable salt of tofacitinib is 0.5% to 5%. Preferably, the pharmaceutical composition, in terms of weight percentage, comprises 0.5%-5% tofacitinib tartrate and 1%-80% diethylene glycol monoethyl ether. Preferably, the pharmaceutical composition, in terms of percentage by weight, comprises 0.5% to 5% of tofacitinib tartrate and 1% to 35% of diethylene glycol monoethyl ether. As a further preference, the pharmaceutical composition, in terms of percentage by weight, comprises 0.5% to 5% of tofacitinib tartrate and 5% to 30% of diethylene glycol monoethyl ether.

作为进一步优选，所述的药物组合物，按照重量百分比计，包括，0.5％～5％的酒石酸托法替尼和5％～20％的二乙二醇单乙基醚。As a further preference, the pharmaceutical composition, in terms of percentage by weight, comprises 0.5%-5% of tofacitinib tartrate and 5%-20% of diethylene glycol monoethyl ether.

作为更进一步优选，所述的药物组合物，按照重量百分比计，包括，0.5％～3％酒石酸托法替尼和5％～15％的二乙二醇单乙基醚。As a further preference, the pharmaceutical composition, in terms of weight percentage, comprises 0.5%-3% of tofacitinib tartrate and 5%-15% of diethylene glycol monoethyl ether.

作为优选，所述的药物组合物还包括赋形剂。Preferably, the pharmaceutical composition further includes excipients.

作为优选，在所述药物组合物中，所述赋形剂的重量百分比含量为70％～98.5％；所述赋形剂至少包括防腐剂和乳化剂。Preferably, in the pharmaceutical composition, the weight percentage of the excipients is 70% to 98.5%; the excipients at least include preservatives and emulsifiers.

作为优选，所述的药物组合物中，所述防腐剂的重量百分比含量为0.1～5％；所述乳化剂的重量百分比含量为0.5～20％。所述乳化剂进一步优选为5～15％。Preferably, in the pharmaceutical composition, the weight percent content of the preservative is 0.1-5%; the weight percent content of the emulsifier is 0.5-20%. The emulsifier is more preferably 5 to 15%.

作为优选，所述的药物组合物由如下重量百分比的组份组成：Preferably, the pharmaceutical composition is made up of the following components by weight:

托法替尼药学上可接受的盐 0.1％～10％Tofacitinib pharmaceutically acceptable salt 0.1% to 10%

促渗剂 1％～39％Penetration enhancer 1%～39%

其余为赋形剂。The rest are excipients.

作为优选，药物组合物中，所述赋形剂的重量百分比为50～98.9％；进一步优选为55～98.9％；更进一步优选为60～98.9％；或者优选为70～98.9％；或者优选为75～98.5％。Preferably, in the pharmaceutical composition, the weight percentage of the excipient is 50-98.9%; more preferably 55-98.9%; still more preferably 60-98.9%; or preferably 70-98.9%; or preferably 75 to 98.5%.

作为优选，所述赋形剂包括溶剂、稀释剂、抗氧化剂、螯合剂、乳化剂、防腐剂、抗菌剂、遮光剂、着色剂、凝胶剂、调味剂、pH调节剂以及其他适用的油性物质、水性物质中的一种或多种。作为优选，所述抗氧化剂选自2,6-二叔丁基-4-甲基苯酚、丁基羟基茴香醚、丁基羟基甲苯(BHT，2,6-二叔丁基对甲苯酚)、抗坏血酸(维生素C)、抗坏血酸衍生物、多酚、生育酚、生育酚衍生物、维生素A、叶黄素、番茄红素、次亚硫酸氢钠、硫代硫酸钠、没食子酸丙酯、硫辛酸、亚硫酸盐中的一种或多种。作为进一步优选，在所述组合物中，所述抗氧化剂质量百分比含量为0.05％至5％。Preferably, the excipients include solvents, diluents, antioxidants, chelating agents, emulsifiers, preservatives, antibacterial agents, opacifiers, colorants, gelling agents, flavoring agents, pH adjusters and other suitable oils One or more of substances and water-based substances. Preferably, the antioxidant is selected from 2,6-di-tert-butyl-4-methylphenol, butylated hydroxyanisole, butylated hydroxytoluene (BHT, 2,6-di-tert-butyl-p-cresol), Ascorbic acid (vitamin C), ascorbic acid derivatives, polyphenols, tocopherols, tocopherol derivatives, vitamin A, lutein, lycopene, sodium sulfoxylate, sodium thiosulfate, propyl gallate, lipoic acid , one or more of sulfites. As a further preference, in the composition, the mass percentage content of the antioxidant is 0.05% to 5%.

作为优选，所述的药物组合物，按照重量百分比计，包括：Preferably, the pharmaceutical composition, by weight percentage, comprises:

0.5～5％托法替尼药学上可接受的盐0.5-5% pharmaceutically acceptable salt of tofacitinib

5～20％二乙二醇单乙基醚5～20% Diethylene glycol monoethyl ether

0.1～5％稳定剂0.1～5% Stabilizer

余量赋形剂。Balance of excipients.

作为优选，所述稳定剂为包含抗氧化剂的稳定剂或者其他形式的稳定剂。Preferably, the stabilizer is an antioxidant-containing stabilizer or other forms of stabilizer.

作为优选，按照重量百分比计，所述的药物组合物包括：Preferably, according to weight percentage, the pharmaceutical composition comprises:

余量为其他促渗剂或/和赋形剂。The balance is other penetration enhancers or/and excipients.

在一些实施例中，本发明所述的组合物包括：(a)治疗有效量的托法替尼托法替尼药学上可接受的盐；(b)二乙二醇单乙基醚；(c)任选地，其它促渗剂；(d)任选地，乳化剂；(e)任选地，防腐剂；(f)任选地，抗氧化剂；(g)任选地，一种或多种其他药学上可接受的赋形剂。In some embodiments, the compositions of the present invention comprise: (a) a therapeutically effective amount of a pharmaceutically acceptable salt of tofacitinib; (b) diethylene glycol monoethyl ether; ( c) optionally, other penetration enhancers; (d) optionally, an emulsifier; (e) optionally, a preservative; (f) optionally, an antioxidant; (g) optionally, a or various other pharmaceutically acceptable excipients.

所述稳定剂包括但不限于抗菌剂、防腐剂或者其他抗氧化剂等。The stabilizers include, but are not limited to, antibacterial agents, preservatives, or other antioxidants.

在一些实施例中，本发明所述的组合物包括：(a)有效治疗量的托法替尼药学上可接受的盐；(b)二乙二醇单乙基醚；(c)纯化水；(d)二甲基硅油、聚乙二醇-7硬脂酸酯、十六醇、液体石蜡、聚甘油脂肪酸酯；(e)可选的，一种多种抗氧化剂；(f)可选的，一种或多种防腐剂。In some embodiments, the compositions of the present invention comprise: (a) a therapeutically effective amount of a pharmaceutically acceptable salt of tofacitinib; (b) diethylene glycol monoethyl ether; (c) purified water ; (d) dimethicone, polyethylene glycol-7 stearate, cetyl alcohol, liquid paraffin, polyglycerol fatty acid ester; (e) optional, one or more antioxidants; (f) Optionally, one or more preservatives.

作为一种实施方案，按照重量百分比计，所述组合物包括：As an embodiment, by weight percentage, the composition comprises:

0.5～5％酒石酸托法替尼0.5～5% tofacitinib tartrate

1％～80％促渗剂1%～80% Penetration enhancer

余量赋形剂。Balance of excipients.

作为进一步优选，按照重量百分比计，所述组合物包括：As a further preference, in terms of weight percentage, the composition comprises:

0.5～5％酒石酸托法替尼0.5-5% tofacitinib tartrate

5％～20％二乙二醇单乙基醚5%～20% Diethylene glycol monoethyl ether

0.1～10％包括抗氧化剂在内的稳定剂或者其他稳定剂0.1～10% Stabilizers including antioxidants or other stabilizers

其余为赋形剂。The rest are excipients.

0.5～5％酒石酸托法替尼0.5-5% tofacitinib tartrate

5～20％二乙二醇单乙基醚5～20% Diethylene glycol monoethyl ether

31～80％纯化水31～80% Purified water

9～50％二甲基硅油、聚乙二醇-7硬脂酸酯、十六醇、甘油、丙二醇、十八醇、凡士林、十二烷基硫酸钠、液体石蜡、聚甘油脂肪酸酯、单硬脂酸甘油酯、双硬脂酸甘油酯、三乙醇胺、硬脂酸、羊毛脂、凡士林中的一种或多种中的一种或多种。9～50% Dimethicone, polyethylene glycol-7 stearate, cetyl alcohol, glycerin, propylene glycol, stearyl alcohol, petrolatum, sodium lauryl sulfate, liquid paraffin, polyglycerol fatty acid ester, One or more of glycerol monostearate, glyceryl distearate, triethanolamine, stearic acid, lanolin, one or more of petrolatum.

可选的，包括0.01～1％的丁基羟基茴香醚和丁基羟基甲苯组合物。Optionally, 0.01-1% of a composition of butylated hydroxyanisole and butylated hydroxytoluene is included.

可选的，包括0.1～2％的对羟基苯甲酸甲酯、对羟基苯甲酸丙酯与对羟基苯甲酸乙酯的一种或多种。Optionally, it includes 0.1-2% of one or more of methylparaben, propylparaben and ethylparaben.

作为进一步优选，所述组合物包括：As a further preference, the composition includes:

0.5～5％酒石酸托法替尼0.5-5% tofacitinib tartrate

5～20％二乙二醇单乙基醚5～20% Diethylene glycol monoethyl ether

10～15％聚乙二醇-7硬脂酸酯、单硬脂酸甘油酯、双硬脂酸甘油酯、三乙醇胺中的一种或多种；One or more of 10-15% polyethylene glycol-7 stearate, glyceryl monostearate, glyceryl distearate, and triethanolamine;

9～50％二甲基硅油、十六醇、甘油、丙二醇、十八醇、凡士林、十二烷基硫酸钠、液体石蜡、聚甘油脂肪酸酯、硬脂酸、羊毛脂、凡士林中的一种或多种；9-50% of one of dimethicone, cetyl alcohol, glycerin, propylene glycol, stearyl alcohol, petrolatum, sodium lauryl sulfate, liquid paraffin, polyglycerol fatty acid ester, stearic acid, lanolin, petrolatum one or more;

0.05～5％丁基羟基茴香醚、丁基羟基甲苯、维生素E醋酸酯中的一种或多种；0.05～5% one or more of butylated hydroxyanisole, butylated hydroxytoluene and vitamin E acetate;

0.1～2％对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯的组合物中的一种或多种；0.1 to 2% of one or more of the compositions of methylparaben, ethylparaben, and propylparaben;

31％～75％纯化水。31% to 75% purified water.

本发明的还提供了一种制剂，由上述药物组合物制备而来。The present invention also provides a preparation prepared from the above-mentioned pharmaceutical composition.

作为优选，所述制剂优选为乳膏、洗剂、溶液(例如，液体喷雾剂)、凝胶、糊剂、硬膏剂、涂剂。Preferably, the formulations are creams, lotions, solutions (eg, liquid sprays), gels, pastes, plasters, paints.

作为优选，所述制剂为外用制剂。进一步优选为局部制剂，可以采取适于局部施用至身体表面的组合物的形式使用。Preferably, the preparation is an external preparation. Further preferred are topical formulations, which may be used in the form of compositions suitable for topical application to the body surface.

作为进一步优选，该外用制剂为乳膏剂。As a further preference, the external preparation is a cream.

本发明还提供了一种上述乳膏制剂的制备方法，包括：The present invention also provides a preparation method of the above-mentioned cream preparation, comprising:

油相：将制剂配方中的油溶性物质混合溶解；Oil phase: mix and dissolve the oil-soluble substances in the formulation;

水相：将制剂配方中的水溶性物质溶解；Water phase: dissolve the water-soluble substances in the formulation;

外相：所述外相为托法替尼药学上可接受的盐、促渗剂(比如二乙二醇单乙基醚) 或者两者的组合溶液；External phase: the external phase is a pharmaceutically acceptable salt of tofacitinib, a penetration enhancer (such as diethylene glycol monoethyl ether) or a combined solution of the two;

(1)在60～90℃下，在搅拌状态下将水相、油相和外相混合。(1) Mix the water phase, the oil phase and the external phase under stirring at 60 to 90°C.

(2)降温到50～60℃将混合溶液置于剪切机中，保持剪切状态下，保持剪切状态(可以是5～30min)，得到乳膏。(2) Cool the temperature to 50-60°C, place the mixed solution in a shearing machine, keep the shearing state, and keep the shearing state (it can be 5-30 min) to obtain a cream.

在某些情况下，根据托法替尼药学上可接受的盐的溶解性不同；所述外相和水相的组成可能会进行调整；比如当所述托法替尼药学上可接受的盐为磷酸盐或者硫酸盐时，其更容易溶于水，此时，可以作为水相的一部分进行加入。当所述托法替尼药学上可接受的盐为酒石酸盐时，可以直接溶于促渗剂中，此时所述托法替尼药学上可接受的盐作为外相进行制备。In some cases, depending on the solubility of the pharmaceutically acceptable salt of tofacitinib; the composition of the external and aqueous phases may be adjusted; for example, when the pharmaceutically acceptable salt of tofacitinib is Phosphate or sulfate, which are more soluble in water, can be added as part of the aqueous phase. When the pharmaceutically acceptable salt of tofacitinib is tartrate, it can be directly dissolved in the penetration enhancer, and at this time, the pharmaceutically acceptable salt of tofacitinib is prepared as an external phase.

本发明还提供了本发明所述的组合物在制备治疗和/或预防自身免疫性疾病药物中的应用。The present invention also provides the application of the composition of the present invention in preparing a medicine for treating and/or preventing autoimmune diseases.

本发明还提供了一种本发明所述的组合物在治疗和/或预防自身免疫性疾病中的应用。The present invention also provides an application of the composition of the present invention in the treatment and/or prevention of autoimmune diseases.

所述的自身免疫性疾病包括白癜风、斑秃、特应性皮炎、类风湿关节炎、***性红斑狼疮、多发性硬化、炎性肠炎、克罗恩氏病、结肠炎、自身免疫性溶血性贫血、强直性脊柱炎、天疱疮、荨麻疹、哮喘、视神经炎、银屑病、慢性阻塞性气道疾病、皮炎症、硬皮症。The autoimmune diseases include vitiligo, alopecia areata, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, Crohn's disease, colitis, autoimmune hemolytic anemia , Ankylosing spondylitis, pemphigus, urticaria, asthma, optic neuritis, psoriasis, chronic obstructive airway disease, skin inflammation, scleroderma.

所述自身免疫性疾病优选为白癜风、特应性皮炎、斑秃、银屑病、皮炎症、硬皮症。The autoimmune disease is preferably vitiligo, atopic dermatitis, alopecia areata, psoriasis, skin inflammation, scleroderma.

本发明使用的术语“托法替尼”是指托法替尼游离碱或其立体异构体或其立体异构体的混合物。The term "tofacitinib" as used herein refers to tofacitinib free base or a stereoisomer or a mixture of stereoisomers thereof.

本发明中，所述酒石酸可以是L-酒石酸，D-酒石酸，或者外消旋体，或者L-酒石酸和D-酒石酸任意比例的混合物。In the present invention, the tartaric acid can be L-tartaric acid, D-tartaric acid, or a racemate, or a mixture of L-tartaric acid and D-tartaric acid in any ratio.

本发明所述托法替尼药学上可接受的盐，可以由托法替尼与对应的酸反应得到。The pharmaceutically acceptable salt of tofacitinib of the present invention can be obtained by reacting tofacitinib with a corresponding acid.

本发明所使用的术语“有效治疗量”是指减轻一种或多种疾病症状的用量。As used herein, the term "therapeutically effective amount" refers to an amount that reduces symptoms of one or more diseases.

本发明所使用的术语“降解产物”是指在药品生产或者运输储存过程中的会影响药品功效的有害化学物质或者杂质。它会由于温度、pH、湿度、光照、赋形剂等因素影响而改变。The term "degradation product" as used in the present invention refers to harmful chemical substances or impurities that can affect the efficacy of the drug during the production or transportation and storage of the drug. It will change due to factors such as temperature, pH, humidity, light, excipients, etc.

所述赋形剂实际使用时，可能具有单独一种赋形剂的功能，也可能同时兼做其他赋形剂的功能，比如对于某一个乳化剂，它可能只有乳化的功能，也可能既具有乳化的功能，也同时具有溶解的作用或者同时兼具稀释剂的作用，甚至可能具有抗氧化剂或者抗菌剂的作用。When the excipient is actually used, it may have the function of a single excipient, or it may also serve as the function of other excipients. For example, for a certain emulsifier, it may only have the function of emulsifying, or it may have both The emulsifying function also has the function of dissolving or diluting at the same time, and may even have the function of antioxidant or antibacterial agent.

本发明的促渗剂也可以兼做赋形剂的功能，比如具有溶剂的功能等。The penetration enhancer of the present invention may also function as an excipient, for example, as a solvent.

本发明配方所使用的药学上可接受的赋形剂可以有多种方式。例如，水性物质也可以用作为稳定剂、而促渗剂也可以作为溶剂或者稀释剂等。其中水性物质优选为二乙二醇单乙基醚、丙二醇、甘油、聚乙二醇、异丙醇、甲醇、吡咯烷酮羧酸钠、2-羟丙基-γ-环糊精、丙酮、纯净水、乙醇、丙醇、丁二醇或上述化合物中的两种或两种以上组合。当然实际加工时，其他赋形剂也可以同时起到溶剂试剂的作用。The pharmaceutically acceptable excipients used in the formulations of the present invention can be used in a variety of ways. For example, aqueous substances can also be used as stabilizers, and penetration enhancers can also be used as solvents or diluents. Among them, the aqueous substances are preferably diethylene glycol monoethyl ether, propylene glycol, glycerin, polyethylene glycol, isopropanol, methanol, sodium pyrrolidone carboxylate, 2-hydroxypropyl-γ-cyclodextrin, acetone, purified water , ethanol, propanol, butanediol, or a combination of two or more of the above compounds. Of course, in actual processing, other excipients can also play the role of solvent reagents at the same time.

其中螯合剂优选为四乙酸二氨基乙烷、丁二酸、曲恩碱、次氮基三乙酸、反式-二氨基环己烷四乙酸(DCTA)、二亚乙基三胺五乙酸、双(氨基乙酰基)乙二醇醚- N，N，N'，N'-四乙酸、亚氨基二乙酸、枸橼酸、酒石酸、富马酸中的一种或者多种。Among them, the chelating agent is preferably tetraacetic acid diaminoethane, succinic acid, trin's base, nitrilotriacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), diethylenetriaminepentaacetic acid, bis- (Aminoacetyl) glycol ether - one or more of N,N,N',N'-tetraacetic acid, iminodiacetic acid, citric acid, tartaric acid, and fumaric acid.

其中乳化剂优选为十二烷基硫酸钠、聚乙二醇-7-硬脂酸酯、单硬脂酸甘油酯、双硬脂酸甘油酯、三乙醇胺、聚甘油脂肪酸酯的一种或者多种。所述乳化剂的加入量根据乳化剂种类的不同可以进行调整，一般加入量为0.5～20％之间。Wherein the emulsifier is preferably one of sodium lauryl sulfate, polyethylene glycol-7-stearate, glycerol monostearate, glyceryl distearate, triethanolamine, polyglycerol fatty acid ester or variety. The added amount of the emulsifier can be adjusted according to the different types of the emulsifier, and the general added amount is between 0.5% and 20%.

其中抗菌剂优选为对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、环氧乙烷、苯酚、苯甲酸。其中油性基质优选为凡士林、羊毛脂、脂肪醇、矿物油、甘油三酯和硅油。Among them, the antimicrobial agent is preferably methylparaben, ethylparaben, propylparaben, ethylene oxide, phenol, and benzoic acid. Among them, the oily bases are preferably petrolatum, lanolin, fatty alcohols, mineral oils, triglycerides and silicone oils.

其中稀释剂优选为甘油、丙二醇、纯化水、氢氧化钠、氢氧化钾、碳酸氢钠、十二烷基硫酸钠、十六醇、十八醇、白凡士林、液体石蜡、羊毛酯、蜂蜡、醇蜡、硬脂酸、二甲基硅油、聚山梨酯、脂肪酸、油醇、聚乙二醇-7硬脂酸酯、水等。占配方总重量的50％w/w～85％w/w。上述氢氧化钠、氢氧化钾、碳酸氢钠也可以同时兼做pH调节剂。Wherein the diluent is preferably glycerin, propylene glycol, purified water, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium lauryl sulfate, cetyl alcohol, stearyl alcohol, white petrolatum, liquid paraffin, lanolin, beeswax, Alcohol wax, stearic acid, dimethicone, polysorbate, fatty acid, oleyl alcohol, polyethylene glycol-7 stearate, water, etc. 50%w/w～85%w/w of the total weight of the formula. The above-mentioned sodium hydroxide, potassium hydroxide, and sodium bicarbonate can also serve as pH adjusters at the same time.

其中防腐剂优选为对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、环氧乙烷、苯酚、苯甲酸。优选的对羟基苯甲酸甲酯与对羟基苯甲酸乙酯的组合。防腐剂浓度优选为0.5％w/w至5％w/w，根据配方总重量，优选为0.1％w/w至1.0％w/w。Among them, the preservatives are preferably methylparaben, ethylparaben, propylparaben, butylparaben, ethylene oxide, phenol, and benzoic acid. The preferred combination of methylparaben and ethylparaben. The preservative concentration is preferably from 0.5% w/w to 5% w/w, preferably from 0.1% w/w to 1.0% w/w based on the total formulation weight.

其中抗氧化剂优选为丁基羟基茴香醚(叔丁基-4-羟基茴香醚，BHA(包括3-BHA或2-BHA))和丁基羟基甲苯(BHT)以及维生素E衍生物(比如维生素E醋酸酯)以及维生素C衍生物(如维生素C钠)。根据配方总重量，优选为0.1％w/w至5.0％w/w。Among them, the antioxidants are preferably butylated hydroxyanisole (tert-butyl-4-hydroxyanisole, BHA (including 3-BHA or 2-BHA)) and butylated hydroxytoluene (BHT) and vitamin E derivatives (such as vitamin E acetate) and vitamin C derivatives (such as vitamin C sodium). It is preferably from 0.1% w/w to 5.0% w/w based on the total weight of the formulation.

其中所述pH调节剂优选为药物中常用的pH调节剂，包括无机酸或者无机碱，比如氢氧化钠、氢氧化钾，碳酸氢钠、碳酸钠等。所述pH调节剂加入量为保持组合物的pH优选为6～8。The pH adjusting agent is preferably a pH adjusting agent commonly used in medicine, including inorganic acids or inorganic bases, such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, and the like. The added amount of the pH adjuster is to maintain the pH of the composition preferably at 6-8.

其他赋形剂成分的具体组份和加入量均可根据需要，同时参考现有技术进行选择。The specific components and addition amounts of other excipient components can be selected according to needs and with reference to the prior art.

研究已证明，口服枸橼酸托法替尼可能带来上呼吸道感染、感冒、头痛等副作用；而游离态托法替尼的外用制剂稳定性较差(CN103459394B)；枸橼酸托法替尼乳膏(TW201940174A)采用了二甲基亚砜作为溶剂，具有较高刺激性。因此，在本领域中需要具有更高保留率、低刺激性、高稳定性的托法替尼外用制剂以治疗自身免疫性疾病保证药物的安全性和良好的药效。Studies have shown that oral tofacitinib citrate may cause side effects such as upper respiratory tract infection, cold, headache, etc.; while the topical preparation of free tofacitinib is less stable (CN103459394B); tofacitinib citrate milk The paste (TW201940174A) uses dimethyl sulfoxide as a solvent, which is highly irritating. Therefore, a topical formulation of tofacitinib with higher retention rate, low irritation and high stability is required in the art to treat autoimmune diseases to ensure the safety and good efficacy of the drug.

本发明选用的托法替尼的盐型，具有更好的溶解性，简化了制剂加工难度，增加了其在皮肤中的渗透性；本发明通过筛选不同托法替尼盐型和溶剂，保证其完全溶解性的前提下，发现离子态的形式相对于游离态托法替尼具有更高的稳定性，保证了药物的安全性和良好的药效；本发明筛选出二乙二醇单乙基醚作为溶剂、促渗剂，对皮肤也无刺激性；同时由本发明所述的药物组合物制备的制剂在透皮实验中表现出更佳的皮肤内药物暴露，且不增加透皮扩散池内药物浓度，表明药物进入循环***的风险较低；且由该制剂在二硝基氟苯诱导的迟发型超敏反应模型中，具有抗炎效果，本发明的制剂还能减少白癜风患者的白斑面积，可用于治疗和预防包括白癜风、斑秃、硬皮病、银屑病、特应性皮炎等自身免疫性疾病。The salt form of tofacitinib selected in the present invention has better solubility, simplifies the preparation processing difficulty, and increases its permeability in the skin; the present invention ensures that by screening different salt forms and solvents of tofacitinib On the premise of its complete solubility, it is found that the ionic form has higher stability than free tofacitinib, which ensures the safety and good efficacy of the drug; the present invention screened out diethylene glycol monoethyl ether. Ether acts as a solvent and penetration enhancer, and is not irritating to the skin; meanwhile, the preparation prepared from the pharmaceutical composition of the present invention shows better drug exposure in the skin in the transdermal experiment, and does not increase the drug in the transdermal diffusion pool. concentration, indicating that the risk of the drug entering the circulatory system is low; and the preparation has an anti-inflammatory effect in the delayed-type hypersensitivity reaction model induced by dinitrofluorobenzene, and the preparation of the present invention can also reduce the vitiligo patient's leukoplakia area, It can be used to treat and prevent autoimmune diseases including vitiligo, alopecia areata, scleroderma, psoriasis, atopic dermatitis, etc.

附图说明：Description of drawings:

附图1：小鼠耳厚度差；Figure 1: Difference in mouse ear thickness;

附图2：家兔刺激性试验给药侧皮肤照片；Accompanying drawing 2: Rabbit irritation test administration side skin photo;

附图3：脖颈有白癜风女性患者A以本发明的酒石酸托法替尼局部配方治疗4周、8周、12周相较基线白斑消失面积百分比；Accompanying drawing 3: The female patient A with vitiligo on the neck is treated with the topical formulation of tofacitinib tartrate of the present invention for 4 weeks, 8 weeks, and 12 weeks compared with the baseline vitiligo disappearance area percentage;

附图4：额部有白癜风男性患者B以本发明的酒石酸托法替尼局部配方治疗5个月相较基线白斑消失面积百分比；Accompanying drawing 4: the male patient B with vitiligo in the forehead is treated with tofacitinib tartrate topical formulation of the present invention for 5 months compared to baseline vitiligo disappearance area percentage;

附图5：脸部有白癜风男性患者C以本发明的酒石酸托法替尼局部配方治疗5个月相较基线白斑消失面积百分比；Accompanying drawing 5: the male patient C with vitiligo on the face is treated with the topical formulation of tofacitinib tartrate of the present invention for 5 months compared to baseline vitiligo disappearance area percentage;

附图6：患有特应性皮炎的男性患者D以本发明的酒石酸托法替尼局部配方治疗12天后基本治愈。Figure 6: Male patient D suffering from atopic dermatitis was basically cured after 12 days of treatment with the topical formulation of tofacitinib tartrate of the present invention.

具体实施方式detailed description

在以下内容段落中描述了用于本发明的详细技术和优选实施例，目的是使本领域技术人员更好地理解了所要求保护的技术方案。本发明将在以下示例中进一步说明。然而，这些例子只是为了说明目的。不是以任何方式限制本发明的范围。Detailed techniques and preferred embodiments for the present invention are described in the following content paragraphs for the purpose of enabling those skilled in the art to better understand the claimed technical solutions. The invention will be further illustrated in the following examples. However, these examples are for illustrative purposes only. It is not intended to limit the scope of the invention in any way.

实施例1：托法替尼盐型的合成Example 1: Synthesis of Tofacitinib Salt Form

酒石酸托法替尼的合成(1)Synthesis of Tofacitinib Tartrate(1)

将500mg(1.6mmol)游离态托法替尼与288mg(1.9mmol)酒石酸加入25mL烧瓶，加入7.5mL丙酮，搅拌并加热至40℃反应2h，冷却至室温，过滤并收集固体，常温减压干燥的产物717mg，收率96.9％。Add 500 mg (1.6 mmol) of free tofacitinib and 288 mg (1.9 mmol) of tartaric acid to a 25 mL flask, add 7.5 mL of acetone, stir and heat to 40 °C for 2 h, cool to room temperature, filter and collect the solid, dry under reduced pressure at room temperature Product 717 mg, yield 96.9%.

酒石酸托法替尼的放大合成(2)Amplified synthesis of tofacitinib tartrate (2)

称量游离态托法替尼45.0g于1L单口反应瓶中，25℃±5℃加入21.6g L-酒石酸及225ml甲醇，加热至回流，至固体溶清后趁热过滤，回收母液，浓缩至近干，然后加入450ml正己烷于25℃±5℃搅拌打浆1h，抽滤得到固体，在鼓风烘箱中70±5℃干燥48h，得到酒石酸托法替尼，收率95.0％。Weigh 45.0g of free tofacitinib into a 1L single-neck reaction flask, add 21.6g of L-tartaric acid and 225ml of methanol at 25°C ± 5°C, heat to reflux, filter while the solid is dissolved, recover the mother liquor, and concentrate to near dryness , then add 450ml of n-hexane, stir and beat at 25°C±5°C for 1h, suction filtration to obtain a solid, and dry in a blast oven at 70±5°C for 48h to obtain tofacitinib tartrate with a yield of 95.0%.

硫酸托法替尼的合成Synthesis of Tofacitinib Sulfate

将500mg(1.6mmol)游离态托法替尼与50μL(0.9mmol)硫酸加入25mL烧瓶，加入7.5mL丙酮，搅拌并加热至40℃反应2h，冷却至室温，过滤并收集固体，常温减压干燥的产物561mg，收率97.0％。500 mg (1.6 mmol) of free state tofacitinib and 50 μL (0.9 mmol) of sulfuric acid were added to a 25 mL flask, 7.5 mL of acetone was added, stirred and heated to 40 °C for 2 h, cooled to room temperature, filtered and the solid was collected, dried under reduced pressure at room temperature. Product 561 mg, yield 97.0%.

磷酸托法替尼的合成Synthesis of Tofacitinib Phosphate

将500mg(1.6mmol)游离态托法替尼与127μL(1.9mmol)磷酸加入25mL烧瓶，加入7.5mL丙酮，搅拌并加热至40℃反应2h，冷却至室温，过滤并收集固体，常温减压干燥的产物598mg，收率91.0％。Add 500 mg (1.6 mmol) of free tofacitinib and 127 μL (1.9 mmol) of phosphoric acid into a 25 mL flask, add 7.5 mL of acetone, stir and heat to 40°C for 2 h, cool to room temperature, filter and collect the solid, and dry under reduced pressure at room temperature. Product 598 mg, yield 91.0%.

实施例2：不同外用制剂的制备Example 2: Preparation of different external preparations

表1-1酒石酸托法替尼的乳膏配方Table 1-1 Cream formula of tofacitinib tartrate

说明：表1-1中，水相和油相和外相中各组份的百分比是以油相和水相的总量为基准计算得到。Description: In Table 1-1, the percentage of each component in the water phase, oil phase and external phase is calculated based on the total amount of oil phase and water phase.

表1-2酒石酸托法替尼的乳膏配方Table 1-2 Cream formula of tofacitinib tartrate

说明：表1-2中，B6～B11中水相和油相和外相中各组份的百分比是以油相和水相的总量为基准计算得到。Note: In Table 1-2, the percentages of components in the water phase, oil phase and external phase in B6 to B11 are calculated based on the total amount of oil phase and water phase.

表1-3酒石酸托法替尼的乳膏配方Table 1-3 Cream formula of tofacitinib tartrate

说明：表1-3中各组份的百分比是以油相、水相和外相的总量为基准计算得到。Note: The percentage of each component in Table 1-3 is calculated based on the total amount of oil phase, water phase and external phase.

表1-4酒石酸托法替尼的乳膏配方Table 1-4 Cream formula of tofacitinib tartrate

说明：表1-4中各组份的百分比是以油相和水相的总量为基准计算得到。Note: The percentage of each component in Tables 1-4 is calculated based on the total amount of oil phase and water phase.

表1-5酒石酸托法替尼的乳膏配方Table 1-5 Cream formula of tofacitinib tartrate

说明：表1-5中各组份的百分比是以油相和水相和外相的总量为基准计算得到Note: The percentage of each component in Table 1-5 is calculated based on the total amount of oil phase, water phase and external phase

表2磷酸托法替尼与硫酸托法替尼的乳膏配方Table 2 The cream formula of tofacitinib phosphate and tofacitinib sulfate

说明：表2中各组份的百分比是以油相和水相的总量为基准计算得到。Note: The percentage of each component in Table 2 is calculated based on the total amount of oil phase and water phase.

表3托法替尼和枸橼酸托法替尼油膏配方Table 3 Tofacitinib and Tofacitinib Citrate Ointment Formulations

说明：表3中各组份的百分比是以油相和外相的总量为基准计算得到。Note: The percentage of each component in Table 3 is calculated based on the total amount of oil phase and external phase.

以总投料量为100g计算，按照表1-1至表1-5和表2所示物料比：Calculated with the total feeding amount of 100g, according to the material ratio shown in Table 1-1 to Table 1-5 and Table 2:

1、取处方量油相置于100ml烧杯中，80℃搅拌加热溶解。1. Take the prescribed amount of oil phase and place it in a 100ml beaker, stir and heat at 80°C to dissolve.

2、取处方量水相置于100ml烧杯中，60℃搅拌，溶解至澄清。2. Take the prescribed amount of water phase and place it in a 100ml beaker, stir at 60°C, and dissolve until it becomes clear.

3、取处方量外相置于100ml烧杯中，55℃搅拌，溶解至澄清。3. Take the external phase of the recipe and put it in a 100ml beaker, stir at 55°C, and dissolve until it becomes clear.

4、在55℃搅拌状态下，将水相、油相、外相混合均匀，并置于剪切机下，保持剪切状态5-30min。4. Under stirring state at 55℃, mix the water phase, oil phase and external phase evenly, and place it under the shearing machine to keep the shearing state for 5-30min.

5、将剪切完后的乳膏冷却搅拌至室温后，灌装至10ml铝管中。5. Cool and stir the sheared cream to room temperature, and then fill it into a 10ml aluminum tube.

以总投料量为100g计算，按照表3物料比：Calculated with the total feeding amount of 100g, according to the material ratio in Table 3:

3、取处方量外相置于100ml烧杯中，60℃搅拌，溶解至澄清。3. Take the external phase of the recipe and place it in a 100ml beaker, stir at 60°C, and dissolve until it becomes clear.

4、在80℃搅拌状态下，将油相、外相混合均匀，并置于剪切机下，保持剪切状态5-30min。4. Under the stirring state of 80 ℃, mix the oil phase and the external phase evenly, and place it under the shearing machine to keep the shearing state for 5-30min.

5、将剪切完后的油膏冷却搅拌至室温后，称取10g，灌装至10ml铝管中。5. After cooling and stirring the sheared ointment to room temperature, weigh 10g and fill it into a 10ml aluminum tube.

实施例3:不同盐型的托法替尼溶解性质测试Embodiment 3: Tofacitinib dissolution property test of different salt forms

为提高局部制剂的药品透皮能力以及药品的稳定性，药物在辅料中的溶解性非常关键，所以，原料药的溶解性是衡量药物的一个重要指标。故在处方的开发过程中进行了平衡溶解度研究：取过量原料(枸橼酸托法替尼、酒石酸托法替尼、硫酸盐托法替尼、磷酸盐托法替尼)置于2mL PE管中，加入不同的溶剂1ml，在室温进行溶解，震荡24h后用高效液相色谱法计算溶解度。In order to improve the drug transdermal ability of topical preparations and the stability of the drug, the solubility of the drug in the excipients is very important. Therefore, the solubility of the drug substance is an important indicator to measure the drug. Therefore, an equilibrium solubility study was carried out during the development of the prescription: take excess raw materials (tofacitinib citrate, tofacitinib tartrate, tofacitinib sulfate, tofacitinib phosphate) and place them in a 2mL PE tube. , add 1 ml of different solvents, dissolve at room temperature, and calculate the solubility by high performance liquid chromatography after shaking for 24 h.

表4：不同盐型在不同溶剂中的溶解度Table 4: Solubility of different salt forms in different solvents

表中：“﹥”表示“大于”，“<”表示“小于”。In the table: "﹥" means "greater than", "<" means "less than".

本次试验，我们意外地发现：在促渗剂二乙二醇单乙基醚中，与枸橼酸托法替尼相比，酒石酸托法替尼的溶解度显著提升，提示我们，在制剂中，二乙二醇单乙基醚可以作为酒石酸托法替尼的配伍溶剂。在水溶液中，磷酸托法替尼、硫酸托法替尼的溶解度显著提升，提示我们，在制剂中，水溶液可以作为磷酸托法替尼、硫酸托法替尼的配伍溶剂。In this experiment, we unexpectedly found that in the penetration enhancer diethylene glycol monoethyl ether, the solubility of tofacitinib tartrate was significantly improved compared with tofacitinib citrate, suggesting that in the formulation , Diethylene glycol monoethyl ether can be used as a compatible solvent for tofacitinib tartrate. In aqueous solution, the solubility of tofacitinib phosphate and tofacitinib sulfate was significantly improved, suggesting that in the formulation, aqueous solution can be used as a compatible solvent for tofacitinib phosphate and tofacitinib sulfate.

实施例4：托法替尼乳膏与油膏的性状考察Example 4: Investigation of the properties of tofacitinib cream and ointment

选取具有代表性的乳膏，考察所制得乳膏与油膏的性状，选取性状细腻、均匀、水润、易涂抹、稳定的乳膏或油膏。Select representative creams, investigate the properties of the obtained creams and ointments, and select creams or ointments with fine, uniform, moisturizing, easy to spread and stable properties.

表5-1不同托法替尼乳膏与油膏的性状Table 5-1 Properties of different tofacitinib creams and ointments

表5-2不同托法替尼乳膏与油膏的性状Table 5-2 Properties of different tofacitinib creams and ointments

实施例5：托法替尼乳膏在皮肤内渗透数据Example 5: Intradermal penetration data of tofacitinib cream

选用小香猪皮作为透皮实验皮肤，用以测试不同处方的托法替尼在皮肤中的渗透情况。具体而言，渗透池选用垂直扩散池，渗透池体积6.5cm，池口面积2.2cm ²，受体溶液为PBS缓冲溶液(pH＝7.4)，皮肤为8月龄小香猪的背部皮肤，去毛后取厚度1400μm皮肤进行实验。取乳膏约0.2g置于小香猪皮肤上，取样点为1、2、4、6小时，6h后取下皮肤剪碎用有机溶剂超声1h提取，样品过滤后用液相色谱法测定含量。 Xiaoxiang pig skin was selected as the transdermal skin to test the penetration of different formulations of tofacitinib in the skin. Specifically, the permeation cell is a vertical diffusion cell, the volume of the permeation cell is 6.5 cm, the area of the cell mouth is 2.2 cm ² , the acceptor solution is a PBS buffer solution (pH=7.4), and the skin is the back skin of an 8-month-old pig, and the hair is removed. Afterwards, skins with a thickness of 1400 μm were taken for experiments. Take about 0.2g of the cream and place it on the skin of Xiaoxiang pig. The sampling points are 1, 2, 4, and 6 hours. After 6 hours, the skin is removed and cut into pieces and extracted with organic solvent ultrasonic for 1 hour. After the sample is filtered, the content is determined by liquid chromatography. .

表6-1不同处方托法替尼乳膏在皮肤内渗透数据对比Table 6-1 Comparison of skin penetration data of different formulations of tofacitinib cream

表6-2不同处方托法替尼乳膏在皮肤内渗透数据对比Table 6-2 Comparison of skin penetration data of different formulations of tofacitinib cream

注：其中“皮肤内潴留量(μg/g)”由“皮肤内潴留量(μg/cm2)”转化而来，我们采用的小香猪皮其每平方厘米的皮肤为0.196g。Note: The "skin retention (μg/g)" is converted from the "skin retention (μg/cm2)", and the skin per square centimeter of the pig skin we use is 0.196g.

根据透皮实验数据，B1、B3、B13、B16、C1、C2、C3、C5处方在皮肤内潴留量明显高于枸橼酸托法替尼处方(B4)，说明在促渗剂二乙二醇单乙基醚的作用下，对酒石酸托法替尼透过皮肤有明显的促进作用。而与游离态托法替尼的处方E1相比，B1、B3、B13、C1、C3处方在扩散池内药物浓度很低(皮肤内潴留量/透过量比值为50倍以上，E1仅为1.5倍)，说明采用二乙二醇单乙基醚作为促渗剂时，离子态托法替尼过度吸收至循环***的风险显著降低，增加了药物使用过程中的安全性。同样的，相比于E1处方，硫酸托法替尼(处方D1)和磷酸托法替尼(处方D2)的皮肤内潴留量/透过量也大幅度提高，其安全性较E1也明显提高。According to the transdermal test data, the skin retention of B1, B3, B13, B16, C1, C2, C3, and C5 formulations was significantly higher than that of tofacitinib citrate formulation (B4), indicating that in the penetration enhancer diethylenediol Under the action of alcohol monoethyl ether, tofacitinib tartrate can significantly promote the penetration of tofacitinib through the skin. Compared with prescription E1 of free tofacitinib, prescriptions B1, B3, B13, C1, and C3 have very low drug concentrations in the diffusion cell (the ratio of retention/permeation in the skin is more than 50 times, and E1 is only 1.5 times). , indicating that when diethylene glycol monoethyl ether is used as a penetration enhancer, the risk of excessive absorption of ionic tofacitinib into the circulatory system is significantly reduced, which increases the safety of the drug during use. Similarly, compared with the E1 prescription, tofacitinib sulfate (formulation D1) and tofacitinib phosphate (formulation D2) have significantly improved skin retention/penetration, and their safety is also significantly improved compared to E1.

实施例6：酒石酸托法替尼的稳定性Example 6: Stability of tofacitinib tartrate

按照本发明实施例1(2)中的方法制得三批酒石酸托法替尼，分别放置于加速条件(温度：40℃，湿度：75％)、长期条件(温度：25℃，湿度：65％)，测定其稳定性。Three batches of tofacitinib tartrate were prepared according to the method in Example 1 (2) of the present invention, and were placed under accelerated conditions (temperature: 40° C., humidity: 75%) and long-term conditions (temperature: 25° C., humidity: 65° C.) %) to measure its stability.

表7-1酒石酸托法替尼稳定性-2020111901批Table 7-1 Tofacitinib Tartrate Stability - Batch 2020111901

表7-2酒石酸托法替尼稳定性-2020111902批Table 7-2 Stability of tofacitinib tartrate - batch 2020111902

表7-3酒石酸托法替尼稳定性-2020111903批Table 7-3 Stability of Tofacitinib Tartrate - Batch 2020111903

本发明所制得的托法替尼酒石酸盐，在加速条件下，1个月后平均降解0.5％，在长期条件下，1个月平均降解0.1％，说明其稳定性良好。The tofacitinib tartrate prepared by the invention has an average degradation of 0.5% after 1 month under accelerated conditions, and an average degradation of 0.1% in 1 month under long-term conditions, indicating that it has good stability.

实施例7：处方制作过程稳定性研究Example 7: Study on the stability of the recipe making process

根据表4溶解度数据，故制作样品(“游离态托法替尼聚乙二醇400溶液”、“酒石酸托法替尼二乙二醇单乙基醚溶液”、“硫酸托法替尼溶液”以及“磷酸托法替尼溶液”)配置：取原料药(托法替尼、酒石酸托法替尼)各0.2g，置于10ml容量瓶中，加入10ml对应的溶解介质(酒石酸托法替尼对应于二乙二醇单乙基醚、托法替尼对应于PEG400、磷酸托法替尼与硫酸托法替尼对应纯化水)，在60℃下加热溶解。在15min、30min、60min、120min取样约1.0ml，置于20ml容量瓶中，加稀释液(乙腈：水＝50：50(体积比))稀释至刻度，摇匀，进样测定纯度(测定方法：高校液相法(中国药典2015版四部通则0512)测定)。According to the solubility data in Table 4, the samples ("Tofacitinib polyethylene glycol 400 solution in free state", "Tofacitinib tartrate diethylene glycol monoethyl ether solution", "Tofacitinib sulfate solution" and "Tofacitinib phosphate solution") configuration: take 0.2 g of each of the raw materials (tofacitinib and tofacitinib tartrate), put them in a 10ml volumetric flask, and add 10ml of the corresponding dissolution medium (corresponding to tofacitinib tartrate) In diethylene glycol monoethyl ether, tofacitinib corresponds to PEG400, tofacitinib phosphate and tofacitinib sulfate correspond to purified water), heat and dissolve at 60°C. Sampling about 1.0ml at 15min, 30min, 60min and 120min, put it in a 20ml volumetric flask, add diluent (acetonitrile: water = 50:50 (volume ratio)) to dilute to the mark, shake well, inject the sample to determine the purity (measurement method : University liquid phase method (Chinese Pharmacopoeia 2015 Edition Four General Principles 0512) determination).

未破坏溶液(“磷酸托法替尼”、“硫酸托法替尼”、“游离态托法替尼”及“酒石酸托法替尼”)：精密称取磷酸托法替尼、硫酸托法替尼、游离态托法替尼与酒石酸盐托法替尼样品各约50mg，置50mL量瓶，加稀释剂(乙腈：水＝50：50)溶解并稀释至刻度，摇匀，作为供试品溶液，结果如下：Undestructed solution ("Tofacitinib phosphate", "Tofacitinib sulfate", "Tofacitinib free state" and "Tofacitinib tartrate"): Precisely weigh tofacitinib phosphate and tofacitinib sulfate 50mg each of the samples of Nitrate, free tofacitinib and tartrate tofacitinib, placed in a 50mL volumetric flask, add diluent (acetonitrile: water = 50:50) to dissolve and dilute to the mark, shake well, as the test solution , the result is as follows:

表8不同盐型托法替尼60℃稳定性Table 8 Stability of different salt forms of tofacitinib at 60°C

如表8所示，游离态托法替尼在制备过程中，极易降解，在60℃，2小时降解量大于6.0％。酒石酸托法替尼溶解在二乙二醇单乙基醚中、磷酸托法替尼、硫酸托法替尼溶解在水中，在60℃，均未发生明显降解，纯度在99％以上。故制备温度设定为60℃及以下温度，能保证各类盐型原料的稳定性。As shown in Table 8, free state tofacitinib was easily degraded during the preparation process, and the degradation amount was greater than 6.0% at 60° C. in 2 hours. Tofacitinib tartrate was dissolved in diethylene glycol monoethyl ether, and tofacitinib phosphate and tofacitinib sulfate were dissolved in water. At 60°C, no obvious degradation occurred, and the purity was above 99%. Therefore, the preparation temperature is set to 60°C and below, which can ensure the stability of various salt-type raw materials.

实施例8：酒石酸托法替尼外用制剂稳定性研究Example 8: Stability study of tofacitinib tartrate external preparation

选择CN 103459394 B专利文献中的实施例15数据作为对比例，比较本发明乳膏样品B3、B4、B5、B13、D1、D2、E2(参见实施例2)与对比例在40℃，75％条件下放置2周与4周后，处方纯度降低的百分比。Select the data of Example 15 in the CN 103459394 B patent document as a comparative example, and compare the cream samples B3, B4, B5, B13, D1, D2, E2 (see Example 2) of the present invention with the comparative example at 40 ° C, 75% Percentage reduction in formulation purity after 2 and 4 weeks of exposure.

表9 40℃条件存放30天处方稳定性研究Table 9 Stability study of formulations stored at 40°C for 30 days

本发明的托法替尼药学上可接受的盐稳定性明显高于游离态，在优选实施例中，托法替尼药学上可接受的盐所制得的处方在40℃条件放置1个月，稳定性高，未发生明显降解，纯度均在99.2％以上。相较之下，游离体托法替尼乳膏(处方B5)的纯度仅为95.4％，专利CN103459394B中的对比例也仅为97.3％。(参考CN103459394B实施例)。The stability of the pharmaceutically acceptable salt of tofacitinib of the present invention is significantly higher than that of the free state. In a preferred embodiment, the formulation prepared from the pharmaceutically acceptable salt of tofacitinib is placed at 40°C for 1 month, The stability is high, no obvious degradation occurs, and the purity is above 99.2%. In contrast, the purity of free body tofacitinib cream (formulation B5) is only 95.4%, and the comparative proportion in patent CN103459394B is only 97.3%. (refer to CN103459394B embodiment).

实施例9：酒石酸托法替尼乳膏放大批稳定性研究Example 9: Tofacitinib Tartrate Cream Scale-Up Stability Study

选择实施例5所制得的酒石酸托法替尼，依照C1处方，按照批量1kg，制得乳膏。取成品乳膏分别放置于长期条件(25℃，65％)，测定其稳定性。Tofacitinib tartrate prepared in Example 5 was selected, and the cream was prepared according to the C1 prescription and batch 1kg. The finished creams were taken and placed under long-term conditions (25° C., 65%) to measure their stability.

表10酒石酸托法替尼乳膏稳定性-C1批Table 10 Stability of Tofacitinib Tartrate Cream - Lot C1

实施例10：二硝基氟苯诱导的迟发型超敏反应模型Example 10: Dinitrofluorobenzene-induced delayed-type hypersensitivity model

1、15只6-8周雌性BALB/c小鼠，分为A、B、C三组，每组5只。其中A组为对照组，B组为给药组，C组为造模阳性组1. Fifteen 6-8 week old female BALB/c mice were divided into three groups, A, B and C, with 5 mice in each group. Among them, group A is the control group, group B is the administration group, and group C is the modeling positive group

2、对小鼠腹部剃毛，用胶带粘贴数次使致敏部位充分暴露。B组和C组在1cm×1cm范围内均匀涂布20μL 5g/L的DNFB(2,4二硝基氟苯)溶液(溶剂为体积比4:1的丙酮-橄榄油)10μL，每天一次，连续2天，A组只涂抹丙酮-橄榄油。其中B组从第一次DNFB致敏开始，每天进行局部酒石酸托法替尼乳膏(实施例2处方B3)干预。2. Shave the abdomen of the mouse and stick it with tape several times to fully expose the sensitized part. Groups B and C were uniformly coated with 20 μL of 5g/L DNFB (2,4-dinitrofluorobenzene) solution (solvent is acetone-olive oil with a volume ratio of 4:1) 10 μL within a range of 1 cm×1 cm, once a day, For 2 consecutive days, group A only applied acetone-olive oil. Among them, group B received topical tofacitinib tartrate cream (prescription B3 in Example 2) every day since the first DNFB sensitization.

3、所有组别在第二次致敏后5天，进行激发反应。即在所有组别小鼠左耳背面均匀涂抹10μL 2g/L的DNFB溶液。3. All groups were challenged 5 days after the second sensitization. That is, 10 μL of 2g/L DNFB solution was evenly applied to the back of the left ear of the mice in all groups.

4、24小时后，剪下双耳计算耳厚度差，如图1所示，结果表明给药组B组的耳厚度与C组(造模阳性组)相比，显著减少，可有效的抑制炎症。4. After 24 hours, cut off both ears to calculate the difference in ear thickness, as shown in Figure 1. The results show that the ear thickness of group B in administration group is significantly reduced compared with group C (positive model group), which can effectively inhibit the ear thickness. inflammation.

实施例11：家兔皮肤刺激性试验Example 11: Rabbit skin irritation test

取健康的新西兰兔4只，雌雄各半，采用同体左右侧自身对比，供试品给药侧(兔背部左侧皮肤)给予酒石酸托法替尼乳膏(处方B3)，对照品给药侧(兔背部右侧皮肤)给予空白辅料。首次给药前1天(D0)，剃除各组动物背部左、右侧拟贴敷区被毛。将供试品均匀涂敷于备皮拟给药区，每次涂敷0.5ml，用二层纱布和一层玻璃纸覆盖，再用无刺激性胶布固定贴敷4h。每天连续在同一部位给药，连续给药7天。每次贴敷前，以及去除供试品或对照品后1h观察皮肤反应，并进行评分。第7天(D7)去除供试品或对照品后1h、24h、48h和72h对贴敷部位进行观察、评分并拍照。统计评分记录为表11，72h结果拍照记录为图2。Four healthy New Zealand rabbits, half male and half male, were used to compare the left and right sides of the same body. (Rabbit right back skin) was given blank excipients. One day before the first administration (D0), the coats on the left and right sides of the backs of the animals in each group to be applied were shaved. Apply the test sample evenly on the skin preparation area to be administered, 0.5ml each time, cover it with two layers of gauze and a layer of cellophane, and then fix it with a non-irritating tape for 4 hours. The drug was administered at the same site every day for 7 consecutive days. The skin reaction was observed and scored before each application and 1 hour after the test or control product was removed. On the 7th day (D7), the application site was observed, scored and photographed at 1h, 24h, 48h and 72h after the test article or control substance was removed. The statistical scores are recorded in Table 11, and the results of 72 hours are photographed and recorded in Figure 2.

表11皮肤刺激反应评分总分差值均值Table 11 Mean difference of total score of skin irritation response score

注：表11中D1～7表示给药第1～7天。Note: D1 to 7 in Table 11 represent the first to seventh days of administration.

如表11所示，各观察点各给药侧积分均值为0，各观察点总分差值的均值为0，判断无刺激性。由图2可知，酒石酸托法替尼乳膏未对皮肤造成红肿、充血、渗出、变性或坏死等局部刺激反应。综上所述，酒石酸托法替尼乳膏对皮肤没有明显的刺激作用。As shown in Table 11, the mean value of each administration side integral of each observation point is 0, and the mean value of the total score difference of each observation point is 0, and it is judged that there is no irritation. It can be seen from Figure 2 that the tofacitinib tartrate cream did not cause local irritation such as redness, congestion, exudation, degeneration or necrosis to the skin. In conclusion, tofacitinib tartrate cream has no obvious irritating effect on the skin.

实施例12：酒石酸托法替尼局部配方治疗白癜风的临床试验Example 12: Clinical trial of topical formulation of tofacitinib tartrate in the treatment of vitiligo

开展了一项随机、双盲、安慰剂对照的临床试验以明确白癜风患者局部实施本发明所述的酒石酸托法替尼局部配方8周后的疗效。该试验招募了20名患者，随机分组后分别给与安慰剂(不含酒石酸托法替尼空白乳膏)与本发明的处方B3，用量约为3mg/cm ²，每日两次。所有患者在基线及每月一次进行临床改善评估，并拍照。 A randomized, double-blind, placebo-controlled clinical trial was conducted to determine the efficacy of topical tofacitinib tartrate formulations of the present invention for 8 weeks in vitiligo patients. The trial recruited 20 patients, and after randomization, they were respectively given a placebo (blank cream without tofacitinib tartrate) and the prescription B3 of the present invention at a dosage of about 3 mg/cm ² twice a day. All patients were assessed for clinical improvement at baseline and monthly and photographed.

图3显示了一女性患者A在脖颈处涂抹本发明乳膏4周、8周、12周的疗效，相较于基准，8周时白斑消失面积占原白斑面积的80％，12周时，白斑基本消失。Fig. 3 shows the curative effect of smearing the cream of the present invention at the neck of a female patient A for 4 weeks, 8 weeks and 12 weeks, compared with the benchmark, the vanished area of leukoplakia accounted for 80% of the original leukoplakia area at 8 weeks, and at 12 weeks, Vitiligo basically disappeared.

图4显示了一男性患者B在额部涂抹本发明乳膏，5个月后的疗效，相较于基准，白斑消失面积占原白斑面积的90％。Figure 4 shows the curative effect of a male patient B smearing the cream of the present invention on the forehead after 5 months. Compared with the benchmark, the vanishing area of leukoplakia accounts for 90% of the original leukoplakia area.

图5显示了一男性患者C在脸部下颚处涂抹本发明乳膏4周、8周后的疗效，相较于基准，8周后白斑完全消失。Figure 5 shows the curative effect of a male patient C smearing the cream of the present invention on the lower jaw of the face for 4 weeks and 8 weeks. Compared with the benchmark, the leukoplakia completely disappeared after 8 weeks.

综上所述，说明本申请的处方能够有效治疗白癜风患者。To sum up, it shows that the prescription of the present application can effectively treat vitiligo patients.

实施例13：酒石酸托法替尼局部配方治疗特应性皮炎的临床试验Example 13: Clinical trial of topical formulation of tofacitinib tartrate in the treatment of atopic dermatitis

开展了一项临床试验以明确特应性皮炎患者局部实施本发明所述的酒石酸托法替尼局部配方的疗效。该试验招募了6名患者，给与本发明的处方B3，用量约为3mg/cm ²，每日两次。所有患者在基线及每2周一次进行临床改善评估。 A clinical trial was conducted to determine the efficacy of topical tofacitinib tartrate formulations of the present invention in patients with atopic dermatitis. The trial recruited 6 patients and was given prescription B3 of the present invention at a dose of about 3 mg/cm ² twice daily. All patients were assessed for clinical improvement at baseline and every 2 weeks.

图6显示了一男性特应性皮炎患者D，全身皮疹伴瘙痒有皮损，病程3个多月，逐渐加重。在涂抹本发明所述的酒石酸托法替尼局部配方乳膏2周后，皮损褪去，全面开始结痂，痊愈。Figure 6 shows a male patient with atopic dermatitis, D, with a systemic rash with itching and skin lesions. The disease course lasted for more than 3 months and gradually worsened. After smearing the tofacitinib tartrate topical formula cream of the present invention for 2 weeks, the skin lesions faded, scabs began to form in an all-round way, and recovered.

Claims

一种药物组合物，其特征在于，包括托法替尼药学上可接受的盐和一种或多种促渗剂，所述促渗剂包含二乙二醇单乙基醚、聚甘油脂肪酸酯、月桂氮酮、油酸、油醇、聚乙二醇中的一种或多种；所述药物组合物中不含二甲基亚砜。A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable salt of tofacitinib and one or more penetration enhancers, the penetration enhancers comprising diethylene glycol monoethyl ether, polyglycerol fatty acid ester, azone, oleic acid, oleyl alcohol, polyethylene glycol, one or more; the pharmaceutical composition does not contain dimethyl sulfoxide.
根据权利要求1所述的药物组合物，其特征在于，所述托法替尼药学上可接受的盐选自酒石酸托法替尼、硫酸托法替尼、磷酸托法替尼中的一种或多种。The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of tofacitinib is selected from the group consisting of tofacitinib tartrate, tofacitinib sulfate, and tofacitinib phosphate or more.
根据权利要求1所述的药物组合物，其特征在于，所述托法替尼药学上可接受的盐为酒石酸托法替尼。The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of tofacitinib is tofacitinib tartrate.
根据权利要求1所述的药物组合物，其特征在于，所述促渗剂为二乙二醇单乙基醚；或者，所述促渗剂为二乙二醇单乙基醚与聚甘油脂肪酸酯、月桂氮酮、油酸、油醇、聚乙二醇一种或多种的组合；药物组合物中，所述促渗剂的重量百分比含量低于40％。The pharmaceutical composition according to claim 1, wherein the penetration enhancer is diethylene glycol monoethyl ether; or the penetration enhancer is diethylene glycol monoethyl ether and polyglycerol fat A combination of one or more of acid ester, lauroazone, oleic acid, oleyl alcohol, and polyethylene glycol; in the pharmaceutical composition, the content of the penetration enhancer is less than 40% by weight.
根据权利要求1所述的药物组合物，其特征在于，在所述药物组合物中，所述托法替尼药学上可接受的盐的重量百分比含量为0.1％～10％；所述促渗剂的重量百分比含量为1％～35％。The pharmaceutical composition according to claim 1, wherein, in the pharmaceutical composition, the weight percentage of the pharmaceutically acceptable salt of tofacitinib is 0.1% to 10%; The weight percent content of the agent is 1% to 35%.
根据权利要求1所述的药物组合物，其特征在于，在所述药物组合物中，所述托法替尼药学上可接受的盐的重量百分比含量为0.5％～5％；所述促渗剂的重量百分比含量为5％～30％。The pharmaceutical composition according to claim 1, wherein, in the pharmaceutical composition, the weight percentage of the pharmaceutically acceptable salt of tofacitinib is 0.5% to 5%; The weight percent content of the agent is 5% to 30%.
根据权利要求1所述的药物组合物，其特征在于，按照重量百分比计，包括，0.5％～5％的酒石酸托法替尼和5％～20％的二乙二醇单乙基醚。The pharmaceutical composition according to claim 1, characterized in that, by weight percentage, it comprises 0.5% to 5% of tofacitinib tartrate and 5% to 20% of diethylene glycol monoethyl ether.
根据权利要求1-7任一项所述的药物组合物，其特征在于，还包括赋形剂，所述赋形剂包括溶剂、稀释剂、抗氧化剂、螯合剂、乳化剂、防腐剂、抗菌剂、遮光剂、着色剂、凝胶剂、调味剂、pH调节剂以及其他适用的油性物质、水性物质中的一种或多种。The pharmaceutical composition according to any one of claims 1-7, further comprising excipients including solvents, diluents, antioxidants, chelating agents, emulsifiers, preservatives, antibacterial agents One or more of oily substances, opacifiers, colorants, gelling agents, flavoring agents, pH adjusters, and other suitable oily and aqueous substances.
根据权利要求8所述的药物组合物，其特征在于，在所述药物组合物中，所述赋形剂的重量百分比含量为70％～98.5％；所述赋形剂至少包括防腐剂和乳化剂。The pharmaceutical composition according to claim 8, characterized in that, in the pharmaceutical composition, the weight percentage of the excipients is 70% to 98.5%; the excipients at least include preservatives and emulsifying agents agent.
根据权利要求8所述的药物组合物，其特征在于，所述抗氧化剂选自2,6-二叔丁基-4-甲基苯酚、丁基羟基茴香醚、2,6-二叔丁基对甲基苯酚、抗坏血酸、抗坏血酸衍生物、多酚、生育酚、生育酚衍生物、维生素A、叶黄素、番茄红素、次亚硫酸氢钠、硫代硫酸钠、没食子酸丙酯、硫辛酸、亚硫酸盐中的一种或多种。The pharmaceutical composition according to claim 8, wherein the antioxidant is selected from the group consisting of 2,6-di-tert-butyl-4-methylphenol, butylated hydroxyanisole, 2,6-di-tert-butyl p-Cresol, Ascorbic Acid, Ascorbic Acid Derivatives, Polyphenols, Tocopherols, Tocopherol Derivatives, Vitamin A, Lutein, Lycopene, Sodium Sulfoxylate, Sodium Thiosulfate, Propyl Gallate, Sulfur One or more of octanoic acid and sulfite.
根据权利要求8所述的药物组合物，其特征在于，在所述药物组合物中，抗氧化剂重量百分比含量为0.05％至5％。The pharmaceutical composition according to claim 8, characterized in that, in the pharmaceutical composition, the weight percent content of antioxidants is 0.05% to 5%.
根据权利要求8所述的药物组合物，其特征在于，所述防腐剂的重量百分比含量为0.1～5％；所述乳化剂的重量百分比含量为0.5～20％。The pharmaceutical composition according to claim 8, wherein the weight percentage of the preservative is 0.1-5%; the weight percentage of the emulsifier is 0.5-20%.
根据权利要求1所述的药物组合物，其特征在于，按照重量百分比计，包括：The pharmaceutical composition according to claim 1, characterized in that, by weight percentage, comprising:

余量为其他促渗剂或/和赋形剂。The balance is other penetration enhancers or/and excipients.
根据权利要求1所述的药物组合物，其特征在于，按照重量百分比计，包括：The pharmaceutical composition according to claim 1, characterized in that, by weight percentage, comprising:

且上述各组分重量比分比之和为100％。And the sum of the weight ratios of the above components is 100%.
一种制剂，其特征在于，由权利要求1～14任一项所述的组合物制备得到。A preparation is characterized in that, it is prepared from the composition described in any one of claims 1-14.
根据权利要求15所述的制剂，其特征在于，为乳膏剂、溶液剂、悬浮液剂、油膏剂、洗剂、糊剂、硬膏剂、涂剂或凝胶剂。The preparation of claim 15, which is a cream, solution, suspension, ointment, lotion, paste, plaster, paint or gel.
根据权利要求15或16所述的制剂，其特征在于，为局部制剂。The preparation according to claim 15 or 16, which is a topical preparation.
一种权利要求1～17任一项所述的组合物或制剂在制备治疗和/或预防自身免疫性疾病药物中的应用。A use of the composition or preparation according to any one of claims 1 to 17 in the preparation of a medicine for treating and/or preventing autoimmune diseases.
如权利要求18所述的应用，其特征在于，所述自身免疫性疾病包括白癜风、斑秃、特应性皮炎、类风湿关节炎、***性红斑狼疮、多发性硬化、炎性肠炎、克罗恩氏病、结肠炎、自身免疫性溶血性贫血、强直性脊柱炎、天疱疮、荨麻疹、哮喘、视神经炎、银屑病、慢性阻塞性气道疾病、皮炎症、硬皮症。The use according to claim 18, wherein the autoimmune diseases include vitiligo, alopecia areata, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, Crohn's Colitis, autoimmune hemolytic anemia, ankylosing spondylitis, pemphigus, urticaria, asthma, optic neuritis, psoriasis, chronic obstructive airway disease, dermatitis, scleroderma.
如权利要求19所述的应用，其特征在于，所述自身免疫性疾病为白癜风、斑秃、特应性皮炎、银屑病、皮炎症、硬皮症。The use according to claim 19, wherein the autoimmune disease is vitiligo, alopecia areata, atopic dermatitis, psoriasis, skin inflammation, and scleroderma.