Compound preparation for treating alopecia areata

Abstract

The invention relates to a compound preparation for treating alopecia areata, an active component A is a direct or indirect EPO receptor agonist, an active component B is tofacitinib or a pharmaceutically acceptable salt thereof, and the EPO receptor agonist is preferably rosaxostat. The compound preparation has the beneficial effects that the rosaxostat and the tofacitinib or the pharmaceutically acceptable salts thereof are limited when being independently used for treating the alopecia areata, but the rosaxostat and the tofacitinib or the pharmaceutically acceptable salts thereof just act on different targets in the alopecia areata pathogenesis respectively, so that the compound preparation is prepared, a key signal channel in the alopecia areata pathogenesis is inhibited through the rosaxostat, and the curative effect of the rosaxostat on the alopecia areata pathogenesis is improved. The defect that tofacitinib is insufficient in curative effect on moderate and severe patients is made up from the pathogenesis, meanwhile, the defect that tofacitinib is poor in hair repairing effect is improved from the symptom through the good hair growth promoting effect of the rosastat, the medicine effects of the tofacitinib and the rosastat are complementary, both symptoms and root causes are treated, and the tofacitinib and the rosastat can be combined according to the synergistic interaction. Appropriate reduction of the dosage of tofacitinib can reduce the risk of side effects.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a compound preparation for treating alopecia areata. Background Art

[0002] Alopecia areata is a common, non-scarring hair loss disease caused by an inflammatory response of the hair follicles. It can be divided into localized patchy alopecia areata, total alopecia and universal alopecia according to its pathological characteristics and severity. The global incidence rate is about 1% to 2%. Most patients are children and young adults. Alopecia areata affects the appearance and mental health of patients. Conventional treatment drugs (including glucocorticoids, compound glycyrrhizin, contact sensitizers, hair growth promoters, etc.) are limited due to side effects, incomplete treatment and only effective for mild alopecia areata. Therefore, new treatment methods need to be developed.

[0003] Alopecia areata is an inflammatory autoimmune disease associated with the destruction of the immune immunity mechanism of hair follicles, in which the inflammatory cytokine signaling pathway - the JAK (Janus kinase)-STAT pathway plays a key role. In recent years, JAK inhibitors have become a new strategy for the treatment of alopecia areata. Cytokines bind to their receptors, activate the JAK pathway to phosphorylate STAT, and STAT dimers are transported to the cell nucleus to activate gene transcription, leading to further production of cytokines and self-antigens, activating inflammation and immune responses. The JAK / STAT signaling pathway is involved in the hair growth cycle, upregulated in the regression and resting phases, and inhibited in the growth phase. Blocking the related JAK-STAT pathway can reduce the production of self-antigens and inflammatory mediators, and prevent hair follicle immune responses.

[0004] From the above, we can see that JAK inhibitors can block cytokine signaling, which plays a key role in the pathogenesis of alopecia areata. Therefore, compared with other drugs, they are theoretically more effective. Tofacitinib (Pacritinib) is a new type of oral kinase inhibitor that can specifically inhibit JAK2, IRAK1 and CSF1R. Because it does not inhibit JAK1, it can avoid the potential side effects of inhibiting JAK1.

[0005] The collapse of hair follicle immune privilege (IP) is a prerequisite for the development of alopecia areata. Since the failure of the IP mechanism allows AA to develop, it is reasonable to expect that restoring and / or supplementing IP signaling is a highly effective method for treating AA and preventing future relapses. Erythropoietin (EPO) is an evolutionarily conserved hormone that has been well documented to promote erythropoiesis by binding to the homodimeric EPO receptor (EPOR) 2. Over the past few decades, evidence has emerged that EPO's effects extend far beyond erythropoiesis. By binding to tissue protection receptors (TPRs), EPO inhibits proinflammatory cytokines, protects cells from apoptosis, and promotes wound healing. EPO plays a central role in tissue protection and repair. Previously, these effects were thought to be mediated by inhibiting proinflammatory cytokines and downregulating apoptosis. Recent studies have shown that EPO and its derivatives can also act directly on immune cells, restoring IP signaling by regulating the immune environment around hair follicles to achieve the therapeutic effect of AA.

[0006] In summary, by inhibiting the JAK signaling pathway to reduce the attack of immune cells on hair follicle tissue and using EPOR agonists to restore the immune immunity of hair follicles, the normal physiological function of hair follicles can be restored from the source. Currently, there is a lack of sustained, effective or permanent treatment methods to reverse alopecia areata, and there is an urgent need for a compound preparation that can restore the immune immunity of hair follicles. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a compound preparation for treating alopecia areata, which can be administered systemically or locally to overcome the deficiencies in the above-mentioned prior art.

[0008] The technical solution of the present invention to solve the above technical problems is as follows: a compound preparation for treating alopecia areata, comprising: an active ingredient A and an active ingredient B, wherein the active ingredient A is a direct or indirect EPO receptor (Erythropoietin receptor, EPOR) agonist, and the active ingredient B is tofacitinib or a pharmaceutically acceptable salt thereof.

[0009] Based on the above technical solution, the present invention can also be improved as follows.

[0010] Further, the compound preparation is a liniment or a gel;

[0011] Calculated as EPO receptor agonist, the percentage of the active ingredient A in the compound preparation is 0.1wt% to 10wt% or 0.1% (w / v) to 10% (w / v);

[0012] Calculated on the basis of tofacitinib, the percentage of the active ingredient B in the compound preparation is 0.1wt% to 10wt% or 0.1% (w / v) to 10% (w / v).

[0013] Furthermore, the present invention is directed to a composition for treating, preventing or alleviating alopecia areata, which is administered topically or by injection to a subject in need thereof, wherein the composition comprises a therapeutically effective amount of at least one EPO receptor agonist, wherein the EPO receptor agonist is selected from the group consisting of epoetin β, pegisatide, pemosatide, molisin, dapnostat, roxadustat and combinations thereof, and in fact, other common EPO receptor agonists such as epoetin β, pegisatide, pemosatide, molisin, dapnostat, roxadustat and combinations thereof are not limited thereto, and can be used in combination with tofacitinib to achieve this effect.

[0014] Further, the concentration of the EPO receptor agonist is about 0.01% to about 1%, about 1% to about 3%, about 3% to about 5% w / w; from 5% to 10% w / w or from 10% to 20% w / w.

[0015] Furthermore, the EPO receptor agonist is roxadustat.

[0016] Furthermore, the compound preparation also includes pharmaceutically acceptable excipients.

[0017] Commonly used pharmaceutical excipients in liniments and gels in pharmacy include but are not limited to the following:

[0018] Gel matrix: This is the most important component of the gel. Commonly used gel matrices include carbomer, xanthan gum, etc., which provide the necessary consistency and stability for the gel.

[0019] pH adjuster: used to adjust the pH value of the gel to ensure the stability of the drug and reduce irritation. Commonly used pH adjusters include citric acid, sodium hydroxide, phosphate buffer, etc.

[0020] Moisturizer: Increase the moisturizing properties of the gel. Commonly used moisturizers include glycerin, propylene glycol, hyaluronic acid, etc.

[0021] Preservatives: Prevent the growth of microorganisms during the storage and use of gels. Commonly used preservatives include benzalkonium chloride, parabens, etc.

[0022] Stabilizer: used to maintain the stability of drugs in gels. Commonly used stabilizers include EDTA (used to chelate metal ions), cyclodextrins, etc.

[0023] Co-solvents and solubilizing agents: help dissolve drugs, improve drug solubility and bioavailability. Commonly used co-solvents and solubilizing agents include polyethylene glycol (PEG), poloxamer, etc.

[0024] Transdermal absorption enhancers: Increase the absorption of drugs through the skin. Commonly used transdermal absorption enhancers include laurocapram (Azone) and the like.

[0025] Other excipients: such as emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, etc. These excipients are also used in ointments and gels, depending on the specific requirements and purpose of the preparation.

[0026] The selection and use of the above excipients need to be comprehensively considered based on the properties of the drug, the process requirements of the preparation, and the expected efficacy and safety. At the same time, the incompatibility and stability of the excipients also need to be considered to ensure that there will be no adverse reactions between the excipients and the drug, affecting the efficacy and safety of the drug.

[0027] Further, the "pharmaceutically acceptable salt" includes acid and base addition salts selected from citrate, hydrochloride, oxalate, phosphate, sulfate, fumarate, succinate, tartrate, nitrate or maleate; it should be understood that when a compound or example in the present application is shown as a specific salt, it is intended to cover the corresponding free base and other salts of the corresponding free base (including pharmaceutically acceptable salts of the corresponding free base).

[0028] Further, the "pharmaceutically acceptable acid addition salt" refers to those salts formed with inorganic or organic acids, which retain the biological effectiveness and properties of the free base and do not have biological or other undesirable effectiveness and properties, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the organic acid can be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid.

[0029] Further, the "pharmaceutically acceptable base addition salts" include those derived from sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts of inorganic bases; specific base addition salts are ammonium, potassium, sodium, calcium and magnesium salts; salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylolamine, trimethoate ... Amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin; specific organic non-toxic base is isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine. The pharmaceutically acceptable excipients may include at least one selected from penetration enhancers, surfactants, crystal inhibitors, foam adjuvants, thickeners, pH regulators, gel matrix, antioxidants, metal ion chelators, moisturizers and solvents.

[0030] Furthermore, the content of the solvent is 5wt% to 80wt% of the compound external preparation.

[0031] Furthermore, the ointment comprises: active ingredient A, active ingredient B, a solvent and pharmaceutically acceptable excipients; calculated as EPO receptor agonist, the percentage of active ingredient A in the compound external preparation is 0.1wt% to 10wt%; calculated as JAK inhibitor, the percentage of the mass of active ingredient B to the volume of the compound external preparation is 0.1% (w / v) to 10% (w / v); the solvent is a mixture of water and alcohol; the content of the solvent is 50wt% to 99.8wt% of the ointment; the content of the pharmaceutically acceptable excipient is 0 to 20wt% of the ointment.

[0032] Furthermore, the gel comprises: active ingredient A, active ingredient B, a solvent and pharmaceutically acceptable excipients; the pharmaceutically acceptable excipients include a gel matrix and other excipients, and the other excipients include at least one selected from a penetration enhancer, a surfactant, an anti-crystal agent, an antioxidant, and an antibacterial agent; as measured by EPO receptor agonist, the percentage of active ingredient A in the compound external preparation is 0.1wt% to 5wt%; as measured by JAK inhibitor, the percentage of the mass of active ingredient B to the volume of the compound external preparation is 1% (w / v) to 5% (w / v); the solvent is a mixture of water and alcohol; the content of the solvent is 50wt% to 98.8wt% of the compound external preparation; the content of the gel matrix is ​​0.1wt% to 30wt% of the compound external preparation, and the content of the other excipients is 0 to 20wt% of the compound external preparation.

[0033] Furthermore, the active ingredient A is 0.5% to 6.0%, the active ingredient B is 0.5% to 6.0%, the thickener is 0.1% to 1%, the pH regulator is 0.1% to 2.0%, the antioxidant is 0.1% to 2.0%, the metal chelating agent is 0.1% to 0.5%, the moisturizing agent is 1% to 10%, and the rest is the solvent.

[0034] The beneficial effects of the present invention are:

[0035] The EPO receptor agonist roxadustat and tofacitinib or their pharmaceutically acceptable salts both have limitations when used alone to treat alopecia areata, but the two happen to act on different targets in the pathogenesis of alopecia areata, so it is possible to consider making a compound preparation. Roxadustat can inhibit the key signaling pathways in the pathogenesis of alopecia areata, thereby making up for the lack of efficacy of tofacitinib in moderate and severe patients from the etiology. At the same time, roxadustat's good hair growth-promoting effect can improve the shortcomings of tofacitinib in hair repair from the symptomatic point of view. The two have complementary efficacy and treat both the symptoms and the root causes. In addition, the dose of tofacitinib can be appropriately reduced based on the synergistic effect, thereby reducing the risk of side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 To compare the hair growth of each group before and after administration;

[0037] Figure 2 A is a comparison of the back skin growth area.

[0038] Figure 2 B is the comparison of the area of ​​the back skin growth area quantified by ImageJ software

[0039] Figure 2 C is a comparison of hair growth scores assessed using a scoring index (0 = no growth, 1 = 0-20% growth, 2 = 20-40%, 3 = 40-60%, 4 = 60-80%, 5 = 80-100%).

[0040] Figure 2 D is the comparison of the number of hair follicles in the back skin.

[0041] Figure 2 E is the A / T ratio of the back skin hair follicles.

[0042] Figure 2 F and 2G are HE staining of the dorsal skin (×100 magnification). DETAILED DESCRIPTION

[0043] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific implementation disclosed below.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0045] Experimental Example 1: Gel

[0046] (1) Prescription

[0047]

[0048] (2) Preparation method

[0049] Preparation of aqueous phase mixture: dissolve butylated hydroxytoluene, glycerol, roxadustat, and tofacitinib in odorless ethanol;

[0050] Preparation of oil phase mixture: Dissolve lactic acid and anhydrous citric acid in purified water;

[0051] Mix the above two solutions, add Carbomer 980 to disperse evenly, add triethanolamine, and adjust the pH to about 5.0.

[0052] Comparative Example 1: Rosuvastatin-Gel

[0053] (1) Prescription

[0054]

[0055] (2) Preparation method

[0056] Preparation of aqueous phase mixture: dissolve butylated hydroxytoluene, glycerol and rosuvastatin in odorless ethanol; preparation of oil phase mixture: dissolve lactic acid and anhydrous citric acid in purified water;

[0057] Mix the above two solutions, add Carbomer 980 to disperse evenly, add triethanolamine, and adjust the pH to about 5.0.

[0058] Comparative Example 2: Tofacitinib-Gel

[0059] (1) Prescription

[0060]

[0061]

[0062] (2) Preparation method

[0063] Preparation of aqueous phase mixture: dissolve butylated hydroxytoluene, glycerol and tofacitinib in odorless ethanol;

[0064] Preparation of oil phase mixture: Dissolve lactic acid and anhydrous citric acid in purified water;

[0065] Mix the above two solutions, add Carbomer 980 to disperse evenly, add triethanolamine, and adjust the pH to about 5.0.

[0066] Experimental Example 2

[0067] Evaluation of the therapeutic effect of roxadustat combined with tofacitinib for alopecia areata

[0068] (1) Animals

[0069] Mouse model of alopecia areata: C57BL / 6 mice aged 6 to 8 weeks were taken, half male and half female, and after light anesthesia with ether, rosin and paraffin (1:1) were heated and melted and applied to the back. After solidification and hardening, it was removed. After 8 to 9 days, the growth phase hair follicles were induced in the skin of the mouse back. A single dose of 150 mg / kg cyclophosphamide was intraperitoneally injected. After 4 to 5 days, the hair on the back of the mouse began to fall off, and the alopecia areata model was established.

[0070] (2) The test animals were grouped according to the type of drug given:

[0071] ① Normal group (no medication)

[0072] ②Alopecia areata model group (no medication)

[0073] ③ Roxadustat combined with tofacitinib group (Example 1)

[0074] ④Roxadustat group (Comparative Example 1)

[0075] ⑤ Tofacitinib group (Comparative Example 2)

[0076] Note: Normal mice were depilated before administration to induce hair growth; except for the normal group and the alopecia areata model group

[0077] Except for the mice in group 1 that were not medicated, the other groups were medicated with alopecia areata mice.

[0078] (3) Dosage regimen

[0079] Dosage: 1.5 g / time; 2 times / day; continuous administration for 4 weeks;

[0080] Dosage: Apply to the bald spots on the back of mice.

[0081] (4) Evaluate the treatment of alopecia areata in each group of mice according to the following criteria

[0082] Before drug administration, an area of ​​approximately 6 cm was selected on the back of each mouse. 2 The alopecia areata skin of the mice was used as the experimental area. After administration, the hair growth of the mice was observed every day. Five hairs were randomly plucked from each mouse and the length was measured using a vernier caliper, and the average value was taken. 2 The experimental area was removed with the skin, and the hair on the skin was carefully plucked with tweezers and weighed. The skin tissue of the experimental area was then fixed with 10% formaldehyde, and 4 pieces of tissue were taken continuously along the longitudinal section of the hair follicle, each 1.5 cm long, and routine tissue dehydration, paraffin embedding, HE staining, and light microscopy were performed to observe the indicators related to mouse skin tissue and hair growth, including:

[0083] ① Diameter of superficial dermal blood vessels (μm): Randomly measure the diameters of 5 cross-sectioned capillaries and calculate the average;

[0084] ②Number of blood vessels in the superficial dermis: count at 200 times the visual field size, count 5 visual fields, and calculate the average number;

[0085] ③ Number of newly formed hair follicles in the superficial dermis: Count at 100 times the visual field size, count 5 visual fields, and calculate the average.

[0086] The mean values ​​of the data in each group were statistically analyzed using t-test, *P<0.05, **P<0.01, compared with the mice in the alopecia areata model group. The results are as follows:

[0087] Table 1. Effects of each drug group on mouse hair growth

[0088]

[0089]

[0090] Table 2. Effects of each drug group on mouse skin capillaries and hair follicles

[0091] Group n Number of hair follicles Number of capillaries Capillary diameter (μm) Normal group 16 9.42±0.34** 7.46±0.73** 7.53±1.15** Alopecia areata model group 16 7.61±1.17 6.47±1.85 6.29±0.73 Example 1 Group 16 9.25±0.62** 7.45±1.11** 7.82±1.51** Comparative Example 1 16 8.85±1.66** 7.59±1.56** 8.01±1.83** Comparative Example 2 16 9.28±0.97** 7.35±1.30** 6.99±1.55**

[0092] Analysis of results: From the results in Tables 1 and 2, it can be seen that the hair growth rate of the group using roxadustat combined with tofacitinib is faster than that of the group using either component alone, and the number of hair follicles, capillaries and capillary diameter can be significantly increased, indicating that roxadustat combined with tofacitinib can play a synergistic role.

[0093] Example 3

[0094] Roxadustat combined with tofacitinib promotes hair growth in C3H / HEJ mice

[0095] Male C3H / HEJ mice were selected, and imiquimod cream was applied to the back of the mice every 3 days for two weeks before administration, and the hair on the back of the mice was removed one day before administration. The single-dose group of roxadustat (roxadustat concentration was 4 mg / mL, 0.1 mL each time), the single-dose group of tofacitinib (tofacitinib concentration was 10 mg / mL, 0.1 mL each time), and the roxadustat combined with tofacitinib group (roxadustat concentration was 4 mg / mL, 0.1 mL each time, tofacitinib concentration was 10 mg / mL, 0.1 mL each time), and the positive control was minoxidil (minoxidil 50 mg / mL, 0.2 mL). The single-dose group of roxadustat, the single-dose group of tofacitinib, and the tofacitinib group were locally injected intradermally once a day; minoxidil was applied to the hair removal area twice a day; and the drug was administered continuously for 15 days.

[0096] Hair growth was recorded daily using a digital camera. Changes in hair area were assessed using ImageJ image analysis software. The area under the hair area-time curve was calculated.

[0097] After the administration, the animals were euthanized and the experimental areas of some animals were observed for pathological reasons. Figure 2 As shown, (A) Comparison of dorsal skin growth areas. (B) Comparison of dorsal skin growth areas quantified using ImageJ software. (C) Comparison of hair growth scores assessed using scoring indicators (0 = no growth, 1 = 0% to 20% growth, 2 = 20% to 40%, 3 = 40% to 60%, 4 = 60% to 80%, 5 = 80% to 100%). (D) Comparison of the number of dorsal skin hair follicles. (E) A / T ratio of dorsal skin hair follicles. (F, G) HE staining of dorsal skin. (*, p<0.05; **, p<0.01; ***, p<0.001.).

Claims

1. A compound preparation for treating alopecia areata, characterized in that: include: Active ingredient A and active ingredient B, wherein the active ingredient A is a direct or indirect EPO receptor agonist, and the active ingredient B is tofacitinib or a pharmaceutically acceptable salt thereof.

2. A compound preparation for treating alopecia areata according to claim 1, characterized in that: The compound preparation is a liniment or a gel; Calculated as EPO receptor agonist, the percentage of the active ingredient A in the compound preparation is 0.1wt% to 10wt% or 0.1% (w / v) to 10% (w / v); Calculated on the basis of tofacitinib, the percentage of the active ingredient B in the compound preparation is 0.1wt% to 10wt% or 0.1% (w / v) to 10% (w / v).

3. A compound preparation for treating alopecia areata according to claim 1, characterized in that: The EPO receptor agonist is selected from the group consisting of epoetin beta, pegisatide, pemosatide, molistat, dapsastat, roxadustat and combinations thereof.

4. A compound preparation for treating alopecia areata according to claim 3, characterized in that: The concentration of the EPO receptor agonist is about 0.01% to 1%, about 1% to 3%, about 3% to 5% w / w; from 5% to 10% w / w or from 10% to 20% w / w.

5. A compound preparation for treating alopecia areata according to claim 3 or 4, characterized in that: The EPO receptor agonist is roxadustat.

6. A compound preparation for treating alopecia areata according to claim 1, characterized in that: The compound preparation also includes pharmaceutically acceptable excipients.

7. The compound external preparation according to claim 1, characterized in that: The content of the solvent is 5wt% to 80wt% of the compound external preparation.

8. The compound external preparation according to claim 2, characterized in that: The ointment comprises: an active ingredient A, an active ingredient B, a solvent and a pharmaceutically acceptable excipient; calculated as an EPO receptor agonist, the percentage of the active ingredient A in the compound external preparation is 0.1wt% to 10wt%; calculated as a JAK inhibitor, the percentage of the mass of the active ingredient B to the volume of the compound external preparation is 0.1% (w / v) to 10% (w / v); the solvent is a mixture of water and alcohol; the content of the solvent is 50wt% to 99.8wt% of the ointment; the content of the pharmaceutically acceptable excipient is 0 to 20wt% of the ointment.

9. The compound external preparation according to claim 2, characterized in that: The gel comprises: active ingredient A, active ingredient B, a solvent and pharmaceutically acceptable excipients; the pharmaceutically acceptable excipients comprise a gel matrix and other excipients, the other excipients comprising at least one selected from a penetration enhancer, a surfactant, an anti-crystal agent, an antioxidant and an antibacterial agent; the percentage of the active ingredient A in the compound external preparation is 0.1wt% to 5wt% based on the EPO receptor agonist; the percentage of the mass of the active ingredient B to the volume of the compound external preparation is 1% (w / v) to 5% (w / v) based on the JAK inhibitor; the solvent is a mixture of water and alcohol; the content of the solvent is 50wt% to 98.8wt% of the compound external preparation; the content of the gel matrix is ​​0.1wt% to 30wt% of the compound external preparation, and the content of the other excipients is 0 to 20wt% of the compound external preparation.

10. A gel for treating alopecia areata according to claim 2, characterized in that The invention comprises, by weight percentage, 0.5% to 6.0% of active ingredient A, 0.5% to 6.0% of active ingredient B, 0.1% to 1% of thickener, 0.1% to 2.0% of pH regulator, 0.1% to 2.0% of antioxidant, 0.1% to 0.5% of metal chelating agent, 1% to 10% of moisturizing agent, and the rest is solvent.

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