Combined drug, and pharmaceutical composition and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a combined drug, and a pharmaceutical composition and a preparation method therefor and a use thereof. The present invention provides the combined drug. Active ingredients of the combined drug comprise an active ingredient A and an active ingredient B, wherein the active ingredient A is a compound as represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, and the active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The combined drug and the pharmaceutical composition of the present invention have good permeability, stability and safety, have a good therapeutic effect on alopecia areata, and are suitable for topical administration.

Description

Combination medicine, pharmaceutical composition, preparation method and use thereof

[0001] This application claims priority to Chinese Patent Application No. 2023109236146, filed on July 25, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention belongs to the field of medical technology, and specifically relates to a combination drug, a pharmaceutical composition, a preparation method and use thereof. Background Art

[0003] Alopecia areata (AA) is a common, inflammatory, non-scarring hair loss. Clinically, it manifests as the sudden onset of well-defined, circular patches of hair loss on the scalp. While most mild cases resolve spontaneously, about half experience recurrent episodes, which can persist for years or even decades. A small number of patients experience severe disease, with hair loss affecting the entire scalp and even all the hair on the body. The disease can occur at any age, but is more common in young and middle-aged individuals, with no significant gender differences. Epidemiological studies have shown a 0.27% prevalence of AA in my country, while international studies have shown a lifetime prevalence of approximately 2%. The disease affects aesthetics and can negatively impact patients' mental health and quality of life.

[0004] Studies have found that due to genetic or external stimuli, the NKG2D protein is highly expressed in the hair follicle cells of patients with alopecia areata, causing CD4, CD8 T cells, NK cells, etc. to attack the hair follicles. The IL-15 secreted by the hair follicles activates T cells by binding to JAK1 and JAK3, thereby leading to an increase in IFN-γ secretion. After binding to the IFN-γ receptor on the hair follicle cells, it can activate more IL-15 secretion, forming a continuous stimulation loop, and T cells are also constantly proliferating. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases transmit intracellular signals through the JAK / STAT signaling pathway. Currently, JAK inhibitors have become one of the popular candidate drugs for the treatment of AA. The compound shown in Formula I (2-[1-(ethylsulfonyl)-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]thieno[3,2-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile) (the compound is further described in patents CN103936757A and WO2014111037A) is a JAK inhibitor that has inhibitory effects on JAK1, JAK2 and JAK3.

[0005] Minoxidil directly stimulates the proliferation and differentiation of hair follicle epithelial cells; promotes angiogenesis, increasing local blood flow; opens potassium ion channels; and shifts hair follicles from the resting phase to the anagen phase. It is suitable for patients with stable AA and those with relatively small areas of hair loss. Long-term medication is required to maintain efficacy, and it is often used in combination with other treatments. It should not be used alone in patients with progressive AA. It has minimal effect in patients with moderate to severe hair loss. Topical minoxidil concentrations are typically 2% and 5%, and are dose-dependent. 5% may be more effective, but adverse reactions are more common, primarily local irritation and hirsutism.

[0006] Currently, the minoxidil formulations approved for the treatment of hair loss and alopecia areata are all topical preparations. Meanwhile, the JAK inhibitors approved for marketing are all oral preparations, which are systemic and can cause significant side effects.

[0007] Summary of the Invention

[0008] The present invention aims to overcome the limited availability of JAK inhibitors for treating alopecia areata in the prior art by providing a combination drug, a pharmaceutical composition, and methods for preparing and using the combination drug. The combination drug and pharmaceutical composition of the present invention exhibit excellent permeability, stability, and safety, exhibit a good therapeutic effect for treating alopecia areata, and are suitable for topical application.

[0009] The present invention provides a combination drug, the active ingredients of which include active ingredient A and active ingredient B;

[0010] Wherein, the active ingredient A is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0011] The active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0012] In one embodiment of the present invention, the active ingredient consists of the active ingredient A and the active ingredient B.

[0013] In one embodiment of the present invention, the mass ratio of the active ingredient A to the active ingredient B may be 1:100 to 100:1, preferably 1:10 to 10:1, for example, 1:2, 1:1.7, 1:1.3, 1:1.1 or 1:1.

[0014] In one embodiment of the present invention, the dosage form of the combination drug can be a paste, a paint, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0015] In a certain embodiment of the present invention, the combination drug is a combination drug for preventing, alleviating or treating alopecia areata.

[0016] In one embodiment of the present invention, the active ingredient A and the active ingredient B can be administered simultaneously or separately.

[0017] The “simultaneous administration” means that the active ingredient A and the active ingredient B are contained in separate pharmaceutical compositions and administered simultaneously; or, alternatively, “a separate pharmaceutical composition comprising the active ingredient A” and a “separate pharmaceutical composition comprising the active ingredient B” are administered simultaneously.

[0018] The term "separate administration" means that the "separate pharmaceutical composition comprising the active ingredient A" and the "separate pharmaceutical composition comprising the active ingredient B" are administered separately at different times. For example, one of the "separate pharmaceutical composition comprising the active ingredient A" and the "separate pharmaceutical composition comprising the active ingredient B" is administered first, and the other is administered subsequently. The separate administration may be close in time or remote in time.

[0019] The present invention provides a pharmaceutical composition A, which comprises a first pharmaceutical composition and a second pharmaceutical composition;

[0020] Wherein, the first pharmaceutical composition comprises active ingredient A and a pharmaceutically acceptable carrier, wherein the active ingredient A is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0021] The second pharmaceutical composition comprises an active ingredient B and a pharmaceutically acceptable carrier, wherein the active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0022] In one embodiment of the present invention, the pharmaceutical composition A consists of the first pharmaceutical composition and the second pharmaceutical composition.

[0023] In one embodiment of the present invention, the first pharmaceutical composition consists of the active ingredient A and the pharmaceutically acceptable carrier.

[0024] In one embodiment of the present invention, the second pharmaceutical composition consists of the active ingredient B and the pharmaceutically acceptable carrier.

[0025] In one embodiment of the present invention, the mass ratio of the active ingredient A to the active ingredient B may be 1:100 to 100:1, preferably 1:10 to 10:1, for example, 1:2, 1:1.7, 1:1.3, 1:1.1 or 1:1.

[0026] In one embodiment of the present invention, the dosage form of the first pharmaceutical composition can be a paste, a paint, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0027] In one embodiment of the present invention, the dosage form of the second pharmaceutical composition can be a paste, a paint, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0028] In one embodiment of the present invention, the dosage form of the pharmaceutical composition A can be a paste, a paint, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0029] In one embodiment of the present invention, the pharmaceutical composition A is a pharmaceutical composition for preventing, alleviating or treating alopecia areata.

[0030] In a certain embodiment of the present invention, the first pharmaceutical composition and the second pharmaceutical composition can be administered simultaneously or separately.

[0031] The present invention provides a combination kit comprising:

[0032] a first container comprising a first pharmaceutical composition as described above; and

[0033] A second container comprises a second pharmaceutical composition as described above.

[0034] The present invention provides a pharmaceutical composition B, which comprises an active ingredient and a pharmaceutically acceptable carrier;

[0035] Wherein, the active ingredients include active ingredient A and active ingredient B;

[0036] The active ingredient A is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0037] The active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0038] In one embodiment of the present invention, the pharmaceutical composition B is a pharmaceutical composition for preventing, alleviating or treating alopecia areata.

[0039] In one embodiment of the present invention, the active ingredient consists of the active ingredient A and the active ingredient B.

[0040] In one embodiment of the present invention, the mass percentage of the active ingredient in pharmaceutical composition B is 0.2% to 20%, preferably 1% to 10%, for example 3%, 3.2%, 3.5%, 3.8% or 4%.

[0041] In one embodiment of the present invention, the mass ratio of the active ingredient A to the active ingredient B may be 1:100 to 100:1, preferably 1:10 to 10:1, for example, 1:2, 1:1.7, 1:1.3, 1:1.1 or 1:1.

[0042] In one embodiment of the present invention, the mass percentage of the active ingredient A in the pharmaceutical composition B is 0.1% to 10%, preferably 0.5% to 5%, for example, 1%, 1.2%, 1.5%, 1.8% or 2%.

[0043] In one embodiment of the present invention, the mass percentage of the active ingredient B in the pharmaceutical composition B is 0.1% to 10%, preferably 0.5% to 5%, for example 2%.

[0044] In one embodiment of the present invention, the pharmaceutically acceptable carrier comprises a solvent.

[0045] In one embodiment of the present invention, the pharmaceutically acceptable carrier comprises a transdermal enhancer.

[0046] In one embodiment of the present invention, the pharmaceutically acceptable carrier may be a solvent and a transdermal enhancer.

[0047] In one embodiment of the present invention, the solvent is selected from one or more of water, a sulfoxide solvent, and an alcohol solvent; preferably, a mixed solvent of a sulfoxide solvent and an alcohol solvent. The sulfoxide solvent is preferably dimethyl sulfoxide. The alcohol solvent is preferably selected from one or more of propylene glycol, ethanol, glycerol, and polyethylene glycol 400, more preferably one or more of propylene glycol, ethanol, and polyethylene glycol 400, and even more preferably propylene glycol and / or polyethylene glycol 400.

[0048] In one embodiment of the present invention, the solvent is selected from one or more of water, dimethyl sulfoxide, propylene glycol, ethanol, glycerol and polyethylene glycol 400, preferably selected from one or more of dimethyl sulfoxide, polyethylene glycol 400, propylene glycol and ethanol, more preferably selected from a mixed solvent of dimethyl sulfoxide, propylene glycol and polyethylene glycol 400, or a mixed solvent of dimethyl sulfoxide and propylene glycol.

[0049] In one embodiment of the present invention, the solvent at least includes a sulfoxide solvent, preferably dimethyl sulfoxide.

[0050] In one embodiment of the present invention, the mass percentage of the solvent in pharmaceutical composition B is 20% to 50%, preferably 30% to 50%, for example, 27%, 28%, 32%, 33%, 37%, 37.2%, 37.5%, 37.8%, 38%, 42%, 43% or 48%.

[0051] In one embodiment of the present invention, when the solvent is a mixed solvent of an alcohol solvent and a sulfoxide solvent, and the alcohol solvent is propylene glycol, the mass ratio of the propylene glycol to the sulfoxide solvent is 3:1 to 9:1; preferably 4:1 to 8:1, for example, 4.6:1, 5.6:1, 6.6:1 or 7.6:1.

[0052] In one embodiment of the present invention, when the solvent is a mixed solvent of a sulfoxide solvent and an alcohol solvent, and the alcohol solvent is propylene glycol and polyethylene glycol 400, the mass ratio of the propylene glycol to the sulfoxide solvent is 10:1 to 1:1, preferably 7:1 to 4:1, for example, 6.4:1 or 5.4:1; the mass ratio of the polyethylene glycol 400 to the sulfoxide solvent is 0.5:1 to 5:1, preferably 1:1 to 3:1, for example, 1:1 or 2:1.

[0053] In one embodiment of the present invention, the transdermal enhancer is selected from one or more of ester agents, surfactants, ether agents, bile salt agents, alcohol agents, terpenoid agents, sulfoxide agents and cyclodextrin agents. The ether agent is preferably selected from one or more of diethylene glycol monoethyl ether, polyoxyethylene lauryl ether and polyethylene glycol cetyl ether. The bile salt agent is preferably selected from deoxycholate and / or glycocholate. The ester agent is preferably selected from one or more of propylene glycol monolaurate, caprylic and capric mono- and diglycerides, monocaprylic glyceryl, ethyl oleate, isopropyl myristate, caprylic and capric macrogol glycerides, propylene glycol monocaprylate, polyglycerol oleate, vitamin E succinate polyethylene glycol ester and soybean lecithin. The surfactant is preferably selected from one or more of Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, sodium lauryl sulfate, polyoxyethylene (35) castor oil, and polyoxyethylene 40 hydrogenated castor oil. The alcohol reagent is preferably selected from fatty alcohol reagents and polyol reagents; the fatty alcohol reagent is preferably selected from one or more of ethanol, oleyl alcohol, and octyl lauryl alcohol; the polyol reagent is preferably selected from propylene glycol. The terpene reagent is preferably selected from menthol. The sulfoxide reagent is preferably selected from dimethyl sulfoxide. The cyclodextrin reagent is preferably selected from hydroxypropyl-β-cyclodextrin.

[0054] In one embodiment of the present invention, the transdermal enhancer is selected from one or more of diethylene glycol monoethyl ether, hydroxypropyl-β-cyclodextrin, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, propylene glycol monolaurate, caprylic and capric mono- and diglycerides, monocaprylic glyceride, ethyl oleate, isopropyl myristate, caprylic and capric macrogol glycerides, propylene glycol monocaprylate, sodium lauryl sulfate, polyoxyethylene lauryl ether, polyethylene glycol cetyl ether, menthol, polyglycerol oleate, polyoxyethylene (35) castor oil, oleyl alcohol, octyl lauryl alcohol, polyoxyethylene 40 hydrogenated castor oil, vitamin E succinate macrogol ester and soybean lecithin.

[0055] In a certain embodiment of the present invention, the transdermal enhancer is preferably selected from one or more of diethylene glycol monoethyl ether, hydroxypropyl-β-cyclodextrin, Tween 80, propylene glycol monolaurate, caprylic acid capric acid mono- and diglycerides, monocaprylic glyceride, ethyl oleate, caprylic acid capric acid polyethylene glycol glyceride and propylene glycol monocaprylate, for example, a mixed transdermal enhancer of diethylene glycol monoethyl ether and hydroxypropyl-β-cyclodextrin; a mixed transdermal enhancer of diethylene glycol monoethyl ether, Tween 80 and propylene glycol monolaurate; a mixed transdermal enhancer of diethylene glycol monoethyl ether and caprylic acid capric acid mono- and diglycerides; a mixed transdermal enhancer of diethylene glycol monoethyl ether and caprylic acid capric acid polyethylene glycol glyceride; a mixed transdermal enhancer of diethylene glycol monoethyl ether, Tween 80 and monocaprylic glyceride. The present invention relates to a skin-penetrating enhancer; a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether and monocaprylic glyceryl; a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether and ethyl oleate; a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether and propylene glycol monolaurate; a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether, caprylic-capric mono- and diglyceryl and caprylic-capric polyethylene glycol glyceryl; a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether and propylene glycol monocaprylate; a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether, monocaprylic- and diglyceryl and caprylic-capric polyethylene glycol glyceryl; a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether, caprylic-capric mono- and diglyceryl and monocaprylic glyceryl; or a mixed skin-penetrating enhancer of diethylene glycol monoethyl ether, monocaprylic- and propylene glycol monocaprylate.

[0056] In one embodiment of the present invention, the transdermal enhancer is more preferably a mixed transdermal enhancer of diethylene glycol monoethyl ether and propylene glycol monocaprylate or a mixed transdermal enhancer of diethylene glycol monoethyl ether, monocaprylin and propylene glycol monocaprylate.

[0057] In one embodiment of the present invention, the mass percentage of the transdermal enhancer in pharmaceutical composition B is 40% to 80%, preferably 50% to 70%, for example 49%, 54%, 59%, 64% or 69%.

[0058] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal enhancer of diethylene glycol monoethyl ether and hydroxypropyl-β-cyclodextrin, the mass ratio of diethylene glycol monoethyl ether to hydroxypropyl-β-cyclodextrin is 2:1 to 4:1, for example, 3.27:1.

[0059] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, Tween 80, and propylene glycol monolaurate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monolaurate is 8:1 to 10:1, for example, 9.8:1. The mass ratio of Tween 80 to propylene glycol monolaurate is 2:1 to 4:1, for example, 3:1.

[0060] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and caprylic acid capric acid mono- and diglycerides, the mass ratio of diethylene glycol monoethyl ether to caprylic acid capric acid mono- and diglycerides is 4:1 to 10:1, for example, 4.9:1 or 9.8:1.

[0061] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal enhancer of diethylene glycol monoethyl ether and caprylic acid capric acid macrogol glyceride, the mass ratio of diethylene glycol monoethyl ether and caprylic acid capric acid macrogol glyceride is 8:1 to 10:1, for example, 9.8:1.

[0062] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, Tween 80, and monocaprylin, the mass ratio of diethylene glycol monoethyl ether to monocaprylin is 8:1 to 10:1, for example, 9.8:1. The mass ratio of Tween 80 to monocaprylin is 0.5:1 to 2:1, for example, 1:1.

[0063] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and monocaprylin, the mass ratio of diethylene glycol monoethyl ether to monocaprylin is 4:1 to 10:1, for example, 4.9:1 or 9.8:1.

[0064] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and ethyl oleate, the mass ratio of diethylene glycol monoethyl ether to ethyl oleate is 8:1 to 10:1, for example, 9.8:1.

[0065] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal enhancer of diethylene glycol monoethyl ether and propylene glycol monolaurate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monolaurate is 8:1 to 10:1, for example, 9.8:1.

[0066] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, caprylic capric mono- and diglycerides, and caprylic capric macrogol glyceride, the mass ratio of diethylene glycol monoethyl ether to caprylic capric macrogol glyceride is 8:1 to 10:1, for example, 9.8:1. The mass ratio of caprylic capric mono- and diglycerides to caprylic capric macrogol glyceride is 0.5:1 to 2:1, for example, 1:1.

[0067] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal enhancer of diethylene glycol monoethyl ether and propylene glycol monocaprylate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monocaprylate is 3:1 to 6:1, for example, 4.9:1.

[0068] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, monocaprylin and caprylic capric macrogol glyceride, the mass ratio of diethylene glycol monoethyl ether to caprylic capric macrogol glyceride is 8:1 to 10:1, for example, 9.8:1. The mass ratio of monocaprylin to caprylic capric macrogol glyceride is 0.5:1 to 2:1, for example, 1:1.

[0069] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, caprylic and capric mono- and diglycerides, and monocaprylic glyceryl, the mass ratio of diethylene glycol monoethyl ether to monocaprylic glyceryl is 8:1 to 10:1, for example, 9.8:1. The mass ratio of caprylic and capric mono- and diglycerides to monocaprylic glyceryl is 0.5:1 to 2:1, for example, 1:1.

[0070] In one embodiment of the present invention, when the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, monocaprylin, and propylene glycol monocaprylate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monocaprylate is 8:1 to 10:1, for example, 9.8:1. The mass ratio of monocaprylin to propylene glycol monocaprylate is 0.5:1 to 2:1, for example, 1:1.

[0071] In one embodiment of the present invention, the pharmaceutical composition B consists of the active ingredient A, the active ingredient B, the solvent and the transdermal enhancer.

[0072] In one embodiment of the present invention, the pharmaceutical composition B is preferably composed of the components shown in any of the following schemes:

[0073] Scheme 1: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 28% of propylene glycol, 5% of dimethyl sulfoxide and 15% of hydroxypropyl-β-cyclodextrin;

[0074] Scheme 2: 1% of the compound of formula I, 2% minoxidil, 49% diethylene glycol monoethyl ether, 23% propylene glycol, 5% dimethyl sulfoxide, 15% Tween 80 and 5% propylene glycol monolaurate;

[0075] Scheme 3: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of caprylic and capric mono- and diglycerides;

[0076] Scheme 4: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of caprylic / capric macrogol glyceride;

[0077] Scheme 5: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of Tween 80 and 5% of monocaprylin;

[0078] Scheme 6: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of monocaprylin;

[0079] Scheme 7: 1% of the compound represented by formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of ethyl oleate;

[0080] Scheme 8: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of propylene glycol monolaurate;

[0081] Scheme 9: 1% of the compound represented by formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide and 10% of caprylic and capric mono- and diglycerides;

[0082] Scheme 10: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of caprylic and capric mono- and diglycerides, and 5% caprylic and capric macrogol glycerides;

[0083] Scheme 11: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide and 10% of propylene glycol monocaprylate;

[0084] Scheme 12: 1% of the compound represented by formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide and 10% of monocaprylin;

[0085] Scheme 13: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of monocaprylin and 5% of caprylic / capric macrogol glyceride;

[0086] Scheme 14: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of caprylic and capric monoglycerides, and 5% of caprylic glyceride;

[0087] Scheme 15: 1% of the compound represented by formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of monocaprylin and 5% of propylene glycol monocaprylate.

[0088] The above percentages are all by mass.

[0089] In one embodiment of the present invention, the pharmaceutical composition B is preferably composed of 1% of the compound of Formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 0-5% of monocaprylin, and 5-10% of propylene glycol monocaprylate. (The above percentages are by mass).

[0090] In a certain embodiment of the present invention, the pharmaceutical composition B is more preferably Scheme 11 and Scheme 15.

[0091] In one embodiment of the present invention, the dosage form of the pharmaceutical composition B can be a paste, a paint, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0092] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition B, which comprises the following steps: mixing the active ingredient A, the active ingredient B and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a solvent and a transdermal enhancer.

[0093] In one embodiment of the present invention, when the solvent includes a sulfoxide solvent, the preparation method of the pharmaceutical composition B preferably includes the following steps:

[0094] (1) mixing the active ingredient A, the active ingredient B and the sulfoxide solvent to obtain a mixed solution 1;

[0095] (2) Mixing the mixed solution 1 of step (1) with the other solvent and the transdermal enhancer to obtain the pharmaceutical composition B. Preferably, the active ingredient A is preferably a compound represented by formula I, and / or the active ingredient B is preferably minoxidil.

[0096] In one embodiment of the present invention, in step (2), the mixing may be adding the other solvent and the transdermal enhancer to the mixed solution 1 of step (1).

[0097] In one embodiment of the present invention, in step (2), the mixing can be carried out by stirring to achieve uniform mixing.

[0098] The present invention also provides a use of a compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, the above-mentioned combined drug, the above-mentioned pharmaceutical composition A, the above-mentioned pharmaceutical composition B, or the above-mentioned combined kit in preparing a drug for preventing, alleviating, or treating alopecia areata, wherein the use is not the use of pharmaceutical composition C in preparing a drug for preventing, alleviating, or treating alopecia areata, and the pharmaceutical composition C comprises the following components by mass: 0.1%-3% of a compound of formula I or a pharmaceutically acceptable salt thereof, 35%-93% of a solvent, and 5%-63% of a transdermal enhancer; the solvent is selected from water, glycerol, polyethylene glycol, One or more of alcohol 400, dimethyl sulfoxide, ethyl acetate, propylene glycol and ethanol; the transdermal enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, urea, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea, propyl gallate, isopropyl myristate, cyclodextrin, sodium lauryl sulfate, polyoxyethylene lauryl ether, polyethylene glycol cetyl ether, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, monocaprylic glyceryl, caprylic acid mono- and diglyceryl, propylene glycol monolaurate, propylene glycol monocaprylate and behenic acid glyceryl,

[0099] The present invention also provides a method for treating alopecia areata, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound of formula I as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, a combination drug as described above, a pharmaceutical composition A as described above, a pharmaceutical composition B as described above, or a combination kit as described above, wherein the method does not administer to a subject (e.g., a human) in need thereof a therapeutically effective amount of a pharmaceutical composition C, wherein the pharmaceutical composition C comprises the following components by mass: 0.1%-3% of a compound of formula I or a pharmaceutically acceptable salt thereof, 35%-93% of a solvent, and 5%-63% of a transdermal enhancer; the solvent The transdermal enhancer is selected from one or more of water, glycerol, polyethylene glycol 400, dimethyl sulfoxide, ethyl acetate, propylene glycol and ethanol; the transdermal enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, urea, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea, propyl gallate, isopropyl myristate, cyclodextrin, sodium lauryl sulfate, polyoxyethylene lauryl ether, polyethylene glycol cetyl ether, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, monocaprylic glyceryl, caprylic acid mono- and diglyceryl, propylene glycol monolaurate, propylene glycol monocaprylate and behenic acid glyceryl,

[0100] In addition to the foregoing, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the following meanings:

[0101] The term "pharmaceutically acceptable salt" refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.

[0102] The term "solvate" refers to a substance formed by crystallization of a compound with a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0103] The term "pharmaceutically acceptable salt solvate" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, and a solvent (including but not limited to water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric.

[0104] The term "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, in addition to the active ingredient. For more information, see the Pharmacopoeia of the People's Republic of China (2015 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0105] The term "transdermal enhancer," also known as a "transdermal absorption enhancer," refers to a material that penetrates the skin and reduces the resistance of drugs to passage through the skin. This material helps the drug penetrate the stratum corneum, diffuse through the skin, and enter the systemic circulation through the capillaries. Transdermal enhancers should meet the following requirements: ① They should have no pharmacological effects on the skin and body, and be non-toxic, non-irritating, or non-allergic; ② They should work immediately after application and restore the skin's normal barrier function after removal; ③ They should not cause loss of nutrients and water through the skin; and ④ They should not interact physically or chemically with the drug or other excipients.

[0106] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0107] The reagents and raw materials used in the present invention are commercially available.

[0108] The positive progress of the present invention is that the combined drug and pharmaceutical composition of the present invention have better permeability, stability and safety, have a better therapeutic effect on treating alopecia areata, and are suitable for topical external use. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] FIG1 is a curve diagram showing the changes in hair growth scores of mice in each group. DETAILED DESCRIPTION

[0110] The present invention is further illustrated by way of examples below, but the present invention 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.

[0111] Diethylene glycol monoethyl ether (Transcutol P); Hydroxypropyl-β-cyclodextrin (HP-β-CD); Propylene glycol monolaurate (Lauroglycol FCC); Caprylic and capric mono- and diglycerides (Capmul MCM); Caprylic and capric glycerides (Capmul MCM-C8); Caprylic and capric macrogol glycerides (Labrasol); Propylene glycol monocaprylate (Capmul PG-8); Polyoxyethylene (35) castor oil (Kolliphor ELP); Oleyl alcohol (Kollicream OA); Octyl lauryl alcohol (Kollicream OD); Polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40); Polyglyceryl oleate (PLUROL OLEIQUE CC497), Vitamin E succinate polyethylene glycol ester (VE TPGS NF(1000)), Polyoxyethylene lauryl ether (Brij L23), Polyoxyethylene glycol cetyl ether (Brij C10); Compound of formula I Produced by Guangzhou Zaiji Pharmaceutical Technology Co., Ltd.; minoxidil API: purchased from Tianjin Institute of Pharmaceutical Research Pharmaceutical Co., Ltd., batch number: 2011052.

[0112] Example 1: Pharmaceutical composition prescription and preparation method

[0113] Table 1-1 Composition of pharmaceutical composition prescription (w / w%)

[0114] Table 1-2 Composition of pharmaceutical composition prescription (w / w%)

[0115] Note: The percentages in the above table are all mass percentages.

[0116] The results showed that when the above pharmaceutical composition samples were placed at room temperature for 3 months, visual observation revealed that oil droplets were precipitated from pharmaceutical composition 7 and solid precipitates were precipitated from pharmaceutical composition 10, while the other pharmaceutical composition samples were relatively stable.

[0117] Table 2-1 Composition of pharmaceutical composition prescription (w / w%)

[0118] Table 2-2 Composition of pharmaceutical composition prescription (w / w%)

[0119] Note: The percentages in the above table are all mass percentages.

[0120] Table 3-1 Composition of pharmaceutical composition prescription (w / w%)

[0121] Table 3-2 Composition of pharmaceutical composition prescription (w / w%)

[0122] Note: The percentages in the above table are all mass percentages.

[0123] Preparation method: dissolve the compound of formula I and minoxidil API in dimethyl sulfoxide, add other solvents and transdermal enhancers, and stir evenly.

[0124] The prescriptions in Tables 1 to 3 can all be used to prepare corresponding pharmaceutical compositions according to the above preparation methods.

[0125] Example 2: In vitro transdermal experiment

[0126] (1) Preparation before the experiment

[0127] Preparation of receiving solution: Weigh 400g of propylene glycol and 600g of purified water, and stir them evenly in a beaker.

[0128] Skin preparation: Take the Bama pork skin, remove the hair and fat, and set aside.

[0129] (2) Experimental process

[0130] Turn on the transdermal diffusion instrument, set the temperature to 32°C and the speed to 200 rpm;

[0131] Add a stirring bar and receiving solution to the diffusion cell and preheat to 32°C on the instrument;

[0132] The treated pigskin was added to the diffusion cell, and about 20 mg of the sample to be tested (i.e., the pharmaceutical composition prepared according to the prescription in Example 1) was added;

[0133] After 24 hours, the receiving solution was filtered and the drug content was detected, which was recorded as the 24-hour cumulative permeation amount.

[0134] (3) Pigskin treatment after the experiment

[0135] Remove the pigskin and rinse the surface with a diluent (a mixed solution of 50% acetonitrile and 50% purified water). Cut the pigskin at the administration site into pieces and soak it in 10 mL of extract (a mixed solution of 50% acetonitrile and 50% purified water) for 1 hour to extract the drug from the pigskin. After filtering, detect the drug content in the extract, which is recorded as the skin retention amount.

[0136] (4) Experimental results

[0137] Table 4

[0138] The results showed that: a comprehensive comparison of the skin retention amount and the 24h cumulative penetration amount showed that the pharmaceutical composition prescription 15 had a better penetration effect. Further combined with the stability effect, the pharmaceutical composition prescription 15 was selected as the preferred prescription.

[0139] Example 3: Preparation method of pharmaceutical composition

[0140] Table 5

[0141] According to the formulation composition in Table 5, the compound of formula I and the minoxidil API were dissolved in dimethyl sulfoxide, and Transcutol P, propylene glycol, Capmul PG-8 and / or Capmul MCM-C8 were added in sequence and stirred evenly.

[0142] Example 4: Experimental study on the efficacy of a pharmaceutical composition in treating alopecia areata

[0143] (1) Experimental animals

[0144] Sixty female C57BL / 6N mice, 49 days old, weighing 16-19 g, SPF grade, were selected based on the condition of their backs after shaving. Animals with a pink, smooth, and spot-free back were selected for the experiment. Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd., SCXK(Zhe)2019-000120221117Abzz0619000331.

[0145] (2) Pharmaceutical composition prescription

[0146] Table 6

[0147] (3) Dosage regimen

[0148] Table 7

[0149] (4) Experimental process

[0150] One day before dosing, 30 animals with pink back skin, no dark spots, and no lesions were selected based on skin color and hair growth. They were randomly divided into cages of three animals each and tail-numbered using a permanent marker. Dosing was performed twice daily. Starting on the second day of dosing, hair growth was photographed and scored between dosing sessions. Mice were weighed and weights were recorded daily.

[0151] (5) Experimental results

[0152] 5.1 Hair Growth Rating Assessment

[0153] 0 points: The skin is pink and tender, the same as the initial state after shaving

[0154] 1 point: The skin in the administration area turns gray to black, with no obvious hair growth

[0155] 2 points: Short hair growth can be seen in the drug administration area

[0156] 3 points: Short hair growth can be seen in most of the administration area, and sparse long hair appears

[0157] 4 points: There is dense long hair growth, but it does not cover the entire administration area

[0158] 5 points: Thick, long hair covers the entire administration area

[0159] 5.2 Hair Growth Score

[0160] Table 8

[0161] The results showed that compared with the blank control group, the therapeutic effects of Prescription 11 and Prescription 15 liniments showed significant differences in hair growth scores starting on the 12th day of transdermal administration. Both Prescription 11 and Prescription 15 liniments were more effective than single-ingredient minoxidil liniment and single-ingredient compound I liniment (see Table 8 and Figure 1). Furthermore, no significant changes in animal body weight were observed during the administration period, indicating that Prescription 11 and Prescription 15 liniments had no significant toxic or side effects.

Claims

1. A combination drug, characterized in that: Its active ingredients include active ingredient A and active ingredient B; Wherein, the active ingredient A is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; The active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; 2. The combination drug according to claim 1, characterized in that The combination drug meets one or more of the following conditions: (1) The mass ratio of the active ingredient A to the active ingredient B is 1:100 to 100:1, preferably 1:10 to 10:1, for example 1:2, 1:1.7, 1:1.3, 1:1.1 or 1:1; (2) The combination drug is in the form of a paste, paint, film, liniment, emulsion, ointment, cream, tincture, patch, plaster or gel; preferably a liniment; (3) The combination drug is a combination drug for preventing, alleviating or treating alopecia areata; (4) The active ingredient consists of the active ingredient A and the active ingredient B; (5) The active ingredient A and the active ingredient B are administered simultaneously or separately.

3. A pharmaceutical composition A, characterized in that: It includes a first pharmaceutical composition and a second pharmaceutical composition; Wherein, the first pharmaceutical composition comprises an active ingredient A and a pharmaceutically acceptable carrier, wherein the active ingredient A is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a pharmaceutically acceptable carrier. solvates of pharmaceutically acceptable salts; The second pharmaceutical composition comprises an active ingredient B and a pharmaceutically acceptable carrier, wherein the active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; 4. The pharmaceutical composition A according to claim 3, characterized in that: The pharmaceutical composition A satisfies one or more of the following conditions: (1) The mass ratio of the active ingredient A to the active ingredient B is 1:100 to 100:1, preferably 1:10 to 10:1, for example 1:2, 1:1.7, 1:1.3, 1:1.1 or 1:1; (2) The first pharmaceutical composition is in the form of a paste, a paint, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment; (3) The dosage form of the second pharmaceutical composition is a paste, a paint, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment; (4) The dosage form of the pharmaceutical composition A is a paste, a coating, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment; (5) The pharmaceutical composition A is a pharmaceutical composition for preventing, alleviating or treating alopecia areata; (6) The pharmaceutical composition A consists of the first pharmaceutical composition and the second pharmaceutical composition; (7) The first pharmaceutical composition consists of the active ingredient A and the pharmaceutically acceptable carrier; (8) The second pharmaceutical composition comprises the active ingredient B and the pharmaceutically acceptable carrier Body composition; (9) The first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously or separately.

5. A pharmaceutical composition B, characterized in that: It includes an active ingredient and a pharmaceutically acceptable carrier; Wherein, the active ingredients include active ingredient A and active ingredient B; The active ingredient A is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; The active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; 6. The pharmaceutical composition B according to claim 5, characterized in that The pharmaceutical composition B satisfies one or more of the following conditions: (1) The pharmaceutical composition B is a pharmaceutical composition for preventing, alleviating or treating alopecia areata; (2) The mass percentage of the active ingredient in the pharmaceutical composition B is 0.2% to 20%, preferably 1% to 10%, for example 3%, 3.2%, 3.5%, 3.8% or 4%; (3) The pharmaceutically acceptable carrier includes a solvent; (4) The pharmaceutically acceptable carrier includes a transdermal enhancer; (5) The dosage form of the pharmaceutical composition B is a paste, a coating, a film, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment; (6) The active ingredient consists of the active ingredient A and the active ingredient B.

7. The pharmaceutical composition B according to claim 6, characterized in that The pharmaceutical composition B satisfies one or more of the following conditions: (1) The mass ratio of the active ingredient A to the active ingredient B is 1:100 to 100:1, preferably 1:10 to 10:1, for example 1:2, 1:1.7, 1:1.3, 1:1.1 or 1:1; (2) The mass percentage of the active ingredient A in the pharmaceutical composition B is 0.1% to 10%, preferably 0.5% to 5%, for example 1%, 1.2%, 1.5%, 1.8% or 2%; (3) The mass percentage of the active ingredient B in the pharmaceutical composition B is 0.1% to 10%; preferably 0.5% to 5%, for example 2%; (4) The pharmaceutically acceptable carrier is a solvent and a transdermal enhancer; (5) The solvent is selected from one or more of water, sulfoxide solvents and alcohol solvents; preferably, it is a mixed solvent of a sulfoxide solvent and an alcohol solvent; the sulfoxide solvent is preferably dimethyl sulfoxide; the alcohol solvent is preferably selected from one or more of propylene glycol, ethanol, glycerol and polyethylene glycol 400, more preferably selected from one or more of propylene glycol, ethanol and polyethylene glycol 400, and further preferably selected from propylene glycol and / or polyethylene glycol 400; Preferably, the solvent includes at least a sulfoxide solvent, preferably dimethyl sulfoxide; (6) The mass percentage of the solvent in the pharmaceutical composition B is 20% to 50%, preferably 30% to 50%, for example, 27%, 28%, 32%, 33%, 37%, 37.2%, 37.5%, 37.8%, 38%, 42%, 43% or 48%; (7) The transdermal enhancer is selected from one or more of ester agents, surfactants, ether agents, bile salt agents, alcohol agents, terpenoid agents, sulfoxide agents and cyclodextrin agents; the ether agents are preferably selected from one or more of diethylene glycol monoethyl ether, polyoxyethylene lauryl ether and polyethylene glycol hexadecyl ether; the bile salt agents are preferably selected from deoxycholate and / or glycocholate; the ester agents are preferably selected from one or more of propylene glycol monolaurate, caprylic and capric mono- and diglycerides, caprylic glyceride, ethyl oleate, isopropyl myristate, caprylic and capric polyethylene glycol glyceride, propylene glycol monocaprylate, polyglycerol oleate, vitamin E succinate polyethylene glycol ester and soybean lecithin; the surfactant is preferably selected from one or more of Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, sodium lauryl sulfate, polyoxyethylene (35) one or more of castor oil and polyoxyethylene 40 hydrogenated castor oil; the alcohol agent is preferably selected from fatty alcohol agents or polyol agents; the fatty alcohol agent is preferably selected from one or more of ethanol, oleyl alcohol and octyl lauryl alcohol; the polyol agent is preferably selected from propylene glycol; the terpene agent is preferably selected from menthol; the sulfoxide agent is preferably selected from dimethyl sulfoxide; the cyclodextrin agent is preferably selected from hydroxypropyl-β-cyclodextrin; (8) The mass percentage of the transdermal enhancer in the pharmaceutical composition B is 40% to 80%, preferably 50% to 70%, for example 49%, 54%, 59%, 64% or 69%.

8. The pharmaceutical composition B according to claim 7, characterized in that The pharmaceutical composition B satisfies one or more of the following conditions: (1) The solvent is selected from one or more of water, dimethyl sulfoxide, propylene glycol, ethanol, glycerol and polyethylene glycol 400, preferably selected from one or more of dimethyl sulfoxide, polyethylene glycol 400, propylene glycol and ethanol, more preferably selected from a mixed solvent of dimethyl sulfoxide, propylene glycol and polyethylene glycol 400, or a mixed solvent of dimethyl sulfoxide and propylene glycol; (2) When the solvent is a mixed solvent of an alcohol solvent and a sulfoxide solvent, and the alcohol solvent is propylene glycol, the mass ratio of the propylene glycol to the sulfoxide solvent is 3:1 to 9:1; preferably 4:1 to 8:1, for example, 4.6:1, 5.6:1, 6.6:1 or 7.6:1; (3) When the solvent is a mixed solvent of a sulfoxide solvent and an alcohol solvent, and the alcohol solvent is propylene glycol and polyethylene glycol 400, the mass ratio of propylene glycol to the sulfoxide solvent is 10:1 to 1:1, preferably 7:1 to 4:1, for example, 6.4:1 or 5.4:1; the mass ratio of polyethylene glycol 400 to the sulfoxide solvent is 0.5:1 to 5:1, preferably 1:1 to 3:1, for example, 1:1 or 2:1; (4) The transdermal enhancer is selected from diethylene glycol monoethyl ether, hydroxypropyl-β-cyclodextrin, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, propylene glycol monolaurate, caprylic and capric mono- and diglycerides, caprylic glyceride, ethyl oleate, isopropyl myristate, caprylic and capric macrogol glyceride, propylene glycol monocaprylate, sodium lauryl sulfate, polyoxyethylene lauryl ether, polyethylene glycol cetyl ether, menthol, polyglycerol oleate, polyoxyethylene (35) castor oil, oleyl alcohol, octyl lauryl alcohol, polyoxyethylene One or more of ethylene 40 hydrogenated castor oil, vitamin E succinate polyethylene glycol ester and soybean lecithin; Preferably, the composition is selected from one or more of diethylene glycol monoethyl ether, hydroxypropyl-β-cyclodextrin, Tween 80, propylene glycol monolaurate, caprylic capric mono- and diglycerides, monocaprylic glyceride, ethyl oleate, caprylic capric macrogol glyceride and propylene glycol monocaprylate, for example, a mixed transdermal enhancer of diethylene glycol monoethyl ether and hydroxypropyl-β-cyclodextrin; a mixed transdermal enhancer of diethylene glycol monoethyl ether, Tween 80 and propylene glycol monolaurate; a mixed transdermal enhancer of diethylene glycol monoethyl ether and caprylic capric mono- and diglycerides; a mixed transdermal enhancer of diethylene glycol monoethyl ether and caprylic capric macrogol glyceride; a mixed transdermal enhancer of diethylene glycol monoethyl ether, Tween 80 and monocaprylic glyceride; A mixed transdermal enhancer of monoethyl ether and monocaprylic glyceryl; a mixed transdermal enhancer of diethylene glycol monoethyl ether and ethyl oleate; a mixed transdermal enhancer of diethylene glycol monoethyl ether and propylene glycol monolaurate; a mixed transdermal enhancer of diethylene glycol monoethyl ether, caprylic capric acid mono- and diglyceryl, and caprylic capric acid polyethylene glycol glyceryl; a mixed transdermal enhancer of diethylene glycol monoethyl ether and propylene glycol monocaprylate; a mixed transdermal enhancer of diethylene glycol monoethyl ether, caprylic acid glyceryl and caprylic capric acid polyethylene glycol glyceryl; a mixed transdermal enhancer of diethylene glycol monoethyl ether, caprylic capric acid mono- and diglyceryl, and caprylic acid glyceryl; or a mixed transdermal enhancer of diethylene glycol monoethyl ether, caprylic acid glyceryl and propylene glycol monocaprylate; More preferably, a mixed transdermal enhancer selected from diethylene glycol monoethyl ether and propylene glycol monocaprylate or a mixed transdermal enhancer selected from diethylene glycol monoethyl ether, monocaprylic glyceryl and propylene glycol monocaprylate; (5) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and hydroxypropyl-β-cyclodextrin, the mass ratio of diethylene glycol monoethyl ether to hydroxypropyl-β-cyclodextrin is 2:1 to 4:1, for example, 3.27:1; (6) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, Tween 80 and propylene glycol monolaurate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monolaurate is 8:1 to 10:1, for example, 9.8:1; the mass ratio of Tween 80 to propylene glycol monolaurate is 2:1 to 4:1, for example, 3:1; (7) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and caprylic acid capric acid mono- and diglyceryl, the mass ratio of diethylene glycol monoethyl ether to caprylic acid capric acid mono- and diglyceryl is 4:1 to 10:1, for example, 4.9:1 or 9.8:1; (8) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and caprylic acid capric acid macrogol glyceride, the mass ratio of diethylene glycol monoethyl ether to caprylic acid capric acid macrogol glyceride is 8:1 to 10:1, for example, 9.8:1; (9) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, Tween 80 and monocaprylic glyceryl, the mass ratio of diethylene glycol monoethyl ether to monocaprylic glyceryl is 8:1 to 10:1, for example, 9.8:1; the mass ratio of Tween 80 to monocaprylic glyceryl is 0.5:1 to 2:1, for example, 1:1; (10) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and monocaprylic glyceryl, the mass ratio of diethylene glycol monoethyl ether to monocaprylic glyceryl is 4:1 to 10:1, for example, 4.9:1 or 9.8:1; (11) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and ethyl oleate, the mass ratio of diethylene glycol monoethyl ether to ethyl oleate is 8:1 to 10:1, for example, 9.8:1; (12) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and propylene glycol monolaurate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monolaurate is 8:1 to 10:1, for example, 9.8:1; (13) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, caprylic capric acid mono- and diglycerides, and caprylic capric acid macrogol glycerides, the mass ratio of diethylene glycol monoethyl ether to caprylic capric acid macrogol glycerides is 8:1 to 10:1, for example, 9.8:1; the mass ratio of caprylic capric acid mono- and diglycerides to caprylic capric acid macrogol glycerides is 0.5:1 to 2:1, for example, 1:1; (14) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether and propylene glycol monocaprylate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monocaprylate is 3:1 to 6:1, for example, 4.9:1; (15) The transdermal enhancer is diethylene glycol monoethyl ether, monocaprylic glyceryl and caprylic acid capric acid When the polyethylene glycol glyceride is a mixed transdermal enhancer, the mass ratio of diethylene glycol monoethyl ether to caprylic acid capric acid polyethylene glycol glyceride is 8:1-10:1, for example, 9.8:1; the mass ratio of monocaprylic acid glyceride to caprylic acid capric acid polyethylene glycol glyceride is 0.5:1-2:1, for example, 1:1; (16) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, caprylic acid capric acid mono- and diglyceryl and monocaprylic acid glyceryl, the mass ratio of diethylene glycol monoethyl ether to monocaprylic acid glyceryl is 8:1 to 10:1, for example, 9.8:1; the mass ratio of caprylic acid capric acid mono- and diglyceryl and monocaprylic acid glyceryl is 0.5:1 to 2:1, for example, 1:1; (17) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, monocaprylin and propylene glycol monocaprylate, the mass ratio of diethylene glycol monoethyl ether to propylene glycol monocaprylate is 8:1 to 10:1, for example, 9.8:1; the mass ratio of monocaprylin to propylene glycol monocaprylate is 0.5:1 to 2:1, for example, 1:

1.

9. The pharmaceutical composition B according to any one of claims 5 to 8, characterized in that The pharmaceutical composition B satisfies one or more of the following conditions: (1) The pharmaceutical composition B is composed of the active ingredient A, the active ingredient B, the solvent and the transdermal enhancer; (2) The pharmaceutical composition B is preferably composed of the components shown in any of the following schemes: Scheme 1: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 28% of propylene glycol, 5% of dimethyl sulfoxide and 15% of hydroxypropyl-β-cyclodextrin; Scheme 2: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 23% of propylene glycol, 5% of dimethyl sulfoxide, 15% of Tween 80 and 5% of propylene glycol monolaurate; Scheme 3: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of caprylic and capric mono- and di-glycerides; Scheme 4: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of caprylic acid capric acid macrogol glyceride; Scheme 5: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% propylene glycol, 5% dimethyl sulfoxide, 5% Tween 80, and 5% monocaprylin; Scheme 6: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of monocaprylic glyceryl; Scheme 7: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of ethyl oleate; Scheme 8: 1% of the compound represented by formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 38% of propylene glycol, 5% of dimethyl sulfoxide and 5% of propylene glycol monolaurate; Scheme 9: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide and 10% of caprylic and capric mono- and di-glycerides; Scheme 10: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of caprylic and capric mono- and di-glycerides, and 5% caprylic and capric macrogol glycerides; Scheme 11: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide and 10% of propylene glycol monocaprylate; Scheme 12: 1% of the compound represented by formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide and 10% of monocaprylic glyceryl; Scheme 13: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of monocaprylic glyceryl and 5% of caprylic-capric macrogol glyceride; Scheme 14: 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of caprylic and capric monoglycerides and 5% of caprylic glyceride; Scheme 15: 1% of the compound represented by formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 5% of monocaprylin and 5% of propylene glycol monocaprylate; Preferably, the pharmaceutical composition B is Scheme 11 and Scheme 15; (3) The pharmaceutical composition B is composed of 1% of the compound of formula I, 2% of minoxidil, 49% of diethylene glycol monoethyl ether, 33% of propylene glycol, 5% of dimethyl sulfoxide, 0-5% of monocaprylin and 5-10% of propylene glycol monocaprylate.

10. A combination medicine kit, characterized in that: It includes: A first container comprising the first pharmaceutical composition according to claim 3 or 4; and A second container comprising the second pharmaceutical composition according to claim 3 or 4.

11. A method for preparing the pharmaceutical composition B according to any one of claims 5 to 9, characterized in that: The preparation method comprises the following steps: mixing the active ingredient A, the active ingredient B and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a solvent and a transdermal enhancer; Preferably, when the solvent includes a sulfoxide solvent, the preparation method of the pharmaceutical composition B comprises the following steps: (1) mixing the active ingredient A, the active ingredient B and the sulfoxide solvent to obtain a mixed solution 1; (2) mixing the mixed solution 1 of step (1) with the other solvents and the transdermal enhancer to obtain the pharmaceutical composition B; More preferably, the reaction conditions of the preparation method meet one or more of the following conditions: (1) The active ingredient A is a compound represented by formula I, and / or the active ingredient B is minoxidil; (2) In step (2), the mixing is to add the other solvents and the transdermal enhancer to the mixed solution 1 of step (1); (3) In step (2), the mixing is carried out by stirring to achieve uniform mixing.

12. Use of a compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, a combination drug as claimed in claim 1 or 2, a pharmaceutical composition A as claimed in claim 3 or 4, a pharmaceutical composition B as claimed in any one of claims 5 to 9, or a combination kit as claimed in claim 10 in the preparation of a medicament for preventing, alleviating or treating alopecia areata, wherein the use is not the use of a pharmaceutical composition C in the preparation of a medicament for preventing, alleviating or treating alopecia areata, wherein the pharmaceutical composition C comprises the following components by mass fraction: 0.1% to 3% of a compound of formula I or a pharmaceutically acceptable salt thereof, 35% to 93% of a solvent and 5% to 63% of a transdermal enhancer; the solvent The transdermal enhancer is selected from one or more of water, glycerol, polyethylene glycol 400, dimethyl sulfoxide, ethyl acetate, propylene glycol and ethanol; the transdermal enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, urea, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea, propyl gallate, isopropyl myristate, cyclodextrin, sodium lauryl sulfate, polyoxyethylene lauryl ether, polyethylene glycol cetyl ether, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, monocaprylic glyceryl, caprylic acid caprylic acid mono- and diglyceryl, propylene glycol monolaurate, propylene glycol monocaprylate and behenic acid glyceryl, 13. A method for treating alopecia areata, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, a combination drug as claimed in claim 1 or 2, a pharmaceutical composition A as claimed in claim 3 or 4, a pharmaceutical composition B as claimed in any one of claims 5 to 9, or a combination kit as claimed in claim 10, wherein the method is not administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition C, wherein the pharmaceutical composition C comprises the following components by mass fraction: 0.1% to 3% of a compound of formula I or a pharmaceutically acceptable salt thereof, 35% to 93% of a solvent, and 5% to 63% of a transdermal enhancer; The solvent is selected from one or more of water, glycerol, polyethylene glycol 400, dimethyl sulfoxide, ethyl acetate, propylene glycol and ethanol; the transdermal enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, urea, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea, propyl gallate, isopropyl myristate, cyclodextrin, sodium lauryl sulfate, polyoxyethylene lauryl ether, polyethylene glycol cetyl ether, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, monocaprylic glyceryl, caprylic acid caprylic acid mono- and diglyceryl, propylene glycol monolaurate, propylene glycol monocaprylate and behenic acid glyceryl,

Images