A topical combination of an androgen receptor antagonist and minoxidil and uses thereof

Abstract

The application provides a composition of a locally acting androgen receptor antagonist and minoxidil and application thereof, and the composition comprises 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioximidazolin-1-yl)-2-fluorobenzoic acid sec-butyl ester or stereoisomers thereof and minoxidil or pharmaceutically acceptable salts thereof. The composition provided by the application increases the stability of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioximidazolin-1-yl)-2-fluorobenzoic acid sec-butyl ester and stereoisomers thereof in an aqueous solution. And the efficacy of the compound composition is better than that of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioximidazolin-1-yl)-2-fluorobenzoic acid sec-butyl ester or minoxidil alone.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a composition of a locally acting androgen receptor antagonist and minoxidil, and its application. Background Technology

[0002] Hair loss is a group of diseases that cause the loss of body hair, with a variety of different causes. The most common form of hair loss is androgenetic alopecia (AGA). AGA is also commonly known as male pattern baldness, male pattern hair loss, or male or female pattern hair loss. AGA is reported to affect approximately 50% of men over the age of 40. By age 70, this form of hair loss may eventually affect 80% of white men and about half of all women. Hair loss often causes significant concern for patients due to aesthetic and psychological reasons, and it can also be an important symptom of systemic diseases.

[0003] Alopecia areata (AGA) is a hereditary hair follicle disorder that is also dependent on androgens. Dihydrotestosterone (DHT) plays a particularly significant role in the occurrence and development of AGA. AGA-related hair loss is progressive, causing patients to experience a reduction in the normal 4:1 ratio of terminal hair to vellus hair over a period of time. During this process, terminal hair is converted into indeterminate hair, eventually becoming vellus hair. As AGA progresses, men exhibit thinning hair in the temporal region, which then progresses to thinning hair in the crown (vertex area). Women typically exhibit more diffuse thinning in the crown area, which is less common in male pattern baldness.

[0004] In living organisms, AGA is characterized by increased levels and activity of 5α-reductase isoenzymes. These enzymes convert testosterone (T) into its active metabolite, dihydrotestosterone (DHT). Due to the increased binding affinity of the hormone to androgen receptors in hair follicles, high concentrations of DHT in the follicles shorten the hair growth cycle and gradually shrink the hair follicles. Even after the follicles shrink, the fiber bundles remain. In most cases, these DHT-dependent effects are considered reversible, making it possible to treat AGA with medications that reduce DHT production or antagonize the DHT / T interaction with androgen receptors in hair follicles.

[0005] Currently, medical management of AGA includes surgical and drug treatment options. The most common surgical intervention for AGA is hair transplantation. This procedure has been successfully performed over the past four decades. Hair transplantation involves harvesting intact hair follicles from the safe donor area (SDA) of the patient's scalp through follicular unit stripping surgery (FUSS) or follicular unit extraction (FUE). In the past decade, these procedures have been improved, resulting in significantly higher hair survival rates and more natural-looking results.

[0006] The aesthetic results after surgery are often satisfactory, but the procedure should only be performed when there are enough transplantable hair follicles to cover one or more bald areas. Furthermore, hair transplantation is typically used for patients who have experienced extensive hair loss and those whose AGA (aerobically bald patches) has not yet progressed. For example, hair transplantation is generally not recommended in younger patients because androgens, especially DHT, can act on newly transplanted follicles, leading to the same thinning hair and eventual alopecia, thus affecting existing follicles. For this reason, medical intervention is preferred at the onset and initial stages of AGA.

[0007] Currently, only two drugs are approved for the treatment of AGA: minoxidil and finasteride. Minoxidil is a topical drug formulation available in two concentration levels—2% (topical solution) and 5% (topical solution or foam). To exert its effect, minoxidil needs to be converted into its active metabolite, minoxidil sulfate, by sulfotransferase. This enzyme is present in the outer root sheath of hair follicles during the anagen phase.

[0008] While the exact mechanism by which minoxidil promotes hair growth is not fully understood, it is believed that minoxidil sulfate opens ATP-sensitive potassium channels in cell membranes, leading to vasodilation. However, vasodilation does not appear to be the cause of minoxidil's hair growth effect. Other possible effects of minoxidil on hair follicles include: a) increased expression of vascular endothelial growth factor (VEGF) mRNA in the dermal papilla, suggesting that the drug induces angiogenesis in the dermal papilla; b) activation of cytoprotective prostaglandin synthase-1 (a cytoprotective enzyme that stimulates hair growth); and c) increased expression of hepatocyte growth factor (HGF, a hair growth promoting factor). In various clinical trials, minoxidil has effectively and significantly improved total hair volume and non-vellus hair volume after 6 to 12 months of treatment compared to placebo. Despite these beneficial effects, minoxidil does not reduce dihydrotestosterone (DHT) or the enzyme that causes DHT to accumulate around the hair follicle, 5-α reductase, which is a major mediator of male pattern baldness in genetically susceptible individuals. Therefore, when treatment is stopped, DHT causes genetically predisposed hair follicles to atrophy and eventually destroy them. Furthermore, the clinically recommended topical minoxidil concentrations are mainly 2% and 5%. Although studies have shown that 5% minoxidil is more effective than 2%, more cases of local irritation and allergic dermatitis have been reported in patients using the 5% formulation than the 2% formulation, indicating a dose-dependent effect.

[0009] On the other hand, finasteride inhibits type 5-αII reductase, an enzyme responsible for converting testosterone to DHT at the hair follicle. Finasteride is administered orally in 1 mg tablet form. A single oral dose of 1 mg finasteride reduces serum and scalp DHT by up to 70% compared to baseline. In several published clinical trials, total hair volume was significantly improved after 6 months of treatment with 1 mg finasteride compared to placebo. The significant increase in total hair volume in patients treated with 1 mg finasteride compared to placebo remained unchanged during long-term treatment (up to 60 months).

[0010] While finasteride effectively stops hair loss and improves new hair growth, side effects associated with its use may also exist. First, finasteride is contraindicated in women due to suspected teratogenic effects. Therefore, women who are pregnant or may become pregnant, regardless of whether they have AGA, are strongly advised to avoid contact with broken or crushed tablets. Furthermore, because finasteride is systemically distributed, it lowers DHT levels not only in hair follicles but also in plasma. This systemic activity contributes to the major side effects of finasteride, including decreased libido, erectile dysfunction (impotence), ejaculation disorders, and reduced ejaculate volume. Other less common side effects include breast swelling, palpitations, testicular pain, persistent decreased libido after discontinuation, infertility, and depression.

[0011] Given the shortcomings and drawbacks associated with finasteride and minoxidil therapy, there is clearly a need in the art for new approaches and active agents for the treatment of alopecia, particularly AGA. Summary of the Invention

[0012] Objective of the invention: The technical problem to be solved by the present invention is to provide a composition of a locally acting androgen receptor antagonist and minoxidil, which addresses the shortcomings of the prior art.

[0013] Another technical problem to be solved by the present invention is to provide the application of the above composition.

[0014] To address the aforementioned technical problems, this invention discloses a composition comprising (a) sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or a stereoisomer thereof and (b) minoxidil or a pharmaceutically acceptable salt thereof; in some embodiments, the sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate is (R / S)4-(3- Any one or a combination of several of the following: (4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester, (R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester, and (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester.

[0015] In some embodiments, the molar ratio of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer to minoxidil or its pharmaceutically acceptable salt is 1:1 to 20; in some embodiments, the molar ratio of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate is 1:1 to 20. The molar ratio of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester or its stereoisomer to minoxidil or its pharmaceutically acceptable salt is 1:3 to 20; in some embodiments, the molar ratio of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester or its stereoisomer to minoxidil or its pharmaceutically acceptable salt is 1:9 to 10.

[0016] In some embodiments, the composition further includes a solvent.

[0017] In some embodiments, the composition contains 0.5% to 2% g / mL of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer; in some embodiments, the composition contains any one of 0.5% g / mL, 1.0% g / mL, 1.5% g / mL, and 2% g / mL.

[0018] In some embodiments, the composition contains 2% to 4% g / mL minoxidil or a pharmaceutically acceptable salt thereof; in some embodiments, the composition contains 2% g / mL or 4% g / mL minoxidil or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the solvent is one or more pharmaceutically acceptable solvents; in some embodiments, the solvent is any one or a combination of water, polyols, polyol ethers, and C1-C7 alcohols; in some embodiments, the solvent is a combination of polyol ethers and C1-C7 alcohols.

[0020] In some embodiments, the polyol is any one or a combination of ethylene glycol, propylene glycol, glycerol, and hexanetriol; in some embodiments, the polyol is propylene glycol.

[0021] In some embodiments, the polyol ether is any one or a combination of several of polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, and diethylene glycol monoethyl ether; in some embodiments, the polyol ether is diethylene glycol monoethyl ether.

[0022] In some embodiments, the C1-C7 alcohol is ethanol; in some embodiments, the C1-C7 alcohol is 95% ethanol or anhydrous ethanol.

[0023] In some embodiments, the composition contains 25% to 50% g / mL of 95% ethanol or anhydrous ethanol and 25% to 50% g / mL of diethylene glycol monoethyl ether; in some embodiments, the composition contains 46% g / mL of 95% ethanol or anhydrous ethanol and 30% g / mL of diethylene glycol monoethyl ether.

[0024] In some embodiments, the composition further comprises at least one emulsifier.

[0025] In some embodiments, the emulsifier is PEG-15 hydroxystearate (also known as polyethylene glycol-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbate 20, polysorbate 60, polysorbate 80, PEG-20 cetearyl ether, polyethylene glycol 25 cetearyl ether, polyethylene glycol 1000 monoceryl ether, dehydrated sorbitol monolaurate, dehydrated sorbitol... The emulsifier is any one or a combination of several of the following: sugar alcohol monopalmitate, sorbitan monooleate, propylene glycol ester of fatty acid, polyglycerol ester of fatty acid, polyoxyethylene 5 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, capryloyl-decyl polyethylene glycol-8 glycerol ester, capryloyl-hexyl polyethylene glycol glycerol ester, lauroyl polyethylene glycol glycerol ester, and oleoyl polyethylene glycol glycerol ester; in some embodiments, the emulsifier is polysorbate 80.

[0026] In some embodiments, the emulsifier content in the composition is 0.05% to 0.2% g / mL; in some embodiments, the polysorbate 80 content in the composition is 0.05% to 0.2% g / mL; in some embodiments, the polysorbate 80 content in the composition is 0.1% g / mL.

[0027] In some embodiments, the composition further comprises at least one antioxidant.

[0028] In some embodiments, the antioxidant is any one or a combination of several of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, α-tocopherol, and propyl gallate; in some embodiments, the antioxidant is ascorbyl palmitate.

[0029] In some embodiments, the antioxidant content in the composition is 0.1% to 1% g / mL; in some embodiments, the ascorbate palmitate content in the composition is 0.1% to 1% g / mL; in some embodiments, the ascorbate palmitate content in the composition is 0.5% g / mL.

[0030] In some embodiments, the composition further comprises at least one pH adjuster.

[0031] In some embodiments, the pH adjuster is any one or a combination of several of citric acid monohydrate, citric acid, hydrochloric acid, phosphoric acid, maleic acid, tartaric acid, acetic acid, and sulfuric acid; in some embodiments, the pH adjuster is citric acid and / or citric acid monohydrate.

[0032] In some embodiments, the pH of the composition is 4.0 to 6.0; in some embodiments, the pH of the composition is 4.0 to 5.5.

[0033] To address the second technical problem mentioned above, this invention discloses the application of the above composition in the preparation of products for treating hair loss.

[0034] In some embodiments, the application is in the preparation of a treatment for androgenetic alopecia.

[0035] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0036] The compositions provided by this invention enhance the stability of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate and its stereoisomers in aqueous solutions. Furthermore, in a mouse model of androgenetic alopecia, the combination of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate and minoxidil exhibits superior efficacy compared to sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or minoxidil alone. Attached Figure Description

[0037] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0038] Figure 1 Hair growth was scored for C57BL / 6 mice.

[0039] Figure 2 Image showing hair growth in C57BL / 6 mice. Detailed Implementation

[0040] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0041] The articles “a,” “a kind,” and “described” are used in this text to refer to one or more (i.e., at least one) grammatical objects of an item. For example, “an element” refers to one or more elements.

[0042] As used in this article, the term “hair loss” generally refers to, or individually as specified, androgenetic alopecia (AGA), alopecia areata (including diffuse alopecia areata, unilateral alopecia areata, multiple alopecia areata, serpentine alopecia, total alopecia and universal alopecia), telogen effluvium, anagen effluvium and traction alopecia.

[0043] As used herein, the term "antioxidant" includes pharmaceutically acceptable antioxidants known to those skilled in the art. Examples include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, α-tocopherol (also known as vitamin E), propyl gallate, etc.

[0044] As used herein, the phrase "C1-C7 alcohol" refers to an alcohol having up to seven carbons suitable for use in topical pharmaceutical formulations. Examples of such C1-C7 alcohols include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, benzyl alcohol, etc. Without wishing to be bound by any particular theory, it is believed that C1-C7 alcohols, particularly short-chain C1-C7 alcohols such as ethanol, propanol, or isopropanol, exert a solubilizing effect on sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate. It is also believed that such C1-C7 alcohols contribute to the spreadability of the compositions described herein.

[0045] As used herein, the term "polyol" refers to an organic molecule containing two or more hydroxyl groups. Exemplary polyols include, but are not limited to, ethylene glycol, propylene glycol, glycerol, and hexanetriol.

[0046] As used herein, the phrase "polyol ether" refers to a polyol ether suitable for use in topical pharmaceutical formulations. Exemplary polyol ethers include, but are not limited to, polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether, etc.

[0047] As used herein, the term "solvent" means a pharmaceutically acceptable solvent, or a mixture of one or more such solvents, suitable for topical application to, but not limited to, the scalp, for solubilizing sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate in the compositions described herein.

[0048] The term "treatment" refers to the successful treatment or improvement of any symptom of an injury, disease, or condition, including any objective or subjective parameters such as relief; mitigation; reduction of symptoms or increased tolerance of the injury, disease, or condition; slowing of the rate of degeneration or decline; or improvement of the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including physical examination results, neuropsychiatric examinations, or psychiatric evaluations.

[0049] The term "prevention" refers to avoiding, having, or delaying the onset or recurrence of a disease, disorder, or condition to which the term is used, or the onset or recurrence of one or more symptoms associated with a disease, disorder, or condition. The term "prevention" also refers to reducing the incidence of a disease, disorder, or condition. The term "prevention" refers to preventing this behavior.

[0050] As used herein, the phrase "weight percentage (w / v)" is intended to cover and disclose embodiments in which, for a given value, the weight percentage is a weight percentage by volume (w / v) and a weight percentage by total weight (w / w). For example, an embodiment containing 10 wt% of element "X" discloses an embodiment containing both 10 wt% of "X" (w / v) and 10 wt% of "X" (w / w). Similarly, again by example, an embodiment containing 10 wt% of "X", 20 wt% of "Y", and 60 wt% of "Z" discloses an embodiment containing: a) 10 wt% of "X" (w / v), 20 wt% of "Y" (w / v), and 60 wt% of "Z" (w / v); and b) 10 wt% of "X" (w / w), 20 wt% of "Y" (w / w), and 60 wt% of "Z" (w / w). Nevertheless, in some implementations, a value will be specifically labeled as "(w / w)" or "(w / v)". In these cases, the value should be interpreted as only disclosing the label value, i.e., only disclosing (w / w) or only disclosing (w / v), rather than both.

[0051] As used herein, the terms “comprising,” “including,” “having,” “containing,” etc., are open-ended terms meaning “including but not limited to.” With respect to the given embodiments disclosed herein, “comprising” certain elements should be understood to mean that this disclosure also expressly considers and discloses embodiments that “consist substantially of” and “comprise” these elements.

[0052] As used herein, the terms “substantially composed of”, “substantially constituted by”, etc., should be interpreted as semi-closed terms, meaning that other components that substantially affect the basis and novel features of the implementation are excluded. As used herein, the terms “composed of”, “constituting by”, etc., should be interpreted as closed terms, such that an implementation “composed of a specific set of elements” excludes any elements, steps, or components not specified in that implementation.

[0053] As used herein, the term "ethanol" refers to alcohol, namely CH3CH2OH, and includes pure (completely) ethanol and 95% ethanol, the latter being ethanol with a water content typically from about 4% to about 5.1% by volume.

[0054] Example 1: Preparation of (R / S)4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester (compound 1)

[0055]

[0056] Step 1: Synthesis of Compound 1-1

[0057] In a 250 mL three-necked flask, 150 mL of N,N-dimethylformamide and 15 mL of water were added. Then, 10 g of 2-fluoro-4-bromobenzoic acid, 7.25 g of 2-methylalanine, 15.8 g of potassium carbonate, 1.7 g of cuprous iodide, 1.2 g of 2-acetylcyclohexanone, and 0.8 g of triethylamine were added sequentially. The mixture was heated and stirred at 110 °C for 6 h. The mixture was then diluted with 500 mL of water, and the pH was adjusted to 3-4 with citric acid. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. 50 mL of dichloromethane was added to the resulting crude solid, and the mixture was stirred at room temperature for 1 h. The mixture was then filtered, and the filter cake was washed with dichloromethane. The filter cake was collected and dried to give 9.3 g of compound 1-1.

[0058] Step 2: Synthesis of Compounds 1-2

[0059] 100 mL of methanol and 13 g of compound 1-1 prepared in step 1 were added to a 250 mL three-necked flask. After stirring and dissolving, the mixture was cooled in an ice bath. 25.6 g of thionyl chloride was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was heated to reflux. After the reaction was complete, the heating was turned off, and the mixture was allowed to cool to room temperature. 50 mL of toluene was added, and the mixture was concentrated under reduced pressure. The resulting residue was redissolved in 300 mL of ethyl acetate, washed once with saturated brine, and then washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 11.3 g of compound 1-2.

[0060] Step 3: Synthesis of compounds 1-3

[0061] In a 50 mL three-necked flask, 5 mL of dimethyl sulfoxide, 10 mL of isopropyl acetate, 5 g of compounds 1-2 prepared in step 2 above, and 8.9 g of 4-isothiocyano-2-(trifluoromethyl)benzonitrile were added sequentially. The mixture was heated and stirred at 90 °C for 20 h. Heating was then turned off, and the mixture was allowed to cool naturally to room temperature. The reaction solution was diluted with 50 mL of water and extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting oily substance was added to 35 mL of methanol and stirred at room temperature for 2 h. The mixture was filtered, the filter cake was collected and dried, yielding 5.8 g of compounds 1-3.

[0062] Step 4: Synthesis of compounds 1-4

[0063] Dissolve 3.8 g of compounds 1-3 prepared in step 3 above in 15 mL of tetrahydrofuran, add 15 mL of an aqueous solution containing 0.68 g of sodium hydroxide, and stir the mixture overnight at room temperature. After the reaction is complete, dilute with 50 mL of water, adjust the pH to 3-4 with 1 M dilute hydrochloric acid, and extract three times with ethyl acetate. Combine the organic phases, dry them over anhydrous sodium sulfate, and concentrate the organic phase to obtain 3.0 g of compounds 1-4.

[0064] Step 5: Synthesis of Compound 1

[0065] In a 25 mL round-bottom flask, 0.2 g of compounds 1-4 obtained in step 4, 5 mL of N,N-dimethylformamide, 0.25 g of 2-iodobutane, and 0.15 g of potassium carbonate were added sequentially. The mixture was heated at 60 °C overnight. After the reaction was complete, the heating was removed, and the mixture was cooled to room temperature. 25 mL of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give 0.34 g of a white solid.

[0066] 1 H NMR(400MHz,Chloroform-d)δ8.13(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2.1Hz ,1H),7.25–7.11(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.64(s,6H),1.39(d,J=6.3Hz,3H),1.02(t,J=7.5Hz,3H).

[0067] MS(ESI,[M+H) + )m / z:508.4.

[0068] Example 2: Preparation of (R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester (compound 2)

[0069]

[0070] Compound 2 was prepared by reacting compounds 1-4 obtained in step 4 of Example 1 with (R)-2-butanol, following the method in step 5 of Example 1.

[0071] 1H NMR (400MHz, Chloroform-d) δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.2,2.1Hz ,1H),7.25–7.11(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.65(s,6H),1.38(d,J=6.4Hz,3H),1.01(t,J=7.3Hz,3H).

[0072] MS(ESI,[M+H) + )m / z:508.3.

[0073] Example 3: Preparation of (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester (compound 3)

[0074]

[0075] Compound 3 was prepared by reacting compounds 1-4 obtained in step 4 of Example 1 with (S)-2-butanol, following the method in step 5 of Example 1.

[0076] 1 H NMR(400MHz,Chloroform-d)δ8.13(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2.1Hz,1H),7 .25–7.10(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.64(s,6H),1.39(d,J=6.3Hz,3H),1.02(t,J=7.5Hz,3H).MS(ESI,[M+H] + )m / z:508.3.

[0077] Unless otherwise specified, in the following examples, the 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester is the (R / S)4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester (compound 1) prepared in Example 1.

[0078] The stability studies described in the following examples involved detecting impurities in compound preparations stored for different times using chromatography to determine the stability of each composition. Specific chromatographic conditions were as follows: Waters SunFire column. TM C 18 Column (4.6 mm × 250 mm, 5 μm); mobile phase 0.05% trifluoroacetic acid aqueous solution (A): acetonitrile (B), linear gradient elution, program shown in Table 1; detection wavelength 220 nm; flow rate 1.0 mL / min; column temperature 30 °C; injection volume 10 μL.

[0079] Table 1 Linear gradient elution procedure

[0080] t / min A / ％ B / ％ 0 80 20 50 10 90 51 80 20 60 80 20

[0081] Unless otherwise specified, the impurities mentioned in the following examples refer to all impurities other than the raw materials.

[0082] Example 4: Evaluation of the effect of pH on the stability of compound preparations

[0083] Diethylene glycol monoethyl ether and anhydrous ethanol were mixed, and 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester was added to dissolve it. Minoxidil was then added, followed by the antioxidant (ascorbic acid palmitate) and the emulsifier (polysorbate 80). The mixture was diluted with 10 mL of purified water, and the pH was adjusted with citric acid monohydrate. The final volume was brought to 100 mL with purified water to prepare a solution with the components shown in Table 2 below.

[0084] Table 2

[0085]

[0086] The four batches of samples prepared were subjected to short-term stability studies at 30℃, and the results are shown in Table 3.

[0087] Table 3

[0088]

[0089] The results showed that when the pH was below 5.5, the amount of hydrolysis product (enzalutamide, CAS: 1242137-15-0) of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate was significantly reduced.

[0090] Example 5: Effect of different antioxidants on the stability of the composition.

[0091] Mix 30g of diethylene glycol monoethyl ether and 46g of anhydrous ethanol, add 0.5g of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate to dissolve, then add 2g of minoxidil, followed by the addition of antioxidants (0.3g α-tocopherol, 0.01g butylated hydroxyanisole, 0.1g butylated hydroxytoluene, 0.1g propyl gallate, 0.1g ascorbate palmitate, 0.5g ascorbate palmitate or 1g ascorbate palmitate) and 0.1g polysorbate 80, dilute with 10mL of purified water, adjust the pH to 5.0 with citric acid monohydrate, and bring the volume to 100mL with purified water to prepare a solution with the components shown in Table 4 below.

[0092] Table 4

[0093]

[0094] The results showed that ascorbyl palmitate at a concentration of 0.1%–1.0% g / mL could effectively inhibit the formation of impurities when used as an antioxidant.

[0095] Examples 6-11: Preparation of a compound solution composition of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate and minoxidil

[0096] Diethylene glycol monoethyl ether and anhydrous ethanol were mixed, and sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate was added to dissolve it. Minoxidil was then added, followed by an antioxidant (ascorbic acid palmitate) and an emulsifier (polysorbate 80). The mixture was diluted with 10 mL of purified water, and the pH was adjusted to 5.0 with citric acid monohydrate. The final volume was brought to 100 mL with purified water to prepare a solution with the components shown in Table 5. Table 5: Amounts of each component in the 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate and minoxidil compound solution.

[0097]

[0098] Examples 12-17: Preparation of solutions of ethanol or diethylene glycol monoethyl ether at different concentrations

[0099] Diethylene glycol monoethyl ether and anhydrous ethanol were mixed, and 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester was added to dissolve it. Minoxidil was then added, followed by the antioxidant (ascorbic acid palmitate) and the emulsifier (polysorbate 80). The mixture was diluted with 10 mL of purified water, and the pH was adjusted by adding citric acid monohydrate. The final volume was brought to 100 mL with purified water to prepare a solution with the components shown in Table 6 below.

[0100] Table 6. Solution composition of ethanol or diethylene glycol monoethyl ether at different concentrations

[0101]

[0102] Examples 18-21: Preparation of composition solutions with different polysorbate contents

[0103] Diethylene glycol monoethyl ether and anhydrous ethanol were mixed, and 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate sec-butyl ester was added to dissolve it. Minoxidil was then added, followed by the antioxidant (ascorbic acid palmitate) and the emulsifier (polysorbate 80). The mixture was diluted with 10 mL of purified water, and the pH was adjusted by adding citric acid monohydrate. The final volume was brought to 100 mL with purified water to prepare a solution with the components shown in Table 7 below.

[0104] Table 7 Composition of compositions with different polysorbate contents

[0105]

[0106] Application Experiment Example 1: Hair Growth Model in C57BL / 6 Mice

[0107] Male C57BL / 6 mice aged 6 to 7 weeks in the telogen effluvium stage were purchased and housed in groups under standard conditions. The lower back was shaved with an electric shaver under mild anesthesia, followed by hair removal cream, leaving approximately 2cm x 2cm of bare skin. The following day, mice with intact, pinkish skin on their backs were randomly assigned to three groups: a control group, a model group, and a treatment group, with 6 mice in each group.

[0108] Blank control group: Daily subcutaneous injection of solvent (glycerin:DMSO = 1:1), and application of the composition of Example 6 without active substances to the hair removal area twice daily;

[0109] Model group: Daily subcutaneous injection of dihydrotestosterone solution (solvent: glycerol: DMSO = 1:1) at a dose of 30 mg / kg, and application of the composition of Example 6 without active substances to the hair removal area twice daily;

[0110] Treatment group:

[0111] Example 6: Daily subcutaneous injection of dihydrotestosterone solution (solvent: glycerol: DMSO = 1:1) at a dose of 30 mg / kg, and application of 100 μL to the hair removal area twice daily.

[0112] Example 10: Daily subcutaneous injection of dihydrotestosterone solution (solvent: glycerol: DMSO = 1:1) at a dose of 30 mg / kg, and application of 100 μL to the hair removal area twice daily.

[0113] Example 11: Daily subcutaneous injection of dihydrotestosterone solution (solvent: glycerol: DMSO = 1:1) at a dose of 30 mg / kg, and application of 100 μL to the hair removal area twice daily.

[0114] Record hair growth scores every two days.

[0115] The scoring system used for mouse hair growth is as follows:

[0116] a) 0: No hair growth, pink skin tone;

[0117] b)1: The skin color in the shaved area changes from pink to gray, and there is no visible hair growth, indicating that the hair growth phase has started.

[0118] c)2: The skin in the shaved area is black with tiny hairs;

[0119] d)3: Short black hair in the shaved area;

[0120] e)4: The hair in the shaved area is almost indistinguishable from the surrounding area.

[0121] Hair score Figure 1 As shown, the hair growth of mice is as follows: Figure 2 As shown. The results showed that after 12 days of treatment, Example 6 had a significant effect on promoting hair growth, and its effect was superior to that of Examples 10 and 11. Application Example 2: Antagonistic activity of the compound against androgen receptors

[0122] 1) All test compounds were dissolved in DMSO to prepare a 15 mM solution, and then serially diluted 3-fold 10 times to prepare 15 mM, 5 mM, 1.6667 mM, 0.5576 mM, 0.1852 mM, 0.0617 mM, 0.0206 mM, 0.0069 mM, 0.0023 mM and 0.0008 mM solutions.

[0123] 2) Culture HEK293T cells (ATCC, CRL-3216) according to ATCC recommendations (https: / / www.atcc.org / ). Assay the cells during the exponential growth phase.

[0124] 3) Remove the culture medium from the culture dish, rinse the cells with phosphate buffer, add trypsin solution to the culture dish to separate the cells. Wash the cells once with complete culture medium.

[0125] 4) Wash the cells twice with phosphate buffer to remove phenol red and resuspend them in the culture medium to the appropriate concentration.

[0126] 5) 6*10 6 HEK293T cells were seeded in 100 mm culture dishes (only cells with a survival rate greater than 90% were used for analysis) and cultured at 37°C and 5% CO2 for 16 h.

[0127] 6) The plasmids (pGL4.36[luc2P / MMTV / Hygro], Promega, E1360; pBIND-AR Vector, Kanglong) were transformed; LTX&Plus Reagent (Invitrogen, 15338-100) was transfected into HEK293T cells and cultured at 37°C and 5% CO2 for 5-6 hours.

[0128] 7) Use a non-contact nano-level ultrasonic pipetting system (Labcyte, Echo550) to transfer 50 nml of compound dilution to a 384-well analytical plate.

[0129] 8) HEK293T cells were seeded into 384-well analytical plates at a final concentration of 15,000 cells / well and 1 nM DHT (MCE, HY-A0120) (25 μl).

[0130] 9) The cells were cultured at 37°C and 5% CO2 for 18-20 hours.

[0131] 10) Add 25 μl of luciferase assay reagent (britelite plus, PerkinElmer, 6066769) to each well of the 384-well assay plate.

[0132] 11) Record the luminescence value using an ELISA reader (Envision 2105, PerkinElmer) and calculate the IC50. 50 .

[0133] Table 8. Antagonistic activity of compounds against androgen receptors

[0134] Example <![CDATA[IC 50 (μM)]]> 1 0.778 2 1.032 3 0.508 Ethyl enzalutamide 1.527 Enzalutamide 0.776 Enzalutamide >30

[0135] The results indicate that the compound of this application has androgen receptor antagonistic activity.

[0136] Wherein, the ethyl enzalutamide is Application Example 3: Chemical Stability

[0137] Preparation of warm incubation solution: Add 10 mL of 0.02 M phosphate buffer (PBS) pH 7.4 to 9.8 mL of DMSO, cool in an ice bath, and vortex for 30 s to prepare the warm incubation solution.

[0138] The test compound was prepared as a 10 mM stock solution using DMSO. The test compound was then diluted to 2 mM with DMSO. 15 μL of the 2 mM test compound solution was added to 1485 μL of warm incubation buffer, vortexed for 30 s, and then allowed to stand at room temperature. Samples of 300 μL were taken at 0 h, 2 h, 4 h, 6 h, and 8 h, centrifuged at 14400 rpm for 3 min, and 200 μL of the supernatant was collected for HPLC analysis. The concentration was calculated and determined according to formula T. 1 / 2 = -0.693 / k to calculate the half-life.

[0139] Table 9 Chemical Stability

[0140] Example half life 1 NA 2 NA 3 NA Ethyl enzalutamide NA Enzalutamide NA

[0141] a No significant degradation was observed after 8 hours, making it impossible to calculate the half-life.

[0142] The results showed that the compounds of this invention have good stability at pH 7.4.

[0143] Application Example 4: Rat Plasma Stability

[0144] The test compound was prepared as a 10 mM stock solution using DMSO. The test compound was diluted to a 2 mM working solution using DMSO. 10 μL of the 2 mM working solution was added to 990 μL of rat plasma, vortexed for 5 s to prepare a reaction system with an initial concentration of 20 μM. The system was incubated at 37 °C, and 80 μL of plasma samples were collected at 0 min, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, and 6 h. 240 μL of methanol was added to the plasma sample, vortexed for 3 min, centrifuged at 14400 rpm for 3 min, and 200 μL of the supernatant was collected. The concentration was analyzed by HPLC, and the concentration was calculated according to formula T. 1 / 2 The half-life was calculated using -0.693 / k, and the results are shown in Table 9.

[0145] Table 10. Half-life and degradation products of rat plasma

[0146] Example half life Degradation products 1 <5min Enzalutamide 2 <5min Enzalutamide 3 <5min Enzalutamide Ethyl enzalutamide <5min Enzalutamide Enzalutamide <![CDATA[NA a ]]> none

[0147] a No obvious degradation was observed after 6 h, and the half-life could not be calculated by fitting.

[0148] The results showed that the compound provided by the present invention was extremely unstable in plasma. Almost all of it could be degraded into the inactive metabolite enzalutamide acid after 5 min of plasma incubation, and the prototype compound could not be detected at all after 10 min. Therefore, the compound of the present invention was rapidly inactivated after entering the blood and could not be distributed throughout the body, thus unable to cause systemic androgen antagonism, and would not cause side effects such as decreased libido, reduced sperm production, and ED. It could effectively solve the problem that existing drugs such as finasteride were systemically distributed, resulting in systemic androgen inhibition and causing side effects such as decreased libido, reduced sperm production, and ED.

[0149] Application Example 5: Stability of 10% skin homogenate of mice

[0150] 1) The test compound was prepared into a 10 mM stock solution with DMSO. Take 20 μL of the test compound stock solution and add it to 80 μL of DMSO, vortex for 10 s to prepare a 2 mM working solution.

[0151] 2) The backs of C57BL / 6 male mice (license number SCXK(Yu)2020 - 0005) were depilated with depilatory cream.

[0152] 3) The back skin was peeled off under anesthesia, blood vessels, subcutaneous tissues and fats were removed, and it was rinsed thoroughly with pre-cooled physiological saline.

[0153] 4) Take 2.3 g of skin, add it to 23 mL of pre-cooled physiological saline, and homogenize it充分 under ice bath conditions (homogenize for 15 s each time and pause for 10 s), centrifuge at 5000 rpm for 5 min, aspirate the supernatant, that is, the skin tissue homogenate, and place it on ice for use.

[0154] 5) Take 990 μL of the skin tissue homogenate, add 10 μL of the 2 mM test compound working solution, vortex for 5 s, and place it in a 37 °C water bath for incubation. Take 80 μL of samples at 0 min, 5 min, 10 min, 15 min, 30 min, 1 h and 2 h respectively, and add 240 μL of methanol.

[0155] 6) After vortexing for 3 min, centrifuge at 13000 rpm for 5 min.

[0156] 7) Aspirate 200 μL of the supernatant, analyze it by HPLC injection, calculate the concentration, and calculate the half-life according to the formula T 1 / 2 = -0.693 / k. The results are shown in Table 10.

[0157] Table 11 Stability and degradation products of 10% mouse skin homogenate

[0158] Example half life Degradation products 1 57.75min Enzalutamide 2 51.34min Enzalutamide 3 62.71min Enzalutamide Ethyl enzalutamide 4.03min Enzalutamide Enzalutamide <![CDATA[NA a ]]> none

[0159] a No significant degradation was observed after 2 hours, making it impossible to calculate the half-life.

[0160] The compound of this invention has a long half-life and good stability in skin homogenate. It is slowly degraded into the inactive metabolite enzalutamide.

[0161] This invention provides a composition of a locally acting androgen receptor antagonist and minoxidil, and its application, along with a method and approach. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A composition, characterized in that, Includes (a) sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer and (b) minoxidil or its pharmaceutically acceptable salt; said stereoisomer is (R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate.

2. The composition according to claim 1, characterized in that, The molar ratio of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer to minoxidil or its pharmaceutically acceptable salt is 1:1 to 20.

3. The composition according to claim 1, characterized in that, The molar ratio of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer to minoxidil or its pharmaceutically acceptable salt is 1:3 to 20.

4. The composition according to claim 1, characterized in that, The molar ratio of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer to minoxidil or its pharmaceutically acceptable salt is 1:9~10.

5. The composition according to claim 1, characterized in that, It also includes solvents.

6. The composition according to claim 5, characterized in that, In the composition, the content of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer is 0.5%~2% g / mL; in the composition, the content of minoxidil or its pharmaceutically acceptable salt is 2%~4% g / mL.

7. The composition according to claim 6, characterized in that, In the composition, the content of sec-butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolin-1-yl)-2-fluorobenzoate or its stereoisomer is any one of 0.5% g / mL, 1.0% g / mL, 1.5% g / mL and 2% g / mL; in the composition, the content of minoxidil or its pharmaceutically acceptable salt is 2% g / mL or 4% g / mL.

8. The composition according to claim 5, characterized in that, The solvent is any one or a combination of several of the following: water, polyol, polyol ether, and C1-C7 alcohol; the C1-C7 alcohol is ethanol.

9. The composition according to claim 8, characterized in that, The polyol is any one or a combination of several of ethylene glycol, propylene glycol, glycerol, and hexanetriol; the polyol ether is any one or a combination of several of polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, and diethylene glycol monoethyl ether; the C1-C7 alcohol is 95% ethanol or anhydrous ethanol.

10. The composition according to claim 9, characterized in that, In the composition, the content of 95% ethanol or anhydrous ethanol is 25%~50% g / mL, and the content of diethylene glycol monoethyl ether is 25%~50% g / mL.

11. The composition according to claim 9, characterized in that, The composition contains 46% g / mL of 95% ethanol or anhydrous ethanol and 30% g / mL of diethylene glycol monoethyl ether.

12. The composition according to claim 1, characterized in that, It also contains at least one emulsifier.

13. The composition according to claim 12, characterized in that, The emulsifier is any one or a combination of several of the following: PEG-15 hydroxystearate, PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbate 20, polysorbate 60, polysorbate 80, PEG-20 cetearyl ether, polyethylene glycol 25 cetearyl ether, polyethylene glycol 1000 monoceryl ether, sorbitol monolaurate, sorbitol monopalmitate, sorbitol monooleate, propylene glycol esters of fatty acids, polyglycerol esters of fatty acids, polyoxyethylene 5 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, capryloyl decanyl polyethylene glycol-8 glycerol ester, capryloyl hexanoyl polyethylene glycol glycerol ester, lauroyl polyethylene glycol glycerol ester, and oleoyl polyethylene glycol glycerol ester.

14. The composition according to claim 12, characterized in that, The emulsifier content in the composition is 0.05%~0.2% g / mL.

15. The composition according to claim 12, characterized in that, The composition contains 0.05% to 0.2% g / mL of polysorbate 80.

16. The composition of claim 12, characterized in that, The composition contains 0.1% g / mL of polysorbate 80.

17. The composition according to claim 1, characterized in that, It also contains at least one antioxidant.

18. The composition of claim 17, characterized in that, The antioxidant is any one or a combination of several of the following: butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate, ascorbic acid, α-tocopherol, and propyl gallate.

19. The composition of claim 17, characterized in that, The antioxidant content in the composition is 0.1%~1% g / mL.

20. The composition of claim 17, characterized in that, The composition contains 0.1-1% g / mL of ascorbate palmitate.

21. The composition of claim 17, characterized in that, The composition contains 0.5% g / mL of ascorbyl palmitate.

22. The composition according to claim 1, characterized in that, It also contains at least one pH adjuster.

23. The composition according to claim 22, characterized in that, The pH adjuster is any one or a combination of several of the following: citric acid monohydrate, citric acid, hydrochloric acid, phosphoric acid, maleic acid, tartaric acid, acetic acid, and sulfuric acid.

24. The composition of claim 22, characterized in that, The pH of the composition is 4.0 to 6.

0.

25. The composition according to claim 22, characterized in that, The pH of the composition is 4.0 to 5.

5.

26. Use of the composition according to any one of claims 1 to 25 in the preparation of a product for treating hair loss.

27. The application as described in claim 26, characterized in that, Application in the preparation of products for treating androgenetic alopecia.

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