Combined medicine, pharmaceutical composition and preparation method and application thereof

Abstract

The invention discloses a combined medicine, a medicine composition and a preparation method and application of the medicine composition. The invention provides a combined medicine. Active ingredients of the combined medicine comprise an active ingredient A and an active ingredient B, wherein the active ingredient A is a compound as shown in a 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, pharmaceutically acceptable salt of minoxidil, solvate of minoxidil or solvate of pharmaceutically acceptable salt of minoxidil. The combined medicine and the pharmaceutical composition have better permeability, stability and safety, have a better treatment effect on alopecia areata, and are suitable for local external use.

Description

[0001] This application claims the priority of Chinese Patent Application No. 2023109236146 filed on July 25, 2023. This application cites the entire text of the above Chinese Patent Application. Technical Field

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

[0003] Alopecia areata (AA) is a common inflammatory non-scarring hair loss. The clinical manifestations of this disease are sudden circular patchy hair loss with clear boundaries on the scalp. Most patients with mild symptoms can heal themselves, while about half of the patients have repeated attacks, which can last for years or decades. A small number of patients have severe conditions, and hair loss can affect the entire scalp and even the hair on the body. This disease can occur at any age, but is more common in young and middle-aged people, with no obvious gender differences. Epidemiological studies have shown that the prevalence of AA in my country is 0.27%, and foreign studies have shown that the lifetime prevalence of the population is about 2%. This disease affects the appearance and can have a negative impact on the patient's mental health and quality of life.

[0004] Studies have found that the NKG2D protein is highly expressed in the hair follicle cells of patients with alopecia areata due to genetic or external stimulation, 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 upregulation of 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. At present, 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 kind of inhibitory agent that has effects on JAK1, JAK2 and JAK3 at the same time. JAK inhibitors with inhibitory effects.

[0005]

[0006] Minoxidil can directly stimulate the proliferation and differentiation of hair follicle epithelial cells; promote angiogenesis, increase local blood flow; open potassium ion channels; and transform hair follicles from the resting phase to the growth phase. It is suitable for AA patients in the stable phase and with a small area of ​​hair loss, and requires long-term medication to maintain efficacy. It often needs to be used in combination with other treatments to avoid being used alone in progressive AA. It has little effect on patients with moderate and severe hair loss. The concentration of topical minoxidil is generally 2% and 5%, and it is dose-dependent. The treatment effect of 5% may be better, but adverse reactions are relatively more common. Adverse reactions are mainly local irritation and hirsutism.

[0007] The minoxidil dosage forms currently approved for the treatment of hair loss and alopecia areata are all topical preparations, while the JAK inhibitors currently approved for the market are all oral preparations, which are systemic medications and have significant side effects. Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the fact that there are few types of JAK inhibitors for treating alopecia areata in the prior art, and to provide a combination drug, a pharmaceutical composition, and a preparation method and use thereof. The combination drug and the 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.

[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]

[0013] In one embodiment of the present invention, the active ingredient consists of the active ingredient A and the active ingredient B.

[0014] 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.

[0015] 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.

[0016] In one embodiment of the present invention, the combination drug is a combination drug for preventing, alleviating or treating alopecia areata.

[0017] In one embodiment of the present invention, the active ingredient A and the active ingredient B can be administered simultaneously or separately.

[0018] The “simultaneous administration” means that the active ingredient A and the active ingredient B are contained in separate pharmaceutical compositions and administered simultaneously; or, “a separate pharmaceutical composition containing the active ingredient A” and a “separate pharmaceutical composition containing the active ingredient B” are administered simultaneously.

[0019] The “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:

[0020] 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 far in time.

[0021] The present invention provides a pharmaceutical composition A, which comprises a first pharmaceutical composition and a second pharmaceutical composition;

[0022] 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 solvate of a pharmaceutically acceptable salt thereof;

[0023] 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;

[0024]

[0025] In one embodiment of the present invention, the pharmaceutical composition A consists of the first pharmaceutical composition and the second pharmaceutical composition.

[0026] In a certain embodiment of the present invention, the first pharmaceutical composition consists of the active ingredient A and the pharmaceutically acceptable carrier.

[0027] In a certain embodiment of the present invention, the second pharmaceutical composition consists of the active ingredient B and the pharmaceutically acceptable carrier.

[0028] 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.

[0029] In one embodiment of the present invention, the dosage form of the first pharmaceutical composition can be a paste, a paint, a film coating, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0030] In one embodiment of the present invention, the dosage form of the second pharmaceutical composition can be a paste, a paint, a film coating, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0031] In one embodiment of the present invention, the dosage form of the pharmaceutical composition A can be a paste, a coating, a film coating, a liniment, an emulsion, an ointment, a cream, a tincture, a patch, a plaster or a gel; preferably a liniment.

[0032] In one embodiment of the present invention, the pharmaceutical composition A is a pharmaceutical composition for preventing, alleviating or treating alopecia areata.

[0033] In one embodiment of the present invention, the first pharmaceutical composition and the second pharmaceutical composition can be administered simultaneously or separately.

[0034] The present invention provides a combination medicine kit, which comprises:

[0035] A first container comprising a first pharmaceutical composition as described above; and

[0036] A second container comprises a second pharmaceutical composition as described above.

[0037] The present invention provides a pharmaceutical composition B, which comprises an active ingredient and a pharmaceutically acceptable carrier;

[0038] Wherein, the active ingredients include active ingredient A and active ingredient B;

[0039] 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;

[0040] The active ingredient B is minoxidil, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof;

[0041]

[0042] In a certain embodiment of the present invention, the pharmaceutical composition B is a pharmaceutical composition for preventing, alleviating or treating alopecia areata.

[0043] In one embodiment of the present invention, the active ingredient consists of the active ingredient A and the active ingredient B.

[0044] 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%.

[0045] 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.

[0046] 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%.

[0047] 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%.

[0048] In one embodiment of the present invention, the pharmaceutically acceptable carrier comprises a solvent.

[0049] In one embodiment of the present invention, the pharmaceutically acceptable carrier comprises a transdermal enhancer.

[0050] In one embodiment of the present invention, the pharmaceutically acceptable carrier may be a solvent and a skin penetration enhancer.

[0051] In one embodiment of the present invention, the solvent is selected from one or more of water, sulfoxide solvents and alcohol solvents; preferably, it is a mixed solvent of sulfoxide solvents and alcohol solvents. The sulfoxide solvent is preferably dimethyl sulfoxide. The alcohol solvent is preferably 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 further preferably propylene glycol and / or polyethylene glycol 400.

[0052] 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.

[0053] In one embodiment of the present invention, the solvent at least includes a sulfoxide solvent, preferably dimethyl sulfoxide.

[0054] 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%.

[0055] 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.

[0056] 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 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.

[0057] In a certain 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 hexadecyl 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 acid capric acid mono- and diglycerides, caprylic acid glyceride, ethyl oleate, isopropyl myristate, caprylic acid capric acid polyethylene glycol glyceride, propylene glycol monocaprylate, polyglycerol oleate, vitamin E succinic acid 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.

[0058] In one embodiment of the present invention, 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 / capric mono- and di-glycerides, caprylic / monoglyceride, ethyl oleate, myristic acid Isopropyl octanoate One or more of polyethylene glycol glyceride, propylene glycol monocaprylate, sodium lauryl sulfate, polyoxyethylene lauryl ether, polyethylene glycol cetyl ether, menthol, polyglyceryl oleate, polyoxyethylene (35) castor oil, oleyl alcohol, octyl lauryl alcohol, polyoxyethylene 40 hydrogenated castor oil, vitamin E succinate polyethylene glycol ester and soybean lecithin.

[0059] 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 capric acid mono- and diglycerides, monocaprylic glyceride, ethyl oleate, caprylic 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 capric acid mono- and diglycerides; a mixed transdermal enhancer of diethylene glycol monoethyl ether and caprylic capric acid polyethylene glycol glyceride; a mixed transdermal enhancer of diethylene glycol monoethyl ether, Tween 80 and monocaprylic glyceride. The invention relates to a transdermal enhancer for diethylene glycol monoethyl ether and monocaprylic acid 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 acid capric acid mono- and diglyceryl and caprylic acid 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, monocaprylic acid glyceryl and caprylic acid capric acid polyethylene glycol glyceryl; a mixed transdermal enhancer of diethylene glycol monoethyl ether, caprylic acid capric acid mono- and diglyceryl and monocaprylic acid glyceryl; or a mixed transdermal enhancer of diethylene glycol monoethyl ether, monocaprylic acid glyceryl and propylene glycol monocaprylate.

[0060] 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, monocaprylic glyceryl and propylene glycol monocaprylate.

[0061] 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%.

[0062] 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.

[0063] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal 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.

[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 caprylic capric mono- and diglycerides, the mass ratio of diethylene glycol monoethyl ether to caprylic capric mono- and diglycerides is 4:1 to 10:1, for example, 4.9:1 or 9.8:1.

[0065] 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 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.

[0066] 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.

[0067] In one embodiment of the present invention, 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.

[0068] 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.

[0069] 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.

[0070] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal 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 and caprylic capric acid macrogol glycerides is 8:1 to 10:1, for example, 9.8:1. The caprylic acid capric acid mono-diglyceride and caprylic acid capric acid The mass ratio of glycerol polyol is 0.5:1 to 2:1. For example, 1:1.

[0071] 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.

[0072] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal enhancer of diethylene glycol monoethyl ether, monocaprylic glyceryl and caprylic capric acid polyethylene glycol glyceride, the mass ratio of diethylene glycol monoethyl ether to caprylic capric acid polyethylene glycol glyceride is 8:1 to 10:1, for example, 9.8:1. The mass ratio of monocaprylic glyceryl and caprylic capric acid polyethylene glycol glyceride is 0.5:1 to 2:1, for example, 1:1.

[0073] In one embodiment of the present invention, 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.

[0074] In one embodiment of the present invention, when the transdermal enhancer is a mixed transdermal enhancer of diethylene glycol monoethyl ether, monocaprylic glyceryl 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 monocaprylic glyceryl and propylene glycol monocaprylate is 0.5:1 to 2:1, for example, 1:1.

[0075] 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.

[0076] In one embodiment of the present invention, the pharmaceutical composition B is preferably composed of the components shown in any of the following schemes:

[0077] 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;

[0078] 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;

[0079] 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;

[0080] 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;

[0081] 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;

[0082] 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;

[0083] 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;

[0084] 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;

[0085] 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;

[0086] 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;

[0087] 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;

[0088] 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;

[0089] 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;

[0090] 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;

[0091] 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.

[0092] The above percentages are all mass percentages.

[0093] 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 monocaprylic glyceride and 5-10% of propylene glycol monocaprylate. (The above percentages are mass percentages).

[0094] In a certain embodiment of the present invention, the pharmaceutical composition B is more preferably Scheme 11 and Scheme 15.

[0095] In one embodiment of the present invention, the dosage form of the pharmaceutical composition B can be 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.

[0096] 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.

[0097] 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:

[0098] (1) mixing the active ingredient A, the active ingredient B and the sulfoxide solvent to obtain a mixed solution 1;

[0099] (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.

[0100] In one embodiment of the present invention, in step (2), the mixing may be performed by adding the other solvent and the transdermal enhancer into the mixed solution 1 of step (1).

[0101] In one embodiment of the present invention, in step (2), the mixing can be carried out by stirring to achieve uniform mixing.

[0102] The present invention also provides 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 described above, and a combination drug as described above. Compound A, as described above In the preparation of the combination kit of drug B or as described above for preventing, alleviating or treating The use of the pharmaceutical composition C in a drug for treating alopecia areata, wherein the use is not the use of the pharmaceutical composition C in the preparation of a drug for preventing, alleviating or treating alopecia areata, and the pharmaceutical composition C comprises the following components by mass fraction: 0.1%-3% of the 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 one or more of water, glycerol, polyethylene glycol 400, dimethyl sulfoxide, ethyl acetate, propylene glycol and ethanol; the transdermal enhancer is selected from diethylene glycol monoethyl ether, nitrogen One or more of ketone, 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,

[0103]

[0104] 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 the 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 fraction: 0.1%-3% of the 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 caprylic acid mono- and diglyceryl, propylene glycol monolaurate, propylene glycol monocaprylate and behenic acid glyceryl,

[0105]

[0106] 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:

[0107] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0108] The term "solvate" refers to a substance formed after 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.

[0109] 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, suitable for patient use) acid or base, and a solvent (including but not limited to: water, methanol, ethanol, etc.), wherein a pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric.

[0110] The term "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of drugs and the preparation of prescriptions, and is all substances contained in drug preparations except the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0111] The term "transdermal enhancer" is also called "transdermal absorption enhancer", which refers to materials that can penetrate into the skin to reduce the resistance of drugs passing through the skin, and can assist drugs to pass through the stratum corneum, diffuse through the skin, and enter the systemic circulation through the capillaries. Transdermal enhancers should meet the following conditions: ① No pharmacological effects on the skin and body, non-toxic, non-irritating and non-allergic reactions; ② Take effect immediately after application, and the skin can restore normal barrier function after removal; ③ Do not cause the loss of nutrients and water in the body through the skin; ④ Do not produce physical and chemical reactions with drugs and other excipients.

[0112] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0113] The reagents and raw materials used in the present invention are commercially available.

[0114] The positive and progressive effects of the present invention are that the combined drug and the pharmaceutical composition of the present invention have better permeability, stability and safety, have better therapeutic effects on alopecia areata, and are suitable for topical external use. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1 The figure is a curve chart showing the changes in hair growth scores of mice in each group. DETAILED DESCRIPTION

[0116] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0117] Diethylene glycol monoethyl ether (Transcutol P); Hydroxypropyl-β-cyclodextrin (HP-β-CD); Single month Propylene glycol cinnamate Alcohol esters (Lauroglycol FCC); Caprylic and capric mono- and di-glycerides (Capmul MCM); Glyceryl monocaprylate (Capmul MCM-C8); Caprylic capric macrogol glyceride (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); Polyglycerol oleate (PLUROL OLEIQUE CC497), Vitamin E succinate polyethylene glycol ester (VE TPGS NF (1000)) polyoxyethylene lauryl ether (Brij L23), polyethylene glycol cetyl ether (BrijC10); 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.

[0118] Example 1: Pharmaceutical composition prescription and preparation method

[0119] Table 1-1 Composition of pharmaceutical composition prescription (w / w%)

[0120]

[0121]

[0122] Table 1-2 Composition of pharmaceutical composition prescription (w / w%)

[0123]

[0124] Note: The percentages in the above table are all mass percentages.

[0125] The results showed that when the above pharmaceutical composition prescription samples were placed at room temperature for 3 months, visual observation revealed that pharmaceutical composition prescription 7 had oil droplets precipitated, pharmaceutical composition prescription 10 had solid precipitates precipitated, and the other pharmaceutical composition prescriptions were relatively stable.

[0126] Table 2-1 Composition of pharmaceutical composition prescription (w / w%)

[0127]

[0128] Table 2-2 Composition of pharmaceutical composition prescription (w / w%)

[0129]

[0130]

[0131] Note: The percentages in the above table are all mass percentages.

[0132] Table 3-1 Composition of pharmaceutical composition prescription (w / w%)

[0133]

[0134]

[0135] Table 3-2 Composition of pharmaceutical composition prescription (w / w%)

[0136]

[0137]

[0138] Note: The percentages in the above table are all mass percentages.

[0139] Preparation method: dissolve the compound of formula I and minoxidil raw material in dimethyl sulfoxide, add other solvents and transdermal enhancers, and stir evenly.

[0140] The prescriptions in Table 1 to Table 3 can all be used to prepare the corresponding pharmaceutical compositions according to the above preparation methods.

[0141] Example 2: In vitro skin permeation experiment

[0142] (1) Preparation before the experiment

[0143] Preparation of receiving solution: Weigh 400g of propylene glycol and 600g of purified water, and stir them evenly in a beaker.

[0144] Skin preparation: Take the Bama pork skin, remove the hair and fat, and set aside.

[0145] (2) Experimental process

[0146] Turn on the transdermal diffusion instrument, set the temperature to 32°C and the speed to 200 rpm;

[0147] Add a stir bar and receiving solution to the diffusion cell and place it on the instrument to preheat to 32°C;

[0148] Add the treated pigskin to the diffusion cell, and add about 20 mg of the sample to be tested (i.e., the pharmaceutical composition prepared by the prescription in Example 1);

[0149] After 24 hours, the receiving solution was filtered and the drug content was detected, which was recorded as the 24-hour cumulative permeation amount.

[0150] (3) Pigskin treatment after the experiment

[0151] Remove the pig skin and rinse the surface with a diluent (a mixed solution of 50% acetonitrile and 50% purified water). Cut the pig skin 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 pig skin. After filtering, detect the drug content in the extract, which is recorded as the skin retention amount.

[0152] (4) Experimental results

[0153] Table 4

[0154]

[0155]

[0156] The results showed that: a comprehensive comparison of the skin retention amount and the 24h cumulative penetration amount revealed that the drug composition prescription 15 had a better penetration effect, and further combined with the stability effect, the drug composition prescription 15 was selected as the preferred prescription.

[0157] Example 3: Preparation method of pharmaceutical composition

[0158] Table 5

[0159] Composition / drug composition Prescription 11 Prescription 15 Compounds of formula I 1 1 Minoxidil API 2 2 Transcutol P 49 49 Propylene glycol 33 33 DMSO 5 5 Capmul PG-8 10 5 Capmul MCM-C8 0 5 total 100 100

[0160] According to the formulation composition in Table 5, the compound of formula I and the minoxidil API are dissolved in dimethyl sulfoxide, and Transcutol P, propylene glycol, Capmul PG-8 and / or Capmul MCM-C8 are added in sequence and stirred evenly.

[0161] Example 4: Experimental study on the efficacy of the pharmaceutical composition in treating alopecia areata

[0162] (1) Experimental animals

[0163] 60 female C57BL / 6N mice, 49 days old, weighing 16-19 g, SPF grade, were selected according to the condition of the animals' backs after shaving, and animals with pink and spot-free backs after shaving were selected for the experiment. Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., SCXK (Zhe) 2019-000120221117Abzz0619000331.

[0164] (2) Prescription of pharmaceutical composition

[0165] Table 6

[0166]

[0167]

[0168] (3) Dosage regimen

[0169] Table 7

[0170]

[0171] (4) Experimental process

[0172] One day before the start of drug administration, 30 animals with pink back skin, no dark spots, and no damage were selected based on skin color and hair growth. They were randomly divided into cages with 3 animals per cage, and the tails of the animals were numbered and recorded using a permanent marker. The drug was administered twice a day. From the second day of drug administration, photos were taken between the two doses to record the hair growth and score the results. The weight of the mice was weighed and recorded every day.

[0173] (5) Experimental results

[0174] 5.1 Hair growth rating

[0175] 0 points: The skin is pink and tender, the same as the initial state after shaving

[0176] 1 point: The skin in the administration area turns gray to black, with no obvious hair growth

[0177] 2 points: Short hair growth can be seen in the drug administration area

[0178] 3 points: Short hair growth can be seen in most of the administration area, and sparse long hair appears

[0179] 4 points: There is dense long hair growth, but it does not cover the entire administration area

[0180] 5 points: Dense long hair covers the entire administration area

[0181] 5.2 Hair growth score

[0182] Table 8

[0183]

[0184] The results showed that compared with the blank control group, the treatment effects of prescription 11 and prescription 15 showed significant differences in the hair growth scores starting from the 12th day of transdermal administration; the treatment effects of prescription 11 and prescription 15 were better than those of single minoxidil lotion and single compound I lotion (see Table 8 and Figure 1 ). At the same time, there was no obvious abnormality in the weight of the animals during the administration period, indicating that the ointment of prescription 11 and the ointment of prescription 15 had no obvious toxic 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 solvate of a pharmaceutically acceptable salt thereof; 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 consists of the active ingredient B and the pharmaceutically acceptable carrier; (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 agent is preferably selected from one or more of diethylene glycol monoethyl ether, polyoxyethylene lauryl ether and polyethylene glycol hexadecyl ether; the bile salt agent is preferably selected from deoxycholate and / or glycocholate; the ester agent is preferably selected from 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 phospholipids. 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 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 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, caprylic 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; 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) When the transdermal penetration enhancer is a mixed transdermal penetration enhancer of diethylene glycol monoethyl ether, monocaprylic acid glyceryl and caprylic acid capric acid polyethylene glycol glyceride, the mass ratio of diethylene glycol monoethyl ether to caprylic acid capric acid polyethylene glycol glyceride is 8:1 to 10:1, for example, 9.8:1; the mass ratio of monocaprylic acid glyceryl and caprylic acid capric acid polyethylene glycol glyceride is 0.5:1 to 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% of propylene glycol, 5% of dimethyl sulfoxide, 5% of Tween 80 and 5% of 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 drug for preventing, alleviating or treating alopecia areata, wherein: The use is not the use of the pharmaceutical composition C in the preparation of a drug for preventing, alleviating or treating alopecia areata, and the pharmaceutical composition C comprises the following components by mass fraction: 0.1%-3% of the 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 one or more of water, glycerol, polyethylene glycol 400, dimethyl sulfoxide, ethyl acetate, propylene glycol and ethanol; the transdermal enhancer is selected from 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,

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