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KR-20260065905-A - Pharmaceutical composition, method, and use containing androgen receptor inhibitor/antagonist

KR20260065905AKR 20260065905 AKR20260065905 AKR 20260065905AKR-20260065905-A

Abstract

The present invention belongs to the field of pharmaceutical technology and, specifically, relates to pharmaceutical compositions, methods, and uses containing androgen receptor inhibitors/antagonists. The use of said androgen receptor inhibitors/antagonists, in particular the combination of a compound of Formula I or crystalline form D of a compound of Formula I and minoxidil, improves the effects obtained by the use of a single drug of an androgen receptor inhibitor/antagonist or minoxidil. In fact, this improvement is essentially synergistic, as the effect of improving or promoting hair growth is greater than that obtained by using an androgen receptor inhibitor/antagonist or minoxidil alone. The method is not merely a simple physical combination, but provides good additional therapeutic effects and has the advantage of good safety.

Inventors

  • 통 유지
  • 런 지화
  • 옌 홍화
  • 차이 시앙

Assignees

  • 수조우 킨터 제약회사(주)

Dates

Publication Date
20260511
Application Date
20240906
Priority Date
20230908

Claims (14)

  1. A pharmaceutical composition comprising an androgen inhibitor/antagonist and minoxidil, or a pharmaceutically acceptable excipient thereof.
  2. In paragraph 1, The above androgen inhibitors/antagonists are clascoterone, nilutamide, enzalutamide, tofillutamide, bicalutamide, flutamide, hydrochlorothiazide, spironolactone, niclosamide, rezvillutamide, darolutamide, althiazide, apalutamide, deutenzalutamide, enovosarm, proxalutamide, ANA-001, 18F-dihydrotestosterone, 2-hydroxyflutamide, AKP-009, ASC-J9, AZD5312, EG017, LY2452473, MK-0773, VK5211, varbdegallutamide, dimethandrolone undecanoate, ceviteronel, inocoteron, zanoteron, CP-COV03, FW-1022, APC-100, ARV-766, EM-5854, EPI-7386, MVI-118, ODM-204, TRC253, UT-34, Lalaniten Acetate, Bolillasarme, FW-424, AC0176, AZD3514, BMS-641988, CB-03-10, CC-94676, DT-200, EZN-4176, GSK2849466, GSK971086, HP518, HRS-5041, HSK38008, MK-3984, ONC1-13B, PF-06260414, RO7656594, SXL01, TAS3681, TQB3720, TFF NIC, UNI911, FW-420, A031, AB001, AB006, AC-262536, ADA-308, AH-001, AR-V7 PROTAC, ARCC-4, ARD-2051, ARD-2128, ARD-2585, ARD-266, ARD-61, ARD-69, ASN-1780, ASR-600, BMS-564929, BWA-522, CA103, CB-03-04, CH4892280, CH5137291, CL-AR-100, CZ-212-3, DA-4210, EM 6537, HC-X022, HYG-410, HYG-420, HYG-430, HYG-440, ID119160021, IMB-A6, JMKX002992, JNJ-26146900, JNJ-28330835, JNJ-37654032, LG121071, LGD-2941, LGD-3303, LGD2226, LHJ-647, MTX-23, NUV-1156, NUV-1511, OLX104C, ONC2-13B, PARD-33, PF-0998425, PRX-304, RD162, RU 56187, RU 58642, RU 58841, RU 59063, SKLB-C2807, TD-802, VPC-13789, A pharmaceutical composition characterized by comprising WS9761, XY-32, YM-175735, YM-92088, YM580, ZD3980, Zeta55, SCAI-502, XNTR-934, or XNTR-936.
  3. A pharmaceutical composition comprising an androgen inhibitor/antagonist and minoxidil, or a pharmaceutically acceptable excipient thereof, wherein the androgen inhibitor/antagonist is a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, and [Chemical Formula I] ; Preferably, the pharmaceutical composition is characterized in that the androgen inhibitor/antagonist is an anhydrous polymorph of a compound of Formula I.
  4. In paragraph 3, The anhydrous polymorph of the compound of the above chemical formula I is crystalline form D, and the crystalline form D satisfies at least one of the following conditions, and I. The above crystalline form D has an XRPD pattern including peaks at 2θ values: 5.3 ± 0.2°, 10.7 ± 0.2°, 13.5 ± 0.2°, 15.1 ± 0.2°, and 21.3 ± 0.2°; Preferably, the crystalline form D has an XRPD pattern further comprising peaks at 2θ values: 12.0 ± 0.2°, 12.7 ± 0.2°, 14.8 ± 0.2°, 16.4 ± 0.2°, 17.3 ± 0.2°, 20.3 ± 0.2°, 24.2 ± 0.2°, and 24.8 ± 0.2°; More preferably, the crystalline form D has an XRPD pattern further comprising peaks at 2θ values: 19.7 ± 0.2°, 22.5 ± 0.2°, 23.1 ± 0.2°, 27.3 ± 0.2°, 28.5 ± 0.2°, 29.7 ± 0.2°, and 32.3 ± 0.2°; More preferably, the crystalline form D has an XRPD pattern substantially consistent with FIG. 1; II. The above crystalline form D has a TGA pattern exhibiting a weight loss of approximately 1.6% at 150 ± 1℃; Preferably, the crystalline form D has a TGA pattern substantially consistent with FIG. 2; and III. The above crystalline form D has a DSC pattern exhibiting endothermic behavior at 167 ± 1℃; Preferably, the crystalline form D has a DSC pattern substantially consistent with FIG. 2; Or the above anhydrous polymorph is a crystalline form C, and the crystalline form C satisfies at least one of the following conditions: I. The above crystalline form C has an XRPD pattern including peaks at 2θ values: 5.2 ± 0.2°, 10.4 ± 0.2°, 13.4 ± 0.2°, 15.0 ± 0.2°, 16.4 ± 0.2°, and 29.1 ± 0.2°; Preferably, the crystalline form C has an XRPD pattern further comprising peaks at 2θ values: 19.6 ± 0.2°, 20.1 ± 0.2°, 22.8 ± 0.2°, and 24.4 ± 0.2°; More preferably, the crystalline form C has an XRPD pattern further comprising peaks at 2θ values: 11.9 ± 0.2°, 17.3 ± 0.2°, 23.6 ± 0.2°, 31.6 ± 0.2°, and 34.1 ± 0.2°; More preferably, the crystalline form C has an XRPD pattern substantially consistent with FIG. 6; II. The above crystalline form C has a TGA pattern exhibiting a weight loss of approximately 1.6% at 150 ± 1℃; Preferably, the crystalline form C has a TGA pattern substantially consistent with FIG. 7; and III. The above crystalline form C has a DSC pattern exhibiting endothermicity at 148 ± 1℃, 167 ± 1℃, and 177 ± 1℃; Preferably, the crystalline form C has a DSC pattern substantially consistent with FIG. 7; Or the above anhydrous polymorph is crystalline form B, and the crystalline form B satisfies at least one of the following conditions: I. The above crystalline form B has an XRPD pattern including peaks at 2θ values: 7.3 ± 0.2°, 9.9 ± 0.2°, 12.5 ± 0.2°, 16.5 ± 0.2°, and 17.1 ± 0.2°; Preferably, the crystalline form B has an XRPD pattern further comprising peaks at 2θ values: 13.1 ± 0.2°, 20.3 ± 0.2°, 24.0 ± 0.2°, 25.2 ± 0.2°, and 26.7 ± 0.2°; More preferably, the crystalline form B has an XRPD pattern further comprising peaks at 2θ values: 21.3 ± 0.2°, 27.8 ± 0.2°, 28.6 ± 0.2°, 29.5 ± 0.2°, and 31.3 ± 0.2°; More preferably, the crystal form B has an XRPD pattern substantially consistent with FIG. 8; II. The above crystalline form B has a TGA pattern exhibiting a weight loss of approximately 1.5% at 150 ± 1℃; Preferably, the crystal form B has a TGA pattern substantially consistent with FIG. 9; and III. The above crystalline form B has a DSC pattern exhibiting endothermic behavior at 177 ± 1℃; Preferably, the crystal form B has a DSC pattern substantially consistent with FIG. 9; Or the above anhydrous polymorph is crystalline form A, and crystalline form A satisfies at least one of the following conditions: The above crystalline form A has an XRPD pattern including peaks at 2θ values: 9.0 ± 0.2°, 12.5 ± 0.2°, 15.7 ± 0.2°, 17.2 ± 0.2°, 18.1 ± 0.2°, and 23.2 ± 0.2°; Preferably, the crystalline form A has an XRPD pattern further comprising peaks at 2θ values: 3.3 ± 0.2°, 7.5 ± 0.2°, 12.9 ± 0.2°, 15.2 ± 0.2°, 24.4 ± 0.2°, 28.4 ± 0.2°, and 29.8 ± 0.2°; More preferably, the crystalline form A has an XRPD pattern further comprising peaks at 2θ values: 14.4 ± 0.2°, 17.7 ± 0.2°, 19.9 ± 0.2°, and 21.8 ± 0.2°; More preferably, the crystal form A has an XRPD pattern substantially consistent with FIG. 10; II. The above crystalline form A has a TGA pattern exhibiting a weight loss of approximately 1.0% at 150 ± 1℃; Preferably, the crystal form A has a TGA pattern substantially consistent with FIG. 11; and III. The above-mentioned crystalline form A has a DSC pattern exhibiting endothermic behavior at 160 ± 1℃ and 177 ± 1℃, and exothermic behavior at 162 ± 1℃; Preferably, the crystal form A has a DSC pattern substantially consistent with FIG. 11; A pharmaceutical composition characterized by
  5. In any one of paragraphs 1 through 4, A therapeutically effective amount of the above androgen inhibitor/antagonist is administered to the subject as a continuous daily dosing regimen until progression of a disease or condition related to androgen receptor activity or the occurrence of unacceptable toxicity; and/or, the subject is a male or female patient with androgenetic alopecia, preferably a male patient with androgenetic alopecia, more preferably a male patient with Hamilton-Norwood grade IIIv-V androgenetic alopecia; and/or, the androgen inhibitor/antagonist is administered in an amount of 0.05% (0.5 mg/mL or mg/g) to 10% (100 mg/mL or mg/g); and/or, the androgen inhibitor/antagonist is administered in an amount of 0.25% (2.5 mg/mL or mg/g) to 1% (10 mg/mL or mg/g); and/or, the androgen inhibitor/antagonist is administered in an amount of 0.1 mg/day to 1000 mg/day; and/or, the androgen inhibitor/antagonist is administered in an amount of 0.5 mg/day to 100 mg/day; and/or, the androgen inhibitor/antagonist is administered in amounts of 1.8 mg/day, 2.5 mg/day, 1.8 mg/day, 3.6 mg/day, 5 mg/day, 10 mg/day, or 20 mg/day; and/or, the above androgen inhibitor/antagonist is administered QD or BID; and/or, a pharmaceutical composition characterized in that the androgen inhibitor/antagonist is administered as a QD or BID in an amount of 0.25% (2.5 mg/mL or mg/g), 0.5% (5 mg/mL or mg/g), or 1% (10 mg/mL or mg/g).
  6. In any one of paragraphs 1 through 5, A therapeutically effective amount of the above minoxidil or its pharmaceutically acceptable excipients is administered to an individual in a continuous daily administration regimen until progression of a disease or condition related to androgen receptor activity or the occurrence of unacceptable toxicity; and/or, the minoxidil or pharmaceutically acceptable excipients thereof are administered in an amount of 2 mg/day to 500 mg/day; and/or, the minoxidil or its pharmaceutically acceptable excipients are administered in amounts of 14.4 mg/day, 20 mg/day, 36 mg/day, 40 mg/day, 44 mg/day, 50 mg/day, or 100 mg/day; and/or, the minoxidil or pharmaceutically acceptable excipients thereof are administered in an amount of 0.1% (1 mg/mL or mg/g) to 15% (150 mg/mL or mg/g); and/or, the minoxidil or pharmaceutically acceptable excipients thereof are administered in an amount of 2% (20 mg/mL or mg/g) to 5% (50 mg/mL or mg/g); and/or, the above minoxidil is administered QD or BID; A pharmaceutical composition characterized by the fact that the minoxidil or the pharmaceutically acceptable excipient thereof is administered as a QD or BID in an amount of 2% (20 mg/mL or mg/g) or 5% (50 mg/mL or mg/g).
  7. In any one of paragraphs 1 through 6, The above pharmaceutical composition is used for the prevention, alleviation, and/or treatment of diseases or conditions related to androgen receptor activity; Preferably, the disease or condition associated with the androgen receptor activity is selected from prostate cancer, benign prostatic hyperplasia, acne, hirsutism, seborrhea, and androgenic alopecia; A pharmaceutical composition characterized in that the patient having the above-mentioned related disease or condition is a male or female patient with androgenic alopecia, preferably a male patient with androgenic alopecia, and more preferably a male patient with Hamilton-Norwood grade IIIv-V androgenic alopecia.
  8. In the manufacture of a drug for preventing, alleviating, and/or treating a disease or condition related to androgen receptor activity, as a use of a pharmaceutical composition of any one of claims 1 to 6, Preferably, the disease or condition associated with the androgen receptor activity is selected from prostate cancer, benign prostatic hyperplasia, acne, hirsutism, seborrhea, and androgenic alopecia; and/or, the use is characterized in that the patient having the above-mentioned related disease or condition is a male or female patient with androgenic alopecia, preferably a male patient with androgenic alopecia, and more preferably a male patient with Hamilton-Norwood grade IIIv-V androgenic alopecia.
  9. A method for preventing, alleviating, and/or treating a disease or condition related to androgen receptor activity, wherein the method comprises the step of administering a preventive, alleviative, and/or therapeutically effective amount of a pharmaceutical composition of any one of claims 1 to 6 to an individual in need thereof; Preferably, the disease or condition associated with the androgen receptor activity is selected from prostate cancer, benign prostatic hyperplasia, acne, hirsutism, seborrhea, and androgenic alopecia; and/or, the androgen inhibitor/antagonist and minoxidil included in the above pharmaceutical composition are co-formulated or separately formulated, and are administered in combination, simultaneously, or at intervals; and/or, the above pharmaceutical composition is administered topically to an individual in need thereof; and/or, the method is characterized in that the subject is a male or female patient with androgenic alopecia, preferably a male patient with androgenic alopecia, and more preferably a male patient with Hamilton-Norwood grade IIIv-V androgenic alopecia.
  10. A pharmaceutical composition for preventing, alleviating, and/or treating androgenetic alopecia, wherein the pharmaceutical composition comprises a compound of Formula I or crystalline form D of a compound of Formula I, and minoxidil or a pharmaceutically acceptable excipient thereof: [Chemical Formula I] .
  11. In Paragraph 10, A therapeutically effective amount of the compound of Formula I or the crystalline form D of the compound of Formula I is administered to an individual in a continuous daily dosing regimen until progression of a disease or condition related to androgen receptor activity or the occurrence of unacceptable toxicity; and/or, the subject is a male or female patient with androgenetic alopecia, preferably a male patient with androgenetic alopecia, more preferably a male patient with Hamilton-Norwood grade IIIv-V androgenetic alopecia; and/or, the androgen inhibitor/antagonist is administered in an amount of 0.05% (0.5 mg/mL or mg/g) to 10% (100 mg/mL or mg/g); and/or, the androgen inhibitor/antagonist is administered in an amount of 0.25% (2.5 mg/mL or mg/g) to 1% (10 mg/mL or mg/g); and/or, the androgen inhibitor/antagonist is administered in an amount of 0.1 mg/day to 1000 mg/day; and/or, the androgen inhibitor/antagonist is administered in an amount of 0.5 mg/day to 100 mg/day; and/or, the androgen inhibitor/antagonist is administered in an amount of 1 mg/day to 50 mg/day; and/or, the androgen inhibitor/antagonist is administered in amounts of 2.5 mg/day, 5 mg/day, 10 mg/day, or 20 mg/day; and/or, the above androgen inhibitor/antagonist is administered QD or BID; and/or, the androgen inhibitor/antagonist is administered QD or BID in amounts of 0.25% (2.5 mg/mL or mg/g), 0.5% (5 mg/mL or mg/g), or 1% (10 mg/mL or mg/g); A therapeutically effective amount of the above minoxidil or its pharmaceutically acceptable excipients is administered to an individual in a continuous daily administration regimen until progression of a disease or condition related to androgen receptor activity or the occurrence of unacceptable toxicity; and/or, the minoxidil or pharmaceutically acceptable excipients thereof are administered in an amount of 2 mg/day to 500 mg/day; and/or, the minoxidil or its pharmaceutically acceptable excipients are administered in amounts of 20 mg/day, 40 mg/day, 44 mg/day, 50 mg/day, or 100 mg/day; and/or, the minoxidil or pharmaceutically acceptable excipients thereof are administered in an amount of 0.1% (1 mg/mL or mg/g) to 15% (150 mg/mL or mg/g); and/or, the minoxidil or pharmaceutically acceptable excipients thereof are administered in an amount of 2% (20 mg/mL or mg/g) to 5% (50 mg/mL or mg/g); and/or, the above androgen inhibitor/antagonist is administered QD or BID; A pharmaceutical composition characterized by the fact that the minoxidil or the pharmaceutically acceptable excipient thereof is administered as a QD or BID in an amount of 2% (20 mg/mL or mg/g) or 5% (50 mg/mL or mg/g).
  12. In Paragraph 11, (1) The compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 0.5% (5 mg/mL or mg/g), and the minoxidil is administered in an amount of 2% (20 mg/mL or mg/g); and/or, the compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 5 mg/day; and/or, the minoxidil is administered in an amount of 20 mg/day; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered as QD; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered simultaneously; Or (2) the compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 0.25% (2.5 mg/mL or mg/g) and the minoxidil is administered in an amount of 5% (50 mg/mL or mg/g); and/or, the compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 2.5 mg/day; and/or, the minoxidil is administered in an amount of 50 mg/day; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered as QD; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered simultaneously; Or (3) the compound of Formula I or the crystalline form D of the compound of Formula I is administered in an amount of 0.5% (5 mg/mL or mg/g), and the minoxidil is administered in an amount of 5% (50 mg/mL or mg/g); and/or, the compound of Formula I or the crystalline form D of the compound of Formula I is administered in an amount of 5 mg/day; and/or, the minoxidil is administered in an amount of 50 mg/day; and/or, the compound of Formula I or the crystalline form D of the compound of Formula I and the minoxidil are administered as QD; and/or, the compound of Formula I or the crystalline form D of the compound of Formula I and the minoxidil are administered simultaneously; Or (4) the compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 1% (10 mg/mL or mg/g) and the minoxidil is administered in an amount of 5% (50 mg/mL or mg/g); and/or, the compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 10 mg/day; and/or, the minoxidil is administered in an amount of 50 mg/day; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered as QDs; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered simultaneously; Or (5) the compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 0.25% (2.5 mg/mL or mg/g) and the minoxidil is administered in an amount of 5% (50 mg/mL or mg/g); and/or, the compound of Formula I or crystalline form D of the compound of Formula I is administered in an amount of 5 mg/day; and/or, the minoxidil is administered in an amount of 100 mg/day; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered BID; and/or, the compound of Formula I or crystalline form D of the compound of Formula I and minoxidil are administered at intervals; Or (6) the compound of formula I or the crystalline form D of the compound of formula I is administered in an amount of 0.5% (5 mg/mL or mg/g) and the minoxidil is administered in an amount of 5% (50 mg/mL or mg/g); and/or, the compound of formula I or the crystalline form D of the compound of formula I is administered in an amount of 10 mg/day; and/or, the minoxidil is administered in an amount of 100 mg/day; and/or, the compound of formula I or the crystalline form D of the compound of formula I and the minoxidil are administered BID; and/or, the compound of formula I or the crystalline form D of the compound of formula I and the minoxidil are administered at intervals, characterized by a pharmaceutical composition.
  13. A method for preventing, alleviating, and/or treating androgenetic alopecia, wherein the method comprises the step of administering a prophylactic, alleviative, and/or therapeutically effective amount of a compound of Formula I and minoxidil to an individual in need thereof; and/or, the subject is a male or female patient with androgenetic alopecia, preferably a male patient with androgenetic alopecia, more preferably a male patient with Hamilton-Norwood grade IIIv-V androgenetic alopecia; and/or, in the above method, the compound of Formula I and minoxidil are administered via a combination administration method selected from simultaneous administration, co-administration after separate formulation, or sequential administration after separate formulation; and/or, in the above method, the administration route is selected from oral administration, parenteral administration, topical administration, and transdermal administration; preferably, in the above method, the administration route is selected from topical administration and transdermal administration; and/or, a therapeutically effective amount of the compound of Formula I is administered to an individual in a continuous daily administration regimen until progression of the androgenetic alopecia disease or condition or the occurrence of unacceptable toxicity; and/or, a formulation containing the compound of Formula I is administered by being formulated such that the concentration of the compound of Formula I in the formulation is about 0.05% (0.5 mg/mL or mg/g) to 10% (100 mg/mL or mg/g); said formulation is a solid formulation, a liquid formulation (e.g., topical solution), a foam, an aerosol, or a gel, preferably a liquid formulation (e.g., topical solution); preferably, a solution of the compound of Formula I is administered by being formulated such that the concentration of the compound of Formula I in the solution is about 0.25% (2.5 mg/mL or mg/g) to 5% (50 mg/mL or mg/g); and/or, the compound of Formula I is administered in an amount of about 0.1 mg/day to about 1000 mg/day; and/or, the compound of Formula I is administered in an amount of about 0.5 mg/day to about 100 mg/day; and/or, the compound of Formula I is administered in an amount of about 1 mg/day to about 50 mg/day; and/or, the compound of Formula I is administered in an amount of about 1.8 mg/day, about 2.5 mg/day, about 3.6 mg/day, about 5 mg/day, about 7.2 mg/day, about 10 mg/day, or about 20 mg/day; and/or, the compound of Formula I above is administered as a QD or BID; and/or, a solution of the compound of Formula I is formulated such that the concentration of the compound of Formula I in the solution is about 0.25% (2.5 mg/mL), 0.5% (5 mg/mL), or 1% (10 mg/mL) and is administered topically as a QD or BID, with a dosage of about 1 mL per dose; The therapeutically effective amount of the above minoxidil is administered to the individual as a continuous daily administration regimen until the progression of androgenetic alopecia disease or condition or the occurrence of unacceptable toxicity; and/or, the minoxidil is administered in an amount of about 2 mg/day to about 500 mg/day; and/or, the minoxidil is administered in an amount of about 14.4 mg/day, about 20 mg/day, about 36 mg/day, about 40 mg/day, about 44 mg/day, about 50 mg/day, or about 100 mg/day; and/or, the formulation containing minoxidil is administered in a formulation in which the concentration of minoxidil in the formulation is about 0.1% (1 mg/mL or mg/g) to 15% (150 mg/mL or mg/g); said formulation is a solid formulation, a liquid formulation (e.g., a topical solution), a foam, an aerosol, or a gel, preferably a liquid formulation, a foam, and an aerosol; and/or, the formulation containing minoxidil is administered in a formulation in which the concentration of minoxidil in the formulation is about 2% (20 mg/mL or mg/g) to 5% (50 mg/mL or mg/g); said formulation is a solid formulation, a liquid formulation (e.g., a topical solution), a foam, an aerosol, or a gel, preferably a liquid formulation, a foam, and an aerosol; and/or, the above minoxidil is administered QD or BID; and/or, the solution, foam, or aerosol containing the minoxidil is administered in a formulation in which the concentration of minoxidil in the formulation is about 2% (20 mg/mL or mg/g) to 5% (50 mg/mL or mg/g); and/or, the solution, foam, or aerosol of the minoxidil is formulated with a concentration of minoxidil in the preparation of about 2% (20 mg/mL or mg/g) or 5% (50 mg/mL or mg/g) and is administered via topical administration in QD or BID, with a dosage of about 1 mL per administration; and/or, the liquid formulations of the compound of Formula I and minoxidil are formulated separately and independently, and the formulation having a concentration of the compound of Formula I of about 0.25% (2.5 mg/mL), 0.5% (5 mg/mL), or 1% (10 mg/mL) is administered in combination with a formulation having a concentration of minoxidil of about 2% (20 mg/mL) or 5% (50 mg/mL); preferably, the compound of Formula I and minoxidil are administered topically as a QD or BID; preferably, the dosage is about 1 mL each time.
  14. In Paragraph 13, (1) In the above method: the liquid formulation of the compound of Formula I and minoxidil is formulated separately and independently, the concentration of the compound of Formula I is about 0.5% (5 mg/mL) and the concentration of minoxidil is about 2% (20 mg/mL); and/or, the compound of Formula I and minoxidil are administered as QD; and/or, the dosage is about 1 mL each time, i.e., the compound of Formula I is administered in an amount of about 5 mg/day and the minoxidil is administered in an amount of 20 mg/day; Or (2) in the above method: the liquid formulation of the compound of Formula I and minoxidil is formulated separately and independently, the concentration of the compound of Formula I is about 0.25% (2.5 mg/mL) and the concentration of minoxidil is about 5% (50 mg/mL); and/or, the compound of Formula I and minoxidil are administered as QD; and/or, the dosage is about 1 mL each time, i.e., the compound of Formula I is administered in an amount of about 2.5 mg/day and the minoxidil is administered in an amount of 50 mg/day; Or (3) in the above method: the liquid formulation of the compound of Formula I and minoxidil is formulated separately and independently, the concentration of the compound of Formula I is about 0.5% (5 mg/mL) and the concentration of minoxidil is about 5% (50 mg/mL); and/or, the compound of Formula I and minoxidil are administered as QDs; and/or, the dosage is about 1 mL each time, i.e., the compound of Formula I is administered in an amount of about 5 mg/day and the minoxidil is administered in an amount of 50 mg/day; Or (4) in the above method: the liquid formulations of the compound of Formula I and minoxidil are formulated separately and independently, the concentration of the compound of Formula I is about 1% (10 mg/mL) and the concentration of minoxidil is about 5% (50 mg/mL); and/or, the compound of Formula I and minoxidil are administered as QDs; preferably, the compound of Formula I and minoxidil are administered simultaneously; and/or, the dosage is about 1 mL each time, i.e., the compound of Formula I is administered in an amount of about 10 mg/day and the minoxidil is administered in an amount of 50 mg/day; Or (5) in the above method: the liquid formulations of the compound of Formula I and minoxidil are formulated separately and independently, the concentration of the compound of Formula I is about 0.25% (2.5 mg/mL) and the concentration of minoxidil is about 5% (50 mg/mL); and/or, the compound of Formula I and minoxidil are administered BID; preferably, the compound of Formula I and minoxidil are administered at intervals; and/or, the dose administered is about 1 mL each time, i.e., the compound of Formula I is administered in an amount of about 5 mg/day and the minoxidil is administered in an amount of 100 mg/day; Or (6) in the above method: the liquid formulations of the compound of formula I and minoxidil are formulated separately and independently, the concentration of the compound of formula I is about 0.5% (5 mg/mL) and the concentration of minoxidil is about 5% (50 mg/mL); and/or, the compound of formula I and minoxidil are administered BID; preferably, the compound of formula I and minoxidil are administered at intervals; and/or, the dosage is about 1 mL each time, i.e., the compound of formula I is administered in an amount of about 10 mg/day and the minoxidil is administered in an amount of 100 mg/day.

Description

Pharmaceutical composition, method, and use containing androgen receptor inhibitor/antagonist Cross-reference regarding related applications The present disclosure claims priority to the invention patent application filed in China on September 8, 2023, with the title of the invention "Pharmaceutical composition, method and use containing an androgen receptor inhibitor/antagonist" and application number CN 2023111578546, and the invention patent application filed in China on February 6, 2024, with the title of the invention "Pharmaceutical composition, method and use containing an androgen receptor inhibitor/antagonist" and application number CN 2024101716421, the entire contents of which are incorporated herein by reference. Technology field The present disclosure belongs to the field of pharmaceutical technology and, specifically, relates to pharmaceutical compositions, methods, and uses containing androgen receptor inhibitors/antagonists and minoxidil as active ingredients. Minoxidil is a potassium channel opener, and when used for antihypertensive treatment, such drugs are often associated with reflex tachycardia and increased cardiac output. Additionally, minoxidil can reduce or stop hair loss and promote hair regrowth. Among drugs approved in China for the treatment of hair loss and alopecia areata, minoxidil demonstrates good efficacy in promoting hair growth. The mechanism of action of minoxidil is as follows: stimulating the proliferation of hair follicle epithelial cells and extending the anagen phase of hair growth; promoting angiogenesis and increasing local blood supply to provide nutrients for hair growth; and opening potassium ion channels, preventing the influx of calcium ions into cells, and increasing cellular DNA synthesis and hair follicle cell proliferation. Currently, various topical formulations of minoxidil are available in domestic and international markets and possess a high safety profile. However, minoxidil acts primarily by improving microcirculatory disorders and accelerating hair growth, which constitutes a symptomatic treatment. Therefore, while minoxidil demonstrates satisfactory efficacy only for general alopecia areata and hair loss, its efficacy is unsatisfactory for more severe conditions such as alopecia totalis and alopecia universalis. Androgenetic alopecia is an androgen-dependent hereditary disease and the most common clinical type of hair loss, characterized by a progressive decrease in hair density. In men, androgenetic alopecia is also known as male-pattern hair loss, while in women, it is known as female-pattern hair loss. Androgenetic alopecia is a polygenic disease inherited in an autosomal dominant manner. Local scalp hair follicles in patients exhibit increased sensitivity to androgens (primarily dihydrotestosterone (DHT)), which leads to follicle miniaturization and hair shaft thinning, clinically manifesting as sparse and thinning hair. Chinese invention patent CN 102757389B discloses a small molecule androgen receptor antagonist (chemical name: 4-(4,4-dimethyl-3-(6-methylpyridine-3-yl)-5-oxo-2-thioxomidazolidine-1-yl)-3-fluoro-2-methoxybenzonitrile (represented by chemical formula I, currently in the clinical study phase)). In the prior art, minoxidil is typically used in combination with active ingredients of traditional Chinese medicines that promote hair growth (e.g., Publication No. CN 109010432A and Publication No. CN 113712968A), or with 5α-reductase inhibitors such as finasteride (Publication No. CN 111973607A) and dutasteride (Publication No. CN 109674762A). Most of these dual or multiple drug combinations are merely simple physical mixtures of individual agents, each exerting a hair growth-promoting effect as monotherapy, resulting in limited efficacy. Therefore, it is particularly important to develop products and methods to improve the monotherapy efficacy of minoxidil or androgen receptor inhibitors/antagonists. The problem to be solved by initiation The primary objective of the present disclosure is to provide a new pharmaceutical composition, a method of treatment, and the use thereof for a disease or condition related to androgen receptor activity. means of solving the problem In a first aspect, the present disclosure provides a pharmaceutical composition comprising an androgen inhibitor/antagonist and minoxidil, or a pharmaceutically acceptable excipient thereof. Additionally, the above androgen inhibitors/antagonists include clascoterone, nilutamide, enzalutamide, topilutamide, bicalutamide, flutamide, hydrochlorothiazide, spironolactone, niclosamine, rezvilutamide, darolutamide, althiazide, apalutamide, deutenzalutamide, enovosarm, proxalutamide, ANA-001, 18F-dihydrotestosterone, 2-hydroxylflutamide, AKP-009, ASC-J9, AZD5312, EG017, LY2452473, MK-0773, VK5211, bavdegalutamide, dimethandrolone undecanoate, seviteronel, inocoteronone, zanoterone, CP-COV03, FW-1022, APC-100, ARV-766, EM-5854, EPI-7386, MVI-118, ODM-204, TRC253, UT-34, ralani