Composition comprising thiohydantoin compound

Abstract

A composition capable of producing foam. The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. The foam composition is convenient to use and has high stability, and can be used for treating, preventing, or alleviating androgen-mediated disorders, diseases, or conditions, such as acne, hirsutism, sebaceous gland enlargement, or androgenic alopecia.

Description

A composition containing a thiohydantoin compound

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese patent application No. 202510076243.1, filed on January 17, 2025, entitled "A Composition Containing a Thiohydantoin Compound", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to a foam-generating composition, specifically to a foam composition containing a thiohydantoin compound, a method for preparing the same, and its use in treating androgen-mediated diseases. Background Technology

[0004] The androgen receptor (AR) belongs to the androgen-activated nuclear hormone receptor family. In the absence of androgens, AR is bound to heat shock protein 90 (Hsp90) in the cytosol. When androgens bind to AR, AR is released from the complex formed by heat shock protein, undergoes phosphorylation, forms a dimer, and translocates into the nucleus, binding to its associated DNA fragment and stimulating the transcription of its target gene. Several pathological diseases have been confirmed to be dependent on androgens, such as prostate cancer, alopecia, and other androgen excess syndromes.

[0005] Compound 4-(4,4-dimethyl-3-(6-methylpyridin-3-yl)-5-carbonyl-2-thioimidazolidine-1-yl)-3-fluoro-2-methoxybenzonitrile is a thiohydantoin compound that can be used as an androgen receptor antagonist or inhibitor. Its structural formula is shown in Formula (I). Clinical trials have confirmed that this compound can be used to treat diseases such as hair loss and acne.

[0006] PCT / CN2024 / 080801 discloses a pharmaceutical composition of compound (I), specifically disclosing two dosage forms: gel and tincture. A foaming agent is a formulation composed of surfactants, drugs, and other components. Foaming agents can be formed by adding a propellant, sealing in a pressurized container, and then spraying out; alternatively, they can be formed by sealing in an unpressurized container and then spraying out using a specific nozzle. Foaming agents can be classified into water-alcohol type foaming agents, emulsion type foaming agents, nanoemulsion foaming agents, oil foaming agents, ointment type foaming agents, suspension type foaming agents, etc. Compared to gels and tinctures, foaming agents have a lower density, making them easier to apply and penetrate onto skin surfaces with hair or lesions. They can be evenly applied with only a small shear force, or even without shear force after defoaming, reducing patient discomfort and improving patient compliance. Furthermore, foaming agents only require spraying during use; the drug is sealed in the container, reducing contact with the external environment and thus avoiding contamination of the drug solution.

[0007] Compound (I) possesses unique physicochemical properties, such as low solubility. Its solubility is significantly lower than that of minoxidil (minoxidil has a solubility of approximately 2.2 mg / ml in water and approximately 6.5 mg / ml in propylene glycol). According to the applicant's tests, compound (I) is practically insoluble in water (solubility approximately 0.001 mg / ml) and has a solubility of approximately 1.5 mg / ml in propylene glycol. Therefore, the development of foaming agents for aqueous systems cannot follow the approach used for highly soluble drugs like minoxidil. Thus, developing a stable foaming agent containing compound (I) is a pressing issue that needs to be addressed. Summary of the Invention

[0008] The purpose of this application is to address the low solubility of compound (I) in water and to provide a foaming agent containing a high concentration of compound (I) with excellent stability.

[0009] To solve the above-mentioned technical problems, in a first aspect, this application provides a liquid composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvent, and a surfactant;

[0010] The solvent is an organic solvent, or a combination of an organic solvent and water; preferably, the organic solvent includes one or more of alcohol solvents, ester solvents, and ether solvents; the surfactant is one or more of nonionic surfactants or anionic surfactants.

[0011] In one embodiment of this application, the liquid composition contains, by weight percentage, 0.10%-20% of the compound of formula (I), preferably 0.5%-5%, and more preferably 2% ± 0.5%.

[0012] In one embodiment of this application, the alcohol solvent is selected from ethanol, denatured ethanol, propylene glycol, hexanediol, pentanediol, glycerol, isopropanol, butanediol, dipropylene glycol, butanol, and polyethylene glycol; the ester solvent is selected from medium-chain triglycerides and ethyl acetate; and the ether solvent is selected from diethylene glycol monoethyl ether and isosorbide dimethyl ether.

[0013] In one embodiment of this application, the organic solvent is preferably one or any combination of diethylene glycol monoethyl ether, propylene glycol, ethanol, polyethylene glycol, isosorbide dimethyl ether, and medium-chain triglycerides; more preferably one or any combination of medium-chain triglycerides, diethylene glycol monoethyl ether, and propylene glycol.

[0014] In one embodiment of this application, the nonionic surfactant is selected from polyethylene glycol glycerol caprylate, polyglyceryl-3-dioleate, lauroyl polyoxyl-32-glycerides, stearoyl polyoxyl-32-glycerides, propylene glycol monolaurate, glyceryl mono and dicaprylocaprate, propylene glycol monocaprylate, polysorbate, and poloxamer; preferably, it is one or any combination of polyethylene glycol glycerol caprylate, polyglyceryl fatty acid ester, and poloxamer; the anionic surfactant is selected from sodium dodecyl sulfate, fatty alcohol polyoxyethylene ether sulfate, sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, sodium lauryl ether sulfate, and sodium lauryl ether sulfate, preferably sodium dodecyl sulfate.

[0015] In one embodiment of this application, the liquid composition further includes an antioxidant, which is one or any combination of butylated hydroxytoluene, vitamin C, sodium bisulfite, butylated hydroxyanisole (BHA), and vitamin E (VE); in the liquid composition, the antioxidant has a weight percentage of 0.01%-1.0%, preferably 0.01%-0.10%.

[0016] In one embodiment of this application, in the liquid composition, the compound of formula (I) is 0.10%-20% by weight, the solvent is 30%-55%, and the surfactant is 35%-65%; in the solvent, the weight of water is 10%-50% of the weight of the liquid composition.

[0017] In one embodiment of this application, the liquid composition contains 10%-25% medium-chain triglycerides by weight, preferably 12%-22%.

[0018] In one embodiment of this application, the liquid composition contains 5%-25% diethylene glycol monoethyl ether by weight percentage, preferably 7-20%.

[0019] In one embodiment of this application, the liquid composition contains 1%-10% propylene glycol by weight, preferably 3-8%.

[0020] In one embodiment of this application, the liquid composition contains 5%-65% by weight of polyethylene glycol glycerol caprylate, preferably 30%-65% by weight.

[0021] In one embodiment of this application, the liquid composition contains 2%-10% polyglycerol fatty acid ester by weight, preferably 5%-8%.

[0022] In one embodiment of this application, the liquid composition contains 5%-15% sodium dodecyl sulfate by weight, preferably 8%-12%.

[0023] In one embodiment of this application, the liquid composition contains poloxamer at a weight percentage of 0.01%-10%, preferably 1.5%-3.5%.

[0024] In one embodiment of this application, the liquid composition comprises a compound of formula (I), polyethylene glycol glycerol caprylate, polyglycerol fatty acid ester, medium-chain triglyceride, sodium dodecyl sulfate, and water.

[0025] In one embodiment of this application, the liquid composition comprises, by weight percentage, 2% ± 0.5% of compound (I), 30%-35% of polyethylene glycol glycerol octanoate-capric acid, 5%-8% of polyglycerol fatty acid ester, 10%-25% of medium-chain triglycerides, 8%-12% of sodium dodecyl sulfate, and the balance being water.

[0026] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 30% of polyethylene glycol glycerol octanoate-capric acid, 6% of polyglycerol fatty acid ester, 12% of medium-chain triglycerides, 10% of sodium dodecyl sulfate, and 40% of water.

[0027] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 30% of polyethylene glycol glycerol octanoate / capric acid ester, 6% of polyglycerol fatty acid ester, 17% of medium-chain triglycerides, 10% of sodium dodecyl sulfate, and 35% of water.

[0028] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 30% of polyethylene glycol glycerol octanoate-capric acid ester, 6% of polyglycerol fatty acid ester, 22% of medium-chain triglycerides, 10% of sodium dodecyl sulfate, and 30% of water.

[0029] In one embodiment of this application, the liquid composition comprises a compound of formula (I), diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol glycerol caprylate, poloxamer, and water.

[0030] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2.0% ± 0.5% of compound (I), 7-20% of diethylene glycol monoethyl ether, 3%-8% of propylene glycol, 50%-65% of polyethylene glycol glycerol caprylate and caprylic acid, 1.5%-3.5% of poloxamer, and the balance being water.

[0031] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 10% of diethylene glycol monoethyl ether, 5% of propylene glycol, 60.5% of polyethylene glycol glycerol octanoate-decanoate, 2.5% of poloxamer, and 20% of water.

[0032] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 15% of diethylene glycol monoethyl ether, 5% of propylene glycol, 55.5% of polyethylene glycol glycerol octanoate-decanoate, 2.5% of poloxamer, and 20% of water.

[0033] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 20% of diethylene glycol monoethyl ether, 5% of propylene glycol, 50.5% of polyethylene glycol glycerol octanoate-decanoate, 2.5% of poloxamer, and 20% of water.

[0034] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 7% of diethylene glycol monoethyl ether, 5% of propylene glycol, 63.5% of polyethylene glycol glycerol octanoate-decanoate, 2.5% of poloxamer, and 20% of water.

[0035] In one embodiment of this application, the liquid composition comprises, by weight percentage: 2% of compound (I), 7% of diethylene glycol monoethyl ether, 5% of propylene glycol, 58.5% of polyethylene glycol glycerol octanoate-decanoate, 2.5% of poloxamer, and 25% of water.

[0036] In one embodiment of this application, the liquid composition described in the first aspect may further include a foam stabilizer. The foam stabilizer can increase the viscosity of the liquid composition and the stability of the foam. The foam stabilizer may be one or a combination of higher fatty alcohols containing 15 or more carbon atoms and higher fatty acids containing 16 or more carbon atoms; the higher fatty alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol, a mixture of cetyl alcohol and stearyl alcohol, arachidonic acid, behenol, 1-triacontanol, and oleyl alcohol; the higher fatty acids include, but are not limited to, palmitic acid, stearic acid, arachidic acid, behenic acid, and octacosanic acid; the amount of foam stabilizer added may be 0.1%-10% of the total weight of the liquid composition.

[0037] In one embodiment of this application, the liquid composition described in the first aspect is sprayed as foam using a specific nozzle after filling.

[0038] According to a second aspect of this application, this application provides a foam composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvent, a surfactant, and a propellant;

[0039] The solvent is an organic solvent, or a combination of an organic solvent and water; preferably, the organic solvent includes one or more of alcohol solvents, ester solvents, and ether solvents.

[0040] The surfactant is a nonionic surfactant.

[0041] In one embodiment of this application, the alcohol solvent is selected from ethanol, denatured ethanol, propylene glycol, hexanediol, pentanediol, glycerol, isopropanol, butanediol, dipropylene glycol, butanol, and polyethylene glycol, preferably one or any combination of propylene glycol, denatured ethanol, dipropylene glycol, butanediol, and polyethylene glycol; the ester solvent is selected from medium-chain triglycerides and ethyl acetate; the ether solvent is selected from diethylene glycol monoethyl ether and isosorbide dimethyl ether; the organic solvent is preferably one or any combination of diethylene glycol monoethyl ether, propylene glycol, denatured ethanol, polyethylene glycol, isosorbide dimethyl ether, butanediol, and dipropylene glycol; more preferably a combination of diethylene glycol monoethyl ether and propylene glycol.

[0042] In one embodiment of this application, the nonionic surfactant in the foam composition is selected from one or more of polyethylene glycol glycerol octanoate, polyglycerol fatty acid ester, lauroyl polyoxyethylene (32) glycerol ester, stearoyl polyoxyethylene (32) glycerol ester, propylene glycol monolaurate, glycerol mono- and dicaprylic / capric acid ester, propylene glycol monocaprylic acid ester, polysorbate, and poloxamer; preferably, any one or any combination of poloxamer, polyethylene glycol glycerol octanoate, and polysorbate.

[0043] In one embodiment of this application, the propellant in the foam composition is a liquefied gas propellant and a compressed gas propellant, preferably a liquefied gas propellant; the liquefied gas propellant includes perchlorofluorocarbon propellants, hydrocarbon propellants (preferably any one or more of propane, butane, and isobutane), hydrofluoroalkane propellants, and oxygen-containing compound propellants, preferably hydrofluoroalkane propellants. The hydrofluoroalkane propellant includes 1,1,1,2-tetrafluoroethane (tetrafluoroethane, HFA-134a), heptafluoropropane (HFA-227ea), 1,3,3,3-tetrafluoropropylene (HFO-1234ze), or difluoroethane (HFC-152a), preferably 1,1,1,2-tetrafluoroethane.

[0044] In one embodiment of this application, the foam composition further includes an antioxidant, which is one or any combination of butylated hydroxytoluene, vitamin C, sodium bisulfite, butylated hydroxyanisole, and vitamin E; preferably, the antioxidant in the composition is 0.01%-1% by weight, more preferably 0.01%-0.1% by weight.

[0045] In one embodiment of this application, the foam composition further includes a foam stabilizer, which is one or more of higher fatty alcohols containing 15 or more carbon atoms and higher fatty acids containing 16 or more carbon atoms; the higher fatty alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol, a mixture of cetyl alcohol and octadecyl alcohol, arachidonic acid, behenol, 1-triacontanol, and oleyl alcohol; the higher fatty acids include, but are not limited to, palmitic acid, stearic acid, arachidic acid, behenic acid, and octadecanoic acid; preferably, the foam stabilizer in the composition is 0.01% to 5% by weight; more preferably, it is 0.5% to 3% by weight.

[0046] In one embodiment of this application, the foam composition further includes a gelling agent, which is one or more of natural polymers, semi-synthetic polymers, and synthetic polymers; the natural polymers include, but are not limited to, locust bean gum, sodium alginate, xanthan gum, and tragacanth gum; the semi-synthetic polymers include, but are not limited to, cellulose ethers (such as methylcellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), etc.) and guar gum derivatives; the synthetic polymers include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol polyacrylic acid copolymer, and carbomer; preferably, in the composition, the weight percentage of the gelling agent is 0.01%-2%, more preferably 0.05%-0.5%.

[0047] In one embodiment of this application, the foam composition, calculated by weight percentage, comprises 0.1%-20% of the compound of formula (I), preferably 0.5%-5%, more preferably 2% ± 0.5%; 35%-60% of the solvent; 20%-45% of the surfactant; and 5%-25% of the propellant.

[0048] In one embodiment of this application, when the foam composition contains diethylene glycol monoethyl ether, the weight percentage of diethylene glycol monoethyl ether is 0.1%-45%; preferably 10%-42%.

[0049] In one embodiment of this application, the foam composition, when containing propylene glycol, contains 0.1%-15% by weight; more preferably 3%-8%.

[0050] In one embodiment of this application, when the foam composition contains polyethylene glycol glycerol caprylate, the weight percentage of polyethylene glycol glycerol caprylate is 5%-45%; preferably 10%-42%.

[0051] In one embodiment of this application, the foam composition, when the surfactant is poloxamer, has a weight percentage of 0.5%-5%, preferably 1-2.5%.

[0052] In one embodiment of this application, when the surfactant is polysorbate, the polysorbate in the foam composition is 1%-50% by weight; preferably 10%-35%; preferably, the polysorbate includes any one or more of polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

[0053] In one embodiment of this application, the stabilizer in the foam composition is a mixture of hexadecyl alcohol and octadecyl alcohol; in the composition, the weight percentage of the mixture of hexadecyl alcohol and octadecyl alcohol is 0.5-3%, more preferably 0.5-1.5%; the weight ratio of hexadecyl alcohol to octadecyl alcohol in the mixture of hexadecyl alcohol and octadecyl alcohol is (25%-75%):(75%-25%), preferably 25%:75%, 50%:50%, or 75%:25%; more preferably a mixture of hexadecyl alcohol and octadecyl alcohol with a weight ratio of 50%:50%.

[0054] In one embodiment of this application, the propellant in the foam composition is 1,1,1,2-tetrafluoroethane; preferably, the weight percentage of 1,1,1,2-tetrafluoroethane in the composition is 5% to 25%, more preferably 15% to 25%.

[0055] In one embodiment of this application, the foam composition comprises a compound of formula (I), diethylene glycol monoethyl ether, polyethylene glycol glycerol caprylate, propylene glycol, 1,1,1,2-tetrafluoroethane, and water; preferably, it further comprises an antioxidant, any one or more of poloxamer or xanthan gum.

[0056] In one embodiment of this application, the foam composition, by weight percentage, comprises 2% ± 0.5% of compound (I), 10%-30% of diethylene glycol monoethyl ether, 20%-42% of polyethylene glycol glycerol octanoate-capric acid, 3-8% of propylene glycol, 0%-0.1% of xanthan gum, 1%-2.5% of poloxamer, 15%-25% of 1,1,1,2-tetrafluoroethane, and the balance being water; more preferably, when the composition contains an antioxidant, the antioxidant is 0.01%-0.10%.

[0057] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 10% of diethylene glycol monoethyl ether, 41.9% of polyethylene glycol glycerol octanoate-decanoate, 5% of propylene glycol, 0.1% of xanthan gum, 1% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water.

[0058] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 20% of diethylene glycol monoethyl ether, 31.9% of polyethylene glycol glycerol octanoate-decanoate, 5% of propylene glycol, 0.1% of xanthan gum, 1% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water.

[0059] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 10% of diethylene glycol monoethyl ether, 40.5% of polyethylene glycol glycerol octanoate-decanoate, 5% of propylene glycol, 2.5% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water.

[0060] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 30% of diethylene glycol monoethyl ether, 21.9% of polyethylene glycol glycerol octanoate-capric acid, 5% of propylene glycol, 0.1% of xanthan gum, 1% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water.

[0061] In one embodiment of this application, the foam composition comprises a compound of formula (I), diethylene glycol monoethyl ether, polysorbate, polyethylene glycol glycerol caprylate, propylene glycol, an antioxidant, cetearyl alcohol, 1,1,1,2-tetrafluoroethane, and water; wherein the polysorbate is preferably polysorbate 60.

[0062] In one embodiment of this application, the foam composition, by weight percentage, comprises: 2% ± 0.5% of compound (I), 22%-35% of diethylene glycol monoethyl ether, 10%-15% of polysorbate 60, 10%-20% of polyethylene glycol glycerol caprylate, 3-8% of propylene glycol, 0.01%-0.10% of antioxidant, 0.5%-1.5% of cetearyl alcohol, 15%-25% of 1,1,1,2-tetrafluoroethane, and the balance being water.

[0063] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 35% of diethylene glycol monoethyl ether, 10% of polysorbate 60, 10% of polyethylene glycol glycerol caprylate, 7% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water.

[0064] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 32% of diethylene glycol monoethyl ether, 10% of polysorbate 60, 15% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water.

[0065] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 27% of diethylene glycol monoethyl ether, 15% of polysorbate 60, 15% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water.

[0066] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 27% of diethylene glycol monoethyl ether, 10% of polysorbate 60, 20% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water.

[0067] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 22% of diethylene glycol monoethyl ether, 15% of polysorbate 60, 20% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water.

[0068] In one embodiment of this application, the foam composition comprises a compound of formula (I), diethylene glycol monoethyl ether, polysorbate, propylene glycol, cetearyl alcohol, 1,1,1,2-tetrafluoroethane, and water; preferably, the polysorbate is selected from one or any combination of polysorbate 20, polysorbate 60, and polysorbate 80; preferably, the foam composition further comprises one or more of an antioxidant, an antibacterial agent, or xanthan gum.

[0069] In one embodiment of this application, the foam composition, by weight percentage, comprises: 2% ± 0.5% of compound (I), 20%-32% of diethylene glycol monoethyl ether, 30%-35% of polysorbate, 3%-8% of propylene glycol, 0.5%-1.5% of cetearyl alcohol, 15%-25% of 1,1,1,2-tetrafluoroethane, and the balance being water; more preferably, when the composition contains an antioxidant, the antioxidant is 0.01%-0.10%; when the composition contains xanthan gum, the xanthan gum is 0.01%-0.10%.

[0070] In one embodiment of this application, the foam composition, by weight percentage, comprises: 2% of compound (I), 25.5% of diethylene glycol monoethyl ether, 10.2% of polysorbate 20, 12.2% of polysorbate 60, 10.2% of polysorbate 80, 5.1% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20.4% of 1,1,1,2-tetrafluoroethane, and 13.24% of water.

[0071] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 27% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 15% of water.

[0072] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 32% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 10% of water.

[0073] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 22% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water.

[0074] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 21.95% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 0.05% of xanthan gum, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water.

[0075] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 25.5% of diethylene glycol monoethyl ether, 15.3% of polysorbate 20, 2% of polysorbate 60, 15.3% of polysorbate 80, 5.1% of propylene glycol, 1% of cetearyl alcohol, 20.4% of 1,1,1,2-tetrafluoroethane, and 13.3% of water.

[0076] In one embodiment of this application, the foam composition comprises a compound of formula (I), diethylene glycol monoethyl ether, polysorbate, propylene glycol, cetearyl alcohol, and 1,1,1,2-tetrafluoroethane; the polysorbate is selected from one or any combination of polysorbate 20, polysorbate 60, and polysorbate 80; preferably, the foam composition further comprises one or more of an antioxidant, an antibacterial agent, or xanthan gum.

[0077] In one embodiment of this application, the foam composition, by weight percentage, comprises: 2% ± 0.5% of compound (I), 20%-42% of diethylene glycol monoethyl ether, 30%-35% of polysorbate, 3%-8% of propylene glycol, 0.5%-1.5% of cetearyl alcohol, and 15%-25% of 1,1,1,2-tetrafluoroethane; more preferably, when the composition contains an antioxidant, the antioxidant is 0.01%-0.10%; when the composition contains xanthan gum, the xanthan gum is 0.01%-0.10%.

[0078] In one embodiment of this application, the foam composition comprises, by weight percentage: 2% of compound (I), 42% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, and 20% of 1,1,1,2-tetrafluoroethane.

[0079] The liquid composition described in the first aspect of this application and the foam composition described in the second aspect may further include at least one of an antibacterial agent, a chelating agent, a pH adjuster, and a colorant; the antibacterial agent helps to extend the shelf life of the composition and prevent bacterial contamination; the selected antibacterial agents include, but are not limited to, benzoic acid, sodium benzoate, parabens, sorbic acid, potassium sorbate, etc.; the specific amount added can be added according to the commonly used concentration range; the colorant can color the foam composition, modify and beautify the shape of the foam composition, and adjust the influence of certain raw materials in the formulation on the color of the foam composition.

[0080] According to a third aspect of this application, this application provides the use of the liquid composition of the first aspect or the foam composition of the second aspect in the preparation of a medicament for treating, preventing or alleviating androgen-mediated disorders, diseases or symptoms in a subject; preferably, the androgen-mediated disorders, diseases or symptoms are selected from acne, hirsutism, sebaceous gland enlargement or androgenic alopecia (AGA).

[0081] According to a fourth aspect of this application, this application provides a liquid composition as described in the first aspect or a foam composition as described in the second aspect for treating, preventing, or alleviating androgen-mediated disorders, diseases, or symptoms in a subject; preferably, the androgen-mediated disorders, diseases, or symptoms are selected from acne, hirsutism, sebaceous gland enlargement, or androgenetic alopecia.

[0082] According to a fifth aspect of this application, this application provides a method for treating, preventing, or alleviating androgen-mediated disorders, diseases, or symptoms in a subject, comprising administering to a subject in need a therapeutically effective amount of either the liquid composition described in the first aspect or the foam composition described in the second aspect; preferably, the androgen-mediated disorder, disease, or symptom is selected from acne, hirsutism, sebaceous gland enlargement, or androgenetic alopecia.

[0083] Compounds of Formula (I) or pharmaceutically acceptable salts thereof described in this application exhibit polymorphism. In topical pharmaceutical formulations (such as foams), compounds of Formula I are typically in a dissolved molecular state. Therefore, the crystal form of compounds of Formula I or pharmaceutically acceptable salts thereof has a relatively small impact on pharmaceutical formulations.

[0084] In one embodiment of this application, the active ingredient of the liquid composition described in the first aspect or the foaming agent composition described in the second aspect is a compound (I) and its crystal form, pharmaceutically acceptable salt, or solvate. The active ingredient can be a free base of the compound of formula I involved in CN102757389B, or a compound of formula I involved in PCT / CN2022 / 082274 or CN2023112287590, or its pharmaceutically acceptable salt or crystal form, to prepare the pharmaceutical composition or formulation of this application. To ensure good stability of the active ingredient compound of formula I during the preparation of the pharmaceutical composition or formulation of this application, it is preferred to use a compound of formula I or its pharmaceutically acceptable polymorph.

[0085] In one embodiment of this application, the active ingredient is a compound of formula I, in crystal form A, B, D, F, 1,4-dioxane solvate E, in crystal form A, B, C, D, or E of hydrobromide (see CN2023112287590, the entire contents of which are incorporated herein by reference).

[0086] In one embodiment of this application, the active ingredient is a free base of compound of formula I, crystal form D, crystal form C, crystal form B or crystal form A (see PCT / CN2022 / 082274, the entire contents of which are incorporated herein by reference).

[0087] Unless otherwise stated, the term "comprising" and its variations, such as "containing" and "including," as used herein mean that the collection not only covers the one or more integers, steps, or combinations thereof explicitly disclosed, but also excludes any other integers, steps, or combinations thereof. Furthermore, in certain circumstances, the term "comprising" may be replaced by the terms "containing," "including," or "having."

[0088] Unless otherwise stated, the term "effective amount" as used herein refers to the amount of a pharmaceutically active ingredient that, when administered to an individual / subject / patient, is sufficient to affect the disease or symptom of the disease or condition in order to treat, prevent, or alleviate it. This "effective amount" can vary depending on factors such as the active pharmaceutical ingredient, the symptoms or severity of the disease or condition, and individual circumstances of the individual / subject / patient (e.g., age, sex, weight).

[0089] The term "pharmaceutically acceptable" refers to compounds, raw materials, compositions, and / or dosage forms that, within the bounds of reasonable medical judgment, are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0090] The terms “optional,” “optional,” or “optionally” mean that an event or situation described below may, but is not guaranteed to, occur, and that the description includes both the possibility that said event or situation occurs and the possibility that it does not occur. For example, “optional pharmaceutically acceptable excipient” means that a pharmaceutically acceptable excipient may or may not be present.

[0091] The term "room temperature" refers to the indoor ambient temperature, which can range from 10℃ to 30℃.

[0092] The term “weight percentage” or “percentage by weight” or “wt%” is defined as the weight of a single component in the composition divided by the total weight of all components in the composition and then multiplied by 100%.

[0093] The term "% (w / w)" means the weight of a single component in the composition divided by the total weight of the composition and then multiplied by 100%.

[0094] The term "% (v / v)" means the volume of a single component in the composition divided by the total volume of the composition and then multiplied by 100%.

[0095] The term "% (w / v)" means the weight of a single component in the composition divided by the total volume of the composition and then multiplied by 100%.

[0096] Those skilled in the art, when preparing compositions or pharmaceutical formulations according to the "weight percentage", "percentage by weight", "wt%", "% (w / w)", "% (v / v)", "% (w / v)", etc. in the specification, may have an error of up to 30% in specific values, such as up to 1%, 2%, 5%, 10%, 15%, 20%, or 30%, provided that the compound of formula (I) is soluble and does not precipitate. Technical solutions within these error ranges should be understood as being within the scope of protection of this application and are considered as the same or equivalent technical solutions.

[0097] The term “and / or” should be understood to mean any one of the options or any combination of two or more of the options.

[0098] The term "carbomer," also known as carbop or carbomer resin, refers to an acrylic crosslinked resin obtained by crosslinking pentaerythritol and acrylic acid.

[0099] The term "foam stabilizer" refers to a class of excipients that enhance the stabilizing ability of surfactants on emulsions and increase foam stability. These are primarily higher fatty alcohols and fatty acids, such as fatty alcohols with 15 or more carbon atoms or fatty acids with 16 or more carbon atoms listed in this application. The fatty alcohols and fatty acids can also be higher unsaturated fatty alcohols and higher unsaturated fatty acids, such as oleyl alcohol (octadecenol). In the embodiments of this application, cetearyl alcohol refers to a mixture of cetearyl alcohol and octadecyl alcohol (the weight ratio of cetearyl alcohol to octadecyl alcohol is 50%:50%).

[0100] The term "gelling agent" refers to a useful component used to generate foams with desired texture and spreading properties, promoting the formation of foams with fine bubble structures, making the foam less prone to collapse, and prolonging the foam's duration. Some gelling agents also have film-forming properties, which can increase the product's residence time at the site of action. Commonly used gelling agents, as listed in this application, include natural polymers, semi-synthetic polymers, and synthetic polymers.

[0101] In the foam composition of this application, poloxamer is selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407; poloxamer 188 is preferred. The poloxamer used in the embodiments of this application is poloxamer 188.

[0102] In the formulations of this application, the component "water" refers to "purified water". Beneficial effects

[0103] Compared with the prior art, this application includes at least one of the following beneficial effects:

[0104] (1) The liquid composition and foam composition of this application are easier to distribute on the skin surface (especially hair areas such as the scalp) than gels and tinctures, and are more conducive to the uniform dispersion of the drug after application.

[0105] (2) The liquid and foam compositions of this application are easy to use and store, and increase the long-term compliance of subjects.

[0106] (3) The liquid form composition and foam composition of this application can not only dissolve the poorly soluble compound of formula (I), but also have a high concentration of compound of formula (I) in the composition and are stable without precipitation.

[0107] (4) The liquid form composition and foam composition of this application, especially the foam composition described in the second aspect, have good foam molding, good uniformity, high stability and low impurity growth.

[0108] (5) The preparation methods of the liquid form composition and foam composition of this application are simple and suitable for industrial scale-up production. Attached Figure Description

[0109] Figure 1. Foam formed after prescription 14-1 is sprayed.

[0110] Figure 2. Foam formed after prescription 19A-1 is sprayed.

[0111] Figure 3. Foam formed after Formula 20C is sprayed. Detailed Implementation

[0112] Many specific details are set forth in the following description to provide a full understanding of this application. However, this application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of this application. Therefore, this application is not limited to the specific embodiments disclosed below. The compound of formula (I) of this application or its pharmaceutically acceptable salt, solvate, crystalline form or amorphous form can be prepared according to the methods described in CN102757389B, PCT / CN2022 / 082274 or CN2023112287590, and other excipients are commercially available.

[0113] The sources of some of the excipients are as follows: PEG-134a (caprylic / capric acid glyceride, batch number 190913); PEG-134a (polyglycerol fatty acid ester, batch number 193946); PEG-134a (medium-chain triglycerides, batch number 192258); PEG-134a (diethylene glycol monoethyl ether, batch number 194768); PEG-400 (Liaoning Aoke, batch number QS231207915); hydroxypropyl-β-cyclodextrin (Xi'an Deli Biochemical Co., Ltd., batch number 20221210); cetearyl alcohol (Alfaesa (China) Chemical Co., Ltd., batch number 20230501); In the embodiments of this application, tetrafluoroethane is an abbreviation for 1,1,1,2-tetrafluoroethane (HFA-134a).

[0114] The HPLC detection method used in this article is as follows:

[0115] High Performance Liquid Chromatography (HPLC): Agilent HPLC system (equivalent instruments can be used).

[0116] Chromatographic column: Waters CSH TM C18 4.6*150mm, 3.5μm (equipped with a Ghost-Buster Column 4.6×50mm)

[0117] Detector wavelength: 234nm;

[0118] Column temperature: 35℃;

[0119] Flow rate: 0.8 mL / min

[0120] Mobile phase A: 0.1% aqueous phosphoric acid solution;

[0121] Mobile phase B: Acetonitrile: Methanol = 1:1;

[0122] Gradient elution, the elution procedure is shown in the table below:

[0123] Table 1. Gradient Elution Table

[0124] Example 1: Raw material compatibility test

[0125] The purpose of the raw material and excipient compatibility test is to identify compatible excipients that can be used in the development of foaming agents for compound (I). Referring to the "Technical Guidelines for Stability Studies of Chemical Drugs (Active Pharmaceutical Ingredients and Preparations)," excipients with different functional components are selected for raw material and excipient compatibility tests based on the physicochemical properties of compound (I).

[0126] 1.1 Raw material compatibility test procedure

[0127] After mixing the compound of formula (I) with the excipients in a certain proportion, weigh an appropriate amount of the mixture into a vial. The vial is then exposed to high temperature and high humidity (40℃±2℃ / 75%RH±5%RH) conditions for 15 days, high temperature (60℃±2℃) conditions for 10 days, and light (5000±500Lux, 90±5μw / cm²) conditions respectively. 2 The excipients were left exposed for 10 days, and their properties were observed and related substances were tested to examine the compatibility of the excipients with the compound of formula (I). Simultaneously, all excipients were placed individually under the above two conditions, and their properties were observed and tested. By evaluating the changes in the properties and related substances of the raw materials and excipients under different conditions, the compatibility of the raw materials with each excipient was assessed, and the selection of excipients for this product formulation was made. The sample information table and weight ratios of the raw material and excipient compatibility are shown in Table 2.

[0128] Table 2. Sample Information Table and Proportion

[0129] 1.2 Results of Raw Material Compatibility Tests

[0130] The results of the compatibility study of raw materials and excipients are shown in Table 3. Due to the volatility of ethanol and ethyl acetate and the open storage of the bottles, the appearance of samples 2 and 4 changed from suspension to white powder. Furthermore, the appearance of the suspension of formula (I) with triethyl glycerol and polyethylene glycol 400 changed from white to yellow, indicating that formula (I) is incompatible with triethyl glycerol and polyethylene glycol 400. No shape change was observed in the mixture of compound (I) with other excipients, indicating good compatibility.

[0131] Table 3. Results of Compatibility Tests of Raw Materials and Auxiliary Materials

[0132] 1.3 Compatibility Study of Raw Materials and Auxiliary Materials: Detection of Related Substances

[0133] The samples in Table 1 were placed in the open for 15 days under high temperature and high humidity (40℃±2℃ / 75%RH±5%RH), 10 days under high temperature (60℃±2℃), and 1 day under light (5000±500Lux, 90±5μw / cm²). 2 The samples were left exposed for 10 days, and the content of related substances under different conditions was tested. The total impurity results are shown in Table 4.

[0134] Under illumination (5000±500 Lux, 90±5 μw / cm²) 2After being left exposed for 10 days under certain conditions, the mixture of compound (I) with excipients such as PEG-1, PEG-1, PEG-1, PEG-1, PEG-400, etc., was unstable, and the impurities all showed an increasing trend, with PEG-1 showing the largest increase in impurities. Compound (I) showed good compatibility with other excipients. Therefore, the influence of light should be considered when selecting the above excipients during the formulation research process.

[0135] After being left exposed to high temperature (60℃±2℃) for 10 days, the mixture of compound (I) with excipients such as PEG-1, PEG-1, PEG-1, PEG-1, PEG-1, and ...

[0136] After being left open for 15 days under high temperature and high humidity conditions (40℃±2℃ / 75%RH±5%RH), the mixture of compound (I) with excipients such as octanoic acid-capric acid-polyethylene glycol glycerol ester, polyglycerol fatty acid ester, diethylene glycol monoethyl ether, and polyethylene glycol 400 was unstable. Among them, the unknown impurities of octanoic acid-capric acid-polyethylene glycol glycerol ester increased significantly. Compound (I) showed good compatibility with other excipients.

[0137] Table 4. Results of tests on compatibility-related substances of raw materials and auxiliary materials

[0138] Given the low solubility of compound (I) in water, and considering the above stability results, developing a suitable solvent system and creating a high-concentration foaming agent presents a significant challenge.

[0139] Example 2: Study on solubility and foaming agent composition

[0140] 2.1 Solvent Screening (Part 1)

[0141] Based on the results of the compatibility of raw materials and excipients, and combined with the physicochemical properties of formula (I) (formula (I) is almost insoluble in water), in order to develop its foaming agent, it is first necessary to dissolve the compound of formula (I). Therefore, solvents are screened to achieve the target concentration of compound (I), and the dissolution of formula (I) in solution is used as the observation indicator for solvent selection. The formulation components are shown in Table 5.

[0142] Table 5. Formulation Composition - Solvent Screening (Part 1)

[0143] Process:

[0144] Weigh out the prescribed amounts of compound (I), anhydrous ethanol / propylene glycol, and ethyl acetate in sequence and stir in a 60°C water bath for 5 min.

[0145] Experimental results and analysis:

[0146] In the formulations in Table 5, the solvent combinations in formulations 01A-1, 01A-2, 01A-3, and 01B-3 can dissolve formula (I). When using ethanol and ethyl acetate as solvents, formula (I) can dissolve when its concentration is less than or equal to 12.5%; when using propylene glycol and ethyl acetate as solvents, formula (I) can dissolve when the amount of ethyl acetate is greater than 44.4% and its concentration is less than or equal to 11.1%. This indicates that formula (I) is more soluble in ethanol than in propylene glycol.

[0147] However, both ethanol and ethyl acetate are volatile and may cause the precipitation of compound (I). Therefore, hydroxypropyl-β-cyclodextrin was added as a solubilizer to the 01A-2 and 01B-3 formulations to inhibit the precipitation of compound (I). The formulation composition is shown in Table 6.

[0148] Table 6. Formulation Composition - Solvent Screening (I) - Solubilizers

[0149] Process:

[0150] 1. Weigh out the prescribed amounts of compound formula (I), ethanol (anhydrous), propylene glycol 1, and ethyl acetate in sequence and stir in a 60°C water bath until completely dissolved.

[0151] 2. Weigh propylene glycol 2 and pure water, and add hydroxypropyl-β-cyclodextrin under a 60°C water bath. Stir until completely dissolved.

[0152] 3. Slowly add the solution from step 1 to the solution from step 2, stir at 60°C for 1 hour, let stand overnight, and observe whether precipitation occurs.

[0153] Experimental results and analysis:

[0154] As shown in Table 6, both formulations precipitated after the addition of hydroxypropyl-β-cyclodextrin, and did not increase the solubility of formula (I). Further solvent screening is needed to improve the solubility of formula (I).

[0155] Experimental results show that even if the solubility requirements are met, attention still needs to be paid to product stability and whether there will be technical issues such as precipitation of formula (I) when developing a formulation.

[0156] 2.2 Solvent Screening (Part Two)

[0157] In solvent screening (I), the combination of ethanol and ethyl acetate dissolved compound (I), but both are organic solvents and are irritating to the skin. To reduce the risk of subsequent foaming agent research, it is necessary to screen for new solvents that can dissolve compound (I). The solvent selection was based on whether compound (I) dissolves in solution. The specific formulation compositions are shown in Table 7. The results showed that the compounds of formula (I) in formulations 03-4, 03-5, and 03-6 all dissolved, while the other formulations were insoluble or only slightly insoluble.

[0158] Table 7. Formulation Composition - Solvent Screening (Part Two)

[0159] Process:

[0160] Weigh out each ingredient in the prescription in sequence, mix them, stir in a 60°C water bath, and observe the dissolution.

[0161] Although formula (I) in formulations 03-4, 03-5, and 03-6 can all be completely dissolved, considering that the foaming agent requires the addition of pure water to form foam, and the presence of pure water may cause formula (I) to precipitate, formulation 03-6, which has the highest proportion of diethylene glycol monoethyl ether, was chosen to reduce the risk of precipitation. Furthermore, based on the solvent ratio of formulation 03-6, a solubilizer (hydroxypropyl-β-cyclodextrin) was used for solubilization to prevent the precipitation of formula (I). Whether formula (I) precipitates in the solution was used as the observation indicator. The formulation composition is shown in Table 8.

[0162] Table 8. Formulation Composition - Solvent Screening (Part 2)

[0163] Process:

[0164] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, propylene glycol 1, and octanoic acid-capric acid-polyethylene glycol glycerol ester in sequence and stir in a 60°C water bath until completely dissolved.

[0165] 2. Weigh out the prescribed amount of propylene glycol 2 and pure water, and add the prescribed amount of hydroxypropyl-β-cyclodextrin under a 60°C water bath, stirring until completely dissolved.

[0166] 3. Slowly add the solution from step 1 to the solution from step 2, stir for 2 hours in a 60°C water bath, and let stand at room temperature for two days to observe whether precipitation occurs.

[0167] Experimental results and analysis:

[0168] After being left at room temperature for 2 days, the two prescription samples in Table 7 showed that prescription 04-1 precipitated a very small amount, but dissolved upon shaking, while prescription 04-2 precipitated a small amount. This indicates that the use of hydroxypropyl-β-cyclodextrin aqueous solution did not inhibit the precipitation of formula (I); on the contrary, the addition of pure water caused the precipitation of formula (I). Therefore, hydroxypropyl-β-cyclodextrin will not be used for the time being, and foam formulation research will be conducted based on prescription 03-6.

[0169] Example 3: Study on the composition of blank foaming agent

[0170] To avoid wasting compound formula (I), the blank foam basic formulation and process were first studied. Based on the properties of each excipient and in conjunction with the formulation of 04-6, a blank foam formulation was designed, with the generation of foam as the evaluation index.

[0171] 3.1 Study on the Composition of Blank Foaming Agent (Part 1)

[0172] 3.1.1 Due to the low solubility of formula (I), crystallization is difficult to avoid, and different solvents and co-solvent systems need to be studied in the formulation of foaming agents. Therefore, the basic formulation of the foaming agent uses polyethylene glycol glycerol ester (PEG-C-C-C) as the surfactant and also as the solvent; polyglycerol fatty acid ester as the co-surfactant; and medium-chain triglycerides as the oil phase. Since the blank foaming agent does not contain formula (I), only foam formation (without propellant) is studied. The formulation composition of different blank foaming agents (without 2% formula (I)) is shown in Table 9.

[0173] Table 9. Blank Foaming Agent Formulation Composition (I) - Without Formula (I)

[0174] Process:

[0175] 1. First, weigh out the prescribed amounts of diethylene glycol monoethyl ether, propylene glycol, and caprylic / capric acid glyceride ① and stir well;

[0176] 2. Weigh out the prescribed amounts of caprylic / capric acid glyceride, polyethylene glycol glycerol ester ②, pure water, polyglycerol fatty acid ester, and medium-chain triglyceride, and mix them evenly in a mixer.

[0177] 3. Add the solution from step 1 to the solution from step 2 and stir until well combined;

[0178] 4. Pour the solution from step 3 into a foam bottle (plastic bottle), press it out, and observe the foam.

[0179] Experimental results and analysis:

[0180] None of the four prescription samples in Table 9 produced foam after spraying; all remained pure solutions. This may be because propylene glycol and diethylene glycol monoethyl ether are organic solvents, and their high concentrations prevented foam formation.

[0181] 3.1.2 Study on the dosage of medium-chain triglycerides and polyethylene glycol glycerol octanoate / capric acid decanoate

[0182] None of the four formulations in Table 8 could form foam, so it was necessary to study different solvents that could both dissolve formula (I) and generate foam. Based on the foam-based formulation, medium-chain triglycerides and polyethylene glycol glycerol octanoate and decanoate were selected as solvents for the study, with the precipitation of formula (I) in the solution as the observation indicator. The formulation composition is shown in Table 10 (excluding foam components).

[0183] Table 10. Formulation Composition - Solvent Screening (Part 3)

[0184] Process:

[0185] Weigh out the prescribed amounts of compound (I), medium-chain triglyceride, and caprylic / capric acid glyceride in sequence and stir in a 60°C water bath. Observe the dissolution phenomenon.

[0186] Experimental results and analysis:

[0187] Of the above formulations, only the solvent combination in formulation 06-7 can dissolve formula (I); the solvent combinations in the other formulations do not reach a concentration sufficient to dissolve formula (I). The amount of octanoic acid-capric acid-polyethylene glycol glyceride and medium-chain triglyceride in formulation 06-7 is sufficient to dissolve 2% of formula (I).

[0188] 3.2 Study on the composition of blank foaming agent (II) - Different amounts of surfactant, co-surfactant and oil phase

[0189] Based on a comparison of the amounts of PEG-3-caprylate and medium-chain triglycerides in the 06-7 formulation, the composition of the blank foaming agent was studied. Different amounts of the surfactant PEG-3-caprylate, co-surfactant, and oil-phase medium-chain triglycerides were used to conduct a blank foaming agent study, with foam generation as the evaluation index. The formulation composition is shown in Table 11.

[0190] Table 11. Blank Foaming Agent Formulation Composition (II) - Without Formula (I)

[0191] Process:

[0192] Add the prescribed amounts of caprylic / capric acid glyceride, polyglycerol fatty acid ester, and medium-chain triglyceride to pure water, stir well, pour into a foam bottle, and observe the foaming behavior.

[0193] Experimental results and analysis:

[0194] None of the seven formulation samples in Table 11 could produce foam because the amount of oil phase and surfactant was too large, the amount of water was too small, the material was too viscous, and foam bottles were used instead of foam bottles.

[0195] 3.3 Study on the composition of blank foam (Part 3) - Different water consumption

[0196] Since the water content in each formulation in Table 11 is relatively low and cannot generate foam, the effect of different water volumes on foam formation was studied. Simultaneously, because surfactants and oil phases have high viscosity and are not prone to foam formation, while the viscosity of sodium dodecyl sulfate aqueous solution is generally low, sodium dodecyl sulfate was used as a foaming agent in a blank foaming agent study, with foam generation as the evaluation index. The formulation composition is shown in Table 12 (excluding 2% of formula (I)).

[0197] Table 12. Foam Formulation Composition (III) - Excluding Formula (I)

[0198] Process:

[0199] Add the prescribed amounts of caprylic / capric acid glyceride, polyglycerol fatty acid ester, medium-chain triglyceride, and sodium lauryl sulfate to pure water, stir well, pour into a foam bottle, and observe the foaming behavior.

[0200] Experimental results and analysis:

[0201] All three prescriptions listed in Table 12 can produce uniform foam.

[0202] Example 4: Study on the formulation of foaming agents containing compound (I)

[0203] 4.1 Study on the dosage of medium-chain triglycerides

[0204] Based on the three formulations 08-1, 08-2, and 08-3 in Table 12, formula (I) was added to study the effect of different amounts of medium-chain triglycerides on the formulations. Since sodium lauryl sulfate is irritating to the skin, the effect of its dosage on the formulation was also studied, with the precipitation of formula (I) and the foaming of the formulation as evaluation indicators. The formulation composition is shown in Table 13.

[0205] Table 13. Formulation composition for the study of medium-chain triglyceride dosage.

[0206] Process:

[0207] 1. Weigh out the prescribed amount of formula (I), 20g of caprylic / capric acid decanoic acid polyethylene glycol glyceride, and the prescribed amount of medium-chain triglycerides into a 60°C water bath and stir until dissolved;

[0208] 2. Take the remaining caprylic / capric acid glyceride, the prescribed amount of polyglycerol fatty acid ester, and the prescribed amount of sodium dodecyl sulfate, add them to pure water, and stir until completely dissolved;

[0209] 3. Add the solution from step 1 to the solution from step 2 and stir until well combined;

[0210] 4. Finally, pour the solution from step 3 into a foam bottle.

[0211] Experimental results and analysis:

[0212] Formulas 09-1, 09-2, and 09-3 all produced foam, but after standing for 1 hour, formula (I) precipitated in all of them. This indicates that different amounts of medium-chain triglycerides have little effect on the solubility of formula (I), because formula (I) with low solubility is prone to supersaturation, leading to precipitation. Therefore, using diethylene glycol monoethyl ether, propylene glycol, or hydroxypropyl β-cyclodextrin as solvents can solve the precipitation problem of compound (I).

[0213] Prescriptions 09-4 and 09-5 failed to produce foam; this may be due to the reduced amount of sodium dodecyl sulfate and pure water, and the increased amount of octanoic acid, caprylic acid, PEG-1,5-glycerol and medium-chain triglycerides, which led to an increase in solution viscosity and thus prevented foam production.

[0214] 4.2 Effects of propylene glycol and polyethylene glycol glycerol octanoate / capric acid on the solubility of formula (I)

[0215] Because all three formulations (09-1, 09-2, and 09-3) exhibited precipitation upon standing, this study investigates whether propylene glycol and polyethylene glycol glycerol (PEG-1, octanoic acid and decanoic acid) can dissolve compound (I) without precipitation. The evaluation criteria are whether compound (I) precipitates and whether the formulation foams. If precipitation occurs, foaming is not further investigated. The formulation composition is shown in Table 14.

[0216] Table 14. Formulation composition of propylene glycol and polyethylene glycol glycerol octanoate / capric acid glyceride

[0217] Process:

[0218] 1. Weigh out the prescribed amounts of compound formula (I), propylene glycol, a portion of caprylic / capric acid glyceride (20g of 10-1, 14g of 10-2, and 4g of 10-3), and medium-chain triglycerides, and stir in a 60°C water bath until dissolved;

[0219] Prescriptions 10-2 and 10-3 cannot be dissolved, so further preparation steps should not be continued.

[0220] 2. Separately weigh the remaining caprylic / capric acid, decanoic acid, polyethylene glycol glycerol ester, polyglycerol fatty acid ester, and sodium dodecyl sulfate, add them to pure water, and stir until completely dissolved;

[0221] 3. Add the solution from step 1 to the solution from step 2 and stir well.

[0222] Experimental results and analysis:

[0223] Precipitation 10-1 occurred after 30 minutes, indicating that using propylene glycol and polyethylene glycol glycerol caprylate and caprylic acid as solvents did not improve the solubility of formula (I) in the formulation. Based on the dissolution phenomenon, the higher the amount of polyethylene glycol glycerol caprylate used, the better the solubility, but precipitation still occurred. Therefore, further research on other solvents is needed.

[0224] 4.3 Study on Combinations of Multiple Solvents and Cyclodextrins

[0225] Because propylene glycol and polyethylene glycol glycerol octanoate and caprylic / capric acid were used, compound (I) still precipitated. Therefore, this study used two techniques: multiple solvents and hydroxypropyl-β-cyclodextrin, to dissolve compound (I) without precipitation. The precipitation of compound (I) and the foaming of the formulation were used as evaluation indicators. If the solution precipitated, foaming studies were not conducted. The formulation composition is shown in Table 15.

[0226] Table 15. Formulation composition in studies involving combinations of multiple solvents and cyclodextrins

[0227] Process:

[0228] (1) The production steps for batch numbers 11A-1 and 11A-2 are as follows:

[0229] 1. Weigh out the prescribed amounts of formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decanoic acid polyethylene glycol glyceride and stir in a 60°C water bath until dissolved;

[0230] 2. Separately weigh hydroxypropyl-β-cyclodextrin and add it to 10g of pure water, stirring until completely dissolved;

[0231] 3. Weigh out sodium dodecyl sulfate and add it to 20g of pure water, then stir to dissolve.

[0232] 4. Add the solution from step 1 to the solution from step 2, and stir overnight in a 60°C water bath.

[0233] 5. Prescription 11A-2 showed precipitation; therefore, the preparation process was terminated.

[0234] 6. Add the solution from step 3 to the solution from step 4, stir for 1 hour, and observe the phenomenon.

[0235] (2) The production steps for batches 11B-1 and 11B-2 are as follows:

[0236] 1. Weigh out formula (I) and add it to octanoic acid, caprylic acid, polyethylene glycol glycerol ester and medium-chain triglycerides in a water bath at 60-70℃, and stir until dissolved;

[0237] 2. Separately weigh hydroxypropyl-β-cyclodextrin and add it to 10g of pure water, stirring until completely dissolved;

[0238] 3. Weigh out sodium dodecyl sulfate and add it to the remaining pure water, stirring to dissolve;

[0239] 4. Add the solution from step 1 to the solution from step 2, and stir at 60°C for 2 hours;

[0240] 5. Add the solution from step 3 to the solution from step 4 and stir for 1 hour;

[0241] 6. Leave overnight.

[0242] (3) The production steps for batch number 11C are as follows:

[0243] 1. Weigh out the prescribed amounts of formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decanoic acid polyethylene glycol glyceride and stir in a 60°C water bath until dissolved;

[0244] 2. Weigh out sodium dodecyl sulfate and add it to the remaining pure water, stirring to dissolve;

[0245] 3. Add the solution from step 1 to the solution from step 2, and stir at 60°C for 2 hours;

[0246] 4. Add the solution from step 3 to the solution from step 4 and stir for 1 hour; Experimental results and analysis:

[0247] Formulas 11A-1, 11B-1, 11B-2, and 11C all precipitated, possibly due to the large amount of water used. Additionally, the solution became viscous and pasty, possibly due to the increased viscosity caused by hydroxypropyl-β-cyclodextrin. However, experimental results showed that the use of hydroxypropyl-β-cyclodextrin failed to inhibit the precipitation of the compounds.

[0248] 4.4 Research on Polosham

[0249] Because sodium dodecyl sulfate is an anionic surfactant and can irritate the skin, to reduce patient discomfort during use and to ensure that compound (I) dissolves without precipitation, the effect of the nonionic surfactant poloxamer on the formulation was studied. The precipitation of formula (I) and the foaming of the formulation were used as evaluation indicators. If the solution precipitated, foaming was not further investigated. The formulation composition is shown in Table 16.

[0250] Table 16. Composition of prescriptions containing poloxamer

[0251] Process:

[0252] (1) Production steps of formula No. 12A-1:

[0253] 1. Weigh out the prescribed amounts of formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decanoic acid polyethylene glycol glyceride and stir in a 60°C water bath until dissolved;

[0254] 2. Take another amount of the prescribed amount of hydroxypropyl-β-cyclodextrin and add it to 20g of pure water, stirring until completely dissolved;

[0255] 3. Add the solution from step 2 to the solution from step 1 and stir until well combined;

[0256] 4. Weigh the prescribed amount of poloxamer and add it to 13g of pure water, stir to dissolve; then add it to the solution from step 3, and stir under 60℃ water bath conditions.

[0257] Experimental results and analysis:

[0258] There was precipitation, and the solution was quite viscous. The use of hydroxypropyl-β-cyclodextrin resulted in a viscous solution that could not be filled, so this excipient was no longer used in subsequent studies. In addition, the use of poloxamer as a surfactant failed to prevent the precipitation of formula (I).

[0259] (2) Production steps of formula No. 12A-2:

[0260] 1. Weigh out the prescribed amounts of formula (I), caprylic / capric acid, polyethylene glycol glyceride, and medium-chain triglycerides and place them in a 70°C water bath, stirring until dissolved;

[0261] 2. Weigh out the prescribed amount of poloxamer and add it to pure water, stirring to dissolve; then add it to the solution from step 1 and stir well.

[0262] Experimental results and analysis:

[0263] The solution is viscous and cloudy. Poloxamer is a polymer, and its viscosity is high in aqueous solutions at higher concentrations. The formulation uses 20% poloxamer, hence the viscous solution.

[0264] (3) Production steps for batches 12B-1, 12B-2, and 12B-3:

[0265] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decalcium glyceride in a 60°C water bath and stir until dissolved;

[0266] 2. Weigh out the prescribed amount of poloxamer and add it to pure water, stirring to dissolve;

[0267] 3. Add the solution from step 2 to the solution from step 1 and stir.

[0268] Experimental results and analysis:

[0269] Initially, all solutions were clear, but precipitation occurred after 1 hour. The precipitation decreased sequentially for formulations 12B-1, 12B-2, and 12B-3. Combined with formulation 12A-2, increasing the amount of poloxamer failed to inhibit precipitation. The sequentially decreasing precipitation for formulations 12B-1, 12B-2, and 12B-3 indicates that, under the same water volume, the higher the amount of octanoic acid / capric acid / polyethylene glycol glycerol ester, the greater the solubility of formula (I) and the less precipitation. To further avoid precipitation, the effect of different water volumes on the formulations was investigated.

[0270] 4.5 Study on the dosage of pure water

[0271] From the three formulations 12B-1, 12B-2, and 12B-3, it can be seen that when the water content is 38%, the more octanoic acid-capric acid-polyethylene glycol glycerol ester is used, the better the solubility of formula (I) and the less precipitation. The precipitation of the drug is also related to the amount of pure water used; the more pure water used, the more likely compound (I) will precipitate. Therefore, the effect of the amount of pure water on the formulation was studied, with whether formula (I) precipitated and whether the formulation foamed as evaluation indicators. If the solution precipitated, no further foaming studies were conducted. The formulation composition is shown in Table 17.

[0272] Table 17. Formulation of Pure Water Usage

[0273] Process:

[0274] 1. Weigh out the prescribed amounts of formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decanoic acid polyethylene glycol glyceride and stir in a 60°C water bath until dissolved;

[0275] 2. Weigh out poloxamer and add it to pure water, then stir to dissolve.

[0276] 3. Add the solution from step 2 to the solution from step 1 and stir.

[0277] Experimental results and analysis:

[0278] Formulas 13-1 and 13-2 are clear solutions and show no precipitation after being left at room temperature overnight, while formula 13-3 shows precipitation. This indicates that formula (I) has good solubility when the water content is below 25%; if the water content is too high, for example, 30%, formula (I) will precipitate. However, when 13-1 and 13-2 are placed in a foam bottle, foam can be formed, but the foam morphology is poor, possibly because this formulation system is difficult to generate abundant foam by relying solely on a foam bottle.

[0279] 4.6 Study on the dosage of solvent diethylene glycol monoethyl ether

[0280] The effect of different amounts of diethylene glycol monoethyl ether on the formulation was studied, with the precipitation of formula (I) and the foaming of the formulation as evaluation indicators. If the solution precipitated, no further foaming studies were conducted. The formulation composition is shown in Table 18.

[0281] Table 18. Formulation Composition of Diethylene Glycol Monoethyl Ether Dosage

[0282] Process:

[0283] 1. Weigh the prescribed amounts of formula (I), diethylene glycol monoethyl ether, propylene glycol, and caprylic / capric acid decanoic acid polyethylene glycol glyceride / medium-chain triglyceride into a 60°C water bath and stir until dissolved;

[0284] 2. Weigh out the prescribed amount of poloxamer and add it to pure water, stirring to dissolve;

[0285] 3. Add the solution from step 2 to the solution from step 1 and stir well.

[0286] Experimental results and analysis:

[0287] Formulas 14-1, 14-2, and 14-3 are clear solutions. No precipitation occurred after standing at room temperature overnight, indicating that when the amount of pure water is 20%, the amount of diethylene glycol monoethyl ether is increased, and formula (I) does not precipitate, indicating good solubility. After being placed in a foam bottle, the foam formed is not good. The foam formed by formula 14-1 is shown in Figure 1. Formula 14-4 precipitates after standing at room temperature overnight, indicating that the combination of medium-chain triglycerides and diethylene glycol monoethyl ether fails to completely dissolve formula (I).

[0288] In summary, none of the above-mentioned clarified solution formulations could generate foam. The reason for this is likely the high viscosity of the solutions, which prevents commercially available foam bottle valves from achieving the desired foaming effect. Therefore, using ordinary foam bottles is insufficient. Thus, the use of a propellant is considered. The pressure of the propellant will force the liquid in the container to spray out, thereby generating foam.

[0289] Example 5: Foaming Agent Formulation Study - Containing Propellant

[0290] 5.1 Study on the dosage of propellant and xanthan gum

[0291] Based on the properties of the propellant, as well as safety, environmental protection, and packaging equipment requirements, tetrafluoroethane, a pharmaceutical excipient, was selected as the propellant. Its advantages include chemical stability, non-flammability and non-explosiveness, low toxicity, no ozone layer depletion, and low pressure resistance requirements for containers. Furthermore, since propellants are generally volatile gases, xanthan gum was used in the formulation to increase solution viscosity and thus improve foam stability. The formulation study used foam generation as the evaluation index; the formulation composition is shown in Table 19.

[0292] Table 19. Formulation Composition of Propellant and Xanthan Gum Dosage

[0293] Process:

[0294] (1) Production steps for batch number 15A:

[0295] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decalcium glyceride in a 60°C water bath and stir until dissolved;

[0296] 2. Weigh out the prescribed amount of poloxamer and add it to pure water, stirring to dissolve;

[0297] 3. Add the solution from step 2 to the solution from step 1 and stir until well combined;

[0298] 4. Pour the solution from step 3 into an aluminum can, cover it with the valve, seal it, and fill it with the prescribed amount of tetrafluoroethane.

[0299] (2) Production steps for batches 15B-1 and 15B-2:

[0300] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decalcium glyceride in a 60°C water bath and stir until dissolved;

[0301] 2. Weigh out the prescribed amount of poloxamer and add it to pure water, stirring to dissolve;

[0302] 3. Weigh out the prescribed amount of xanthan gum and add it to the solution from step 2, then stir to dissolve.

[0303] 4. Add the solution from step 3 to the solution from step 1 and stir until well mixed;

[0304] 5. Pour the solution from step 4 into an aluminum can, cover it with the valve, seal it, and fill it with the prescribed amount of tetrafluoroethane.

[0305] Experimental results and analysis:

[0306] Formulas 15A and 15B-1 can produce foam, but the foam disappears quickly, indicating that xanthan gum has a stabilizing effect on the foam, but the effect is small; Formula 15B-2 has a large amount of xanthan gum, resulting in a high solution viscosity, causing the solution to clump together and not be aerated.

[0307] 5.2 Study on the surfactant octanoic acid-capric acid-polyethylene glycol glycerol ester

[0308] Because the foam in the prescription in Table 19 disappears quickly, the effect of different amounts of the surfactant octanoic acid-capric acid-polyethylene glycol glyceride on foam stability was studied. The prescription is shown in Table 20.

[0309] Table 20. Formulation composition of polyethylene glycol glycerol caprylate / capric acid decanoate

[0310] Process:

[0311] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, propylene glycol, and octanoic acid-capric acid-decalcium glyceride in a 60°C water bath and stir until dissolved;

[0312] 2. Weigh out the prescribed amount of poloxamer and add it to pure water, stirring to dissolve;

[0313] 3. Weigh out the prescribed amount of xanthan gum and add it to the solution from step 2, then stir to dissolve.

[0314] 4. Add the solution from step 3 to the solution from step 1 and stir well.

[0315] 5. Pour the solution from step 4 into an aluminum can, cover it with the valve, seal it, and fill it with tetrafluoroethane.

[0316] Experimental results and analysis:

[0317] Formula 16-1 produces foam that disappears in about 1 minute; Formula 16-2 produces more stable foam that disappears in about 1-2 minutes; Formula 16-3 produces precipitation but is not aerated. This indicates that the amount of PEG-16-glycerol octanoate or caprylic / capric acid has little effect on the stability of the foam, but a small amount may lead to the precipitation of formula (I).

[0318] 5.3 Research on the surfactant polysorbate

[0319] Formula 16-2 contains a large amount of polyethylene glycol glycerol caprylate and capric acid, and there are no restrictions on the external use of this excipient in the FDA's database of inactive excipients. To reduce the risk of registration application, the effect of replacing polyethylene glycol glycerol caprylate with polysorbate surfactants on the formula was studied. At the same time, to improve the stability of foam, the effect of the stabilizer cetearyl alcohol on foam was studied. In addition, the effect of the combination of cetearyl alcohol and xanthan gum on the foam stabilizer was also studied. The formula was evaluated with the stability of foam. The composition of the formula is shown in Table 21.

[0320] Table 21. Formulation composition of polysorbate

[0321] Process:

[0322] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, polysorbate 20, polysorbate 80, and propylene glycol and stir in a 60°C water bath until dissolved;

[0323] 2. Weigh out the prescribed amount of hexadecanoic acid and add it to the solution from step 1, stirring to dissolve.

[0324] 3. Take the prescribed amount of xanthan gum and add it to pure water, stirring to dissolve;

[0325] 4. Add the solution from step 3 to the solution from step 2 and stir until well combined;

[0326] 5. Bottle the solution from step 4 and aerate it.

[0327] Experimental results and analysis:

[0328] Both formulations in Table 21 produce foam, which lasts for 2 minutes, but both solutions precipitate after prolonged standing. When polysorbate is used instead of polyethylene glycol glycerol caprylate, precipitation occurs with 20% water, indicating that formula (I) has low solubility in polysorbate excipients. Therefore, it is necessary to improve the solubility of compound (I) by increasing the amount of diethylene glycol monoethyl ether or reducing the amount of water. Furthermore, cetearyl alcohol can stabilize the foam, so xanthan gum is no longer necessary.

[0329] 5.4 Study on the dosage of solvents diethylene glycol monoethyl ether and pure water

[0330] Because the two formulations in Table 21 precipitate after prolonged storage, the effects of different amounts of diethylene glycol monoethyl ether and pure water on the formulations were studied to improve the solubility of formula (I) and prevent precipitation. The solubility of formula (I) and the stability of foam were used as evaluation indicators for the formulations. The formulation composition is shown in Table 22.

[0331] Table 22. Formulation composition for solvent usage

[0332] Process:

[0333] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, polysorbate 20, polysorbate 80, and propylene glycol and stir in a 45°C water bath until dissolved;

[0334] 2. After dissolution is complete, weigh out the prescribed amount of cetearyl alcohol and add it to the solution from step 1, then stir to dissolve.

[0335] 3. Finally, add the prescribed amount of pure water and stir well;

[0336] 4. The solution from step 3 is bottled and filled with tetrafluoroethane gas.

[0337] Experimental results and analysis:

[0338] All three formulations in Table 22 produce foam. The foam from formulations 18-1 and 18-2 disappears quickly, within about 20 seconds, while the foam from formulation 18-3 lasts for 2 minutes, although very little foam precipitates out. Therefore, as the amount of diethylene glycol monoethyl ether increases and the amount of pure water decreases, the foam stability deteriorates. Since very little foam precipitates out in formulation 18-3, the next step is to fine-tune the amount of pure water.

[0339] 5.5 Study on the dosage of stabilizer cetearyl alcohol

[0340] The effect of different dosages of the foam stabilizer cetearyl alcohol on the formulation was investigated, with the solubility of compound (I) and foam formation as evaluation indicators. The formulation composition is shown in Table 23.

[0341] Table 23. Formulation composition of hexadecanoic acid dosage

[0342] Process:

[0343] (1) Production steps for formulas with batch numbers 19A-1 and 19A-2:

[0344] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, polysorbate 20, polysorbate 60, polysorbate 80, and propylene glycol and stir in a 45°C water bath until dissolved;

[0345] 2. After dissolution is complete, weigh out the prescribed amount of cetearyl alcohol and add it to the solution from step 1, then stir to dissolve.

[0346] 3. Finally, add pure water and stir well;

[0347] 4. Bottle the solution from step 3 and aerate it.

[0348] (2) Production steps of formula No. 19B:

[0349] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, polysorbate 60, caprylic / capric acid glyceride, and propylene glycol in a 45°C water bath and stir until dissolved;

[0350] 2. After dissolution is complete, weigh out the prescribed amount of butylated hydroxytoluene and add it to the solution from step 1, then stir to dissolve.

[0351] 3. Finally, add the prescribed amount of pure water and stir well;

[0352] 4. Bottle the solution from step 3 and aerate it.

[0353] Experimental results and analysis:

[0354] Formula 19A-1 produced foam, which lasted for 2 minutes; the foam appearance is shown in Figure 2. Formula 19A-2 had a jelly-like solution and was not bottled or aerated, possibly due to an excessive amount of cetearyl alcohol. Formula 19B did not use cetearyl alcohol and therefore could not form foam. Therefore, the amount of cetearyl alcohol in the formula was determined to be 1%.

[0355] 5.6 Study on Combinations of Multiple Surfactants and Their Dosage

[0356] The various surfactants used in this application can achieve the effects described herein. For example, the effects of the combined application and different dosages of two types of surfactants, octanoic acid-capric acid-polyethylene glycol glycerol ester and polysorbate 60, on the formulation were investigated. The formulation composition is shown in Table 24.

[0357] Table 24. Formulation composition of various surfactants and their dosages

[0358] Process:

[0359] 1. Weigh out the prescribed amounts of compound formula (I), diethylene glycol monoethyl ether, polysorbate (polysorbate 20, polysorbate 60, polysorbate 80), caprylic / capric acid glyceride, polyethylene glycol glyceride, and propylene glycol in a 45°C water bath and stir until dissolved;

[0360] 2. Weigh out the prescribed amounts of cetearyl alcohol and butylated hydroxytoluene and add them to the solution from step 1, then stir to dissolve.

[0361] 3. Finally, add pure water and stir well;

[0362] 4. Bottle the solution from step 3 and fill it with tetrafluoroethane gas.

[0363] Experimental results:

[0364] All of the above formulations can produce stable foam, which disappears in 20 minutes to 1 hour. The foam appearance of formulation 20C is shown in Figure 3.

[0365] To quickly screen the stability of the above formulations, a severe high-temperature stability study was conducted on four formulations (20A-1, 20A-3, 20B, and 20C) in Table 24. The conditions were 60°C, and the storage times were 7 and 15 days. The results are shown in Table 25.

[0366] Table 25. Stability results at 60℃

[0367] The above results show that this application can not only solve the problem of the poor solubility of compound (I), but also prevent the precipitation of compound (I) in the prepared foam agent; the prepared foam agent is not only stable in state, but also has stable chemical properties under high temperature conditions (the growth of impurities is small, below the limit of 1%).

Claims

1. A liquid composition, characterized in that, Includes compounds of formula (I) or their pharmaceutically acceptable salts, solvents, and surfactants; The solvent is an organic solvent or a combination of an organic solvent and water; the surfactant is one or more of a nonionic surfactant or anionic surfactant.

2. The liquid composition according to claim 1, characterized in that, The organic solvent is one or more of alcohol solvents, ester solvents, and ether solvents; preferably, the alcohol solvent is selected from ethanol, denatured ethanol, propylene glycol, hexanediol, pentanediol, glycerol, isopropanol, butanediol, dipropylene glycol, butanol, and polyethylene glycol; the ester solvent is selected from medium-chain triglycerides and ethyl acetate; the ether solvent is selected from diethylene glycol monoethyl ether and isosorbide dimethyl ether; more preferably, the organic solvent is one or more of diethylene glycol monoethyl ether, propylene glycol, ethanol, polyethylene glycol, isosorbide dimethyl ether, and medium-chain triglycerides; even more preferably, the organic solvent is one or more of medium-chain triglycerides, diethylene glycol monoethyl ether, and propylene glycol; And / or, the nonionic surfactant is selected from polyethylene glycol glycerol caprylate, polyglycerol fatty acid ester, lauroyl polyoxyethylene (32) glycerol ester, stearoyl polyoxyethylene (32) glycerol ester, propylene glycol monolaurate, glycerol mono- and dicaprylate caprylate, propylene glycol monocaprylate, polysorbate, and poloxamer; preferably, the nonionic surfactant is one or more of polyethylene glycol glycerol caprylate, polyglycerol fatty acid ester, and poloxamer; And / or, the anionic surfactant is selected from sodium dodecyl sulfate, fatty alcohol polyoxyethylene ether sulfate, sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, sodium lauryl ether sulfate, and sodium lauryl ether sulfate; preferably, the anionic surfactant is sodium dodecyl sulfate.

3. The liquid composition according to claim 1 or 2, characterized in that, The composition comprises, by weight percentage, 0.1%-20% of the compound of formula (I), preferably 0.5%-5%, more preferably 2% ± 0.5%; 30%-55% of the solvent and 35%-65% of the surfactant; wherein, the weight of water in the solvent is 10%-50% of the weight of the liquid composition. And / or, in the liquid composition, the weight percentage of medium-chain triglycerides is 10%-25%, preferably 12-22%; And / or, in the liquid composition, the weight percentage of diethylene glycol monoethyl ether is 5%-25%, preferably 7-20%; And / or, in the liquid composition, the weight percentage of propylene glycol is 1%-10%, preferably 3-8%; And / or, in the liquid composition, the weight percentage of polyethylene glycol glycerol caprylate is 5%-65%, preferably 30%-65%; And / or, in the liquid composition, the polyglycerol fatty acid ester accounts for 2%-10% by weight, preferably 5%-8% by weight; And / or, in the liquid composition, the weight percentage of poloxamer is 0.01%-10%, preferably 1.5%-3.5%; And / or, in the liquid composition, the weight percentage of sodium dodecyl sulfate is 5%-15%, preferably 8%-12%.

4. The liquid composition according to any one of claims 1-3, characterized in that, (1) The liquid composition comprises a compound of formula (I), polyethylene glycol glycerol caprylate, polyglycerol fatty acid ester, medium-chain triglyceride, sodium dodecyl sulfate and water; Preferably, the liquid composition comprises, by weight percentage, 2% ± 0.5% of compound (I), 30%-35% of polyethylene glycol glycerol octanoate and caprylic acid, 5%-8% of polyglycerol fatty acid ester, 10%-25% of medium-chain triglycerides, 8%-12% of sodium dodecyl sulfate, and the balance being water; Further preferred: The liquid composition comprises, by weight percentage: 2% of compound (I), 30% of polyethylene glycol glycerol octanoate and caprylic acid 30%, 6% of polyglycerol fatty acid ester, 12% of medium-chain triglycerides, 10% of sodium dodecyl sulfate, and 40% of water. And / or, the liquid composition comprises, by weight percentage: 2% of compound (I), 30% of polyethylene glycol glycerol caprylate, 6% of polyglycerol fatty acid ester, 17% of medium-chain triglycerides, 10% of sodium dodecyl sulfate, and 35% of water; And / or, the liquid composition comprises, by weight percentage: 2% of compound (I), 30% of polyethylene glycol glycerol caprylate, 6% of polyglycerol fatty acid ester, 22% of medium-chain triglycerides, 10% of sodium dodecyl sulfate, and 30% of water; (2) The liquid composition comprises a compound of formula (I), diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol glycerol caprylate, poloxamer and water; Preferably, the liquid composition comprises, by weight percentage: 2.0% ± 0.5% of compound (I), 7-20% of diethylene glycol monoethyl ether, 3%-8% of propylene glycol, 50%-65% of polyethylene glycol glycerol octanoate and caprylic / capric acid, 1.5%-3.5% of poloxamer, and the balance being water; Further preferred: The liquid composition comprises, by weight percentage: 2% of compound (I), 10% of diethylene glycol monoethyl ether, 5% of propylene glycol, 60.5% of polyethylene glycol glycerol octanoate-decanoate, 2.5% of poloxamer, and 20% of water. And / or, the liquid composition comprises, by weight percentage: 2% of compound (I), 15% of diethylene glycol monoethyl ether, 5% of propylene glycol, 55.5% of polyethylene glycol glycerol octanoate-capric acid, 2.5% of poloxamer, and 20% of water; And / or, the liquid composition comprises, by weight percentage: 2% of compound (I), 20% of diethylene glycol monoethyl ether, 5% of propylene glycol, 50.5% of polyethylene glycol glycerol caprylate, 2.5% of poloxamer, and 20% of water; And / or, the liquid composition comprises, by weight percentage: 2% of compound (I), 7% of diethylene glycol monoethyl ether, 5% of propylene glycol, 63.5% of polyethylene glycol glycerol caprylate, 2.5% of poloxamer, and 20% of water; And / or, the liquid composition comprises, by weight percentage: 2% of compound (I), 7% of diethylene glycol monoethyl ether, 5% of propylene glycol, 58.5% of polyethylene glycol glycerol caprylate, 2.5% of poloxamer, and 25% of water.

5. A foam composition, characterized in that, Including compounds of formula (I) or pharmaceutically acceptable salts thereof, solvents, surfactants, and propellants; The solvent is an organic solvent, or a combination of an organic solvent and water; preferably, the organic solvent is selected from one or more of alcohol solvents, ester solvents, and ether solvents. The surfactant is a nonionic surfactant.

6. The foam composition according to claim 5, characterized in that, The alcohol solvent is selected from ethanol, denatured ethanol, propylene glycol, hexanediol, pentanediol, glycerol, isopropanol, butanediol, dipropylene glycol, butanol, and polyethylene glycol; preferably, the alcohol solvent is selected from propylene glycol, denatured ethanol, dipropylene glycol, butanediol, and polyethylene glycol, or any combination thereof; the ester solvent is selected from medium-chain triglycerides and ethyl acetate; the ether solvent is selected from diethylene glycol monoethyl ether and isosorbide dimethyl ether; preferably, the organic solvent is diethylene glycol monoethyl ether, propylene glycol, denatured ethanol, polyethylene glycol, isosorbide dimethyl ether, butanediol, and dipropylene glycol, or any combination thereof; more preferably, the organic solvent is a combination of diethylene glycol monoethyl ether and propylene glycol; And / or, the nonionic surfactant is one or any combination of polyethylene glycol glycerol octanoate / capric acid glyceride, polyglycerol fatty acid ester, lauroyl polyoxyethylene (32) glycerol ester, stearoyl polyoxyethylene (32) glycerol ester, propylene glycol monolaurate, glycerol mono- and dicaprylic / capric acid glyceride, propylene glycol monocaprylic acid ester, polysorbate, and poloxamer; preferably, the nonionic surfactant is one or any combination of poloxamer, polyethylene glycol glycerol octanoate / capric acid glyceride, and polysorbate. And / or, the propellant is a perchlorofluorocarbon propellant, a hydrocarbon propellant, a hydrofluoroalkane propellant, or an oxygen-containing compound propellant; preferably, the propellant is a hydrofluoroalkane propellant; more preferably, the hydrofluoroalkane propellant is 1,1,1,2-tetrafluoroethane, heptafluoropropane, 1,3,3,3-tetrafluoropropene, or difluoroethane, preferably 1,1,1,2-tetrafluoroethane.

7. The foam composition according to claim 5 or 6, characterized in that, The foaming agent composition further includes a foam stabilizer; preferably, the foam stabilizer is one or more of higher fatty alcohols containing 15 or more carbon atoms and higher fatty acids containing 16 or more carbon atoms; more preferably, the higher fatty alcohol is hexadecyl alcohol, octadecyl alcohol, a mixture of hexadecyl alcohol and octadecyl alcohol, arachidyl alcohol, behenyl alcohol, 1-triacontanol, or oleyl alcohol; the higher fatty acid is hexadecanoic acid, octadecanoic acid, arachidic acid, behenic acid, or linaloic acid; more preferably, the foam stabilizer in the composition is 0.01% to 5% by weight; more preferably, it is 0.5% to 3%. And / or, the foam composition further comprises a gelling agent; preferably, the gelling agent is one or more of a natural polymer, a semi-synthetic polymer, and a synthetic polymer; more preferably, the natural polymer is locust bean gum, sodium alginate, xanthan gum, or tragacanth gum; the semi-synthetic polymer is cellulose ether or guar gum derivative; the synthetic polymer is polyvinylpyrrolidone, polyvinyl alcohol-acrylic acid copolymer, or carbomer; more preferably, in the composition, the weight percentage of the gelling agent is 0.01%-2%, more preferably 0.05%-0.5%; And / or, the foaming agent composition further comprises an antioxidant, said antioxidant being one or any combination of butylated hydroxytoluene, vitamin C, sodium bisulfite, butylated hydroxyanisole, and vitamin E; preferably, the antioxidant in the composition is 0.01%-1% by weight, more preferably 0.01%-0.1% by weight.

8. The foam composition according to any one of claims 5-7, characterized in that, The composition comprises, by weight percentage, 0.10%-20% of the compound of formula (I), preferably 0.5%-5%, more preferably 2.0% ± 0.5%; 35%-60% of the solvent; 20%-45% of the surfactant; and 5%-25% of the propellant. And / or, in the composition, the weight percentage of diethylene glycol monoethyl ether is 0.1%-45%; preferably 10%-42%; And / or, in the composition, the weight percentage of propylene glycol is 0.1%-15%; more preferably 3%-8%; And / or, in the composition, the weight percentage of polyethylene glycol glycerol caprylate is 5%-45%; preferably 10%-42%; And / or, in the composition, the weight percentage of poloxamer is 0.5%-5%, preferably 1-2.5%; And / or, in the composition, the weight percentage of polysorbate is 1-50%; preferably 10%-35%; preferably, the polysorbate includes any one or more of polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80; And / or, in the composition, the mixture of hexadecyl alcohol and octadecyl alcohol, calculated by weight percentage, is 0.5-3%, more preferably 0.5-1.5%; In the composition, the weight percentage of 1,1,1,2-tetrafluoroethane is 5% to 25%, preferably 15% to 25%.

9. The foam composition according to any one of claims 5-8, characterized in that, (1) The foam composition comprises (I) compound, diethylene glycol monoethyl ether, glyceryl octanoate-capric acid, propylene glycol, 1,1,1,2-tetrafluoroethane, and water; preferably, the foam composition further comprises an antioxidant, any one or more of poloxamer or xanthan gum; More preferably, the foam composition comprises, by weight percentage: 2.0% ± 0.5% of compound (I), 10%-30% of diethylene glycol monoethyl ether, 20%-42% of polyethylene glycol glycerol caprylate / capric acid, 3-8% of propylene glycol, 0%-0.1% of xanthan gum, 1%-2.5% of poloxamer; 15%-25% of 1,1,1,2-tetrafluoroethane, with the balance being water; and even more preferably, when the composition contains an antioxidant, the antioxidant is 0.01%-0.10%. Further preferred: The foam composition comprises, by weight percentage: 2% of compound (I), 10% of diethylene glycol monoethyl ether, 41.9% of polyethylene glycol glycerol octanoate and caprylic acid, 5% of propylene glycol, 0.1% of xanthan gum, 1% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water. And / or, the composition comprises, by weight percentage: 2% of compound (I), 20% of diethylene glycol monoethyl ether, 31.9% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.1% of xanthan gum, 1% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water. And / or, the composition comprises, by weight percentage: 2% of compound (I), 10% of diethylene glycol monoethyl ether, 40.5% of polyethylene glycol glycerol octanoate-decanoate, 5% of propylene glycol, 2.5% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water. And / or, the composition comprises, by weight percentage: 2% of compound (I), 30% of diethylene glycol monoethyl ether, 21.9% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.1% of xanthan gum, 1% of poloxamer, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water. (2) The foam composition comprises a compound of formula (I), diethylene glycol monoethyl ether, polysorbate, polyethylene glycol glycerol caprylate, propylene glycol, antioxidant, cetearyl alcohol, 1,1,1,2-tetrafluoroethane, and water; preferably, the polysorbate is polysorbate 60. More preferably, the foam composition comprises, by weight percentage: 2% ± 0.5% of compound (I), 22%-35% of diethylene glycol monoethyl ether, 10%-15% of polysorbate 60, 10%-20% of polyethylene glycol glycerol caprylate and caprylic acid, 3-8% of propylene glycol, 0.01%-0.1% of antioxidant, 0.5%-1.5% of cetearyl alcohol, 15%-25% of 1,1,1,2-tetrafluoroethane, and the balance being water; Further preferred: The foam composition comprises, by weight percentage: 2% of compound (I), 35% of diethylene glycol monoethyl ether, 10% of polysorbate 60, 10% of polyethylene glycol glycerol caprylate, 7% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water. And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 32% of diethylene glycol monoethyl ether, 10% of polysorbate 60, 15% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water; And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 27% of diethylene glycol monoethyl ether, 15% of polysorbate 60, 15% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water; And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 27% of diethylene glycol monoethyl ether, 10% of polysorbate 60, 20% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water; And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 22% of diethylene glycol monoethyl ether, 15% of polysorbate 60, 20% of polyethylene glycol glycerol caprylate, 5% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 14.98% of water; (3) The foam composition comprises a compound of formula (I), diethylene glycol monoethyl ether, polysorbate, propylene glycol, cetearyl alcohol, 1,1,1,2-tetrafluoroethane, and water; preferably, the polysorbate is selected from one or any combination of polysorbate 20, polysorbate 60, and polysorbate 80; preferably, the foam composition further comprises one or more of an antioxidant, an antibacterial agent, or xanthan gum; More preferably, the foam composition, by weight percentage, comprises: 2% ± 0.5% of compound (I), 20%-32% of diethylene glycol monoethyl ether, 30%-35% of polysorbate, 3%-8% of propylene glycol, 0.5%-1.5% of cetearyl alcohol, 15%-25% of 1,1,1,2-tetrafluoroethane, and the balance being water; even more preferably, when the composition contains an antioxidant, the antioxidant is 0.01%-0.10%; when the composition contains xanthan gum, the xanthan gum is 0.01%-0.10%. More preferably, The foam composition comprises, by weight percentage: 2% of compound (I), 25.5% of diethylene glycol monoethyl ether, 10.2% of polysorbate 20, 12.2% of polysorbate 60, 10.2% of polysorbate 80, 5.1% of propylene glycol, 0.02% of butylated hydroxytoluene, 1% of cetearyl alcohol, 20.4% of 1,1,1,2-tetrafluoroethane, and 13.24% of water; And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 27% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 15% of water. And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 32% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 10% of water. And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 22% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water. And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 21.95% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 0.05% of xanthan gum, 1% of cetearyl alcohol, 20% of 1,1,1,2-tetrafluoroethane, and 20% of water; And / or, the foam composition comprises, by weight percentage: 2% of compound (I), 25.5% of diethylene glycol monoethyl ether, 15.3% of polysorbate 20, 2% of polysorbate 60, 15.3% of polysorbate 80, 5.1% of propylene glycol, 1% of cetearyl alcohol, 20.4% of 1,1,1,2-tetrafluoroethane, and 13.3% of water; (4) The foam composition comprises a compound of formula (I), diethylene glycol monoethyl ether, polysorbate, propylene glycol, cetearyl alcohol, and 1,1,1,2-tetrafluoroethane; preferably, the polysorbate is selected from one or any combination of polysorbate 20, polysorbate 60, and polysorbate 80; preferably, the foam composition further comprises one or more of an antioxidant, an antibacterial agent, or xanthan gum; More preferably, the foam composition, by weight percentage, comprises: 2% ± 0.5% of compound (I), 20%-42% of diethylene glycol monoethyl ether, 30%-35% of polysorbate, 3%-8% of propylene glycol, 0.5%-1.5% of cetearyl alcohol, and 15%-25% of 1,1,1,2-tetrafluoroethane; even more preferably, when the composition contains an antioxidant, the antioxidant is 0.01%-0.10%; when the composition contains xanthan gum, the xanthan gum is 0.01%-0.10%. More preferably, the foam composition comprises, by weight percentage: 2% of compound (I), 42% of diethylene glycol monoethyl ether, 15% of polysorbate 20, 15% of polysorbate 80, 5% of propylene glycol, 1% of cetearyl alcohol, and 20% of 1,1,1,2-tetrafluoroethane.

10. Use of any one of the liquid composition as described in claims 1-4 or the foam composition as described in claims 5-9 in the preparation of a medicament for treating, preventing or alleviating androgen-mediated disorders, diseases or symptoms in a subject; Preferably, the androgen-mediated disorder, disease, or symptom is selected from acne, hirsutism, sebaceous gland enlargement, or androgenic alopecia.

11. A liquid composition as described in claims 1-4 or a foam composition as described in claims 5-9, for treating, preventing, or alleviating androgen-mediated disorders, diseases, or symptoms in a subject; preferably, the androgen-mediated disorders, diseases, or symptoms are selected from acne, hirsutism, sebaceous gland enlargement, or androgenetic alopecia.

12. A method for treating, preventing, or alleviating androgen-mediated disorders, diseases, or symptoms in a subject, comprising administering to a subject in need a therapeutically effective amount of any one of the liquid composition as described in claims 1-4 or the foam composition as described in claims 5-9; preferably, the androgen-mediated disorder, disease, or symptom is selected from acne, hirsutism, sebaceous gland enlargement, or androgenetic alopecia.

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