Composition comprising androgen receptor inhibitor

Abstract

A composition comprising an androgen receptor inhibitor. The composition can improve the stability of a drug, slow down an increase in impurities, and be stored at room temperature. As a topical dosage form, the composition has bacteriostatic ability, and no additional bacteriostatic agent needs to be added. The composition can achieve the same efficacy while using a lower dose and a lower administration frequency, and has the advantages of significant safety, efficacy and medication compliance.

Description

A composition of an androgen receptor inhibitor

[0001] This application claims priority to the following prior patent applications:

[0002] The applicant filed an earlier application with the China National Intellectual Property Administration on November 15, 2024, with patent application number 2024116372559 and title "A composition of an androgen receptor inhibitor".

[0003] The full text of the aforementioned prior patent applications is incorporated herein by reference. Technical Field

[0004] This invention belongs to the field of pharmaceutical formulations, and specifically relates to a composition of an androgen receptor inhibitor. Background Technology

[0005] Clascoterone (CLCT) is an androgen receptor inhibitor. In August 2020, the U.S. FDA approved Clascoterone cream (1% strength, marketed as Cassiopea SpA) from Cassiopea SpA. It is used for the topical treatment of acne vulgaris in individuals aged 12 years and older. It has also been disclosed that concentrations of 5.0% to 7.5% can be used to treat androgenetic alopecia (AGA), and concentrations of 15% can be used to treat genital warts.

[0006] However, this drug has poor stability and requires stringent storage conditions, including refrigeration. Once opened, its shelf life is only two months, making it inconvenient for patients. Furthermore, the high concentration of the drug increases the risk of potential toxic side effects. The twice-daily topical administration frequency, compared to once-daily dosing, may lead to missed applications and poor patient adherence. Therefore, there is an urgent need for a highly stable, safe, and less frequently administered clacoatetone composition or formulation. Summary of the Invention

[0007] This invention provides a composition or formulation comprising:

[0008] androgen receptor inhibitors, complexes;

[0009] The complex is composed of [A] and [B] (a binary complex);

[0010] Among them, [A] is selected from oleyl alcohol, glycerophosphate choline, glycerol, and triethanolamine; [B] is selected from terpenoid alcohols or organic acids.

[0011] According to an embodiment of the present invention, the androgen receptor inhibitor is selected from: clacoate ketone or a pharmaceutically acceptable salt thereof.

[0012] According to embodiments of the present invention, the terpene alcohols are terpene derivatives containing alcohol hydroxyl groups, preferably C6-30 terpene derivatives containing alcohol hydroxyl groups, and more preferably C10-20 terpene derivatives containing alcohol hydroxyl groups, such as menthol, linalool, eucalyptol, santalol, nerol, geraniol, citronellol, terpineol, retinol, and ambroxol.

[0013] According to embodiments of the present invention, the organic acids are selected from citric acid, malic acid, lauric acid, geranilic acid, lactic acid, oleic acid, ferulic acid, and lactobionic acid.

[0014] According to an embodiment of the present invention, the molar ratio of [A] to [B] is 1:10-10:1, preferably 1:5-5:1, for example 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1.

[0015] In some embodiments, [A] is selected from oleyl alcohol (OLO), and [B] is selected from menthol (MEO), with a molar ratio of 1:5 to 5:1, such as 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, such as 1:1.

[0016] In some embodiments, [A] is selected from oleyl alcohol (OLO), and [B] is selected from citric acid (CA), with a molar ratio of 1:5 to 5:1, such as 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, for example, 1:1.

[0017] In some embodiments, [A] is selected from oleyl alcohol (OLO), and [B] is selected from lauric acid (LRA), with a molar ratio of 1:5 to 5:1, such as 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, such as 2:1.

[0018] In some embodiments, [A] is selected from oleyl alcohol (OLO), and [B] is selected from malic acid (MLA), with a molar ratio of 1:5 to 5:1, such as 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, for example, 4:1.

[0019] In some embodiments, [A] is selected from glycerophosphocholine (CGP), and [B] is selected from citrate (CA), with a molar ratio of 1:5 to 5:1, such as 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, such as 3:1.

[0020] In some embodiments, [A] is selected from glycerol (GLY), and [B] is selected from malic acid (MLA), with a molar ratio of 1:5 to 5:1, such as 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, such as 2:3, 1:1.5.

[0021] According to embodiments of the present invention, the complex is selected from any one, two, or more of the following: oleyl menthol complex, oleyl citric acid complex, oleyl lauric acid complex, oleyl malic acid complex, glycerophosphate choline citrate complex, glycerol malic acid complex, triethanolamine oleic acid complex, triethanolamine ferulic acid complex, triethanolamine lactobionic acid complex, and triethanolamine citrate complex. Preferably, the complex is selected from any one, two, or more of the following: oleyl menthol complex, oleyl citric acid complex, oleyl lauric acid complex, oleyl malic acid complex, glycerophosphate choline citrate complex, and glycerol malic acid complex.

[0022] According to embodiments of the present invention, the complex is selected from any one, two or more of the following: [OLO][MEO] (oleyl menthol complex), [OLO][CA] (oleyl citric acid complex), 2[OLO][LRA] (oleyl lauric acid complex), 4[OLO][MLA] (oleyl malic acid complex), 3[CGP][CA] (glycerophosphate choline citrate complex), 2[GLY]3[MLA] (glyceromalic acid complex).

[0023] According to embodiments of the present invention, the mass percentage of the complex in the composition or formulation is 0.01%-10.0%, preferably 0.1%-8%, for example 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or 5.0%.

[0024] According to embodiments of the invention, the androgen receptor inhibitor (e.g., clacoate ketone or a pharmaceutically acceptable salt thereof) in the composition or formulation comprises 0.01%-15% by mass, preferably 0.05%-10%, for example 0.1%, 0.125%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 7.5%, 8.0%, 9.0%, 10.0%, or 12.0%.

[0025] According to embodiments of the invention, the composition or formulation optionally further comprises an alcohol solvent. According to embodiments of the invention, the alcohol solvent has a mass percentage of 15%-80%, preferably 30%-70%, for example 40%, 45%, 47%, 50%, 55%, 60%, 62.2%, 62.67%, 64.3%, 65%, 65.9%, 68.9%, or 70%.

[0026] According to an embodiment of the present invention, the alcohol solvent includes alcohol solvent-1 and alcohol solvent-2.

[0027] According to an embodiment of the present invention, the alcohol solvent-1 is selected from isopropanol and ethanol.

[0028] According to an embodiment of the present invention, the alcohol solvent-2 is selected from any one, two or more of the following: propylene glycol, glycerol, ethanol, and 1,3-pentanediol.

[0029] According to an embodiment of the present invention, the mass percentage of the alcohol solvent-1 is 10%-50%, preferably 15%-45%, for example 18%, 20%, 23%, 25%, 28%, 30%, 32%, 35%, 38%, or 40%.

[0030] According to embodiments of the present invention, the alcohol solvent-2 has a mass percentage of 5%-50%, preferably 15%-45% or 20%-40%, for example 17%, 20%, 23%, 25%, 25.70%, 28.20%, 30%, 30.70%, 32.2%, 32.45%, 32.67%, 32.70%, 32.95%, 33.08%, 34.30%, 34.7%, 35%, 35.9%, 38%, 38.9%, 40%, or 43%.

[0031] According to embodiments of the present invention, the total mass percentage of alcohol solvent-1 and alcohol solvent-2 is 15%-80%, preferably 30%-70%, for example 40%, 45%, 47%, 50%, 55%, 60%, 62.2%, 62.67%, 64.3%, 65%, 65.9%, 68.9%, and 70%.

[0032] According to embodiments of the present invention, the composition or formulation optionally further comprises an auxiliary penetration enhancer.

[0033] According to embodiments of the present invention, the auxiliary penetration enhancer is selected from any one, two, or more of the following: oleyl alcohol, polysorbate 80, polyethylene glycol glyceryl caprylate, laurocapramone, polyglyceryl oleate, propylene glycol laurate, isopropyl myristate, polyethylene glycol hexadecyl ether, and sorbitan monolaurate. Preferably, the auxiliary penetration enhancer is selected from any one or two of oleyl alcohol and isopropyl myristate.

[0034] According to embodiments of the present invention, the mass percentage of the auxiliary penetration enhancer is 0.1%-20.0%, preferably 0.5%-15%, for example 0.8%, 1.0%, 1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 8.7%, 9.0%, 10.0%, 11.0%, 12.0%, and 13.0%.

[0035] According to embodiments of the present invention, the composition or formulation optionally further comprises a solubilizer.

[0036] According to an embodiment of the present invention, the solubilizer is selected from any one, two or more of the following: ethoxydiethylene glycol, propylene glycol monooctanoate, oleoyl polyoxyethylene glycerol ester, and glycerol mono- and dioctanoate esters.

[0037] According to embodiments of the present invention, the mass percentage of the auxiliary penetration enhancer is 1%-40%, preferably 5%-35%, for example 8%, 10%, 13%, 15%, 18%, 20%, 23%, 25%, 28%, 30%, or 33%.

[0038] According to embodiments of the present invention, the composition or formulation optionally further comprises an antioxidant.

[0039] According to embodiments of the present invention, the antioxidant is selected from any one, two, or more of the following: 2,6-di-tert-butyl-p-cresol (BHT), butylated hydroxyanisole (BHA), vitamin E, and sodium thiosulfate. Preferably, the antioxidant is selected from any two or more of the following: 2,6-di-tert-butyl-p-cresol (BHT), butylated hydroxyanisole (BHA), vitamin E, and sodium thiosulfate. Preferably, the antioxidant is selected from antioxidant-1 and antioxidant-2. Antioxidant-1 and antioxidant-2 may be the same or different, and are independently selected from: 2,6-di-tert-butyl-p-cresol (BHT), butylated hydroxyanisole (BHA), vitamin E, and sodium thiosulfate.

[0040] According to embodiments of the present invention, the antioxidant is present in a mass percentage of 0.01%-10%, preferably 0.1%-8%, for example 0.5%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, or 7.0%.

[0041] According to an embodiment of the present invention, the antioxidant is composed of two antioxidants, for example, 2,6-di-tert-butyl-p-cresol (BHT) and butylated hydroxyanisole (BHA); preferably, the mass percentage of 2,6-di-tert-butyl-p-cresol (BHT) is 0.1%-3.0%, for example 0.5%, 1.5%, 2.0%, 2.5%, 3.0%; preferably, the mass percentage of butylated hydroxyanisole (BHA) is 0.1%-3.0%, for example 0.5%, 1.5%, 2.0%, 2.5%, 3.0%.

[0042] According to embodiments of the present invention, the dosage form of the composition or preparation is a gel, ointment, cream, latex, foam, solution, emulsion, or suspension; preferably a gel.

[0043] According to embodiments of the present invention, the composition or formulation optionally further comprises a gel matrix.

[0044] According to an embodiment of the present invention, the gel matrix is ​​selected from any one, two, or more of the following: hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), and polyvinylpyrrolidone (PVP). According to an embodiment of the present invention, the hydroxypropyl cellulose (HPC) is a high-viscosity type of hydroxypropyl cellulose (HPC-H).

[0045] According to embodiments of the present invention, the mass percentage of the gel matrix is ​​0.01%-10.0%, preferably 0.1%-8%, for example 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, and 5.0%.

[0046] According to embodiments of the present invention, the composition or formulation optionally further comprises water.

[0047] According to embodiments of the present invention, the water mass percentage is 1%-25%, for example 1.63%, 2.1%, 5.0%, 5.8%, 8.0%, 10%, 15%, 17.30%, 18%, 20%, 23%.

[0048] According to an embodiment of the present invention, the mass ratio of water to alcohol solvent-2 is 1:0.1 to 1:40, preferably 1:0.5 to 1:30, for example 1:1, 1:3, 1:5, 1:8, 1:10, 1:13, 1:15, 1:18, 1:20.

[0049] According to an embodiment of the present invention, the mass ratio of water to alcohol solvent is 1:0.1 to 1:40, preferably 1:0.5 to 1:30, for example 1:1, 1:3, 1:5, 1:8, 1:10, 1:13, 1:15, 1:18, 1:20.

[0050] According to embodiments of the present invention, the composition or formulation optionally further comprises a pH adjuster.

[0051] According to an embodiment of the present invention, the pH adjuster is selected from inorganic acids or organic acids; preferably, the pH adjuster is selected from any one, two or more of the following: citric acid, hydrochloric acid, and phosphoric acid.

[0052] According to embodiments of the present invention, the pH of the composition or preparation is 3.0 to 5.0, preferably 3.2 to 5.0, for example 3.5, 3.7, 3.8, 4.0, 4.2, 4.4, 4.5, 4.6, 4.8, 5.0.

[0053] According to embodiments of the present invention, the composition or formulation does not require the addition of preservatives. The compositions or formulations of the present invention possess antibacterial properties, and no preservatives are required in the compositions or formulations.

[0054] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0055] androgen receptor inhibitors (such as clacoate ketone or a pharmaceutically acceptable salt thereof), in a mass percentage of 0.05%-10%;

[0056] The complex, with a mass percentage of 0.1%-8%;

[0057] The gel matrix comprises 0.1%–8% by mass.

[0058] Preferably, the composition or formulation further comprises an auxiliary penetration enhancer; preferably, the auxiliary penetration enhancer has a mass percentage of 0.5%-15%;

[0059] Preferably, the composition or formulation further comprises a solubilizer; preferably, the solubilizer has a mass percentage of 5%-35%;

[0060] Preferably, the composition or formulation further comprises an antioxidant; preferably, the antioxidant has a mass percentage of 0.01%-10%, more preferably 0.1%-8%; preferably, the composition or formulation further comprises antioxidant-1 and antioxidant-2; preferably, antioxidant-1 has a mass percentage of 0.1%-8%; preferably, antioxidant-2 has a mass percentage of 0.1%-8%.

[0061] Preferably, the composition or formulation further comprises an alcohol solvent; preferably, the alcohol solvent has a mass percentage of 15%-80%, more preferably 30%-70%; preferably, the composition or formulation further comprises alcohol solvent-1, such as isopropanol; preferably, the isopropanol has a mass percentage of 15%-45%; preferably, the composition or formulation further comprises alcohol solvent-2; preferably, the alcohol solvent-2 has a mass percentage of 10%-50%.

[0062] Preferably, the composition or formulation further comprises water; preferably, the water content is 1%-25% by mass.

[0063] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0064] Androgen receptor inhibitors (e.g., clacoate ketone or a pharmaceutically acceptable salt thereof), comprising 0.05%-10% by mass (preferably 0.125%-7.5%);

[0065] Isopropanol, in a mass percentage of 15%-45% (e.g., 30.0%);

[0066] Alcohol solvent-2, which has a mass percentage of 10%-50% (preferably 17%-38.9%);

[0067] The auxiliary penetration enhancer has a mass percentage of 0.5%-15% (preferably 2.0%-8.7%).

[0068] The complex has a mass percentage of 0.1%-8% (e.g., 2.0%).

[0069] The solubilizer has a mass percentage of 5%-35% (e.g., 20%).

[0070] The antioxidant has a mass percentage of 0.1%-8% (e.g., 0.5% or 1.5%); preferably, the antioxidant includes antioxidant-1, antioxidant-2, or antioxidant-1 and antioxidant-2; preferably, antioxidant-1 has a mass percentage of 0.1%-8% (e.g., 0.5% or 1.5%); preferably, antioxidant-2 has a mass percentage of 0.1%-8% (e.g., 0.5% or 1.5%).

[0071] The gel matrix has a mass percentage of 0.1%–8% (e.g., 2.0%).

[0072] Water, with a mass percentage of 1%-25% (preferably 1.63%-17.30%).

[0073] According to an embodiment of the present invention, in the composition or formulation, the mass ratio of water to alcohol solvent-2 is 1:1 to 1:20;

[0074] Preferably, the alcohol solvent-2 is selected from: propylene glycol, glycerol, ethanol, and 1,3-pentanediol;

[0075] Preferably, the auxiliary penetration enhancer is selected from: oleyl alcohol, isopropyl myristate, polysorbate 80, PEG-glyceryl caprylate, laurocapramone, polyglyceryl oleate, propylene glycol laurate, polyethylene glycol hexadecyl ether, and sorbitol monolaurate.

[0076] Preferably, the complex is selected from: oleyl menthol complex, oleyl lauric acid complex, oleyl citric acid complex, oleyl malic acid complex, glycerophosphate choline citrate complex, glyceromalic acid complex; for example, oleyl menthol complex and oleyl lauric acid complex.

[0077] Preferably, the solubilizer is selected from: ethoxydiethylene glycol;

[0078] Preferably, antioxidant-1 and antioxidant-2 are the same or different, and are independently selected from: 2,6-di-tert-butyl-p-cresol (BHT), butylated hydroxyanisole (BHA), vitamin E, and sodium thiosulfate;

[0079] Preferably, the gel matrix is ​​selected from: hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), and polyvinylpyrrolidone (PVP).

[0080] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0081] androgen receptor inhibitors (e.g., clacoate ketone or a pharmaceutically acceptable salt thereof) in the range of 0.125%–7.5% by mass (e.g., 0.125%, 0.25%, 0.50%, 0.75%, 1.0%, 2.50%, 5.00%, 7.50%).

[0082] Isopropanol, with a mass percentage of 30.0%;

[0083] Alcohol solvent-2 (e.g., propylene glycol), in a mass percentage of 17%-38.9% (e.g., 17%, 25.70%, 28.20%, 30.70%, 32.2%, 32.45%, 32.67%, 32.70%, 32.95%, 33.08%, 34.30%, 34.7%, 35.9%, 38.9%);

[0084] Auxiliary penetration enhancers (such as oleyl alcohol, isopropyl myristate) at a mass percentage of 2.0%-8.7% (e.g., 2.0%, 5.0%, 8.7%);

[0085] The complex (e.g., oleyl menthol complex, oleyl lauric acid complex) has a mass percentage of 2.0%;

[0086] The solubilizer (e.g., ethoxydiethylene glycol) is 20% by mass;

[0087] Antioxidant-1 (e.g., BHT), at a mass percentage of 0.5%;

[0088] Antioxidant-2 (e.g., BHA), at a mass percentage of 1.5%;

[0089] The gel matrix (e.g., HPC-H) comprises 2.0% by mass.

[0090] Water, with a mass percentage of 1.63%–17.30% (e.g., 1.63%, 2.1%, 5.8%, 17.30%);

[0091] Preferably, the mass ratio of water to alcohol solvent-2 is 1:1 to 1:20.

[0092] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0093] Androgen receptor inhibitors (e.g., clacotone or its pharmaceutically acceptable salts) 1.0%, isopropanol 30.0%, propylene glycol 32.2%, oleyl alcohol 8.7%, oleyl alcohol-menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, water 2.1%.

[0094] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0095] Androgen receptor inhibitors (e.g., clavotene or its pharmaceutically acceptable salts) 1.0%, isopropanol 30.0%, propylene glycol 32.2%, oleyl alcohol 8.7%, complexes (e.g., oleyl alcohol-menthol complex, oleyl alcohol-laurate complex, oleyl alcohol-citric acid complex, oleyl alcohol-malic acid complex, glycerophosphate-choline-citric acid complex, glyceroglycerate-malic acid complex) 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, water 2.1%.

[0096] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0097] Androgen receptor inhibitors (e.g., clavotene or a pharmaceutically acceptable salt thereof) 1.0%, isopropanol 30.0%, propylene glycol 32.2%–38.9% (e.g., 32.2%, 35.9%, 38.9%), adjuvant penetration enhancers (e.g., oleyl alcohol, isopropyl myristate) 2.0%–8.7% (e.g., 2.0%, 5.0%, 8.7%), oleyl alcohol-menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, water 2.1%.

[0098] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0099] Androgen receptor inhibitors (e.g., clacotone or its pharmaceutically acceptable salts) 1.0%, isopropanol 30.0%, oleyl alcohol 8.7%, oleyl alcohol-menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, propylene glycol 17%-32.67%, water 1.63%-17.30%.

[0100] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0101] Androgen receptor inhibitor (e.g., clavotene or a pharmaceutically acceptable salt thereof) 1.0%, isopropanol 30.0%, propylene glycol 32.2%-34.7% (e.g., 32.2%), isopropyl myristate 5.0%, oleyl menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0%-0.5% (e.g., 0.5%), BHA 0-1.5% (e.g., 1.5%), HPC-H 2.0%, water 5.8%.

[0102] According to an embodiment of the present invention, the composition or formulation comprises the following components:

[0103] androgen receptor inhibitors (e.g., clavotene or pharmaceutically acceptable salts thereof) 0.125%–7.5% (e.g., 0.125%, 0.25%, 0.50%, 0.75%, 2.50%, 5.00%, 7.50%), isopropanol 30.0%, propylene glycol 25.70%–33.08% (e.g., 33.08%, 32.95%, 32.70%, 32.45%, 30.70%, 28.20%, 25.70%), isopropyl myristate 5.0%, oleyl menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, water 5.8%.

[0104] According to an embodiment of the present invention, the composition or formulation is further adjusted to a pH of 3.0 to 5.0, preferably 3.2 to 5.0, for example 3.5, 3.7, 3.8, 4.0, 4.2, 4.4, 4.5, 4.6, 4.8, or 5.0, using a pH adjuster.

[0105] The present invention also provides a method for preparing the above-mentioned composition or formulation, wherein the preparation method is as follows:

[0106] The components are stirred and mixed to obtain the composition or preparation.

[0107] According to an embodiment of the present invention, the preparation method specifically comprises: stirring and dissolving an optional antioxidant and a solubilizer; then adding a complex, an optional alcohol solvent, and an auxiliary penetration enhancer and stirring until homogeneous; then adding an androgen receptor inhibitor (e.g., clacoate ketone) or a pharmaceutically acceptable salt thereof and stirring until dissolved; then adding an optional gel matrix and stirring; and further adjusting the pH using a pH adjuster to obtain the composition or formulation (gel formulation).

[0108] According to an embodiment of the present invention, the preparation method specifically comprises: stirring and dissolving an antioxidant and a solubilizer, then adding an alcohol solvent, a complex, and an auxiliary penetration enhancer and stirring until homogeneous, then adding an androgen receptor inhibitor (e.g., clacoate ketone) or a pharmaceutically acceptable salt thereof and stirring until dissolved, then adding a gel matrix and stirring, and further adjusting the pH using a pH adjuster to obtain the composition or formulation.

[0109] According to an embodiment of the present invention, a pH adjuster is used to adjust the pH to 3.0 to 5.0, preferably 3.2 to 5.0, for example 3.5, 3.7, 3.8, 4.0, 4.2, 4.4, 4.5, 4.6, 4.8, 5.0.

[0110] Optionally, according to an embodiment of the invention, the composition or formulation is filled.

[0111] The present invention also provides the use of the above-described composition or preparation in the preparation of a medicament for treating sebaceous hyperplasia, acne, hair loss (e.g. androgenetic alopecia), and genital warts.

[0112] The present invention also provides a method for treating sebaceous hyperplasia, acne, hair loss (e.g., androgenetic alopecia) or genital warts, the method comprising administering a therapeutically effective amount of the above composition or preparation to the subject.

[0113] In this article,

[0114] OLO represents oleyl alcohol, MEO represents menthol, CA represents citric acid, LRA represents lauric acid, MLA represents malic acid, CGP represents glycerophosphate choline, and GLY represents glycerol.

[0115] n[A]m[B] represents the molar ratio of A to B as n∶m. For example, [OLO][MEO] indicates a molar ratio of oleyl alcohol to menthol of 1∶1, [OLO][CA] indicates a molar ratio of oleyl alcohol to citric acid of 1∶1, 2[OLO][LRA] indicates a molar ratio of oleyl alcohol to lauric acid of 2∶1, 4[OLO][MLA] indicates a molar ratio of oleyl alcohol to malic acid of 4∶1, 3[CGP][CA] indicates a molar ratio of glycerophosphate choline to citric acid of 3∶1, and 2[GLY]3[MLA] indicates a molar ratio of glycerol to malic acid of 2∶3. Beneficial effects

[0116] This invention provides a composition of an androgen receptor inhibitor (e.g., clacotone or a pharmaceutically acceptable salt thereof), which improves drug stability, slows impurity growth, and can be stored at room temperature; as a topical dosage form, the composition has antibacterial activity without the need for additional antibacterial agents; the composition can exert the same efficacy with lower doses and lower dosing frequencies, and has significant advantages in safety, efficacy, and medication adherence. Attached Figure Description

[0117] Figure 1: Schematic diagram of the application site and time of skin application to the back of Bama miniature pigs.

[0118] Figure 2: Intradermal distribution curve of the composition.

[0119] Figure 3: Efficacy study of the combined sebaceous gland model - Changes in the area of ​​sebaceous gland spots on the treatment side in each group.

[0120] Figure 4: Efficacy study of the combined sebaceous gland model - treatment effects at different time points in each group.

[0121] Figure 5: Efficacy study of the combined sebaceous gland model - Changes in the area of ​​sebaceous gland spots on the treatment side of each group.

[0122] Figure 6: Efficacy study of the combination sebaceous gland model - Inhibitory effect of each group at each time point.

[0123] Figure 7: Efficacy study of the combined androgen-induced alopecia model: hair growth and hair follicle distribution in different groups of animals at different time points.

[0124] Figure 8: Pharmacodynamic study of the composition using an AGA model - comparison of hair growth scores in each group. The composition of the present invention was applied to the left side, and the control formulation was applied to the right side. Left 1, Right 1 and Left 2, Right 2 were administered 24 hours and 12 hours before animal sacrifice, respectively, and the administered formulations were removed 8 hours after administration; for the other administration sites, the administered formulations were removed after animal euthanasia, and skin samples were taken.

[0125] Figure 9: Pharmacodynamic study of the AGA composition model - comparison of the average length of newly grown hair in each group.

[0126] Figure 10: Pharmacodynamic study of the AGA composition model - comparison of hair weight of newly grown hair in each group.

[0127] Figure 11: Pharmacodynamic study of the AGA composition - comparison of A / T ratio in each group. Detailed Implementation

[0128] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0129] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0130] 1. Study on the formulation, process, and properties of the composition.

[0131] 1.1. Composition Formulation (Composition 1)

[0132] Table 1: Composition Formula (Composition 1)

[0133] 1.2. Composition Preparation Process

[0134] Preparation of [OLO][MEO]: Weigh 8.05g of oleyl alcohol and 4.69g of menthol according to the prescription, stir to dissolve, and then place in a 50℃ water bath and continue stirring for 0.5 to 4 hours. Collect the material and store it in a sealed container for later use.

[0135] The proton NMR spectrum data of [OLO][MEO] can be found in patent application CN202410210343.4.

[0136] Preparation of the composition: Weigh BHT, BHA, and ethoxydiethylene glycol according to the prescribed dosage and dissolve them by stirring at 250 rpm. Then add purified water, propylene glycol, isopropanol, [OLO][MEO]oleyl menthol complex, and oleyl alcohol, and stir until homogeneous. Then weigh the prescribed amount of clacoate ketone and continue stirring to dissolve the active pharmaceutical ingredient. Then weigh the prescribed amount of HPC-H, sieve it, and add it while stirring. During this process, adjust the stirring speed according to the stirring conditions. When HPC-H is completely dissolved, the sample will be a transparent and uniform gel. Adjust the pH of the gel to 4.2-4.6 using citric acid solution. Then fill the gel using aluminum pharmaceutical ointment tubes, with a filling volume of 10g / tube.

[0137] 1.3. Full inspection of prescription compositions

[0138] The obtained composition (composition 1) was subjected to full testing, and the results are shown in Table 2.

[0139] Table 2: Full Inspection Results of Prescription Composition (Composition 1)

[0140] 1.4. Stability Study of the Composition

[0141] The stability of composition 1 was investigated, including stability at 40°C for 24 hours, low-temperature and freeze-thaw cycle tests, accelerated stability (40°C / 75% RH), intermediate stability (30°C / 65% RH), and long-term stability (25°C / 60% RH). In the stability studies at 40°C for 24 hours, accelerated stability (40°C / 75% RH), and intermediate stability (30°C / 65% RH), a commercially available reference formulation was simultaneously placed for comparison. The stability test results are shown in Tables 3 to 7.

[0142] Commercially available reference formulation: Winlevi, 1% clacoterone cream.

[0143] Table 3: Stability of the formulation and reference preparation at 40°C for 24 hours

[0144] Table 4: Low-temperature and freeze-thaw cycle stability of the formulation composition

[0145] Table 5: Stability of Formulation Compositions and Reference Preparations under Accelerated Conditions (40℃ / 75% RH)

[0146] Table 6: Stability of the formulation and reference product under intermediate conditions (30℃ / 65% RH)

[0147] Table 7: Long-term stability of the formulation composition under the following conditions (25°C / 60% RH)

[0148] Impurity 1: 17α,21-dihydroxyprogesterone; Impurity 2: 21-hydroxypregn-4,16-diene-3,20-dione; Impurity 3: 17α-hydroxyprogesterone-21-propionate; Maximum unknown single impurity: the unknown impurity with a relative retention time of 1.25 in the chromatogram; Total impurities = Impurity 1 + Impurity 2 + Impurity 3 + Maximum unknown single impurity.

[0149] As shown in Table 3, when placed at 40°C for 24 hours, the growth of impurity 3 (ester exchange degradation impurities) and total impurities in composition 1 was significantly lower than that in the reference formulation, indicating that composition 1 has better thermal stability.

[0150] As shown in Tables 5 and 6, after being placed under accelerated conditions (40°C / 75%RH) and intermediate conditions (30°C / 65%RH) for 6 months, the impurity levels of composition 1 were better than those of the reference formulation, indicating its excellent stability.

[0151] As shown in Tables 4 and 7, Composition 1 did not exhibit instability during low-temperature cycling and freeze-thaw cycling. Under long-term conditions (25°C / 60% RH) for 12 months, the impurity level of the composition increased slightly, but remained lower than the level of the reference formulation after 2 months of accelerated processing, further demonstrating that Composition 1 has good stability and can be stored at room temperature.

[0152] 1.5. Microbial Detection of the Composition

[0153] 5g of Composition 1 was placed in a flat weighing bottle and left open at room temperature for 7 days before being sent for microbiological testing. Furthermore, the microbiological properties of the composition were tested at 3 and 6 months under accelerated conditions (40℃ / 75%RH) and intermediate conditions (30℃ / 65%RH), and at 3, 6, and 12 months under long-term conditions (25℃ / 60%RH). The method used was in accordance with "1105 Microbial Limit Tests for Non-Sterile Products: Microbial Counting Method" in Part IV of the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 8. The test results indicate that the composition showed no microbial contamination during the 7-day open storage and stability testing. This indicates that the composition itself has a certain antibacterial ability, and no preservatives need to be added to the formulation.

[0154] Table 8: Microbiological detection results in the stability study of the formulation composition

[0155] 2. Composition Study

[0156] 2.1. Effects of the complex on the stability and transdermal properties of the composition

[0157] The active ingredient, clacoate ketone, undergoes an intramolecular transesterification reaction, producing impurity 3, which is its main degradation product. Inhibiting the transesterification reaction significantly improves the stability of the active ingredient. The study found that the complex can inhibit the transesterification reaction and reduce the generation of impurity 3. Therefore, a series of compositions using different complexes were prepared, and their stability (the amount of impurity 3 growth after standing at 40°C for 48 hours) was used as an indicator for evaluation.

[0158] 2.1.1. Preparation of different complex series compositions

[0159] The composition of the series of compositions is shown in Tables 9 and 10. The preparation process is the same as that of composition 1.

[0160] Table 9: Formulations of different complex series compositions

[0161] Table 10: Information on different complexes

[0162] The following information pertains to the manufacturers of the excipients: oleyl alcohol was purchased from Jiangxi Alfa, citric acid from Merck Chemicals, menthol from Takasago, glycerol and triethanolamine from Sinopharm Shanghai Experimental, and lauric acid, malic acid, oleic acid, ferulic acid, lactobionic acid, glycerophosphate, and choline were purchased from Maclean's.

[0163] The preparation and proton NMR data of [OLO][CA]oleyl citric acid complex, 2[OLO][LRA]oleyl lauric acid complex, 4[OLO][MLA]oleyl malic acid complex, and [OLO][MEO]oleyl menthol complex can be found in patent application CN202410210343.4.

[0164] 2.1.2. Stability Study of Different Complex Series Compositions

[0165] The changes in impurity 3 after each formulation was placed at 40°C for 24 hours were investigated, and the results are shown in Table 11. The results indicate that the oleyl alcohol or glycerol complex used in the composition can reduce the increase of impurity 3.

[0166] Table 11: Stability Study of Different Complex Series Compositions

[0167] 2.1.3. Effect of the complex on the skin permeability of the composition

[0168] Select the complex-containing composition formulations from Table 11 and examine their skin penetration properties using an IVPT test.

[0169] IVPT test method: IVPT was conducted on excised skin from Bama miniature pigs (≤3 months of age) in a Franz diffusion cell; the dosage was 100 mg / cm³.2 The receiving solution was collected after 8 hours. After the experiment, the skin was cleaned and then the tissue was broken down to obtain the intradermal retention extract. The obtained sample was analyzed by HPLC to obtain the content of clacoate ketone in the sample.

[0170] The results are shown in Table 12. The results indicate that, compared with the commercially available reference formulation and Formulation 1-1 which contains only the monomeric oleyl alcohol, the addition of the complex can enhance the skin penetration properties of the composition.

[0171] Table 12: IVPT test results of different complex series compositions

[0172] *: To better compare with the reference formulation, a reference formulation comparison test was performed simultaneously with each IVPT test.

[0173] 2.2. Effects of different excipients on the transdermal properties of the composition

[0174] 2.2.1. Preparation of a series of compositions with different auxiliary penetration enhancers

[0175] A series of compositions using different auxiliary penetration enhancers were prepared, and their composition information is shown in Tables 13 and 14. The preparation process is the same as that of composition 1.

[0176] Table 13: Formulations of different adjuvant penetration enhancer series compositions

[0177] Table 14: Types, manufacturers, and dosages of auxiliary penetration enhancer Y

[0178] 2.2.2. Effects of different auxiliary penetration enhancers on the transdermal performance of the composition

[0179] The skin penetration performance of different combinations of adjuvants was examined using IVPT testing.

[0180] IVPT assay method: The IVPT assay was performed on excised skin of Bama miniature pigs (≤3 months old) in a Franz diffusion cell; the receiving fluid was collected after 24 hours; after the experiment, the skin was washed and then the tissue was broken up to obtain intradermal retention extract; the clacoate ketone content in the sample was determined by HPLC.

[0181] The results are shown in Table 15. The results indicate that different adjuvants can synergistically enhance the penetration of DES, significantly increasing the retention of clacoate in the skin, suggesting that the composition can exert better efficacy than the reference formulation. On the other hand, the addition of adjuvants did not significantly increase the transdermal permeation of clacoate; the permeation rates of each group were not significantly different from the reference formulation, indicating that the composition mainly improves the retention of clacoate, rather than making it easier to penetrate the skin and enter the plasma. This means that while improving efficacy, the risk of systemic adverse reactions can be increased.

[0182] Table 15: IVPT Test Results of Combinations with Different Auxiliary Penetration Enhancers

[0183] 2.3. Effect of pH on the stability of the composition

[0184] Composition 1, without the use of citric acid to adjust the pH, was used as Formulation 3-1. Based on this, the amount of citric acid solution added was adjusted to produce formulations with different pH values. Formulations with different pH values ​​were incubated at 40°C for 24 hours, and the increase in impurity 3 was detected by HPLC to assess the stability of the pH-adjusted compositions.

[0185] Table 16 shows the growth of impurity 3 after 24 hours of storage at 40°C for different pH gradient compositions. The experimental results indicate that the pH value of the composition has a significant impact on transesterification; when the pH is higher than 5.0, the increase of impurity 3 (transesterification product) is significant.

[0186] Table 16: Growth of Impurity 3 in Gel Samples with Different pH Gradients after 24 Hours at 40℃

[0187] 2.4. Effect of water-to-alcohol ratio on the composition

[0188] 2.4.1. Preparation of a series of compositions with different water-to-alcohol ratios

[0189] A series of compositions with different water-to-alcohol ratios were prepared, and the effect of the water-to-alcohol ratio on the composition was investigated. The formulation composition is shown in Table 17.

[0190] Table 17: Formulations of a series of compositions with different water-to-alcohol ratios

[0191] 2.4.2. Effects of different water-to-alcohol ratios on composition preparation, stability, and transdermal performance

[0192] When adjusting the pH value using citric acid solution (10%), the preparation becomes cloudy, which may be due to the precipitation of citric acid crystals.

[0193] The IVPT (in vitro phosphotransferase) and stability of formulations 4-2, 4-3, and 4-4 under high temperature (40°C) for 24 hours were investigated. The IVPT test was conducted using isolated skin samples from Bama miniature pigs (≤3 months of age) in a Franz diffusion chamber; the dosage was 5 mg / cm³. 2 The receiving solution was collected after 8 hours. After the experiment, the skin was cleaned and then the tissue was broken down to obtain the intradermal retention extract. The obtained sample was analyzed by HPLC to obtain the content of clacoate ketone in the sample.

[0194] As can be seen from the properties of Formulation 4-1, when the formulation does not contain water, the pH value of the preparation is not easily adjusted, and there is a risk of precipitation and decreased physical stability.

[0195] The stability and IVPT results for formulations with different water-to-propylene glycol ratios are shown in Table 18. When the water content in the formulation is too high and propylene glycol is absent, the stability of the formulation is also affected to some extent, and the transdermal performance decreases. When the water-to-propylene glycol ratio is between 1:1 and 1:20, the formulation exhibits good stability and better transdermal performance than the reference formulation.

[0196] Table 18: IVPT and Impurity 3 Growth Rate of Series Compositions with Different Water-Alcohol Ratios at 40℃-24h

[0197] 2.5. Screening of antioxidants in the composition

[0198] 2.5.1. Preparation of a series of compositions with different types and proportions of antioxidants

[0199] A series of compositions containing different types and proportions of antioxidants were prepared. The types and proportions of antioxidants in the compositions were screened, and the specific formulations are shown in Table 19. The preparation process is the same as that of composition 1.

[0200] Table 19: Formulations of Compositions with Different Types and Proportions of Antioxidants

[0201] 2.5.2. Investigation of light conditions for a series of compositions with different types and proportions of antioxidants

[0202] The series of compositions were placed under light conditions (4500Lx±500Lx) for 5 days and 12 days. The effects of different types and proportions of antioxidants on the stability of the compositions were investigated using the composition content and antioxidant content as indicators. The results are shown in Tables 20 and 21.

[0203] Table 20: Changes in the content of different antioxidant types and proportions in a series of compositions under light irradiation conditions

[0204] Table 21: Changes in antioxidant content in a series of compositions with different types and proportions of antioxidants under light irradiation conditions

[0205] As shown in Table 20, except for formulation 5-2, the content of clacoateone in other drug-containing formulations decreased significantly under light exposure, indicating that clacoateone is unstable under light. The content of formulation 5-1, which does not contain antioxidants, decreased the most significantly, while the content changes in other formulations containing antioxidants were relatively small. Furthermore, as shown in Table 21, formulation 5-2, which does not contain drugs, showed less BHT consumption, while other formulations showed significant BHT consumption, further indicating that clacoateone undergoes oxidative degradation under light exposure. These results demonstrate that the addition of antioxidants can inhibit the oxidative degradation of clacoateone, thereby improving the light stability of the composition. The change in antioxidant content in formulation 5-3 shows that the antioxidant BHT is significantly consumed under light exposure, but the BHA content does not change much, indicating that the antioxidant effect is mainly exerted by consuming BHT. Combining the content changes of formulations 5-4 and 5-5 with the antioxidant content changes, it can be seen that although the antioxidant effect mainly relies on the consumption of BHT, the compositions with added BHA have better stability.

[0206] 3. Preparation of compositions with different specifications

[0207] A series of compositions with different specifications were prepared to verify the robustness of the formulation process and to be used in subsequent pharmacokinetic and pharmacodynamic studies. The formulation composition is shown in Table 22, and the process used is the same as that for composition 1.

[0208] Table 22: Formulation composition of different specification series of compositions

[0209] *: The sources of each component are consistent with the series of compositions with different types and proportions of antioxidants.

[0210] The content, related substances, and IVPT of different specifications of the series of compositions were detected. The IVPT method involved using isolated skin samples from Bama miniature pigs (≤3 months of age) in a Franz diffusion cell; the dosage was 5 mg / cm³. 2 The receiving solution was collected after 8 hours. After the experiment, the skin was cleaned and then the tissue was broken down to obtain the intradermal retention extract. The obtained sample was analyzed by HPLC to obtain the content of clacoate ketone in the sample.

[0211] Table 23: Test results of different specifications of series of compositions

[0212] The results are shown in Table 23. The results indicate that the prepared compositions of different strengths met the expected quality standards, and the levels of related substances were superior to the control reference formulation. The skin penetration of the 0.5% and 0.75% compositions was superior to the 1% control formulation, and the skin penetration of the 0.25% composition was comparable to the 1% control formulation. This suggests that the compositions of the present invention can achieve equivalent efficacy at lower doses or with fewer dosing frequencies compared to marketed formulations.

[0213] 4. Skin distribution dynamics study of the composition

[0214] 4.1. Experimental Procedure

[0215] Nine male Bama miniature pigs were divided into three groups (A, B, and C), with three animals in each group. Each animal was given the composition of this invention on its left side and the commercially available reference formulation Winlevi on its right side. Group A animals were given composition A (Formula 5-3, 1.0%) on their left side, Group B animals were given composition B (Composition 1, 1.0%) on their left side, and Group C animals were given composition C (Formula 6-4, 0.5%) on their left side. Animals were identified using ear tags and cage tags, and were provided with free access to water and normal feed during the experiment.

[0216] The test product was administered to pigs via skin application at specific administration sites, as shown in Figure 1.

[0217] Hair removal at the administration site before drug administration: Remove hair from the back of the animal before drug administration (using an electric shaver to avoid skin damage). Select 10 areas on each side of the center line of the back, for a total of 20 areas, namely left 1 to 10 and right 1 to 10. Each area is 2cm*2cm, with an interval of about 8cm between the left and right areas and a interval of 4cm between areas on the same side.

[0218] Gel application method: Apply 20 mg of gel (using a suitable microinjector) evenly to each 2cm × 2cm area of ​​skin. Minimize waste during application and ensure even coverage.

[0219] Before euthanasia, 2 mL of blood was collected from each animal via vein, anticoagulated with K2EDTA, and centrifuged at 5000 rcf for 5 min at 4°C to separate approximately 1 mL of plasma, which was then stored in an ultra-low temperature freezer until sample transfer.

[0220] After euthanizing the animal, first clean the treatment area with a medical cotton ball soaked in 5% detergent (5 times), then carefully wipe the skin surface with a cotton ball moistened with medical pure water 5 times, and finally dry it with a dry medical cotton ball; when cleaning each piece of skin, be sure to use clean gloves and medical cotton balls. After cleaning the treatment site, repeatedly apply medical pressure-sensitive tape 20 times to remove the stratum corneum.

[0221] Using a 15mm diameter skin sampling drill, skin tissue of 15mm diameter and approximately 8mm depth was extracted from each drug administration site, and subcutaneous fat was removed. Clean gloves and instruments were used during each skin procedure to prevent contamination. The extracted skin was then placed flat with the epidermis facing down and frozen in dry ice.

[0222] Skin tissue homogenization: Weigh each skin tissue sample and add pre-cooled extraction buffer (acetonitrile, containing the internal standard dexamethasone acetate) at a weight-to-volume ratio of 1:2. Homogenize the tissue using a multi-tube homogenizer (setting the grinding temperature to -10℃; grinding time to 180 seconds + 30-second pause, repeated for 4 cycles). Centrifuge the tissue homogenate at 12000 rpm for 5 min, and transfer 200 μL of the supernatant to a 1.5 mL centrifuge tube. Dilute with 50% acetonitrile-water mixture and vortex for 30 seconds to obtain the test solution. Transfer 200 μL of the test solution to a liquid chromatography vial liner and perform LC-MS / MS to detect the concentration and calculate the content of clacoate ketone in the sample.

[0223] 4.2. Experimental Results and Conclusions

[0224] The skin distribution kinetic parameters calculated using a non-compartmental model are summarized in Table 24, and the intradermal distribution time-intensity curve is shown in Figure 2. The experimental results show that the AUC of the two identical (1.0%) compositions A and B of this invention... last These were 3.29 times and 2.96 times that of the reference formulation Winlevi, respectively, with composition A exhibiting higher bioavailability; the AUC of the lower strength (0.5%) composition C was... last and C max Slightly higher than the reference formulation. This indicates that the composition of the present invention can significantly improve the bioavailability of clacoate, suggesting that it can achieve efficacy comparable to the reference formulation at lower doses or dosing frequencies.

[0225] Table 24 Summary of skin distribution dynamics parameters of the composition in Bama miniature pigs

[0226] 5. Pharmacological Study of the Composition in a Sebaceous Gland Model

[0227] 5.1. Experimental Procedure

[0228] This trial aims to investigate the therapeutic effect of the composition on sebaceous gland dysplasia. The treatment method involves pre-androgen stimulation to establish a model, followed by drug administration (the model is maintained during the treatment period to preserve the disease state).

[0229] Forty male Syrian hamsters (SPF grade, 35-42 days old) were acclimatized for two days, then underwent laparotomy and castration. After suturing, ceftriaxone sodium was injected to prevent infection. Modeling began one week after surgery, following a period of recovery.

[0230] One day before the start of the modeling process (D-1), the fur on both sides of the back of the mice was shaved off with an electric shaver (in subsequent experiments, shaving was performed once a week), and the skin on both sides of the back (approximately 2*2 cm) was exposed with depilatory cream. Each animal was treated with dihydrotestosterone (DHT, AR grade, purchased from Aladdin) ethanol solution (0.8 mg / mL) for modeling: 5 μL of DHT solution was pipetted onto the sebaceous gland patch area and then spread evenly with the pipette tip. This was done once daily for two weeks. Successful modeling was considered achieved when the area of ​​the sebaceous gland patch significantly increased.

[0231] After modeling, 30 experimental animals in good condition were selected, and the area of ​​sebaceous gland spots was measured using vernier calipers. Based on the mean and ratio of the measured sebaceous gland areas on both sides, the animals were randomly divided into 6 groups with 5 animals in each group.

[0232] After the initial drug administration, the modeling and administration methods were as follows: the modeling process continued in the bilateral sebaceous gland patches of Syrian hamsters, but the drug was administered only in the left sebaceous gland patch area. Specific experimental groups and administration regimens are shown in Table 25.

[0233] Table 25: Pharmacodynamic Study of the Composition Sebaceous Gland Model - Grouping and Dosing Regimen of the Dosing Trial

[0234] bid: Administer twice daily, with an interval of at least 6 hours between the two doses on the same day.

[0235] Topical application method:

[0236] Drug administration began 30 minutes after modeling each day and continued for 3 weeks. On day 22 of the experiment, the experimental animals were euthanized, and the sebaceous gland patch area was harvested. During the normal experimental period, the animals were shaved weekly. Before each modeling session, both sides of the modeling area were cleaned with sterile water and then wiped clean with cotton balls, taking care to avoid damage during cleaning. DHT was washed off 30 minutes after each DHT modeling session before drug administration. In all drug administration groups, the left drug administration area was cleaned before the second administration.

[0237] Therapeutic efficacy index calculation method:

[0238] Predict the area of ​​sebaceous gland plaques on the other side (left side L) at time t when no drug is administered, based on the change in sebaceous gland plaque area on the untreated side (right R):

[0239] A Lt(predict) =A Rt / A R0 *A L0

[0240] The therapeutic effect index is:

[0241] E = A Lt(predict) -ALt

[0242] Among them, A R0 : Actual area of ​​the right sebaceous patch at time 0; A L0 : Actual area of ​​the left sebaceous gland patch at time point 0; A Rt : Actual area of ​​the right sebaceous patch at time t; A Lt : Actual area of ​​the left sebaceous gland patch at time t; A Lt(predict) : Predicted area of ​​left sebaceous gland patch at time point t; E: Therapeutic efficacy index.

[0243] 5.2. Experimental Results and Conclusions

[0244] Figure 3 shows the changes in sebaceous gland patch area on the treated side in each group; Figure 4 shows the treatment effects at each time point in each group. One-way ANOVA analysis of the efficacy index (E) for each animal on Day 21 showed significant differences between groups. Post-hoc tests indicated that, at the same dosing frequency (twice a day), there was no significant difference in efficacy between the different strengths of the composition compared to the reference formulation (p>0.05), with the same strength (1.0%) and the 0.5% strength showing a trend towards superior efficacy. Furthermore, there was a significant difference in efficacy between the 1.0% and 0.125% compositions (p=0.007<0.01), and a certain dose-response relationship was observed among the strengths (1.0%, 0.5%, 0.25%, and 0.125%).

[0245] Therefore, it can be inferred that the composition of the present invention has better therapeutic effects and can achieve therapeutic effects similar to those of commercially available reference formulations at a lower specification.

[0246] 6. Pharmacological Study of the Composition in a Sebaceous Gland Model (Part Two)

[0247] As shown in the pharmacodynamic study of the composition using a sebaceous gland model, DHT ethanol solution can effectively induce a model. This experiment aims to investigate the antagonistic effect of the composition of this invention on androgens; therefore, the experiment was designed to begin model initiation and drug administration simultaneously.

[0248] 6.1. Experimental Procedure

[0249] Forty male Syrian hamsters (SPF grade, 35–42 days old) were acclimatized for two days, followed by laparotomy and castration. After suturing, ceftriaxone sodium was injected to prevent infection. The formal drug administration experiment (D0) began one week after surgery and a period of recovery.

[0250] Thirty healthy experimental animals were selected. One day before the start of drug administration (D-1), the hair on both sides of the back of the mice was shaved off with an electric shaver, and the skin on both sides of the back (approximately 2*2cm) was exposed with depilatory cream. The area of ​​sebaceous gland patches was measured with calipers. Based on the mean and ratio of the measured sebaceous gland areas on both sides, the animals were randomly divided into 6 groups with 5 animals in each group.

[0251] Each animal was modeled using a 0.8 mg / mL ethanol solution of dihydrotestosterone (DHT, AR grade, purchased from Aladdin): 5 μl of DHT solution was pipetted onto the sebaceous gland patch area and then spread evenly with the pipette tip. The modeling and administration methods were set as follows: Considering that modeling and treatment began simultaneously, a model validation group was set up to verify the successful establishment of the model. This group underwent unilateral (left side only) modeling, with no modeling on the other side. The remaining groups underwent bilateral sebaceous gland modeling, but administration was only performed on the right sebaceous gland patch area. Specific experimental groupings and administration regimens are shown in Table 26.

[0252] Table 26: Pharmacodynamic Study of the Composition Sebaceous Gland Model - Grouping and Dosing Regimen in the Dosing Trial

[0253] qd: once a day; bid: twice a day, with an interval of more than 6 hours between the two doses on the same day.

[0254] Topical application method:

[0255] Drug administration began 30 minutes after modeling each day and continued for 3 weeks. On day 22 of the experiment, the experimental animals were euthanized, and the sebaceous gland patch area was harvested. During the normal experimental period, the animals were shaved weekly. Before each modeling session, both sides of the modeling area were cleaned with sterile water and then wiped clean with cotton balls, taking care to avoid damage during cleaning. DHT was washed off 30 minutes after each DHT modeling session before drug administration. In all drug administration groups, the left drug administration area was cleaned before the second administration.

[0256] Method for calculating the inhibition effect index:

[0257] Based on the change in sebaceous gland patch area on the untreated side (right L), predict the area of ​​the sebaceous gland patch on the treated side (left R) at time t if no medication is administered:

[0258] A Rt(predict) =A Lt / A L0 *A R0

[0259] The inhibition effect index is:

[0260] I = A Rt(predict) -A Rt

[0261] Among them, A R0 : Actual area of ​​the right sebaceous patch at time 0; A L0 : Actual area of ​​the left sebaceous gland patch at time point 0; A Rt : Actual area of ​​the right sebaceous patch at time t; A Lt : Actual area of ​​the left sebaceous gland patch at time t; A Rt(predict) : Predicted area of ​​right sebaceous gland plaque at time t; I: Inhibition effect index.

[0262] 6.2. Experimental Results and Conclusions

[0263] Figure 5 shows the changes in the area of ​​sebaceous gland plaques on the treated side in each group. Figure 6 shows the inhibitory effect at each time point in each group.

[0264] In the model validation group, the sebaceous gland area on the modeling side (left side) was significantly increased (initially 17.30±2.49 cm). 2 On day 21, the measurement was 53.98 ± 6.66 cm. 2 The sebaceous gland area on the unmodeled side (right side) showed a decreasing trend due to the castration of the experimental animals leading to a deficiency in their own androgen secretion (initially 17.59±1.63cm). 2 On day 21, the value was 10.56 ± 2.11 cm. 2 This indicates that the model was successfully established.

[0265] One-way ANOVA analysis of the androgen suppression index (I) in each animal on Day 21 showed significant differences between groups (P<0.05). Post-hoc tests revealed no significant difference in the inhibitory effect between the reference formulation group (1% strength, twice daily) and the same strength composition (1.0% strength, once daily) (p>0.05); however, the inhibitory effect of the reference formulation group (1% strength, twice daily) was significantly different from that of other strength compositions (0.75%, 0.5%, and 0.25% strengths, once daily).

[0266] Therefore, it can be inferred that the composition of the present invention of the same specification can achieve a therapeutic effect similar to that of commercially available reference preparations with a lower dosing frequency, and can significantly improve the convenience during treatment.

[0267] 7. Efficacy study of the combined androgenic alopecia model (AGA model)

[0268] The androgenetic alopecia (AGA) model was established in male C57BL / 6J mice according to the references to investigate the efficacy of the composition of this invention in treating androgenetic alopecia. The modeling method involved shaving the back hair of male C57BL / 6J mice and then subcutaneously injecting them with a 1% (w / v) testosterone propionate soybean oil solution. Considering the pathogenesis of androgenetic alopecia and the mechanism of drug action, this study adopted a simultaneous approach of modeling and drug administration.

[0269] 7.1. Experimental Procedure

[0270] Twenty male C57BL / 6J mice were randomly divided into four groups of five each. The day before the experiment, the back hair of the mice was shaved completely using an electric shaver, with the shaved area approximately 2cm x 3cm in size. Then, depilatory cream was used to completely remove the surface hair. The hair in the shaved area should be in a resting phase (the skin should appear pink). Mice not in a resting phase needed to be replaced. Grouping, model establishment, and administration methods are shown in Table 27.

[0271] Table 27: Pharmacodynamic Study of Composition AGA Model - Dosing Trial Groups and Dosing Regimens

[0272] qd: once a day; bid: twice a day, with an interval of more than 6 hours between the two doses on the same day.

[0273] 7.2. Evaluation Indicators

[0274] (1) Hair growth

[0275] On days 1, 10, 20, and 30 after drug administration, photographs were taken of the bald areas on the backs of mice in each group, and the hair regrowth was recorded. Photos were taken from the same location and at the same height. Hair growth scores for each mouse were statistically analyzed and plotted as a line graph.

[0276] The scoring criteria for hair growth are shown in Table 28.

[0277] Table 28: Scoring Criteria for Hair Growth

[0278] (2) Evaluation of new hair growth in mice

[0279] New hair length: On day 30, 10 hairs were randomly selected from the back and their average growth length was measured under a microscope.

[0280] Newborn hair weight: On day 30, remove the newborn hair, weigh it using a 1 / 100,000 balance and record the weight.

[0281] (3) Ratio of hair follicles in the anagen phase to those in the telogen phase in the hair removal area (A / T ratio)

[0282] On day 30, the experimental animals were euthanized, and the hair growth on their backs was photographed. The hair was then removed, and the skin from their backs was harvested. The obtained mouse skin tissue was paraffin-embedded, sectioned, and stained with Fontana-Masson. After scanning the sections, the hair follicle growth status was observed, and the hair follicle density was counted (at 40X field of view, three areas were randomly selected to count the number of hair follicles).

[0283] 7.3. Test Results

[0284] (1) The growth of back hair and the distribution of hair follicles of each group of animals at different time points are shown in Figure 7.

[0285] (2) The hair growth scores for each group are shown in Figure 8.

[0286] (3) The average length of new hair in each group is shown in Figure 9.

[0287] (4) The comparison of the hair weight of new hair in each group is shown in Figure 10.

[0288] (5) The A / T ratio of each group is shown in Figure 11.

[0289] 7.4. Experimental Conclusions

[0290] Figure 7 shows the hair growth on the backs of mice in each group. Combined with the hair growth scoring trends in Figure 8, it can be seen that in Group-1 (normal group), hair growth in the bald areas on the backs of mice was normal; by approximately 3 weeks, the bald areas were completely covered by new hair, and by 30 days, they had essentially returned to normal. In Group-2 (model group), hair regrowth in the bald areas on the backs of mice was slow; by 30 days, some areas were still hairless, consistent with the characteristics of androgenetic alopecia. A comparison of Group-1 and Group-2 shows that an androgenetic alopecia model was successfully established in the experiment. The hair growth in the bald areas on the backs of mice in Group-3 (commercially available group) and Group-4 (experimental group) was similar, slightly slower than the Group-1 normal group, but significantly faster than the Group-2 model group, demonstrating good efficacy. The hair growth in the experimental group using the composition of this invention was slightly better than that in the commercially available minoxidil group.

[0291] As shown in Figures 9 and 10, from the perspective of new hair growth, the quality of new hair growth in the experimental group and the commercially available group was significantly improved compared to the model group. The efficacy of the composition of the present invention was not significantly different from that of the commercially available group, and showed a slightly better trend.

[0292] As shown in Figure 11, the ratio of anagen follicles to telogen follicles in the commercially available group and the experimental group were similar and significantly higher than those in the model group, indicating that the composition of the present invention can significantly improve hair follicle vitality, thereby reversing hair loss. The ratio of anagen follicles to telogen follicles in the experimental group was slightly lower than that in the commercially available group, possibly because it takes effect faster, and the hair enters the maturation phase earlier, thus inhibiting the vitality of the hair follicles.

[0293] In summary, the composition of this invention can significantly inhibit the symptoms of the AGA model. Compared with commercially available minoxidil formulations, there is no significant difference in efficacy at a lower dosing frequency, and it shows a slightly better trend.

[0294] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A composition or formulation comprising: androgen receptor inhibitors, complexes; The complex is composed of [A] and [B]; Among them, [A] is selected from oleyl alcohol, glycerophosphate choline, glycerol, and triethanolamine; [B] is selected from terpenoid alcohols or organic acids; Preferably, the androgen receptor inhibitor is selected from clacoate ketone or a pharmaceutically acceptable salt thereof.

2. The composition or preparation according to claim 1, characterized in that The terpene alcohols are terpene derivatives containing alcohol hydroxyl groups, preferably C6-30 terpene derivatives containing alcohol hydroxyl groups; Preferably, the organic acids are selected from citric acid, malic acid, lauric acid, geranilic acid, lactic acid, oleic acid, ferulic acid, and lactobionic acid; Preferably, the molar ratio of [A] to [B] is 1:10-10:1; Preferably, the complex is selected from any one, two or more of the following: oleyl menthol complex, oleyl citric acid complex, oleyl lauric acid complex, oleyl malic acid complex, glycerophosphate choline citrate complex, glycero malic acid complex, triethanolamine oleic acid complex, triethanolamine ferulic acid complex, triethanolamine lactobionic acid complex, and triethanolamine citrate complex. Preferably, the mass percentage of the complex in the composition or formulation is 0.01%-10.0%; Preferably, the androgen receptor inhibitor in the composition or formulation is 0.01%-15% by mass.

3. The composition or formulation of claim 1 or 2, wherein The composition or formulation optionally further comprises an alcohol solvent; preferably, the alcohol solvent comprises alcohol solvent-1 and alcohol solvent-2; preferably, alcohol solvent-1 is selected from isopropanol and ethanol; preferably, alcohol solvent-2 is selected from any one, two, or more of the following: propylene glycol, glycerol, ethanol, and 1,3-pentanediol; preferably, the mass percentage of alcohol solvent-1 is 10%-50%; preferably, the mass percentage of alcohol solvent-2 is 5%-50%; preferably, the mass percentage of the sum of the amounts of alcohol solvent-1 and alcohol solvent-2 is 15%-80%. Preferably, the composition or formulation optionally further comprises an auxiliary penetration enhancer; preferably, the auxiliary penetration enhancer is selected from any one, two or more of the following: oleyl alcohol, polysorbate 80, polyethylene glycol glyceryl caprylate, laurocapramone, polyglyceryl oleate, propylene glycol laurate, isopropyl myristate, polyethylene glycol hexadecyl ether, sorbitan monolaurate; preferably, the auxiliary penetration enhancer is present in a mass percentage of 0.1%-20.0%; Preferably, the composition or formulation optionally further comprises a solubilizer; preferably, the solubilizer is selected from any one, two or more of the following: ethoxydiethylene glycol, propylene glycol monocaprylate, oleoyl polyoxyethylene glycerol ester, glyceryl monocaprylate and glyceryl dicaprylate; preferably, the mass percentage of the auxiliary penetration enhancer is 1%-40%; Preferably, the composition or formulation optionally further comprises an antioxidant; preferably, the antioxidant is selected from any one, two or more of the following: 2,6-di-tert-butyl-p-cresol, butylated hydroxyanisole, vitamin E, sodium thiosulfate; preferably, the antioxidant is 0.01%-10% by mass. Preferably, the composition or formulation optionally further comprises water; preferably, the water content is 1%-25% by mass; preferably, the mass ratio of water to alcohol solvent-2 is 1:0.1 to 1:

40. Preferably, the composition or formulation optionally further comprises a pH adjuster; preferably, the pH adjuster is selected from inorganic acids or organic acids; preferably, the pH of the composition or formulation is 3.0 to 5.

0.

4. The composition or formulation according to any one of claims 1 to 3, characterized in that, Preferably, the dosage form of the composition or preparation is a gel, ointment, cream, latex, foam, solution, emulsion, or suspension; preferably, it is a gel. Preferably, the composition or formulation optionally further comprises a gel matrix; preferably, the gel matrix is ​​selected from any one, two or more of the following: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylpyrrolidone; preferably, the mass percentage of the gel matrix is ​​0.01%-10.0%.

5. The composition or formulation according to any one of claims 1-4, characterized in that, The composition or formulation comprises the following components: Androgen receptor inhibitors, with a mass percentage of 0.05%-10%; The complex, with a mass percentage of 0.1%-8%; The gel matrix comprises 0.1%–8% by mass. Preferably, the composition or formulation further comprises an auxiliary penetration enhancer; preferably, the auxiliary penetration enhancer has a mass percentage of 0.5%-15%; Preferably, the composition or formulation further comprises a solubilizer; preferably, the solubilizer has a mass percentage of 5%-35%; Preferably, the composition or formulation further comprises an antioxidant; preferably, the antioxidant has a mass percentage of 0.01%-10%, more preferably 0.1%-8%; preferably, the composition or formulation further comprises antioxidant-1 and antioxidant-2; preferably, antioxidant-1 has a mass percentage of 0.1%-8%; preferably, antioxidant-2 has a mass percentage of 0.1%-8%. Preferably, the composition or formulation further comprises an alcohol solvent; preferably, the alcohol solvent has a mass percentage of 15%-80%, more preferably 30%-70%; preferably, the composition or formulation further comprises alcohol solvent-1; preferably, alcohol solvent-1 (e.g., isopropanol) has a mass percentage of 15%-45%; preferably, the composition or formulation further comprises alcohol solvent-2; preferably, alcohol solvent-2 has a mass percentage of 10%-50%. Preferably, the composition or formulation further comprises water; preferably, the water mass percentage is 1%-25%; Preferably, the composition or formulation is further adjusted to a pH of 3.0 to 5.0 using a pH adjuster.

6. The composition or formulation according to any one of claims 1-4, wherein, The composition or formulation comprises the following components: Androgen receptor inhibitors, with a mass percentage of 0.05%-10%; Isopropanol, with a mass percentage of 15%-45%; Alcohol solvent-2, with a mass percentage of 10%-50%; The auxiliary penetration enhancer has a mass percentage of 0.5%-15%; The complex, with a mass percentage of 0.1%-8%; The solubilizer has a mass percentage of 5%-35%; Antioxidant-1, with a mass percentage of 0.1%-8%; Antioxidant-2, with a mass percentage of 0.1%-8%; The gel matrix comprises 0.1%–8% by mass. Water, with a mass percentage of 1%-25%; Preferably, in the composition or formulation, the mass ratio of water to alcohol solvent-2 is 1:1 to 1:20; Preferably, the alcohol solvent-2 is selected from: propylene glycol, glycerol, ethanol, and 1,3-pentanediol; Preferably, the auxiliary penetration enhancer is selected from: oleyl alcohol, isopropyl myristate, polysorbate 80, PEG-glyceryl caprylate, laurocapramone, polyglyceryl oleate, propylene glycol laurate, polyethylene glycol hexadecyl ether, and sorbitol monolaurate. Preferably, the complex is selected from: oleyl menthol complex, oleyl lauric acid complex, oleyl citric acid complex, oleyl malic acid complex, glycerophosphate choline citrate complex, glyceromalic acid complex; for example, oleyl menthol complex and oleyl lauric acid complex. Preferably, the solubilizer is selected from: ethoxydiethylene glycol; Preferably, antioxidant-1 and antioxidant-2 are the same or different, and are independently selected from: 2,6-di-tert-butyl-p-cresol (BHT), butylated hydroxyanisole (BHA), vitamin E, and sodium thiosulfate; Preferably, the gel matrix is ​​selected from: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, and polyvinylpyrrolidone; Preferably, the composition or formulation is further adjusted to a pH of 3.0 to 5.0 using a pH adjuster.

7. The composition or formulation according to any one of claims 1-4, wherein The composition or formulation comprises the following components: Androgen receptor inhibitors, with a mass percentage of 0.125%-7.5%; Isopropanol, with a mass percentage of 30.0%; Alcohol solvent-2, with a mass percentage of 17%-38.9%; The auxiliary penetration enhancer has a mass percentage of 2.0%-8.7%; The complex, with a mass percentage of 2.0%; The solubilizer has a mass percentage of 20%. Antioxidant-1, with a mass percentage of 0.5%; Antioxidant-2, with a mass percentage of 1.5%; The gel matrix comprises 2.0% by weight. Water, with a mass percentage of 1.63%–17.30%; Preferably, the mass ratio of water to alcohol solvent-2 is 1:1 to 1:20; Preferably, the composition or formulation is further adjusted to a pH of 3.0 to 5.0 using a pH adjuster.

8. The composition or formulation according to any one of claims 1-4, wherein, The composition or formulation comprises the following components: androgen receptor inhibitor 1.0%, isopropanol 30.0%, propylene glycol 32.2%, oleyl alcohol 8.7%, oleyl alcohol-menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, and water 2.1%. Preferably, the composition or formulation comprises the following components: androgen receptor inhibitor 1.0%, isopropanol 30.0%, propylene glycol 32.2%, oleyl alcohol 8.7%, complex 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, and water 2.1%. Preferably, the composition or formulation comprises the following components: androgen receptor inhibitor 1.0%, isopropanol 30.0%, propylene glycol 32.2%-38.9%, adjuvant penetration enhancer 2.0%-8.7%, oleyl menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0.5%, BHA 1.5%, HPC-H 2.0%, and water 2.1%. Preferably, the composition or formulation comprises the following components: 1.0% androgen receptor inhibitor, 30.0% isopropanol, 8.7% oleyl alcohol, 2.0% oleyl alcohol-menthol complex, 20% ethoxydiethylene glycol, 0.5% BHT, 1.5% BHA, 2.0% HPC-H, 17%-32.67% propylene glycol, and 1.63%-17.30% water; Preferably, the composition or formulation comprises the following components: androgen receptor inhibitor 1.0%, isopropanol 30.0%, propylene glycol 32.2%-34.7%, isopropyl myristate 5.0%, oleyl menthol complex 2.0%, ethoxydiethylene glycol 20%, BHT 0%-0.5%, BHA 0-1.5%, HPC-H 2.0%, and water 5.8%; Preferably, the composition or formulation comprises the following components: 0.125%-7.5% androgen receptor inhibitor, 30.0% isopropanol, 25.70%-33.08% propylene glycol, 5.0% isopropyl myristate, 2.0% oleyl menthol complex, 20% ethoxydiethylene glycol, 0.5% BHT, 1.5% BHA, 2.0% HPC-H, and 5.8% water; Preferably, the composition or formulation is further adjusted to a pH of 3.0 to 5.0 using a pH adjuster.

9. A method for preparing the composition or formulation according to any one of claims 1-8, wherein the preparation method is as follows: The components are stirred and mixed to obtain the composition or preparation.

10. The use of the composition or preparation according to any one of claims 1-8 in the preparation of a medicament for treating sebaceous hyperplasia, acne, hair loss, and genital warts.

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