Topical pharmaceutical compositions and uses thereof

Abstract

Provided herein are methods for treating skin-related diseases or disorders (e.g., melasma). Also provided are pharmaceutical compositions of midostaurin or a pharmaceutically acceptable salt thereof formulated for topical administration. Also described are methods for preparing such topical pharmaceutical compositions and methods for using the topical pharmaceutical compositions to treat a subject.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of Patent Application No. PCT / CN2022 / 139952, filed December 19, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Skin hyperpigmentation conditions are characterized by a generalized or localized darkening of an individual's normal skin color. Skin hyperpigmentation conditions include melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, age-related hyperpigmentation, maculopigmentary rash of pregnancy, and nevus of Ota. Hyperpigmentation can appear on any part of the body. Currently, therapies for skin hyperpigmentation use nonselective toxins that reduce tyrosinase activity, including hydroquinone, azelaic acid, and kojic acid. These therapies are only partially effective, toxic, and sometimes cause loss of skin pigmentation or tissue melanosis. Therefore, there is a need for new methods or products to treat hyperpigmentation disorders and limit serious side effects.

[0003] (Incorporated by reference) All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0004] In one aspect, disclosed herein is a method of treating a skin-related disease or disorder, comprising topically applying a multi-targeting protein kinase inhibitor (e.g., midostaurin) or a salt thereof to the skin of a subject, wherein the skin is associated with the skin-related disease or disorder. In some embodiments, the skin-related disease or disorder is a skin pigmentation disorder. In one aspect, disclosed herein is a method of reducing skin pigmentation, comprising topically applying a multi-targeting protein kinase inhibitor (e.g., midostaurin) or a salt thereof to the pigmented skin of a subject. In one aspect, disclosed herein is a method of reducing tyrosinase activity, comprising topically applying a multi-targeting protein kinase inhibitor (e.g., midostaurin) or a salt thereof to the skin of a subject in need thereof. In some embodiments, the subject has a skin hyperpigmentation condition. In some embodiments, the skin hyperpigmentation condition comprises solar lentigines or age spots. In some embodiments, the skin hyperpigmentation condition comprises melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, macules of pregnancy, nevus of Ota, or age-related hyperpigmentation. In one aspect, disclosed herein is a method of treating melasma, comprising topically applying a multi-targeting protein kinase inhibitor (e.g., midostaurin) or a salt thereof to the skin of a subject in need thereof. In some embodiments, the skin is facial skin of the subject. In some embodiments, the melasma is a brown spot. In some embodiments, the melasma is caused or exacerbated by one or more of oral contraceptives, pregnancy, hormone therapy, stress, thyroid disease, sun exposure, inflammation, familial predisposition, or free radicals. In some embodiments, treating comprises reducing the size of the abnormal skin pigmentation, reducing the intensity of the abnormal skin pigmentation, and / or removing the abnormal skin pigmentation associated with melasma. In some embodiments, the method comprises topically applying a pharmaceutical composition, wherein the pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the treatment comprises reducing the amount of melanin in an area of ​​skin by at least 25% compared to a similar area of ​​skin in the same subject not receiving the treatment.In some embodiments, the treatment comprises reducing the amount of melanin in a skin area by at least 1.0 according to a melanin distribution score, compared to a similar skin area in the same subject not receiving the treatment. In some embodiments, the treatment comprises reducing the amount of melanin in a skin area by at least 1.0 according to the Fontana-Masson staining scoring scale, compared to a similar skin area in the same subject not receiving the treatment. In some embodiments, the multi-targeting protein kinase inhibitor or salt thereof is midostaurin or a salt thereof. In some embodiments, the midostaurin or salt thereof is administered in a therapeutically effective amount. In some embodiments, the therapeutically effective amount of the multi-targeting protein kinase inhibitor or salt thereof is a dose that is 80% less than the therapeutically effective amount of hydroquinone.

[0005] In one aspect, disclosed herein is a topical pharmaceutical composition comprising a multi-targeted protein kinase inhibitor (optionally midostaurin) or a pharmaceutically acceptable salt thereof in an amount of 0.001% to about 20% by weight, a carrier vehicle, and excipients, the topical pharmaceutical composition being formulated for topical administration. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 2% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 0.25% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.25% to about 1.5% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 1.5% to about 2.5% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 1.0% by weight. In some embodiments, the multi-targeted protein kinase inhibitor or pharmaceutically acceptable salt thereof is midostaurin. In some embodiments, the topical pharmaceutical composition does not include a phospholipid. In some embodiments, the topical pharmaceutical composition includes a phospholipid. In some embodiments, the carrier vehicle includes an aqueous carrier vehicle. In some embodiments, the carrier vehicle includes water. In some embodiments, the carrier vehicle includes a non-aqueous carrier vehicle. In some embodiments, the carrier vehicle includes polyethylene glycol (PEG), propylene glycol, glycerin (or glycerol), dimethyl sulfoxide (DMSO), petrolatum, mineral oil, wax, liquid paraffin, petrolatum, or a combination thereof. In some embodiments, the carrier vehicle includes water, polyethylene glycol, propylene glycol, or glycerin, or a combination thereof. In some embodiments, the carrier vehicle is present in the composition in an amount of 40% to 99% by weight. In some embodiments, the carrier vehicle is present in the composition in an amount of 70% to 90% by weight.In some embodiments, the excipient comprises a surfactant, a penetration enhancer, an antioxidant, a sunscreen, a viscosity modifier, a pH stabilizer, or a moisturizer, or any combination thereof. In some embodiments, the excipient comprises a surfactant. In some embodiments, the surfactant comprises a non-ionic surfactant. In some embodiments, the surfactant is glyceryl monooleate, glyceryl monolinoleate, polyethylene glycol-hydroxystearate (e.g., macrogol-15-hydroxystearate), polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene(20) sorbitan monooleate, Tween 80, or polysorbate 80), polyoxylglycerides (e.g., caprylocaproyl polyoxyl-8 glyceride, oleoyl polyoxyl-6 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., polyoxyl 35 hydrogenated castor oil), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol stearate), sorbitan monostearate, polyglyceryl-3 dioleate, sodium dodecyl sulfate (SDS), or polyoxyethylene alkyl ethers (e.g., steareth-20, steareth-2), or combinations thereof. In some embodiments, the surfactant comprises an ionic surfactant (e.g., sodium dodecyl sulfate or SDS). In some embodiments, the surfactant comprises an emulsifier.In some embodiments, the emulsifier comprises polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol stearate), sorbitan monostearate, sodium dodecyl sulfate (SDS), oleoyl polyoxyl-6 glyceride), or polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2), or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises two, three, four, or more surfactants. In some embodiments, the surfactant is present in the composition in an amount of about 1% to 50% by weight. In some embodiments, the emulsifier is present in the composition in an amount of about 1% to 50% by weight. In some embodiments, the topical pharmaceutical composition comprises a penetration enhancer. In some embodiments, the penetration enhancer comprises polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, oleoyl polyoxyl-6 glyceride), 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof. In some embodiments, the penetration enhancer is present in the composition in an amount of about 0.1% to 40% by weight. In some embodiments, the topical pharmaceutical composition comprises an antioxidant.In some embodiments, the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, alpha-tocopheryl acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium sulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, or a tocopherol (e.g., d-alpha-tocopherol), or a combination thereof. In some embodiments, the antioxidant is present in the composition in an amount of about 0.001% to 5% by weight. In some embodiments, the topical pharmaceutical composition comprises a sunscreen. In some embodiments, the sunscreen agent comprises avobenzone, bemotrizinol, benzophenone-3 (BZ-3, oxybenzone), bisoctisol, homosalate, octinoxate, octisalate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof. In some embodiments, the sunscreen agent is present in the composition in an amount of about 0.001% to 2% by weight. In some embodiments, the topical pharmaceutical composition comprises a viscosity modifier. In some embodiments, the viscosity modifier comprises aluminum monostearate, bentonite, polyacrylic acid (or PAA) (e.g., cross-linked polyacrylic acid), octadecyl alcohol, glyceryl behenate, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a pH stabilizer. In some embodiments, the pH stabilizer comprises citric acid, glycolic acid, lactic acid, sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof. In some embodiments, the pH stabilizer comprises a pH buffer. In some embodiments, the topical pharmaceutical composition has a pH of about 5 to 8. In some embodiments, the topical pharmaceutical composition has a pH in the range of about 6.5 to about 7.5. In some embodiments, the topical pharmaceutical composition has a pH of about 7.0. In some embodiments, the topical pharmaceutical composition comprises a moisturizer.In some embodiments, the humectant comprises petrolatum, mineral oil, wax, liquid paraffin, petrolatum (e.g., white petrolatum), glycerol (or glycerin), propylene glycol, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a multifunctional excipient, wherein the multifunctional excipient is simultaneously two or more of a surfactant, a penetration enhancer, a viscosity modifier, a carrier vehicle, and a humectant. In some embodiments, the multifunctional excipient is simultaneously a surfactant and a penetration enhancer. In some embodiments, the multifunctional excipient is oleoyl polyoxyl-6 glyceride or polyglyceryl-3 dioleate. In some embodiments, the multifunctional excipient is simultaneously a humectant and a carrier vehicle. In some embodiments, the multifunctional excipient is petrolatum, mineral oil, wax, liquid paraffin, petrolatum, propylene glycol, or glycerol. In some embodiments, the topical pharmaceutical composition is in a form selected from an ointment, gel, cream, lotion, solution, emulsion, paste, patch, wipe, swab, and pad. In some embodiments, the topical pharmaceutical composition is an ointment. In some embodiments, the topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight; b) a surfactant in an amount of about 5% to about 20% by weight; c) a penetration enhancer in an amount of about 0.05% to about 20% by weight; d) a carrier vehicle in an amount of about 70% to about 90% by weight; e) a humectant in an amount of about 5% to about 25% by weight; and e) an antioxidant in an amount of about 0.001% to 5% by weight. In some embodiments, the topical pharmaceutical composition comprises a multifunctional excipient, which simultaneously functions as two or more of a surfactant, a penetration enhancer, a carrier vehicle, and a humectant.In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 2% by weight; a surfactant including glyceryl monolinoleate, glyceryl monooleate, polyoxylglyceride (e.g., caprylocaproyl polyoxyl-8 glyceride, glyceryl polyethylene glycol ricinoleate (e.g., ricinoleic acid 35), polyethylene glycol hydroxystearate (e.g., macrogol-15-hydroxystearate), or a combination thereof; polyglycol dioleate; a penetration enhancer comprising triglyceride-3, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone), or a combination thereof; a carrier vehicle comprising polyethylene glycol (PEG), mineral oil, or a combination thereof; a humectant comprising glycerol or propylene glycol, or a combination thereof; and a soluble ... In some embodiments, the topical pharmaceutical composition is an ointment comprising an antioxidant comprising midostaurin, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 1.5% by weight; a surfactant comprising caprylocaproyl polyoxyl-8 glyceride in an amount of about 7% to about 15% by weight; a penetration enhancer comprising 1-dodecylazacycloheptan-2-one in an amount of about 0.5% to about 3% by weight. a carrier vehicle in an amount of about 70% to about 80% by weight, the carrier vehicle comprising polyethylene glycol having a number average molecular weight of about 300 to 500 g / mol, polyethylene glycol having a number average molecular weight of about 3000 to 5000 g / mol, or a combination thereof; a humectant in an amount of about 10% to about 15% by weight, the humectant comprising glycerol; and an antioxidant in an amount of about 0.001% to 1% by weight, the antioxidant being butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid palmitate, or the like. The topical pharmaceutical composition comprises an antioxidant comprising midostaurin, α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof. In some embodiments, the topical pharmaceutical composition is a gel. In some embodiments, the topical pharmaceutical composition is a gel comprising midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight, a surfactant in an amount of about 5% to about 50% by weight, optionally a penetration enhancer in an amount of about 1% to about 30% by weight, a carrier vehicle in an amount of about 60% to about 95% by weight, a viscosity modifier in an amount of about 0.01% to about 5% by weight, optionally a pH stabilizer, and an antioxidant in an amount of about 0.001% to 5% by weight. In some embodiments, the topical pharmaceutical composition comprises a multifunctional excipient, which is simultaneously a surfactant and a penetration enhancer. In some embodiments, the topical pharmaceutical composition comprises a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% by weight to about 2% by weight; b) surfactants including glyceryl monolinoleate, glyceryl monooleate, polyoxylglycerides (e.g., caprylocaproyl polyoxyl-8 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., macrogolglycerol ricinoleate 35), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), or combinations thereof; and c) optionally surfactants including polyglyceryl-3 dioleate, oleoyl polyoxy-6 glyceride, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone). d) a viscosity modifier comprising polyacrylic acid; e) optionally a pH stabilizer comprising sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof; f) a carrier vehicle comprising water; and g) an antioxidant comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 1.5% by weight; b) a surfactant in an amount of about 5% to about 20% by weight, the surfactant comprising caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, or a combination thereof; c) optionally, a penetration enhancer in an amount of about 5% to about 25% by weight, the penetration enhancer comprising diethylene glycol monoethyl ether; and d) a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 1.5% by weight. e) a viscosity modifier in an amount of about 70% to about 2% by weight, the viscosity modifier comprising crosslinked polyacrylic acid; f) optionally a pH stabilizer comprising triethanolamine; f) an aqueous carrier vehicle in an amount of about 70% to about 90% by weight, the aqueous carrier vehicle comprising water; and g) an antioxidant in an amount of about 0.001% to 2% by weight, the antioxidant comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof.In some embodiments, the topical pharmaceutical composition has a pH of about 6.5 to about 7.5. In some embodiments, the topical pharmaceutical composition has a pH of about 7.0. In some embodiments, the topical pharmaceutical composition is a cream. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight, a carrier vehicle in an amount of about 30% to about 70% by weight, a surfactant in an amount of about 5% to about 50% by weight, optionally a humectant in an amount of about 5% to about 30% by weight, optionally a penetration enhancer in an amount of about 1% to about 40% by weight, optionally a viscosity modifier in an amount of about 0.01% to about 5% by weight, and an antioxidant in an amount of about 0.001% to 5% by weight.In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 5% by weight, a carrier vehicle comprising water and optionally polyethylene glycol (PEG), propylene glycol, liquid paraffin, or petrolatum (e.g., white petrolatum), or a combination thereof, and a carrier vehicle comprising glyceryl monooleate, glyceryl monolinoleate, polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol stearate), sorbitan monostearate, sodium dodecyl sulfate (SDS), polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2), or a combination thereof, and optionally a surfactant comprising glycerol or propylene glycol, or a moisturizer including a combination thereof, and optionally a penetration enhancer including oleoyl polyoxyl-6 glyceride, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof; and an antioxidant including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 2% by weight, a surfactant in an amount of about 5% to about 50% by weight, the surfactant comprising glyceryl monolinoleate, glyceryl monooleate, PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate, polyoxylethylene stearate (e.g., macrogol-75 stearate), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), sorbitan monostearate, sodium dodecyl sulfate, or a combination thereof, and optionally a penetration enhancer in an amount of about 1% to about 35% by weight, the penetration enhancer comprising oleoyl polyoxyl-6 glyceride, polyglyceryl dioleate, or a combination thereof. glycerin, propylene glycol, butylated hydroxyanisole (BHA), ascorbyl palmitate, alpha-tocopherol acetate, sodium acetone bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof; and a carrier vehicle in an amount of about 30% to about 70% by weight, the carrier vehicle comprising water and, optionally, liquid paraffin or white petrolatum.In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 2% by weight, and a surfactant in an amount of about 5% to about 35% by weight, the surfactant being selected from the group consisting of glyceryl monolinoleate or glyceryl monooleate, PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate, polyoxyethylene stearate (e.g., macrogol-75 stearate), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), sorbitan monostearate, or a combination thereof; a penetration enhancer in an amount of about 1% to about 35% by weight, the penetration enhancer comprising polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof; an antioxidant in an amount of about 0.01% to about 0.1% by weight, the antioxidant comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof; and a carrier vehicle in an amount of about 60% to about 70% by weight, the carrier vehicle comprising water. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 1% by weight, glyceryl monooleate in an amount of about 10% by weight, polyoxyethylene sorbitan monooleate (e.g., polysorbate 80) in an amount of about 5% to about 14% by weight, sorbitan monostearate in an amount of about 3.5% by weight, polyglyceryl-3 dioleate in an amount of about 5% by weight, antioxidants comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbyl palmitate in an amount of about 0.06% by weight, and water in an amount of about 66.5% by weight. In some embodiments, the topical pharmaceutical composition further comprises a sunscreen.In some embodiments, the sunscreen comprises avobenzone, bemotrizinol, benzophenone-3 (BZ-3, oxybenzone), bisoctisol, homosalate, octinoxate, octisalate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof. In some embodiments, the topical pharmaceutical composition reduces the amount of melanin in a skin area by at least 25% compared to a similar skin area in the same subject not receiving the treatment, where the amount of melanin is measured by a melanin distribution score using a guinea pig as a model. In some embodiments, the reduction in the amount of melanin in a skin area treated with the topical pharmaceutical composition is at least 100% compared to the amount of melanin in a similar skin area in the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, where the topical pharmaceutical composition is administered at a dose lower than that of the reference topical pharmaceutical composition. In some embodiments, the topical pharmaceutical composition reduces tyrosinase activity in a skin area by at least 25% compared to a similar skin area of ​​the same subject not receiving any treatment, where tyrosinase activity is measured per gram of tissue using a guinea pig as a model. In some embodiments, the reduction in tyrosinase activity in a skin area treated with the topical pharmaceutical composition is at least about 100% compared to a similar skin area of ​​the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, where the topical pharmaceutical composition is administered at a lower dose than the reference topical pharmaceutical composition. In some embodiments, the skin irritation level in a skin area treated with the topical pharmaceutical composition is minimal, where the topical pharmaceutical composition comprises up to 1.0% by weight of midostaurin. In some embodiments, the skin irritation score in a skin area treated with the topical pharmaceutical composition is at most about 50% compared to a similar skin area of ​​the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, where the topical pharmaceutical composition is administered at a lower dose than the reference topical pharmaceutical composition. In some embodiments, the topical pharmaceutical composition is chemically stable for at least 7 days when stored under conditions of 4500 lux (lx) during light exposure or at about 60°C.In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof when stored for 7 days under conditions of 4500 lux (lx) of light exposure and a temperature of about 15°C to about 25°C. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof when stored for 7 days at about 60°C. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after at least one freeze-thaw cycle. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigerated conditions for at least 3, 6, 9, 12, 24, or 36 months. In some embodiments, the topical pharmaceutical composition retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigerated conditions for at least 3, 6, 9, 12, 24, or 36 months. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 3, 6, 9, 12, or 24 months. In some embodiments, the topical pharmaceutical composition retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 3, 6, 9, 12, or 24 months. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 1, 3, or 6 months. In some embodiments, the topical pharmaceutical composition retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 1, 3, or 6 months. In some embodiments, the amount of midostaurin or a pharmaceutically acceptable salt thereof is determined according to a high-performance liquid chromatography (HPLC) assay (e.g., as described in Table A-1). In some embodiments, the topical pharmaceutical composition contains 5% or less by weight of total impurities after storage at refrigerated conditions for at least 3, 6, 9, 12, 24, or 36 months. In some embodiments, the topical pharmaceutical composition contains 2% or less by weight of total impurities after storage at refrigerated conditions for at least 3, 6, 9, 12, 24, or 36 months. In some embodiments, the topical pharmaceutical composition contains 5% or less by weight of total impurities after storage at ambient conditions for at least 3, 6, 9, 12, or 24 months. In some embodiments, the topical pharmaceutical composition contains 2% or less by weight of total impurities after storage at ambient conditions for at least 3, 6, 9, 12, or 24 months. In some embodiments, the topical pharmaceutical composition contains 5% or less by weight of total impurities after storage at about 40° C. for at least 1, 3, or 6 months. In some embodiments, the topical pharmaceutical composition contains 2% or less by weight of total impurities after storage at about 40° C. for at least 1, 3, or 6 months. In some embodiments, the amount of total impurities is determined according to high performance liquid chromatography (HPLC) impurity analysis (eg, as set forth in Table B-2).

[0006] Disclosed herein are methods for treating a skin-related disease or disorder, comprising topically applying a topical pharmaceutical composition to the skin of a subject in need thereof, wherein the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the skin-related disease or disorder comprises a skin pigmentation disorder. In some embodiments, the method comprises applying a topical pharmaceutical composition described herein to the skin of a subject in need thereof.

[0007] Disclosed herein are methods for reducing skin pigmentation, comprising topically applying a topical pharmaceutical composition to the skin of a subject in need thereof, wherein the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises topically applying a topical pharmaceutical composition described herein to the skin of a subject in need thereof.

[0008] Disclosed herein are methods for reducing tyrosinase activity, comprising topically applying a topical pharmaceutical composition to the skin of a subject in need thereof, wherein the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises topically applying a topical pharmaceutical composition described herein to the skin of a subject in need thereof.

[0009] Disclosed herein are kits that include a package enclosing a topical pharmaceutical composition described herein. [Brief explanation of the drawings]

[0010] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Figure 1] FIG. 1 shows the equilibrium solubility of midostaurin in different solvents. [Figure 2] FIG. 2 shows the solubility of midostaurin in various solubilizer-water mixture systems. [Figure 3] FIG. 3 illustrates the different layers of human skin. [Figure 4] FIG. 4 shows a Franz diffusion cell system for performing skin deposition studies. [Figure 5] FIG. 5 shows the skin deposition results of midostaurin and hydroquinone when prepared at various concentrations in a mixture of DMSO and propylene glycol. [Figure 6] FIG. 6 shows the results of skin deposition of midostaurin in gel formulations with different excipients. [Figure 7A] Figure 7A shows the crystallization under a polarized light microscope for midostaurin gel formulations Lot A1, Lot A2, Lot A3, and Lot A4, respectively. The micrographs show needle-like and star-like crystallization of midostaurin in the gel formulations, especially in the Lot A1 gel. [Figure 7B] Figure 7B shows the crystallization under a polarized light microscope for midostaurin gel formulations Lot A1, Lot A2, Lot A3, and Lot A4, respectively. The micrographs show needle-like and star-like crystallization of midostaurin in the gel formulations, especially in the Lot A1 gel. [Figure 7C] Figure 7C shows the crystallization under a polarized microscope for midostaurin gel formulations Lot A1, Lot A2, Lot A3, and Lot A4, respectively. The micrographs show needle-like and star-like crystallization of midostaurin in the gel formulations, especially in the Lot A1 gel. [Figure 7D] Figure 7D shows the crystallization under a polarized microscope for midostaurin gel formulations Lot A1, Lot A2, Lot A3, and Lot A4, respectively. The micrographs show needle-like and star-like crystallization of midostaurin in the gel formulations, especially in the Lot A1 gel. [Figure 8A] 8A shows the crystallization under a polarized microscope of midostaurin cream formulations Lots B1 and B2, respectively. The micrographs show needle-like and snowflake-like crystallization of midostaurin in the cream formulation. [Figure 8B]8B shows the crystallization under a polarized microscope for midostaurin cream formulations Lots B1 and B2, respectively. The micrographs show needle-like and snowflake-like crystallization of midostaurin in the cream formulation. [Figure 9] FIG. 9 shows the skin deposition results of 1% and 0.1% midostaurin cream and 2% hydroquinone cream, where one 2% hydroquinone cream is commercially available and all other formulations are prepared according to the ingredients of Lot B2. [Figure 10A] FIG. 10A shows four ternary phase diagrams, each showing the phase behavior of a system consisting of Azone, water, and a mixture of Tefose 63 and Labrafil M 1944CS in a specific ratio. [Figure 10B] FIG. 10B shows four ternary phase diagrams, each showing the phase behavior of a system consisting of Azone, water, and a mixture of Tefose 63 and Labrafil M 1944CS in a specific ratio. [Figure 10C] FIG. 10C shows four ternary phase diagrams, each showing the phase behavior of a system consisting of a mixture of Azone, water, and Tefose 63 with Labrafil M 1944CS in a specific ratio. [Figure 10D] FIG. 10D shows four ternary phase diagrams, each showing the phase behavior of a system consisting of a mixture of Azone, water, and Tefose 63 with Labrafil M 1944CS in a specific ratio. [Figure 11A] 11A shows the crystallization under a polarized light microscope for midostaurin cream formulations Lots B3, B4, B5, B6, and B7, respectively. The micrographs for Lots B3 and B7 show that the droplets are evenly distributed without needle-like or star-like crystallization. The micrographs for Lots B4 and B5 show that star-like crystallization has occurred. The micrograph for Lot B6 shows that the droplet distribution has become broader and the droplet size has become larger. [Figure 11B]Figure 11B shows crystallization under a polarized microscope for midostaurin cream formulations Lots B3, B4, B5, B6, and B7, respectively. Micrographs of Lots B3 and B7 show that the droplets are evenly distributed without needle-like or star-like crystallization. Micrographs of Lots B4 and B5 show that star-like crystallization has occurred. Micrographs of Lot B6 show that the droplet distribution has become broader and the droplet size has become larger. [Figure 11C] 11C shows the crystallization under a polarized light microscope for midostaurin cream formulations Lots B3, B4, B5, B6, and B7, respectively. The micrographs for Lots B3 and B7 show that the droplets are evenly distributed without needle-like or star-like crystallization. The micrographs for Lots B4 and B5 show that star-like crystallization has occurred. The micrograph for Lot B6 shows that the droplet distribution has become broader and the droplet size has become larger. [Figure 11D] 11D shows crystallization under a polarized light microscope for midostaurin cream formulations Lots B3, B4, B5, B6, and B7, respectively. The micrographs for Lots B3 and B7 show that the droplets are evenly distributed without needle-like or star-like crystallization. The micrographs for Lots B4 and B5 show that star-like crystallization has occurred. The micrograph for Lot B6 shows that the droplet distribution has become broader and the droplet size has become larger. [Figure 11E] Figure 11E shows crystallization under a polarized light microscope for midostaurin cream formulations Lots B3, B4, B5, B6, and B7, respectively. The micrographs for Lots B3 and B7 show that the droplets are evenly distributed without needle-like or star-like crystallization. The micrographs for Lots B4 and B5 show that star-like crystallization has occurred. The micrograph for Lot B6 shows that the droplet distribution has become broader and the droplet size has become larger. [Figure 12] FIG. 12 depicts a ternary phase diagram showing the phase behavior of a system consisting of Peceol, water, and Gelot 64. [Figure 13A]Figure 13A shows the crystallization under polarized light microscopy of midostaurin cream formulation Lot B8 and the blank carrier vehicle of Lot B8, respectively. The photomicrograph of Lot B8 is similar to that of the blank carrier vehicle, indicating a stable state. [Figure 13B] Figure 13B shows the crystallization under polarized light microscopy of midostaurin cream formulation Lot B8 and the blank carrier vehicle of Lot B8, respectively. The photomicrograph of Lot B8 is similar to that of the blank carrier vehicle, indicating a stable state. [Figure 14] FIG. 14 shows the midostaurin deposition results for lots B9, B10, B11, and cream lot B2 used in the pharmacodynamic (PD) efficacy study, comparing the effect of different penetration enhancers on skin deposition of midostaurin in the cream formulation. [Figure 15A] FIG. 15A shows a photograph of a guinea pig whose back was shaved and divided into six regions. [Figure 15B] FIG. 15B shows a photograph of a control group of guinea pigs (N=1) that did not receive UV stimulation. [Figure 15C] FIG. 15C shows a photograph of a control group of guinea pigs (N=1) that did not receive UV stimulation. [Figure 16A] Figure 16A shows two photographs of the back of a guinea pig, each with six regions of different skin color receiving a different treatment: (i) upper left region: no treatment (model), (ii) upper right region: 2% hydroquinone cream, (iii) lower left region: 2% hydroquinone solution, (iv) left center region: 1% midostaurin cream, (v) right center region: 0.1% midostaurin cream, and (vi) lower right region: 1% midostaurin solution. The types of treatments are annotated in Figure 16A. [Figure 16B]Figure 16B shows two photographs of the back of a guinea pig, each with six different skin regions receiving a different treatment: (i) upper left region: no treatment (model), (ii) upper right region: 2% hydroquinone cream, (iii) lower left region: 2% hydroquinone solution, (iv) left center region: 1% midostaurin cream, (v) right center region: 0.1% midostaurin cream, and (vi) lower right region: 1% midostaurin solution. The types of treatments are annotated in Figure 16A. [Figure 17] FIG. 17 shows the tyrosinase activity of seven different groups: control group (no UV stimulation), model group (no treatment after UV stimulation), 2% hydroquinone cream, 2% hydroquinone solution, 1% midostaurin cream, 0.1% midostaurin cream, and 1% midostaurin solution treatment groups. [Figure 18] FIG. 18 shows the melanin distribution scores of seven different groups: control group (no UV stimulation), model group (no treatment after UV stimulation), 2% hydroquinone cream, 2% hydroquinone solution, 1% midostaurin cream, 0.1% midostaurin cream, and 1% midostaurin solution treatment groups. [Figure 19A] FIG. 19A shows the melanin distribution scores for seven different groups: control group (no UV stimulation), model group (no treatment after UV stimulation), 2% hydroquinone positive control (referred to as "2-1"), 0.01% midostaurin cream (referred to as "2-2"), 0.05% midostaurin cream (referred to as "2-3"), 0.25% midostaurin cream (referred to as "2-4"), and 1.5% midostaurin cream (referred to as "2-5"). [Figure 19B] Figure 19B shows the tyrosinase activity of seven different groups: control group (no UV stimulation), model group (no treatment after UV stimulation), 2% hydroquinone positive control (referred to as "2-1"), 0.01% midostaurin cream (referred to as "2-2"), 0.05% midostaurin cream (referred to as "2-3"), 0.25% midostaurin cream (referred to as "2-4"), and 1.5% midostaurin cream (referred to as "2-5"). DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure is generally directed to topical pharmaceutical compositions comprising a multi-targeting protein kinase inhibitor (e.g., midostaurin) or a pharmaceutically acceptable salt thereof, as well as methods of using and making the same. The multi-targeting protein kinase inhibitor can target at least two protein kinases. The multi-targeting protein kinase inhibitor can inhibit two or more protein kinases selected from the group consisting of PKC α / β / γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ, and VEGFR1 / 2. In some cases, the multi-targeting protein kinase inhibitor inhibits PKC α, PKC β, and PKC γ. In some cases, the multi-targeting protein kinase inhibitor inhibits PKC α / β / γ and Syk. In some cases, the multi-targeting protein kinase inhibitor inhibits PKC α / β / γ and Akt. In some cases, the multi-targeting protein kinase inhibitor inhibits PKC α / β / γ and PKA. In some cases, the multi-targeting protein kinase inhibitor targets PKCα / β / γ and c-Kit. In some cases, the multi-targeting protein kinase inhibitor inhibits PKCα / β / γ and c-Fgr. In some cases, the multi-targeting protein kinase inhibitor inhibits PKCα / β / γ and c-Src. In some cases, the multi-targeting protein kinase inhibitor inhibits PKCα / β / γ and FLT3. In some cases, the multi-targeting protein kinase inhibitor inhibits PKCα / β / γ and PDFRβ. In some cases, the multi-targeting protein kinase inhibitor inhibits PKCα / β / γ and VEGFR1 / 2. In some cases, the multi-targeting protein kinase inhibitor inhibits PKCα / β / γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ, and VEGFR1 / 2. In some cases, the multi-targeting protein kinase inhibitor is midostaurin.

[0012] A topical pharmaceutical composition containing a multi-targeting protein kinase inhibitor (e.g., midostaurin) or a pharmaceutically acceptable salt thereof may contain midostaurin or a salt thereof. Rydapt® (midostaurin) was approved by the FDA in 2017 for the treatment of AML (acute myeloid leukemia) and ASM (aggressive systemic mastocytosis). Midostaurin is an oral multi-kinase inhibitor. In one aspect, the present disclosure discloses that topical administration of midostaurin can dose-dependently reduce skin hyperpigmentation in a UV-induced guinea pig model. Without being bound by theory, midostaurin has been found to be more effective and have a better safety profile (e.g., better skin tolerance) when applied topically compared to other currently commercially available treatments for skin hyperpigmentation.

[0013] Midostaurin is a small molecule kinase inhibitor currently available for oral administration. The molecular formula of midostaurin is C 35 H 30 It is N4O4. Its molecular weight is 570.65 g / mol. The structural formula of midostaurin is:

[0014] [ka] .

[0015] Midostaurin has a high log P value of 5.8, making it very difficult to dissolve in aqueous solution. Furthermore, midostaurin is not stable under many conditions, including acid, alkali, oxidation, heat, and photolysis, making development even more difficult. Therefore, developing a suitable topical formulation for midostaurin can be extremely difficult. The various excipients used in topical formulations can affect the amount of midostaurin delivered to different layers of the skin.

[0016] In one aspect, provided herein are midostaurin pharmaceutical compositions for topical administration. Midostaurin topical formulations are useful as therapeutic agents for reducing, ameliorating, or eliminating one or more skin-related conditions in a subject in need thereof, as further described herein. In some embodiments, the skin-related conditions include skin hyperpigmentation conditions, such as melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, maculopapular rash of pregnancy, nevus of Ota, and age-related hyperpigmentation.

[0017] In one aspect, the present embodiments provide novel methods or products for treating skin hyperpigmentation disorders. In some embodiments, the midostaurin used in the topical pharmaceutical compositions described herein is midostaurin free base. In some embodiments, the midostaurin used in the formulations described herein is a midostaurin salt.

[0018] In one aspect, methods using metabolites of midostaurin are also disclosed herein. In some embodiments of the methods disclosed herein, midostaurin or a salt thereof can be replaced with a metabolite of midostaurin. Exemplary metabolites of midostaurin include CGP 52421 and CGP 62221.

[0019] [ka] Examples include:

[0020] Midostaurin topical pharmaceutical composition

[0021] In one aspect, the present disclosure provides a topical pharmaceutical composition comprising midostaurin or a pharmaceutically acceptable salt thereof. The topical formulation may include, but is not limited to, an ointment, a gel, a cream, a lotion, a solution, an emulsion, a paste, a patch, a wipe, a swab, a pad, and any other form suitable for topical delivery of midostaurin or its pharmaceutically acceptable salt. When certain components described herein are in a cream while other components are in a gel or an ointment, lotions, solutions, emulsions, and pastes are also contemplated.

[0022] In some embodiments, the topical pharmaceutical composition also comprises a carrier vehicle. In some embodiments, the topical pharmaceutical composition also comprises an excipient. In some embodiments, the topical pharmaceutical composition is formulated for topical administration.

[0023] In some embodiments, midostaurin is present in the pharmaceutical composition in the form of a free base. In some embodiments, midostaurin is present in the form of a pharmaceutically acceptable salt. As used herein, pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; inorganic acid salts such as hydrochloride, hydrobromide salt, sulfate salt, and phosphate salt; organic acid salts such as formate, acetate, trifluoroacetate, maleate, and tartrate salt; sulfonate salts such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate salt; and amino acid salts such as arginate, aspartate, and glutamate salt. Pharmaceutically acceptable salts include bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate, pentafluoropropionate, hydrobromide, mucate, oleate, dibasic phosphate, monobasic phosphate, acetate trihydrate, bis(heptafluorobutyrate), bis(pentafluoropropionate), bis(pyridinecarboxylate), bis(trifluoroacetate), chlorohydrate, and sulfate pentahydrate.Other representative pharmaceutically acceptable salts include, for example, water soluble and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fiumate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, 15ydroxyapat, lactate, Salts include lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, eimbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triiodide, and valerate. Hydrates are another example of pharmaceutically acceptable salts. In some embodiments, the topical pharmaceutical composition comprises midostaurin.

[0024] Disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001% to about 30% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.001% to about 0.01% by weight, about 0.01% to about 0.1% by weight, about 0.1% to about 0.5% by weight, about 0.5% to about 1% by weight, about 1% to about 2% by weight, about 2% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 20% by weight, or about 20% to about 30% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.001% to about 0.01% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01% to about 0.1% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.1% to about 0.5% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.5% to about 1% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 2% to about 5% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 10% to about 20% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 20% to about 30% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.001% to about 1.0% by weight.In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01% to about 1.0% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01% to about 2% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01% to about 0.25% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.25% to about 1.5% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.1% to about 1.0% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.25% to about 0.75% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.5% to about 1.25% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.8% to about 1.2% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.5% to about 2.5% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.75% to about 2.25% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.8% to about 2.2% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.1% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.2% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.25% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.3% by weight.In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.4% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.5% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.75% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.25% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.5% by weight. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 2% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 2.5% by weight. In some embodiments, the midostaurin or pharmaceutically acceptable salt thereof is midostaurin.

[0025] Disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and an excipient. In some embodiments, the midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.001% to about 20% by weight. In some embodiments, the topical pharmaceutical composition does not comprise a phospholipid. In some embodiments, the excipient comprises a surfactant, a penetration enhancer, an antioxidant, a sunscreen, a viscosity modifier, a pH stabilizer, or a moisturizer, or any combination thereof. In some embodiments, the excipient comprises a surfactant. In some embodiments, the excipient comprises a penetration enhancer. In some embodiments, the excipient comprises an antioxidant. In some embodiments, the excipient comprises a sunscreen. In some embodiments, the excipient comprises a viscosity modifier. In some embodiments, the excipient comprises a pH stabilizer. In some embodiments, the excipient comprises a moisturizer.

[0026] In some embodiments, the topical pharmaceutical compositions described herein are ointments. In some embodiments, the topical pharmaceutical compositions comprise midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 5% by weight. In some embodiments, the topical pharmaceutical compositions comprise a surfactant in an amount of about 5% to about 20% by weight. In some embodiments, the topical pharmaceutical compositions comprise a penetration enhancer in an amount of about 0.05% to about 20% by weight. In some embodiments, the topical pharmaceutical compositions comprise a penetration enhancer in an amount of about 0.05% to about 5% by weight. In some embodiments, the topical pharmaceutical compositions comprise a carrier vehicle in an amount of about 70% to about 90% by weight. In some embodiments, the topical pharmaceutical compositions comprise a humectant in an amount of about 5% to about 25% by weight. In some embodiments, the topical pharmaceutical compositions comprise an antioxidant in an amount of about 0.001% to 5% by weight. In some embodiments, the topical pharmaceutical compositions comprise a multifunctional excipient. In some embodiments, the multifunctional excipient is simultaneously two or more of a surfactant, a penetration enhancer, a carrier vehicle, and a humectant.

[0027] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 2% by weight. In some embodiments, the topical pharmaceutical composition comprises a surfactant, such as glyceryl monolinoleate, glyceryl monooleate, polyoxylglyceride, glyceryl polyethylene glycol ricinoleate, polyethylene glycol hydroxystearate, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a penetration enhancer, such as polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one, or Azone, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle comprising polyethylene glycol (PEG), petrolatum, mineral oil, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a humectant, such as glycerol, propylene glycol, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises an antioxidant, including, for example, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or combinations thereof.

[0028] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.1% to about 1.0% by weight, a surfactant (e.g., caprylocaproyl polyoxyl-8 glyceride) in an amount of about 7% to about 15% by weight, a penetration enhancer (e.g., 1-dodecylazacycloheptan-2-one or Azone) in an amount of about 0.5% to about 3% by weight, a carrier vehicle (e.g., polyethylene glycol or PEG) in an amount of about 70% to about 80% by weight, a humectant (e.g., glycerol) in an amount of about 10% to about 15% by weight, and an antioxidant in an amount of about 0.001% to 1% by weight. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.5% to about 1.5% by weight, a surfactant (e.g., caprylocaproyl polyoxyl-8 glyceride) in an amount of about 7% to about 15% by weight, a penetration enhancer (e.g., 1-dodecylazacycloheptan-2-one or Azone) in an amount of about 0.5% to about 3% by weight, a carrier vehicle (e.g., polyethylene glycol or PEG) in an amount of about 70% to about 80% by weight, a humectant (e.g., glycerol) in an amount of about 10% to about 15% by weight, and an antioxidant in an amount of about 0.001% to 1% by weight. In some embodiments, the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof. In some embodiments, the carrier vehicle comprises polyethylene glycol having a number average molecular weight of about 100-800 g / mol, or a number average molecular weight of about 2000-6000 g / mol, or a combination thereof. In some embodiments, the carrier vehicle comprises polyethylene glycol having a number average molecular weight of about 200-600 g / mol, or a number average molecular weight of about 3000-5000 g / mol, or a combination thereof.In some embodiments, the carrier vehicle comprises polyethylene glycol having a number average molecular weight of about 300-500 g / mol, or polyethylene glycol having a number average molecular weight of about 3500-4500 g / mol, or a combination thereof.

[0029] In some embodiments, the topical pharmaceutical composition described herein is a gel. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 5% by weight. In some embodiments, the topical pharmaceutical composition comprises a surfactant in an amount of about 5% to about 50% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises a penetration enhancer in an amount of about 1% to about 30% by weight. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle in an amount of about 60% to about 95% by weight. In some embodiments, the topical pharmaceutical composition comprises a viscosity modifier in an amount of about 0.01% to about 5% by weight. In some embodiments, the topical pharmaceutical composition comprises a pH stabilizer. In some embodiments, the topical pharmaceutical composition comprises an antioxidant in an amount of about 0.001% to 5% by weight. In some embodiments, the topical pharmaceutical composition comprises a multifunctional excipient. In some embodiments, the multifunctional excipient is simultaneously a surfactant and a penetration enhancer.

[0030] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 2% by weight. In some embodiments, the topical pharmaceutical composition comprises a surfactant, such as glyceryl monolinoleate, glyceryl monooleate, polyoxylglyceride, glyceryl polyethylene glycol ricinoleate, polyoxyethylene sorbitan monooleate, or a combination thereof. In some embodiments, the topical pharmaceutical composition optionally comprises a penetration enhancer, such as polyglyceryl-3 dioleate, oleoyl polyoxyl-6 glyceride, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one, or Azone, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a viscosity modifier, such as polyacrylic acid. In some embodiments, the topical pharmaceutical composition comprises a pH stabilizer, such as sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle (e.g., water). In some embodiments, the topical pharmaceutical composition comprises an antioxidant, including, for example, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or combinations thereof.

[0031] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 1.5% by weight. In some embodiments, the topical pharmaceutical composition comprises a surfactant (e.g., caprylocaproyl polyoxyl-8 glyceride or polysorbate 80) in an amount of about 5% to about 20% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises a penetration enhancer (e.g., diethylene glycol monoethyl ether) in an amount of about 15% to about 25% by weight. In some embodiments, the topical pharmaceutical composition comprises a viscosity modifier (e.g., cross-linked polyacrylic acid such as carbomer) in an amount of about 0.1% to about 2% by weight. In some embodiments, the topical pharmaceutical composition comprises a pH stabilizer such as triethanolamine. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle (e.g., water) in an amount of about 70% to about 90% by weight. In some embodiments, the topical pharmaceutical composition comprises an antioxidant (e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof) in an amount of about 0.001% to 2% by weight.

[0032] In some embodiments, the topical pharmaceutical composition described herein is a cream. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle in an amount of about 30% to about 70% by weight. In some embodiments, the topical pharmaceutical composition comprises a surfactant in an amount of about 5% to about 50% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises a penetration enhancer in an amount of about 1% to about 40% by weight. In some embodiments, the topical pharmaceutical composition comprises a viscosity modifier in an amount of about 0.01% to about 5% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises a humectant in an amount of about 5% to about 30% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises a viscosity enhancer in an amount of about 0.01% to about 5% by weight. In some embodiments, the topical pharmaceutical composition comprises an antioxidant in an amount of about 0.001% to 5% by weight.

[0033] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 5% by weight, hi some embodiments, the topical pharmaceutical composition comprises a carrier vehicle comprising water and optionally polyethylene glycol (PEG), propylene glycol, or liquid paraffin, or petrolatum (e.g., white petrolatum), or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises a surfactant such as glyceryl monooleate, glyceryl monolinoleate, polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol-75 stearate), sorbitan monostearate, sodium dodecyl sulfate (SDS), polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2), or a combination thereof. In some embodiments, the topical pharmaceutical composition optionally comprises a humectant such as glycerol or propylene glycol, or a combination thereof. In some embodiments, the topical pharmaceutical composition optionally comprises a penetration enhancer, such as oleoyl polyoxyl-6 glyceride, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises an antioxidant, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

[0034] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.1% to about 2% by weight. In some embodiments, the topical pharmaceutical composition comprises a surfactant in an amount of about 5% to about 50% by weight. In some embodiments, the surfactant comprises glyceryl monooleate, glyceryl monolinoleate, polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate, polyoxyethylene stearate (or macrogol-75 stearate), sorbitan monostearate, sodium dodecyl sulfate (SDS), or a combination thereof. In some embodiments, the topical pharmaceutical composition optionally comprises a penetration enhancer (e.g., oleoyl polyoxyl-6 glyceride, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one, or Azone, or a combination thereof) in an amount of about 1% to about 35% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises a humectant (e.g., glycerol (glycerin) or propylene glycol, or a combination thereof) in an amount of about 5% to about 25% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises an antioxidant (e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof) in an amount of about 0.01% to about 2% by weight. In some embodiments, the topical pharmaceutical composition optionally comprises a carrier vehicle (e.g., water and optionally liquid paraffin or white petrolatum) in an amount of about 30% to about 70% by weight.

[0035] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.5% to about 2% by weight. In some embodiments, the topical pharmaceutical composition comprises a surfactant (e.g., glyceryl monolinoleate, PEG-6 palmitostearate, PEG-32 palmitostearate, ethylene glycol palmitostearate, polysorbate 80, sorbitan monostearate, macrogol-75 stearate, or a combination thereof) in an amount of about 5% to about 35% by weight. In some embodiments, the topical pharmaceutical composition comprises a penetration enhancer (e.g., polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one, or Azone, or a combination thereof) in an amount of about 1% to about 35% by weight. In some embodiments, the topical pharmaceutical composition comprises an antioxidant (e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof) in an amount of about 0.01% to about 0.1% by weight. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle (e.g., water) in an amount of about 60% to about 70% by weight.

[0036] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 1% by weight. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.5% by weight. In some embodiments, the topical pharmaceutical composition comprises glyceryl monooleate in an amount of about 10% by weight. In some embodiments, the topical pharmaceutical composition comprises polyoxyethylene sorbitan monooleate (e.g., polysorbate 80) in an amount of about 5% to about 14% by weight. In some embodiments, the topical pharmaceutical composition comprises sorbitan monostearate in an amount of about 3.5% by weight. In some embodiments, the topical pharmaceutical composition comprises polyglyceryl-3 dioleate in an amount of about 5% by weight. In some embodiments, the topical pharmaceutical composition comprises an antioxidant (e.g., butylated hydroxytoluene, butylated hydroxyanisole, and ascorbyl palmitate) in an amount of about 0.06% by weight. In some embodiments, the topical pharmaceutical composition comprises water in an amount of about 66.5% by weight.

[0037] In some embodiments, the topical pharmaceutical compositions described herein further comprise a sunscreen, hi some embodiments, the sunscreen comprises avobenzone, bemotrizinol, benzophenone-3 (BZ-3, oxybenzone), bisoctisol, homosalate, octinoxate, octisalate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof.

[0038] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the topical pharmaceutical composition has a pH of about 5.0 to about 8.0, about 5.5 to about 7.5, about 6.0 to about 7.5, about 6.5 to about 7.5, about 6.8 to about 7.2, or about 6.9 to about 7.1. In some embodiments, the topical pharmaceutical composition has a pH of about 5.0 to about 8.0. In some embodiments, the topical pharmaceutical composition has a pH of about 5.5 to about 7.5. In some embodiments, the topical pharmaceutical composition has a pH of about 6.0 to about 7.5. In some embodiments, the topical pharmaceutical composition has a pH of about 6.5 to about 7.5. In some embodiments, the topical pharmaceutical composition has a pH of about 6.8 to about 7.2. In some embodiments, the topical pharmaceutical composition has a pH of about 7.0.

[0039] In some embodiments, an excipient in a topical pharmaceutical composition described herein may have multiple functions in the composition, i.e., may be a multifunctional excipient. In some embodiments, a multifunctional excipient may function as two or more of a surfactant, a penetration enhancer, a viscosity modifier, a carrier vehicle, and a humectant. In some embodiments, a multifunctional excipient may function as a surfactant and a penetration enhancer, such as oleoyl polyoxyl-6 glyceride (e.g., sold under the trademark Labrafil® M 1944 CS) or polyglyceryl-3 dioleate (e.g., sold under the trademark Plurol® Oleique CC 497). In some embodiments, a multifunctional excipient may function as a humectant and a carrier vehicle, such as propylene glycol or glycerol.

[0040] Carrier Vehicle In one aspect, a topical pharmaceutical composition comprising midostaurin or a pharmaceutically acceptable salt thereof and a carrier vehicle is disclosed herein. The carrier vehicle can be any suitable carrier vehicle capable of delivering midostaurin or a pharmaceutically acceptable salt thereof in the topical pharmaceutical composition. The carrier vehicle can be any suitable carrier vehicle capable of delivering midostaurin or a pharmaceutically acceptable salt thereof and suitable excipients. The carrier vehicle can be any suitable carrier vehicle capable of dissolving midostaurin or a pharmaceutically acceptable salt thereof and forming a mixture capable of maintaining acceptable physical and chemical stability. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is dissolved in the carrier vehicle. In some embodiments, the carrier vehicle comprises an aqueous carrier vehicle. In some embodiments, the carrier vehicle comprises water. In some embodiments, the carrier vehicle comprises a non-aqueous carrier vehicle. In some embodiments, the carrier vehicle does not comprise water. Non-aqueous carriers can include oils (e.g., edible vegetable oils or synthetic edible oils), propylene glycol, glycerin, polypropylene glycol, polyethylene glycol (PEG), alcohols (e.g., ethanol), or any combination thereof. In some embodiments, the carrier vehicle includes polyethylene glycol (PEG), propylene glycol, glycerin (or glycerol), dimethyl sulfoxide (DMSO), petrolatum, mineral oil, wax, liquid paraffin, petrolatum, or a combination thereof. In some embodiments, the carrier vehicle includes water, polyethylene glycol, propylene glycol, or glycerin, or a combination thereof. In some embodiments, the carrier vehicle includes water. In some embodiments, the carrier vehicle includes water, liquid paraffin, petrolatum, or a combination thereof.

[0041] In some embodiments, the carrier vehicle comprises propylene glycol. In some embodiments, the carrier vehicle comprises glycerin. In some embodiments, the carrier vehicle comprises PEG. In some embodiments, the PEG has an average molecular weight of about 100 to about 10,000 g / mol. In some embodiments, the PEG has an average molecular weight of about 100 to about 500 g / mol, about 500 to about 1000 g / mol, about 1000 to about 5000 g / mol, or about 5000 to about 10,000 g / mol. In some embodiments, the PEG has an average molecular weight of about 200 to about 500 g / mol. In some embodiments, the PEG has an average molecular weight of about 300 to about 500 g / mol. In some embodiments, the PEG has an average molecular weight of about 350 to about 450 g / mol. In some embodiments, the PEG has an average molecular weight of about 400 g / mol. In some embodiments, the PEG is PEG 400.

[0042] In some embodiments, the carrier vehicle comprises PEG. In some embodiments, the PEG has a number average molecular weight of about 200 to about 20,000 g / mol. In some embodiments, the PEG has a number average molecular weight of about 200 to about 500 g / mol, about 500 to about 1000 g / mol, about 1000 to about 8000 g / mol, about 8000 to about 12,000 g / mol, or about 12,000 to about 20,000 g / mol. In some embodiments, the PEG has a number average molecular weight of about 1000 to about 8000 g / mol, about 2000 to about 7000 g / mol, about 3000 to about 6000 g / mol, about 3500 to about 5500 g / mol, about 3500 to about 5000 g / mol, about 3700 to about 4500 g / mol, or about 3800 to about 4200 g / mol. In some embodiments, the PEG has a number average molecular weight of about 1000 to about 8000 g / mol. In some embodiments, the PEG has a number average molecular weight of about 2000 to about 7000 g / mol. In some embodiments, the PEG has a number average molecular weight of about 3000 to about 6000 g / mol. In some embodiments, the PEG has a number average molecular weight of about 3500 to about 5500 g / mol. In some embodiments, the PEG has a number average molecular weight of about 3500 to about 5000 g / mol. In some embodiments, the PEG has a number average molecular weight of about 3700 to about 4500 g / mol. In some embodiments, the PEG has a number average molecular weight of about 3800 to about 4200 g / mol. In some embodiments, the PEG has a number average molecular weight of about 4000 g / mol. In some embodiments, the PEG is PEG 4000.

[0043] In some embodiments, the carrier vehicle is present in the topical pharmaceutical compositions described herein in an amount of about 35% to about 99% by weight, hi some embodiments, the carrier vehicle is present in the topical pharmaceutical compositions described herein in an amount of about 35% to about 40% by weight, about 40% to about 45% by weight, about 45% to about 50% by weight, about 50% to about 55% by weight, about 55% to about 60% by weight, about 60% to about 65% by weight, about 65% to about 70% by weight, about 70% to about 75% by weight, about 75% to about 80% by weight, about 80% to about 85% by weight, about 85% to about 90% by weight, about 90% to about 93% by weight, about 93% to about 96% by weight, or about 96% to about 99% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 35% to about 40% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 40% to about 45% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 45% to about 50% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 50% to about 55% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 55% to about 60% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 60% to about 65% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 65% to about 70% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 70% to about 75% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 75% to about 80% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 80% to about 85% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 85% to about 90% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 70% to about 95% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 90% to about 99% by weight.In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 90% to about 93% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 93% to about 96% by weight. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 96% to about 99% by weight. In some embodiments, the carrier vehicle comprises water. In some embodiments, the carrier vehicle comprises PEG 400. In some embodiments, the carrier vehicle comprises PEG 4000. In some embodiments, the carrier vehicle comprises PEG 400 and PEG 4000. In some embodiments, the carrier vehicle comprises glycerin. In some embodiments, the carrier vehicle comprises PEG 400, PEG 4000, and glycerin. In some embodiments, the carrier vehicle comprises propylene glycol. In some embodiments, the carrier vehicle comprises water and propylene glycol.

[0044] In some embodiments, the carrier vehicle comprises water. In some embodiments, water is present in the topical pharmaceutical compositions described herein in an amount of about 35% to about 95% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 35% to about 40% by weight, about 40% to about 45% by weight, about 45% to about 50% by weight, about 50% to about 55% by weight, about 55% to about 60% by weight, about 60% to about 65% by weight, about 65% to about 70% by weight, about 70% to about 75% by weight, about 75% to about 80% by weight, about 80% to about 85% by weight, about 85% to about 90% by weight, or about 90% to about 95% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 35% to about 40% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 40% to about 45% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 45% to about 50% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 50% to about 55% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 55% to about 60% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 60% to about 65% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 65% to about 70% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 70% to about 75% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 75% to about 80% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 80% to about 85% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 85% to about 90% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 90% to about 95% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 40% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 50% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 60% by weight. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 65% by weight.In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 67.5% by weight.

[0045] In some embodiments, the carrier vehicle comprises water, propylene glycol, and glycerin. In some embodiments, the carrier vehicle comprises propylene glycol and glycerin in a weight ratio of about 1:1 to about 5:1, about 2:1 to about 4:1, or about 2.5:1 to about 3.5:1. In some embodiments, the carrier vehicle comprises propylene glycol and glycerin in a weight ratio of about 2.5:1 to about 3.5:1. In some embodiments, the carrier vehicle comprises propylene glycol and glycerin in a weight ratio of about 3:1. In some embodiments, the carrier vehicle comprises water and propylene glycol in a weight ratio of about 1:1 to about 5:1, about 2:1 to about 4:1, or about 2.5:1 to about 3.5:1. In some embodiments, the carrier vehicle comprises water and propylene glycol in a weight ratio of about 2.5:1 to about 3.5:1. In some embodiments, the carrier vehicle comprises water and propylene glycol in a weight ratio of about 3:1 to about 10:3.

[0046] In some embodiments, the carrier vehicle comprises water, liquid paraffin, and petrolatum (e.g., white petrolatum). In some embodiments, the carrier vehicle comprises liquid paraffin and petrolatum (e.g., white petrolatum) in a weight ratio of about 1:5 to about 5:1, about 1:4 to about 4:1, or about 1:3 to about 3:1. In some embodiments, the carrier vehicle comprises liquid paraffin and petrolatum (e.g., white petrolatum) in a weight ratio of about 1:1 to about 3:1. In some embodiments, the carrier vehicle comprises liquid paraffin and petrolatum (e.g., white petrolatum) in a weight ratio of about 5:3. In some embodiments, the carrier vehicle comprises water and liquid paraffin in a weight ratio of about 20:1 to about 5:1, about 15:1 to about 6:1, or about 12:1 to about 8:1. In some embodiments, the carrier vehicle comprises water and liquid paraffin in a weight ratio of about 12:1 to about 8:1. In some embodiments, the carrier vehicle comprises water liquid paraffin in a weight ratio of about 11:1 to about 9:1, hi some embodiments, the carrier vehicle comprises water liquid paraffin in a weight ratio of about 10:1.

[0047] In some embodiments, the carrier vehicle comprises PEG. In some embodiments, the carrier vehicle does not comprise water. In some embodiments, the carrier vehicle comprises PEG 400. In some embodiments, the carrier vehicle comprises PEG 4000. In some embodiments, the carrier vehicle comprises PEG 400 and PEG 4000. In some embodiments, the carrier vehicle comprises PEG 400 and PEG 4000 in a weight ratio of about 1:1 to about 10:1, about 2:1 to about 9:1, about 3:1 to about 8:1, about 4:1 to about 7:1, or about 5:1 to about 7:1. In some embodiments, the carrier vehicle comprises PEG 400 and PEG 4000 in a weight ratio of about 5:1 to about 7:1. In some embodiments, the carrier vehicle comprises PEG 400 and PEG 4000 in a weight ratio of about 5.5:1 to about 6.5:1. In some embodiments, the carrier vehicle comprises PEG 400 and PEG 4000 in a weight ratio of about 6.08:1. In some embodiments, the PEG is present in the topical pharmaceutical composition in an amount of about 60% to about 85% by weight. In some embodiments, the PEG is present in the topical pharmaceutical composition in an amount of about 60% to about 65% by weight, about 65% to about 70% by weight, about 70% to about 75% by weight, about 75% to about 80% by weight, or about 80% to about 85% by weight. In some embodiments, the PEG is present in the topical pharmaceutical composition in an amount of about 35% to about 40% by weight. In some embodiments, the PEG is present in the topical pharmaceutical composition in an amount of about 40% to about 45% by weight. In some embodiments, the PEG is present in the topical pharmaceutical composition in an amount of about 45% to about 50% by weight. In some embodiments, the PEG is present in the topical pharmaceutical composition in an amount of about 50% to about 55% by weight. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 55% to about 60% by weight. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 60% to about 65% by weight. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 65% to about 70% by weight. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 70% to about 75% by weight.In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 75% to about 80% by weight. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 70% to about 75% by weight. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 75% by weight.

[0048] surfactants In one aspect, disclosed herein is a topical pharmaceutical composition comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and excipients (including, for example, surfactants).

[0049] In some embodiments, the topical pharmaceutical compositions described herein include a surfactant. In some embodiments, the surfactant is a compound or mixture of compounds that includes a hydrophobic group (usually a hydrocarbon chain) and a hydrophilic group. In some embodiments, the surfactant may include an emulsifier. The surfactant may serve one or more functions, including solubility enhancer, bioavailability enhancer, penetration enhancer, and emulsifier. Examples of surfactants include, but are not limited to, the Kolliphor series (rh40), sorbitan oleate, SDS, solutal, soluplus, sucrose esters of fatty acids, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, macrogol glycerol hydroxystearate oil, PEG-40 castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, sodium dodecyl sulfate, lauromacrogol arlasolve, poloxamer, labrafil, labrasol, Tween 80, and tocopherol polyethylene glycol 1000 succinate (simply TPGS or vitamin E TPGS).

[0050] The surfactant used in the present disclosure may include one or more nonionic surfactants, one or more ionic surfactants, one or more zwitterionic surfactants, or a mixture thereof. In some embodiments, the nonionic surfactant does not have a charged group at its head. Exemplary nonionic surfactants include, but are not limited to, fatty alcohols, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ether (such as Triton X-100), polyethylene glycol alkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such as glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbates), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers), polyethoxylated tallow amine (POEA), and tocopherol polyethylene glycol 1000 succinate (simply TPGS or vitamin E TPGS). In some embodiments, the nonionic surfactant comprises one or more of a fatty alcohol, such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol. In some embodiments, the nonionic surfactant comprises one or more of a C9-C 30 In some embodiments, the nonionic surfactant comprises a fatty alcohol or a fatty acid. 12 ~C 24 In some embodiments, the nonionic surfactant comprises a fatty alcohol or a fatty acid. 12 ~C 18Include fatty alcohols or fatty acids. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ethers (such as Triton X-100), polyethylene glycol alkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such as glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbates), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamer), polyethoxylated tallow amine (POEA), and tocopherol polyethylene glycol 1000 succinate (simply TPGS or vitamin E TPGS).

[0051] In some embodiments, the topical pharmaceutical composition comprises a surfactant. In some embodiments, the topical pharmaceutical composition comprises two or more surfactants. In some embodiments, the topical pharmaceutical composition comprises two, three, four, or more surfactants. In some embodiments, the topical pharmaceutical composition comprises two surfactants. In some embodiments, the topical pharmaceutical composition comprises three surfactants. In some embodiments, the topical pharmaceutical composition comprises four surfactants.

[0052] In some embodiments, the surfactant comprises glyceryl monooleate (e.g., sold under the trademark Peceol™). In some embodiments, the surfactant comprises glyceryl monolinoleate (e.g., sold under the trademark Maisine™ CC). In some embodiments, the surfactant comprises a polyethylene glycol hydroxystearate, such as macrogol-15-hydroxystearate (e.g., sold under the trademark Kolliphor™ HS15). In some embodiments, the surfactant comprises polyoxyethylene sorbitan monooleate, e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80. In some embodiments, the surfactant comprises a polyoxylglyceride, e.g., caprylocaproyl polyoxyl-8 glyceride (e.g., sold under the trademark Labarasol™). In some embodiments, the surfactant comprises oleoyl polyoxyl-6 glyceride (e.g., sold under the trademark Labrafil® M 1944 CS). In some embodiments, the surfactant comprises glyceryl polyethylene glycol ricinoleate, e.g., polyoxyl 35 hydrogenated castor oil (e.g., sold under the trademark Cremophor® EL). In some embodiments, the surfactant comprises PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate). In some embodiments, the surfactant comprises ethylene glycol palmitostearate (e.g., ethylene glycol monopalmitostearate). In some embodiments, the surfactant comprises a mixture of PEG-6 palmitostearate, PEG-32 palmitostearate, and ethylene glycol monopalmitostearate (e.g., sold under the trademark Tefose® 63). In some embodiments, the surfactant comprises glycerol monostearate (or glyceryl monostearate, GMS).In some embodiments, the surfactant comprises polyoxyethylene stearate and macrogol stearate (e.g., a mixture of glycerol monostearate and macrogol-75 stearate sold under the trademark Gelot™ 64). In some embodiments, the surfactant comprises sorbitan monostearate (e.g., sold under the trademark Span® 60). In some embodiments, the surfactant comprises polyglyceryl-3 dioleate (e.g., sold under the trademark Plurol® Oleique CC 497). In some embodiments, the surfactant comprises sodium dodecyl sulfate (SDS). In some embodiments, the surfactant comprises a polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2).

[0053] In some embodiments, the surfactant comprises an emulsifier, such as polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol stearate), sorbitan monostearate, sodium dodecyl sulfate (SDS), oleoyl polyoxyl-6 glyceride, or polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2), or a combination thereof.

[0054] In some embodiments, the surfactant comprises a fatty acid, a sphingolipid, a glycolipid, a polyketide, a sterol lipid, a prenol lipid, etc. In some embodiments, the surfactant does not comprise a phospholipid.

[0055] In some embodiments, the surfactant comprises a nonionic surfactant. In some embodiments, the nonionic surfactant comprises vitamin E, a block copolymer of polyethylene glycol and polypropylene glycol, or any combination thereof. In some embodiments, the surfactant comprises two or more repeating units, such as polyoxyalkylene units. In some embodiments, the surfactant is a nonionic surfactant comprising polyethylene glycol. In some embodiments, the surfactant is a block copolymer of polyethylene glycol and polypropylene glycol.

[0056] In some embodiments, the surfactant comprises an ionic surfactant. An ionic surfactant may have a charged group at its head. An ionic surfactant may have an anionic head group or a cationic head group. In some embodiments, exemplary ionic surfactants include sodium lauryl sulfate (SLS), sodium dodecyl sulfate, calcium oleate, triethanolamine oleate, docusate sodium, benzalkonium chloride, and cetylpyridinium chloride. In some embodiments, the pharmaceutical composition or topical pharmaceutical composition comprises SLS. In some embodiments, the surfactant is a mixture of one or more nonionic surfactants and one or more ionic surfactants. In some embodiments, the surfactant comprises SLS and TPGS.

[0057] In some embodiments, the nonionic surfactant has a number average molecular weight of about 1000 to about 100,000 Da, 2000 to about 20,000 Da, about 4000 to about 15,000 Da, about 6000 to about 12,000 Da, or about 7000 to about 10,000 Da. In some embodiments, the nonionic surfactant has a number average molecular weight of about 7,000 to about 10,000 Da. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 30% to about 99% by weight, about 50% to about 95% by weight, about 60% to about 95% by weight, about 75% to about 90% by weight, or about 80% to about 85% by weight. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 80% to about 85% by weight.

[0058] In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 0.01% to about 55% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 0.01% to about 1% by weight, about 1% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 40% by weight, about 40% to about 45% by weight, about 45% to about 50% by weight, or about 50% to about 55% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 0.01% to about 1% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 10% to about 15% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 20% to about 25% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 25% to about 30% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 30% to about 35% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 35% to about 40% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 40% to about 45% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 45% to about 50% by weight. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 50% to about 55% by weight. In some embodiments, the surfactant comprises a polyoxylglyceride (e.g., caprylocaproyl polyoxyl-8 glyceride). In some embodiments, the surfactant comprises polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80). In some embodiments, the surfactant comprises oleoyl polyoxyl-6 glyceride.In some embodiments, the surfactant comprises PEG-6 palmitostearate, PEG-32 palmitostearate, and ethylene glycol palmitostearate (e.g., Tefose® 63). In some embodiments, the surfactant comprises polyoxyethylene stearate or macrogol stearate (e.g., Gelot™ 64). In some embodiments, the surfactant comprises sorbitan monostearate (e.g., Span® 60). In some embodiments, the surfactant comprises polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497). In some embodiments, the surfactant comprises sodium dodecyl sulfate (SDS). In some embodiments, the surfactant comprises glyceryl monooleate (e.g., Peceol™).

[0059] In some embodiments, glyceryl monooleate (e.g., Peceol™) is present in the topical pharmaceutical composition in an amount of about 1% to about 20% by weight. In some embodiments, glyceryl monooleate (e.g., Peceol™) is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight, or about 15% to about 20% by weight. In some embodiments, glyceryl monooleate (e.g., Peceol™) is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight. In some embodiments, glyceryl monooleate (e.g., Peceol™) is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, glyceryl monooleate (e.g., Peceol™) is present in the topical pharmaceutical composition in an amount of about 10% to about 15% by weight. In some embodiments, glyceryl monooleate (e.g., Peceol™) is present in the topical pharmaceutical composition in an amount of about 15% to about 20% by weight. In some embodiments, glyceryl monooleate (e.g., Peceol™) is present in the topical pharmaceutical composition in an amount of about 10% by weight.

[0060] In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 1% to about 25% by weight. In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, or about 20% to about 25% by weight. In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight. In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 10% to about 15% by weight. In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 15% to about 20% by weight. In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 20% to about 25% by weight. In some embodiments, the polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80) is present in the topical pharmaceutical composition in an amount of about 14% by weight.

[0061] In some embodiments, sorbitan monostearate (e.g., Span® 60) is present in the topical pharmaceutical composition in an amount of about 1% to about 10% by weight. In some embodiments, sorbitan monostearate (e.g., Span® 60) is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight, about 2% to about 5% by weight, about 5% to about 7% by weight, or about 7% to about 10% by weight. In some embodiments, sorbitan monostearate (e.g., Span® 60) is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight. In some embodiments, sorbitan monostearate (e.g., Span® 60) is present in the topical pharmaceutical composition in an amount of about 2% to about 5% by weight. In some embodiments, sorbitan monostearate (e.g., Span® 60) is present in the topical pharmaceutical composition in an amount of about 5% to about 7% by weight. In some embodiments, sorbitan monostearate (e.g., Span® 60) is present in the topical pharmaceutical composition in an amount of about 7% to about 10% by weight. In some embodiments, sorbitan monostearate (e.g., Span® 60) is present in the topical pharmaceutical composition in an amount of about 3.5% by weight.

[0062] In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1% to about 10% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight, about 2% to about 5% by weight, about 5% to about 7% by weight, or about 7% to about 10% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 2% to about 5% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5% to about 7% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 7% to about 10% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5% by weight.

[0063] penetration enhancers In one aspect, disclosed herein is a topical pharmaceutical composition comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and excipients (including, for example, penetration enhancers).

[0064] In some embodiments, the topical pharmaceutical compositions described herein include a penetration enhancer. The penetration enhancer can penetrate the skin, interact with skin components, reduce skin barrier resistance, and promote the flux of a drug, such as midostaurin or a pharmaceutically acceptable salt thereof, in the topical pharmaceutical compositions described herein. In some embodiments, the penetration enhancer can simultaneously fulfill one or more roles, including surfactant, solubility enhancer, bioavailability enhancer, and emulsifier. Other terms in the art for penetration enhancer include penetration enhancer, penetrant, sorption promoter, enhancer, etc. Examples of penetration enhancers include, but are not limited to, pyrrolidones (e.g., 2-pyrrolidone), alcohols (e.g., ethanol), esters, alkanols (e.g., decanol), ester sulfoxides (such as dimethyl sulfoxide) and their derivatives, glycols (e.g., propylene glycol), hydrocarbons, terpenes and derivatives, azone and its analogs, amides (including urea and its derivatives), fatty acids, surfactants (nonionic, cationic, and anionic), oleodendrimers, ionic liquids, and deep eutectic solvents. In some embodiments, the topical pharmaceutical compositions described herein comprise two or more penetration enhancers.

[0065] In some embodiments, the penetration enhancer comprises polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497), diethylene glycol monoethyl ether (e.g., sold under the trademark Transcutol® P), oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M 1944 CS), or 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof.

[0066] In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 0.01% to about 45% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 0.01% to about 1% by weight, about 1% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 40% by weight, or about 40% to about 45% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 0.01% to about 1% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 10% to about 15% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 20% to about 25% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 25% to about 30% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 30% to about 35% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 35% to about 40% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 40% to about 45% by weight. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 45% to about 50% by weight. In some embodiments, the penetration enhancer comprises polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497). In some embodiments, the penetration enhancer comprises diethylene glycol monoethyl ether (e.g., Transcutol® P). In some embodiments, the penetration enhancer comprises oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M 1944 CS). In some embodiments, the penetration enhancer comprises 1-dodecylazacycloheptan-2-one (or Azone).In some embodiments, penetration enhancers include oleoyl polyoxyl-6 glycerides (eg, Labrafil® M 1944 CS) and 1-dodecylazacycloheptan-2-one (or Azone).

[0067] In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, the penetration enhancer comprises polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497). In some embodiments, the penetration enhancer comprises diethylene glycol monoethyl ether (e.g., Transcutol® P). In some embodiments, the penetration enhancer comprises oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M 1944 CS).

[0068] In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1% to about 15% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight, about 2% to about 5% by weight, about 5% to about 7% by weight, about 7% to about 10% by weight, or about 10% to about 15% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 2% to about 5% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5% to about 7% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 7% to about 10% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 10% to about 15% by weight. In some embodiments, polyglyceryl-3 dioleate (e.g., Plurol® Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5% by weight.

[0069] pH stabilizer In one aspect, disclosed herein is a topical pharmaceutical composition comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and an excipient (e.g., a pH stabilizer).

[0070] In some embodiments, the topical pharmaceutical compositions described herein comprise a pH stabilizer. In some embodiments, the topical pharmaceutical compositions described herein comprise a pH stabilizer. In some embodiments, the topical pharmaceutical compositions described herein comprise a means for maintaining pH. In some embodiments, the means for maintaining pH is one or more pH stabilizers. In some embodiments, the topical pharmaceutical compositions described herein comprise two or more pH stabilizers. In some embodiments, the pH stabilizer comprises one or more organic or inorganic acids. Pharmaceutically acceptable organic acids are selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, aliphatic sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, isethionic acid, etc.), and aromatic sulfonic acids (e.g., benzenesulfonic acid, p-toluenesulfonic acid, etc.), and pharmaceutically acceptable inorganic acids are selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, etc. In some embodiments, the pH stabilizer comprises a salt of an organic or inorganic acid.

[0071] In some embodiments, the pH stabilizer comprises citric acid, glycolic acid, lactic acid, sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof. In some embodiments, the pH stabilizer comprises sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof. In some embodiments, the pH stabilizer comprises an amine. In some embodiments, the pH stabilizer comprises triethanolamine. In some embodiments, the pH stabilizer comprises sodium hydroxide. In some embodiments, the topical pharmaceutical composition is a gel formulation.

[0072] In some embodiments, the pH stabilizer includes citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Further examples of pH stabilizers include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, a mixture of an amino acid and a buffer solution, a mixture of an aluminum glycinate and a buffer solution, a mixture of an amino acid acid salt and a buffer solution, and a mixture of an amino acid alkali salt and a buffer solution. In some embodiments, the pH stabilizer includes citric acid. In some embodiments, the topical pharmaceutical composition is a cream formulation.

[0073] In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 5.0 to about 8.0, about 5.5 to about 7.5, about 6.0 to about 7.5, about 6.5 to about 7.5, about 6.7 to about 7.3, about 6.8 to about 7.2, about 6.9 to about 7.1, or about 7.0. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 5.0 to about 8.0. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 5.5 to about 7.5. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 6.0 to about 7.5. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 6.5 to about 7.5. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 6.7 to about 7.3. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 6.8 to about 7.2. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 6.9 to about 7.1. In some embodiments, a pH stabilizer is present in the topical pharmaceutical compositions described herein in an amount suitable to maintain the pH of the composition at about 7.0. In some embodiments, the pH stabilizer is triethanolamine.

[0074] antioxidants In one aspect, the topical pharmaceutical compositions described herein comprise midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and an excipient (e.g., a preservative, including an antioxidant). In some embodiments, the topical pharmaceutical compositions described herein comprise a preservative. The preservative can include an antimicrobial agent, an antioxidant, and an agent that enhances sterility or reduces oxidation. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, citric acid, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben, and their salts), benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like.

[0075] In some embodiments, the topical pharmaceutical compositions described herein comprise an antioxidant. In some embodiments, the topical pharmaceutical compositions described herein comprise two or more antioxidants. In some embodiments, the antioxidant comprises alpha tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, BHA, BHT, cysteine, cysteine ​​hydrochloride, d-alpha tocopherol (natural or synthetic), dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, or a tocopherol (e.g., d-alpha tocopherol), or a combination thereof.

[0076] In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.0001% to about 15% by weight, ie, about 0.0001% to about 0.001%, about 0.0001% to about 0.01%, about 0.0001% to about 0.1%, about 0.0001% to about 1%, about 0.0001% to about 2%, about 0.0001% to about 5%, about 0.0001% to about 7%, about 0.0001% to about 10%, or about 0.0001% to about 15% by weight. %, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.1 wt%, about 0.001 wt% to about 1 wt%, about 0.001 wt% to about 2 wt%, about 0.001 wt% to about 5 wt%, about 0. 001 weight% to about 7 weight%, about 0.001 weight% to about 10 weight%, about 0.001 weight% to about 15 weight%, about 0.01 weight% to about 0.1 weight%, about 0.01 weight% to about 1 weight%, about 0.01 weight% to about 2 Weight %, about 0.01 weight % to about 5 weight %, about 0.01 weight % to about 7 weight %, about 0.01 weight % to about 10 weight %, about 0.01 weight % to about 15 weight %, about 0.1 weight % to about 1 weight %, about 0.1 weight % to about 2 Weight%, about 0.1% to about 5% by weight, about 0.1% to about 7% by weight, about 0.1% to about 10% by weight, about 0.1% to about 15% by weight, about 1% to about 2% by weight, about 1% to about 5% by weight, about 1% by weight In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.0001%, about 0.001%, about 0.01%, about 0.1%, about 1%, about 2%, about 5%, about 7%, about 10%, or about 15% by weight. In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of at least about 0.0001%, about 0.001%, about 0.01%, about 0.1%, about 1%, about 2%, about 5%, about 7%, or about 10% by weight.

[0077] In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.01% to about 0.1% by weight. In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.06% by weight. In some embodiments, the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbyl palmitate.

[0078] Viscosity modifier Viscosity modifiers are agents that can increase or decrease the viscosity or change the texture of a pharmaceutical composition. Viscosity modifiers may include rheology modifiers or other names known in the art. Viscosity modifiers may include viscosity enhancers, viscosity building agents, thickeners, or other names known in the art. Viscosity modifiers may also include viscosity reducers, viscosity reducing agents, or other names known in the art. Examples of viscosity modifiers include, but are not limited to, aluminum monostearate, bentonite, polyacrylic acid (or PAA) (e.g., cross-linked polyacrylic acid sold under the trademark Carbomer), octadecyl alcohol, glyceryl behenate (e.g., sold under the trademark Compritol® 888 ATO), white petrolatum, and silicone compounds (e.g., a mixture of cyclopentasiloxane, dimethicone, and phenyl trimethicone sold under the trademark GELAID®).

[0079] In some embodiments, the midostaurin topical pharmaceutical compositions described herein include a viscosity modifier, such as aluminum monostearate, bentonite, polyacrylic acid (or PAA) (e.g., cross-linked polyacrylic acid sold under the trade name Carbomer), octadecyl alcohol, glyceryl behenate (e.g., Compritol® 888 ATO), white petrolatum, or a combination thereof.

[0080] In some embodiments, the viscosity modifying agent is present in the topical pharmaceutical composition in an amount of about 0.01% to about 15% by weight. In some embodiments, the viscosity modifier is from about 0.01 wt% to about 0.1 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 2 wt%, from about 0.01 wt% to about 5 wt%, from about 0.01 wt% to about 7 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 15 wt%, from about 0.1 wt% to about 0.5 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 2 wt%, from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 7 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 15 wt%, from about 0.5 wt% to about 1 wt%, from about 0.5 wt% to about 2 wt%, or from about 0.5

[0033] The compound is present in the topical pharmaceutical composition in an amount of about 0.5% to about 5% by weight, about 0.5% to about 7% by weight, about 0.5% to about 10% by weight, about 0.5% to about 15% by weight, about 1% to about 2% by weight, about 1% to about 5% by weight, about 1% to about 7% by weight, about 1% to about 10% by weight, about 1% to about 15% by weight, about 2% to about 5% by weight, about 2% to about 7% by weight, about 2% to about 10% by weight, about 2% to about 15% by weight, about 5% to about 7% by weight, about 5% to about 10% by weight, about 5% to about 15% by weight, about 7% to about 10% by weight, about 7% to about 15% by weight, or about 10% to about 15% by weight. In some embodiments, the viscosity modifier is present in the topical pharmaceutical composition in an amount of about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 3.5 wt %, or about 5 wt %. In some embodiments, the viscosity modifier is present in the topical pharmaceutical composition in an amount of about 0.5 wt %. In some embodiments, the viscosity modifier is present in the topical pharmaceutical composition in an amount of about 3 wt %. In some embodiments, the viscosity modifier is present in the topical pharmaceutical composition in an amount of about 3.5 wt %. In some embodiments, the viscosity modifier comprises aluminum monostearate, bentonite, polyacrylic acid (or PAA) (e.g., cross-linked polyacrylic acid or carbomer), octadecyl alcohol, petrolatum (e.g., white petrolatum), or a combination thereof.

[0081] In some embodiments, the crosslinked polyacrylic acid (or carbomer) is present in the topical pharmaceutical composition in an amount of about 0.1% to about 1% by weight. In some embodiments, the crosslinked polyacrylic acid (or carbomer) is present in the topical pharmaceutical composition in an amount of about 0.25% to about 0.75% by weight. In some embodiments, the crosslinked polyacrylic acid (or carbomer) is present in the topical pharmaceutical composition in an amount of about 0.5% by weight.

[0082] In some embodiments, octadecyl alcohol is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight. In some embodiments, octadecyl alcohol is present in the topical pharmaceutical composition in an amount of about 2% to about 4% by weight. In some embodiments, octadecyl alcohol is present in the topical pharmaceutical composition in an amount of about 3.5% by weight.

[0083] moisturizer Moisturizers are agents that bind water or moisture to the skin or allow the skin to retain moisture. Moisturizers can include humectants that can bind water or moisture to the skin. Moisturizers can include occlusives that can create a protective barrier to retain moisture in the skin and prevent water loss. Moisturizers can include emollients that keep the skin hydrated and smooth. Examples of moisturizers include, but are not limited to, petrolatum, mineral oil, wax, liquid paraffin, petrolatum (e.g., white petrolatum), glycerol (or glycerin), propylene glycol, polyethylene glycol (PEG), hexylene glycol, and sorbitol. (See, for example, U.S. Patent Publication No. 2004 / 0191276, which is incorporated herein by reference.)

[0084] In some embodiments, the midostaurin topical pharmaceutical compositions described herein include a moisturizer. In some embodiments, the midostaurin topical pharmaceutical compositions described herein include two or more moisturizers. In some embodiments, the moisturizer includes petrolatum, mineral oil, wax, liquid paraffin, petrolatum, glycerol (or glycerin), propylene glycol, hexylene glycol, or a combination thereof.

[0085] In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 0.01% to about 35% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 0.01% to about 1% by weight, about 1% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, or about 30% to about 35% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 0.01% to about 1% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 1% to about 5% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 10% to about 15% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 20% to about 25% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 25% to about 30% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 30% to about 35% by weight. In some embodiments, the humectant comprises liquid paraffin, petrolatum (e.g., white petrolatum), glycerol (or glycerin), propylene glycol, or a combination thereof.

[0086] In some embodiments, the humectant comprises glycerol. In some embodiments, glycerol is present in the topical pharmaceutical composition in an amount of about 5% to about 10% by weight. In some embodiments, glycerol is present in the topical pharmaceutical composition in an amount of about 10% to about 15% by weight. In some embodiments, glycerol is present in the topical pharmaceutical composition in an amount of about 5% by weight. In some embodiments, glycerol is present in the topical pharmaceutical composition in an amount of about 13% by weight.

[0087] In some embodiments, the humectant comprises glycerol (or glycerin) and propylene glycol. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 10% to about 30% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 15% to about 25% by weight. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 20% by weight.

[0088] sunscreen Sunscreens are agents that can protect the skin from ultraviolet (UV) radiation. Sunscreens can absorb UV and visible sunlight. Sunscreens can also reflect, scatter, or block UV and visible sunlight. Sunscreens can include physical sunblocks. Sunscreens can include chemical sunblocks. Other terms in the art include sunscreen, sunscreen, sunblock, etc. Non-limiting examples of sunscreens include avobenzone, bemotrizinol, benzophenone-3 (BZ-3, oxybenzone), bisoctisol, homosalate, octinoxate, octisalate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or combinations thereof. Other examples of sunscreens are described in Latha MS, Martis J, Shobha V, et al. Sunscreening agents: a review. J Clin Aesthet Dermatol. 2013;6(1):16-26 (incorporated herein by reference).

[0089] In some embodiments, the midostaurin topical pharmaceutical compositions described herein include a sunscreen. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.0001% to about 5% by weight. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.0001% to about 0.001% by weight, about 0.0001% to about 0.01% by weight, about 0.0001% to about 0.1% by weight, about 0.0001% to about 1% by weight, about 0.0001% to about 2% by weight, about 0.0001% to about 5% by weight, about 0.001% to about 0.01% by weight, about 0.001% to about 0.1% by weight, about 0. ...

[0023] In some embodiments, the sunscreen agent is present in the topical pharmaceutical composition in an amount of about 0.01% to about 2% by weight, about 0.001% to about 5% by weight, about 0.01% to about 0.1% by weight, about 0.01% to about 1% by weight, about 0.01% to about 2% by weight, about 0.01% to about 5% by weight, about 0.1% to about 1% by weight, about 0.1% to about 2% by weight, about 0.1% to about 5% by weight, about 1% to about 2% by weight, about 1% to about 5% by weight, about 2% to about 5% by weight, or about 3% to about 5% by weight. In some embodiments, the sunscreen agent is present in the topical pharmaceutical composition in an amount of about 0.001% to about 0.01% by weight. In some embodiments, the sunscreen agent is present in the topical pharmaceutical composition in an amount of about 0.01% to about 0.1% by weight. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.1% to about 0.5% by weight. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.5% to about 1% by weight. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 1% to about 2% by weight. In some embodiments, the sunscreen comprises avobenzone, bemotrizinol, benzophenone-3 (BZ-3, oxybenzone), bisoctisol, homosalate, octinoxate, octisalate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof.

[0090] Other additives The excipients described herein can be used alone or in combination. In some embodiments, other additives conventionally mixed with pharmaceutical compositions can be included in the topical pharmaceutical composition. Additives include, but are not limited to, any suitable agent that can generally improve the condition of the skin, such as a suspending agent (e.g., cellulose ether), an antifoaming agent (e.g., hydrophobic silica), or an alphahydroxy acid (e.g., glycolic acid and lactic acid).

[0091] Additives can also be used in the preparation of food products, such as proteins (e.g., collagen, gelatin, zein, gluten, mussel protein, lipoproteins), carbohydrates (e.g., alginates, carrageenans, cellulose derivatives, pectin, starch, chitosan), gums (e.g., xanthan gum, gum arabic), spermaceti, natural or synthetic waxes, carnauba wax, fatty acids (e.g., stearic acid, hydroxystearic acid), fatty alcohols, sugars, shellacs such as those based on sugars (e.g., lactose, sucrose, dextrose) or starch, polysaccharide-based polymers (e.g., maltodextrin and maltodextrin derivatives, dextrates, cyclodextrin and cyclodextrin derivatives), cellulosic polymers (e.g., The protein may be a material such as microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, cellulose acetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropyl methylcellulose phthalate), minerals (e.g., dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc, and titania), polyols (e.g., mannitol, xylitol, and sorbitol polyethylene glycol esters), and polymers (e.g., alginate, poly(lactide-co-glycolide), gelatin, cross-linked gelatin, and agar). In some embodiments, the protein comprises an amino acid such as glutamic acid, aspartic acid, or an acid salt of glycine, alanine, or serine.

[0092] stability In some embodiments, the topical pharmaceutical compositions described herein are stable under various storage conditions, including refrigerated, ambient, room, and accelerated conditions. In some embodiments, a stable midostaurin composition, as used herein, refers to a midostaurin topical pharmaceutical composition that, at the end of a given storage period, accounts for about 95% or more of the initial midostaurin amount and has about 5% or less by weight of total impurities or related substances. In some embodiments, a stable midostaurin composition, as used herein, refers to a midostaurin topical pharmaceutical composition that, at the end of a given storage period, accounts for about 90% or more by weight of the initial midostaurin amount and has about 10% or less by weight of total impurities or related substances.

[0093] The percentage of impurities can be calculated from the amount of impurities relative to the amount of midostaurin. The percentage of impurities can be assessed by high performance liquid chromatography (HPLC), for example, using the method described in Table B-2, or any other known testing method. In some embodiments, a stable midostaurin topical pharmaceutical composition contains about 10% by weight, about 5% by weight, about 4% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1.5% by weight, about 1% by weight, or about 0.5% by weight or less of total impurities or related substances. In other embodiments, a stable midostaurin topical pharmaceutical composition contains about 10% by weight or less of total impurities or related substances. In other embodiments, a stable midostaurin topical pharmaceutical composition contains about 5% by weight or less of total impurities or related substances. In yet other embodiments, a stable midostaurin topical pharmaceutical composition contains about 4% by weight or less of total impurities or related substances. In yet other embodiments, a stable midostaurin topical pharmaceutical composition contains about 3% by weight or less of total impurities or related substances. In yet another embodiment, the stable midostaurin topical pharmaceutical composition contains about 2% or less by weight of total impurities or related substances. In yet another embodiment, the stable midostaurin topical pharmaceutical composition contains about 1% or less by weight of total impurities or related substances.

[0094] The percentage of midostaurin retained in a composition can be calculated from the amount of midostaurin in the composition at a particular time point relative to the initial amount of midostaurin. Assay or midostaurin content can be assessed by HPLC, for example, using the method described in Table A-1, or any other known testing method. In some embodiments, a stable midostaurin topical pharmaceutical composition retains at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% by weight of the initial midostaurin amount. In yet other embodiments, a stable midostaurin topical pharmaceutical composition retains at least about 90% by weight of the initial midostaurin amount. In yet other embodiments, a stable midostaurin topical pharmaceutical composition retains at least about 91% by weight of the initial midostaurin amount. In yet another embodiment, a stable midostaurin topical pharmaceutical composition retains at least about 92% by weight of the initial midostaurin amount. In yet another embodiment, a stable midostaurin topical pharmaceutical composition retains at least about 93% by weight of the initial midostaurin amount. In yet another embodiment, a stable midostaurin topical pharmaceutical composition retains at least about 94% by weight of the initial midostaurin amount. In yet another embodiment, a stable midostaurin topical pharmaceutical composition retains at least about 95% by weight of the initial midostaurin amount. In yet another embodiment, a stable midostaurin topical pharmaceutical composition retains at least about 96% by weight of the initial midostaurin amount. In yet another embodiment, a stable midostaurin topical pharmaceutical composition retains at least about 97% by weight of the initial midostaurin amount. In yet another embodiment, a stable midostaurin topical pharmaceutical composition retains at least about 98% by weight of the initial midostaurin amount. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 99% by weight of the initial midostaurin amount, hi yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 99.5% by weight of the initial midostaurin amount.In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 99.8% by weight of the initial amount of midostaurin.

[0095] In some embodiments, the midostaurin topical pharmaceutical compositions described herein are stable for at least 1 day, 3 days, 7 days, 14 days, 21 days, or 30 days under light exposure at 4500 lux (lx). In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 1 day under light exposure at 4500 lux (lx). In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 3 days under light exposure at 4500 lux (lx). In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 7 days under light exposure at 4500 lux (lx). In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 21 days under light exposure at 4500 lux (lx). In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 30 days under light exposure at 4500 lux (lx).

[0096] In some embodiments, the midostaurin topical pharmaceutical compositions described herein are stable for at least 1 day, 3 days, 7 days, 14 days, 21 days, or 30 days under light exposure conditions of 4500 lux (lx) and a temperature of about 15°C to about 25°C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 1 day under light exposure conditions of 4500 lux (lx) and a temperature of about 15°C to about 25°C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 3 days under light exposure conditions of 4500 lux (lx) and a temperature of about 15°C to about 25°C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 7 days under light exposure conditions of 4500 lux (lx) and a temperature of about 15°C to about 25°C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 21 days under conditions of 4500 lux (lx) light exposure and a temperature of about 15° C. to about 25° C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 30 days under conditions of 4500 lux (lx) light exposure and a temperature of about 15° C. to about 25° C.

[0097] In some embodiments, the midostaurin topical pharmaceutical compositions described herein are stable for at least 1 day, 3 days, 7 days, 14 days, or 21 days when stored at about 60° C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 1 day when stored at about 60° C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 3 days when stored at about 60° C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 7 days when stored at about 60° C. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 21 days when stored at about 60° C.

[0098] In some embodiments, the midostaurin topical pharmaceutical compositions described herein are stable for at least 1 day, 3 days, 7 days, 14 days, 21 days, or 30 days after at least one freeze-thaw cycle. In some embodiments, a stable topical pharmaceutical composition is chemically and physically stable. In some embodiments, the midostaurin topical pharmaceutical compositions described herein are physically stable after one or more freeze-thaw cycles. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 1 day after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 3 days after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 7 days after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 21 days after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical composition is stable for at least 30 days after at least one freeze-thaw cycle.

[0099] In some embodiments, the midostaurin topical formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 1 month when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 3 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 6 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 9 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 12 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 15 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 18 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 24 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 30 months when stored under refrigerated conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 36 months when stored under refrigerated conditions.

[0100] In some embodiments, the midostaurin topical formulations described herein retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the midostaurin topical formulations retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 1 month. In some embodiments, the midostaurin topical formulations retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 3 months. In some embodiments, the midostaurin topical formulations retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 24 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 30 months.In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 36 months.

[0101] In some embodiments, the midostaurin topical formulations described herein contain 5% or less by weight of total impurities after storage under refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage under refrigerated conditions for at least 1 month. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage under refrigerated conditions for at least 3 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage under refrigerated conditions for at least 6 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage under refrigerated conditions for at least 9 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored under refrigerated conditions for at least 12 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored under refrigerated conditions for at least 15 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored under refrigerated conditions for at least 18 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored under refrigerated conditions for at least 24 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored under refrigerated conditions for at least 30 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored under refrigerated conditions for at least 36 months.

[0102] In some embodiments, the midostaurin topical formulations described herein retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 1 month. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 3 months. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 24 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 30 months.In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored under refrigerated conditions for at least 36 months.

[0103] In some embodiments, the midostaurin topical formulations described herein contain 2% or less by weight of total impurities after storage under refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage under refrigerated conditions for at least 1 month. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage under refrigerated conditions for at least 3 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage under refrigerated conditions for at least 6 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage under refrigerated conditions for at least 9 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored under refrigerated conditions for at least 12 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored under refrigerated conditions for at least 15 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored under refrigerated conditions for at least 18 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored under refrigerated conditions for at least 24 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored under refrigerated conditions for at least 30 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored under refrigerated conditions for at least 36 months.

[0104] In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at ambient conditions for at least 24 months.

[0105] In some embodiments, the midostaurin topical formulations described herein retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the midostaurin topical formulations retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulations retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulations retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 24 months.

[0106] In some embodiments, the midostaurin topical formulations described herein contain 5% or less by weight of total impurities after storage at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation contains 5% or less by weight of total impurities after being stored at ambient conditions for at least 24 months.

[0107] In some embodiments, the midostaurin topical formulations described herein retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at ambient conditions for at least 24 months.

[0108] In some embodiments, the midostaurin topical formulations described herein contain 2% or less by weight of total impurities after storage at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation contains 2% or less by weight of total impurities after being stored at ambient conditions for at least 24 months.

[0109] In some embodiments, the midostaurin topical formulations described herein are stable when stored at about 40° C. for at least 1 month, at least 2 months, at least 3 months, or at least 6 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulations described herein are stable when stored at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulations described herein are stable when stored at about 40° C. for at least 6 months.

[0110] In some embodiments, the midostaurin topical formulations described herein retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 1 month, at least 2 months, at least 3 months, or at least 6 months. In some embodiments, the midostaurin topical formulations described herein retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulations described herein retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulations described herein retain at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulations described herein retain at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 6 months.

[0111] In some embodiments, the midostaurin topical formulations described herein contain 5% or less by weight of total impurities after storage at about 40° C. for at least 1 month, at least 2 months, at least 3 months, or at least 6 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulations contain 5% or less by weight of total impurities after storage at about 40° C. for at least 6 months.

[0112] In some embodiments, the midostaurin topical formulations described herein retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 1 month, at least 2 months, at least 3 months, or at least 6 months. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulations retain at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after being stored at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of the midostaurin or pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 6 months.

[0113] In some embodiments, the midostaurin topical formulations described herein contain 2% or less by weight of total impurities after storage at about 40° C. for at least 1 month, at least 2 months, at least 3 months, or at least 6 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulations contain 2% or less by weight of total impurities after storage at about 40° C. for at least 6 months.

[0114] The refrigeration temperature, also specified by the USP, is between 2 and 8 degrees Celsius, and is sometimes designated by a nominal value of 5 degrees Celsius. In some embodiments, the refrigeration temperature may be specified as 5±3°C. Refrigeration conditions include the temperature and / or relative humidity (RH) in a typical refrigeration unit (e.g., 5±3°C). In some examples, the refrigeration conditions are about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, or about 8°C. In some instances, the refrigeration conditions are about 2°C to about 8°C.

[0115] As used herein, the terms "room temperature," "ambient conditions," or "ambient temperature" refer to room temperature or "controlled room temperature." In some embodiments, room temperature is about 15°C to about 25°C. In some embodiments, ambient conditions include temperatures of about 15°C to about 25°C. In some embodiments, room temperature is 25±5°C. In some embodiments, controlled room temperature is about 20°C to about 25°C. In some embodiments, ambient conditions are about 25±5°C and 60±5% RH. In some embodiments, ambient conditions are about 25±2°C and 60±5% RH. In some embodiments, room temperature is about 25°C and about 60% RH. In some examples, room temperature or ambient temperature is about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, and about 30°C. In other examples, the ambient conditions are about 55% RH, about 60% RH, or about 65% RH.

[0116] The accelerated conditions for the midostaurin topical pharmaceutical formulations described herein include temperatures and / or relative humidity (RH) at or above ambient or room temperature (e.g., 25±5°C, 55±10% RH). In some examples, the accelerated conditions are about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C. In other examples, the accelerated conditions are greater than 55% RH, about 65% RH, about 70% RH, about 75% RH, or about 80% RH. In a further example, the accelerated conditions are about 40°C±2°C or 60°C with ambient humidity. In yet a further example, the accelerated conditions are about 40°C±2°C with humidity of 75±5% RH.

[0117] Freeze-thaw testing can involve subjecting a pharmaceutical composition to a series of extreme temperature changes, called freeze-thaw cycles or freeze-thaw cycles. One example of a freeze-thaw cycle is exposing a pharmaceutical composition to freezing temperatures (e.g., about -15°C to about -25°C) for 24 hours, and then storing it at a higher temperature (e.g., about 25°C) for 24 hours. In some embodiments, a freeze-thaw cycle refers to placing a pharmaceutical composition at about 60°C for about 6 hours, followed by placing the same pharmaceutical composition at about -20°C for about 24 hours.

[0118] dosage The pharmaceutical compositions described herein are administered for the treatment or prevention of diseases. When used to treat or prevent diseases or disorders, the pharmaceutical compositions are administered or applied alone or in combination with other agents. The pharmaceutical compositions may also be administered or applied alone or in combination with other pharmaceutically active agents. Provided herein are methods of treatment and prevention by administering a therapeutically effective amount of the topical pharmaceutical compositions of the present disclosure to a subject in need of such treatment. In some embodiments, the subject is an animal, e.g., a mammal such as a human.

[0119] In some embodiments, the pharmaceutical composition is administered topically. In some embodiments, the pharmaceutical composition is administered in a topical dosage form. In some embodiments, the pharmaceutical composition is administered as an ointment, gel, cream, lotion, solution, emulsion, paste, patch, wipe, swab, pad, or any suitable form. In some embodiments, the pharmaceutical composition is administered as a gel. In some embodiments, the pharmaceutical composition is administered as a cream. In some embodiments, the pharmaceutical composition is administered as an ointment.

[0120] In some embodiments, the pharmaceutical composition is formulated for topical administration. In some embodiments, the pharmaceutical composition is formulated for once-daily administration. In some embodiments, the pharmaceutical composition is formulated for twice-daily administration. In some embodiments, the pharmaceutical composition is formulated for administration three or more times daily.

[0121] The dosage of the midostaurin topical pharmaceutical composition described can be determined by any suitable method. The maximum tolerated dose (MTD) and maximum response dose (MRD) of midostaurin can be determined through established animal and human experimental protocols and in the examples described herein. For example, the toxicity and therapeutic efficacy of midostaurin can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, but not limited to, LD 50 (lethal dose for 50% of the population) and ED 50 The LD can be determined by determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The therapeutic index of midostaurin can be expressed as a ratio between 0.01 and 0.02. Dosages of midostaurin that exhibit a high therapeutic index are of interest. Data obtained from cell culture assays and animal studies can be used to develop a range of dosages for use in humans. The dosage of such compounds is preferably at an ED that results in minimal toxicity. 50 The blood concentration range includes: 0.01 to 0.01; 0.01 to 0.01; and 0.01 to 0.01. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. Additional relative dosages, expressed as a percentage of maximum response or maximum tolerated dose, are readily obtained via protocol.

[0122] In some embodiments, the amount of a given midostaurin topical pharmaceutical composition corresponding to such an amount will vary depending on factors such as the particular midostaurin salt or form, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, and the like, but may nevertheless be determined by the particular circumstances surrounding the case (including, for example, the particular agent being administered, the type of liquid composition, the condition being treated, and the subject or host being treated). In some instances, if a lack of satisfactory response is observed, the midostaurin topical pharmaceutical composition can be discontinued.

[0123] In some embodiments, the midostaurin topical pharmaceutical compositions described herein are provided in a daily dose of midostaurin of about 0.001 mg to about 300 mg, about 0.01 mg to about 200 mg, about 0.1 mg to about 20 mg, or about 0.2 mg to about 10 mg. In certain embodiments, the midostaurin topical pharmaceutical compositions described herein contain from about 0.001 mg to about 0.005 mg, from about 0.005 mg to about 0.05 mg, from about 0.05 mg to about 0.1 mg, from about 0.1 mg to about 0.15 mg, from about 0.15 mg to about 0.2 mg, from about 0.2 mg to about 0.25 mg, from about 0.25 mg to about 0.3 mg, from about 0.3 mg to about 0.35 mg, from about 0.35 mg to about 0.4 mg, from about 0.4 mg to about 0.45 mg, from about 0.45 mg to about 0.5 mg, from about 0.5 mg to about 0.6 mg, from about 0.6 mg to about 0.7 mg, from about 0.7 mg to about 0.8 mg, or from about 0.8 mg to about 0.8 mg. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided in a daily dose of about 0.1 mg to about 0.9 mg, about 0.9 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, about 9 mg to about 10 mg, about 10 mg to about 11 mg, about 11 mg to about 12 mg, about 12 mg to about 15 mg, about 15 mg to about 30 mg, about 30 mg to about 60 mg, about 60 mg to about 90 mg, about 90 mg to about 120 mg, about 120 mg to about 150 mg, about 150 mg to about 200 mg, or about 200 mg to about 300 mg. In certain examples, the midostaurin topical pharmaceutical composition described herein is provided at a dose of about 0.15 mg / day. In certain examples, the midostaurin topical pharmaceutical composition described herein is provided at a dose of about 0.2 mg / day. In certain examples, the midostaurin topical pharmaceutical composition described herein is provided at a dose of about 0.25 mg / day. In certain examples, the midostaurin topical pharmaceutical composition described herein is provided at a dose of about 0.3 mg / day. In certain examples, the midostaurin topical pharmaceutical composition described herein is provided at a dose of about 0.35 mg / day. In certain examples, the midostaurin topical pharmaceutical composition described herein is provided at a dose of about 0.4 mg / day.In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 0.5 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 0.6 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 0.7 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 0.8 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 0.9 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 1 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 2 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 3 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 4 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 5 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 6 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 7 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 8 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 9 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 10 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 11 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 12 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided in a dose of about 13 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided in a dose of about 14 mg / day.In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 15 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 16 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 17 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 18 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 19 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 20 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 25 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 30 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 60 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 90 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 120 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 200 mg / day. In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 300 mg / day. The daily doses described herein can be administered in the form of partial doses administered once a day or multiple times a day, such as bid, tid, qid, etc., where the number of partial doses is equal to the daily dose.

[0124] In other embodiments, the midostaurin topical pharmaceutical composition is provided at the maximum tolerated dose (MTD) of midostaurin or a pharmaceutically acceptable salt thereof. In other embodiments, the amount of the midostaurin topical pharmaceutical composition administered is about 10% to about 90% of the maximum tolerated dose (MTD), about 25% to about 75% of the MTD, or about 50% of the MTD. In certain embodiments, the amount of the midostaurin topical pharmaceutical composition administered is about 5% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 99% or more of the MTD of midostaurin or a pharmaceutically acceptable salt thereof.

[0125] The topical pharmaceutical compositions described herein can be administered at lower doses than commercially available topical pharmaceutical compositions (e.g., 2% hydroquinone cream) for treating the same indication to achieve the same therapeutic effect. In some embodiments, the therapeutically effective amount of a multi-targeted protein kinase inhibitor or a salt thereof (e.g., midostaurin) is 80% less than the therapeutically effective amount of hydroquinone. In some embodiments, the therapeutically effective amount of a topical pharmaceutical composition comprising a multi-targeted protein kinase inhibitor or a salt thereof (e.g., midostaurin) is 80% less than the therapeutically effective amount of 2% hydroquinone cream. In some embodiments, the therapeutically effective amount of a topical pharmaceutical composition comprising a multi-targeted protein kinase inhibitor or a salt thereof (e.g., midostaurin) is 70% less than the therapeutically effective amount of 2% hydroquinone cream. In some embodiments, the therapeutically effective amount of a topical pharmaceutical composition comprising a multi-targeted protein kinase inhibitor or a salt thereof (e.g., midostaurin) is 50% less than the therapeutically effective amount of 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition containing midostaurin is administered at a dose 80% less than that of a 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition containing midostaurin is administered at a dose 60% less than that of a 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition containing midostaurin is administered at a dose 50% less than that of a 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition containing midostaurin is administered at a dose 30% less than that of a 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition contains up to 1.0% by weight of midostaurin and is administered at a dose up to 80% of that of a 2% hydroquinone cream to achieve the same therapeutic effect. In some embodiments, the topical pharmaceutical composition contains 0.5% by weight of midostaurin and is administered at a dose up to 50% of that of a 2% hydroquinone cream to achieve the same therapeutic effect.In some embodiments, the topical pharmaceutical composition contains 0.5% by weight midostaurin and is administered at a dose up to 30% of the dose of a 2% hydroquinone cream to achieve the same therapeutic effect.

[0126] Treatment method In one aspect, disclosed herein is a method of treating a skin-related disease or disorder, comprising topically applying midostaurin or a salt thereof to the skin of a subject, wherein the skin is associated with the skin-related disease or disorder. In one aspect, described herein is a method of treating a disease or condition by topically administering to a subject in need of treatment a composition (e.g., a cosmetic or pharmaceutical composition) comprising midostaurin or a salt thereof. In one aspect, described herein is a method of treating a disease or condition by topically administering to a subject in need of treatment a pharmaceutical composition comprising midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the skin-related disease or disorder is a skin pigmentation disorder. In some embodiments, the subject has a skin hyperpigmentation condition. In one aspect, a midostaurin topical pharmaceutical composition described herein is used to treat a skin-related disease or disorder. In some embodiments, the method comprises topically applying a pharmaceutical composition described herein to the skin of a subject in need thereof. In some embodiments, the pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the skin-related disease or disorder comprises skin hyperpigmentation. In some embodiments, skin hyperpigmentation is characterized by a generalized darkening of an individual's normal skin color. In some embodiments, skin hyperpigmentation is characterized by a localized darkening of an individual's normal skin color. Skin hyperpigmentation conditions can include, for example, melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, maculopigmented skin rash of pregnancy, nevus of Ota, age-related hyperpigmentation, and the like. In some embodiments, skin hyperpigmentation conditions include solar lentigines or age spots. Skin hyperpigmentation can appear on any or all parts of the body. In one aspect, disclosed herein is a method of treating melasma, comprising topically applying midostaurin or a salt thereof to the skin of a subject in need thereof. In some embodiments, the melasma is a brown spot. In some embodiments, treating includes reducing the size of the abnormal skin pigmentation, reducing the intensity of the abnormal skin pigmentation, and / or removing the abnormal skin pigmentation associated with melasma.In some embodiments, the method comprises topically applying a pharmaceutical composition, wherein the pharmaceutical composition comprises midostaurin or a salt thereof. In some embodiments, the salt of midostaurin is a pharmaceutically acceptable salt of midostaurin. In some embodiments, the midostaurin or salt thereof is administered in a therapeutically effective amount.

[0127] In some embodiments, the methods described herein include applying midostaurin or a salt thereof, or a pharmaceutical or cosmetic composition comprising midostaurin or a salt thereof, to the skin of a subject. In some embodiments, the skin is the skin of the subject's face, cheeks, the bridge of the subject's nose, the forehead, the chin, or the subject's upper lip. In some embodiments, the skin is the skin of the subject's face. In some embodiments, the midostaurin or a salt thereof is administered in a composition, such as an ointment, gel, cream, lotion, solution, emulsion, paste, patch, wipe, swab, pad, or any other form suitable for topical delivery. In some embodiments, the midostaurin or a salt thereof is administered in a transdermal composition. In some embodiments, the midostaurin or a salt thereof is administered in a pharmaceutical composition. In some embodiments, the midostaurin or a salt thereof is administered in a cosmetic composition.

[0128] In one aspect, disclosed herein is a method for reducing skin pigmentation, comprising topically applying midostaurin or a salt thereof to the pigmented skin of a subject. In one aspect, a midostaurin topical pharmaceutical composition described herein is used to reduce skin pigmentation. In some embodiments, the method comprises topically applying a pharmaceutical composition described herein to the skin of a subject in need thereof. In some embodiments, the pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a skin-related disorder or condition. In some embodiments, the skin-related disorder or condition comprises a skin pigmentation disorder. In some embodiments, the skin pigmentation disorder comprises a skin hyperpigmentation condition. In some embodiments, the skin hyperpigmentation condition comprises melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, maculopigmented rash of pregnancy, nevus of Ota, age-related hyperpigmentation, etc. In some embodiments, midostaurin or a salt thereof, or a pharmaceutical composition comprising midostaurin or a salt thereof, is applied to pigmented skin. The pigmented skin may be a pigmented nevus, a macular stain, an hemangioma, or a port wine stain. The pigmented skin may be a solar lentigo. The pigmented skin may be a dark spot. The pigmented skin may be a senile lentigo. The pigmented skin may be associated with a skin-related disease or disorder. In some embodiments, the skin-related disease or disorder is melasma or post-inflammatory hyperpigmentation.

[0129] In one aspect, disclosed herein is a method for reducing tyrosinase activity, comprising topically applying midostaurin or a pharmaceutically acceptable salt thereof to the skin of a subject in need thereof. In another aspect, a midostaurin topical pharmaceutical composition described herein is used to reduce tyrosinase activity. In some embodiments, the method comprises topically applying a pharmaceutical composition described herein to the skin of a subject in need thereof. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a skin-related disorder or condition. In some embodiments, the skin-related disorder or condition comprises a skin pigmentation disorder. In some embodiments, the skin pigmentation disorder comprises a skin hyperpigmentation condition. In some embodiments, the skin hyperpigmentation condition comprises melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, maculopigmentosa of pregnancy, nevus of Ota, age-related hyperpigmentation, etc.

[0130] Melasma is a common skin problem that leads to skin pigmentation problems, such as brown to gray-brown patches, usually on the face, cheeks, nose bridge, forehead, chin, and above the upper lip. Melasma is thought to be caused or exacerbated by oral contraceptives, pregnancy, and hormone therapy, stress, thyroid disease, sun exposure, inflammation, familial predisposition, or free radicals. In some embodiments, melasma is caused or exacerbated by one or more of oral contraceptives, hormone therapy, sun exposure, or familial predisposition. Sun exposure is thought to cause melasma because ultraviolet light affects cells that control pigment (melanocytes). UV radiation can cause lipid peroxidation in cell membranes, resulting in free radicals that can stimulate melanocytes to produce excess melanin.

[0131] In one aspect, disclosed herein is a method for reducing skin melanin content in the skin of a subject desiring a lighter skin tone, the method comprising topically applying midostaurin or a salt thereof to the subject's pigmented skin. In one aspect, disclosed herein is a method for reducing skin pigmentation in a subject desiring a lighter skin tone, the method comprising topically applying midostaurin or a salt thereof to the subject's pigmented skin. In some embodiments, the midostaurin or a salt thereof is formulated in a cosmetic composition.

[0132] In some embodiments, the subject is an adult. In some embodiments, the subject is a female. In some embodiments, the subject is a male. In some embodiments, the subject is a child. In some embodiments, the subject is at least 1 year old. In some embodiments, the subject is less than 1 year old. In some embodiments, the subject is 1-12 years old. In some embodiments, the subject is 1-18 years old. In some embodiments, the subject is 12-18 years old. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is at least 24 years old. In some embodiments, the subject is 1-90 years old. In some embodiments, the subject has undergone or is undergoing hormone therapy. In some embodiments, the subject has undergone or is undergoing oral contraceptives. In some embodiments, the subject has a familial predisposition to having hyperpigmentation or melasma.

[0133] In some embodiments, the pharmaceutical compositions described herein can be used in combination therapy with at least one other therapeutic agent. The pharmaceutical composition and the therapeutic agent can act additively, or more preferably, synergistically. In some embodiments, the pharmaceutical composition is administered simultaneously with the administration of another therapeutic agent. In some embodiments, the pharmaceutical composition is administered before or after the administration of another therapeutic agent.

[0134] In one aspect, midostaurin or a salt thereof reduces the amount of melanin in a skin area. In some embodiments, midostaurin or a salt thereof is formulated as a topical pharmaceutical composition described herein. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 25% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 50% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 75% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 10% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 15% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in an area of ​​skin by at least 20% compared to a similar area of ​​skin in the same subject not receiving any treatment.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 25% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 30% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 35% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 40% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 45% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 50% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 60% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 70% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 80% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 90% compared to a similar skin area of ​​the same subject not receiving any treatment.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in an area of ​​skin by at least 95% compared to a similar skin area in the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in an area of ​​skin by at least 99% compared to a similar skin area in the same subject not receiving any treatment. In some embodiments, the amount of melanin is measured by a melanin distribution score, such as the method described in Example G. In some embodiments, the amount of melanin is measured by a melanin distribution score using a guinea pig as a model.

[0135] In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 25% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 50% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 75% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 10% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 20% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 30% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 40% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 50% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 60% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 70% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 80% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 90% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 95% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a skin area by at least 99% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the amount of melanin is measured by a melanin distribution score, such as the method described in Example G. In some embodiments, the amount of melanin is measured by a melanin distribution score using a guinea pig as a model.

[0136] In some embodiments, a topical pharmaceutical composition comprising midostaurin or a salt thereof reduces the amount of melanin in a skin area. In some embodiments, the reduction in the amount of melanin in a skin area treated with the topical pharmaceutical composition is at least 100%, 110%, 120%, 130%, or 150% relative to the amount of melanin in a similar skin area of ​​the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, and the topical pharmaceutical composition is administered at a dose lower than that of the reference topical pharmaceutical composition. In some cases, the reference topical pharmaceutical composition comprising hydroquinone is a commercially available 2% hydroquinone cream. In some cases, the topical pharmaceutical composition comprises up to 1.5% by weight of midostaurin. In some cases, the reduction in the amount of melanin in a skin area treated with the topical pharmaceutical composition is at least 130% relative to the amount of melanin in a similar skin area of ​​the same subject treated with a 2% hydroquinone cream, and the topical pharmaceutical composition comprises 1.5% by weight of midostaurin. In some cases, the reduction in the amount of melanin in a skin area treated with the topical pharmaceutical composition is at least 90% relative to the amount of melanin in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 0.25% by weight of midostaurin. In some cases, the reduction in the amount of melanin in a skin area treated with the topical pharmaceutical composition is at least 50% relative to the amount of melanin in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 0.05% by weight of midostaurin. In some cases, the reduction in the amount of melanin in a skin area treated with the topical pharmaceutical composition is at least 50% relative to the amount of melanin in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 0.01% by weight of midostaurin. In some embodiments, the amount of melanin is measured by a melanin distribution score, such as the method described in Example G. In some embodiments, the amount of melanin is measured by a melanin distribution score using a guinea pig as a model.

[0137] In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 according to the melanin distribution score, compared to a similar skin area of ​​the same subject not receiving treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 1.0 according to the melanin distribution score, compared to a similar skin area of ​​the same subject not receiving treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 2.0 according to the melanin distribution score, compared to a similar skin area of ​​the same subject not receiving treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 1, 2, 3, or 4 according to the Fontana-Masson staining scoring scale, compared to a similar skin area of ​​the same subject not receiving treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a skin area by at least 1 according to the Fontana-Masson staining scoring scale, compared to a similar skin area of ​​the same subject not receiving treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in an area of ​​skin by at least 2, according to the Fontana-Masson staining scoring scale, compared to a similar area of ​​skin in the same subject not receiving treatment. In some embodiments, midostaurin or a salt thereof is formulated as a topical pharmaceutical composition as described herein. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof.

[0138] In one aspect, midostaurin or a salt thereof reduces tyrosinase activity in a skin area. In some embodiments, midostaurin or a salt thereof is formulated as a topical pharmaceutical composition described herein. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a similar skin area in the same subject not receiving any treatment. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 25% compared to a similar skin area in the same subject not receiving any treatment. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 50% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 75% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 10% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in an area of ​​skin by at least 15% compared to a similar skin area in the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in an area of ​​skin by at least 20% compared to a similar skin area in the same subject not receiving any treatment.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 25% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 30% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 35% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 40% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 45% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 50% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 60% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 70% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 80% compared to a similar skin area of ​​the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 90% compared to a similar skin area of ​​the same subject not receiving any treatment.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in an area of ​​skin by at least 95% compared to a similar area of ​​skin in the same subject not receiving any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in an area of ​​skin by at least 99% compared to a similar area of ​​skin in the same subject not receiving any treatment. In some embodiments, tyrosinase activity is measured per gram of tissue, for example, using the method described in Example G. In some embodiments, tyrosinase activity is measured per gram of tissue using a guinea pig as a model.

[0139] In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, midostaurin or a salt thereof is formulated as a topical pharmaceutical composition described herein. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 25% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 55% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a skin area by at least 75% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 10% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 20% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 30% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 40% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 50% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 60% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 70% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 80% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 90% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 95% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a skin area by at least 99% compared to a similar skin area of ​​the same subject treated with a corresponding composition containing hydroquinone. In some embodiments, tyrosinase activity is measured per gram of tissue, for example, using the method described in Example G. In some embodiments, tyrosinase activity is measured per gram of tissue using a guinea pig as a model.

[0140] In some embodiments, midostaurin or a topical pharmaceutical composition comprising midostaurin or a salt thereof reduces tyrosinase activity in a skin area. In some embodiments, the reduction in tyrosinase activity in a skin area treated with the topical pharmaceutical composition is at least 100%, 110%, 120%, 130%, or 150% relative to the tyrosinase activity in a similar skin area of ​​the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, and the topical pharmaceutical composition is administered at a dose lower than that of the reference topical pharmaceutical composition. In some cases, the reference topical pharmaceutical composition comprising hydroquinone is a commercially available 2% hydroquinone cream. In some cases, the topical pharmaceutical composition comprises up to 1.5% by weight of midostaurin. In some cases, the reduction in tyrosinase activity in a skin area treated with the topical pharmaceutical composition is at least 120% relative to the tyrosinase activity in a similar skin area of ​​the same subject treated with a 2% hydroquinone cream, and the topical pharmaceutical composition comprises 1.5% by weight of midostaurin. In some cases, the reduction in tyrosinase activity in a skin area treated with the topical pharmaceutical composition is at least 90% relative to the tyrosinase activity in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 0.25% by weight of midostaurin. In some cases, the reduction in tyrosinase activity in a skin area treated with the topical pharmaceutical composition is at least 50% relative to the tyrosinase activity in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 0.05% by weight of midostaurin. In some cases, the reduction in tyrosinase activity in a skin area treated with the topical pharmaceutical composition is at least 50% relative to the tyrosinase activity in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 0.01% by weight of midostaurin. In some embodiments, tyrosinase activity is measured per gram of tissue, for example, using the method described in Example G. In some embodiments, tyrosinase activity is measured per gram of tissue using guinea pigs as a model.

[0141] In some embodiments, midostaurin or a topical pharmaceutical composition comprising midostaurin or a salt thereof causes low skin irritation. In some embodiments, the level of skin irritation in the skin area treated with the topical pharmaceutical composition is minimal, and the topical pharmaceutical composition comprises up to 1.0% by weight of midostaurin. In some embodiments, the level of skin irritation in the skin area treated with the topical pharmaceutical composition is mild, and the topical pharmaceutical composition comprises 1.0% by weight of midostaurin. In some embodiments, the level of skin irritation in the skin area treated with the topical pharmaceutical composition is mild, and the topical pharmaceutical composition comprises 0.5% by weight of midostaurin. In some embodiments, the level of skin irritation in the skin area treated with the topical pharmaceutical composition is non-irritating, and the topical pharmaceutical composition comprises up to 0.5% by weight of midostaurin. In some embodiments, the skin irritation score in the skin area treated with the topical pharmaceutical composition is up to 2.0, and the topical pharmaceutical composition comprises 1.0% by weight of midostaurin. In some embodiments, the skin irritation score in the skin area treated with the topical pharmaceutical composition is a maximum of 1.5, and the topical pharmaceutical composition comprises 1.0% by weight of midostaurin. In some embodiments, the skin irritation score in the skin area treated with the topical pharmaceutical composition is a maximum of 1.2, and the topical pharmaceutical composition comprises 1.0% by weight of midostaurin. In some embodiments, the skin irritation score in the skin area treated with the topical pharmaceutical composition is a maximum of 1.0, and the topical pharmaceutical composition comprises 0.5% by weight of midostaurin. In some embodiments, the skin irritation score is assessed by suitable standards set forth by regulatory authorities, such as the method described in Example H. In some embodiments, the skin irritation score and irritation level are measured using rabbits as a model.

[0142] In some embodiments, a topical pharmaceutical composition comprising midostaurin or a salt thereof causes less skin irritation than a commercially available reference topical pharmaceutical composition comprising an active ingredient other than midostaurin (e.g., a 2% hydroquinone cream). In some embodiments, the methods described herein do not cause any skin irritation. In some embodiments, the methods described herein do not cause any mild skin irritation. In some embodiments, the methods described herein do not cause any moderate skin irritation. In some embodiments, the methods described herein do not cause any moderate or severe skin irritation. In some cases, the skin irritation score in a skin area treated with the topical pharmaceutical composition is at most about 20%, 30%, 40%, 50%, 60%, or 70% of the skin irritation score in a similar skin area of ​​the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, and the topical pharmaceutical composition is administered at a dose lower than that of the reference topical pharmaceutical composition. In some cases, the reference topical pharmaceutical composition comprising hydroquinone is a commercially available 2% hydroquinone cream. In some cases, the skin irritation score in a skin area treated with the topical pharmaceutical composition is at most about 30% of the skin irritation score in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 1.0% by weight midostaurin. In some cases, the skin irritation score in a skin area treated with the topical pharmaceutical composition is at most about 30% of the skin irritation score in a similar skin area of ​​the same subject treated with 2% hydroquinone cream, and the topical pharmaceutical composition comprises 0.5% by weight midostaurin. In some embodiments, the skin irritation score is evaluated by a suitable standard set forth by a regulatory agency, such as the method described in Example H. In some embodiments, the skin irritation score and irritation level are measured using a rabbit as a model. In some embodiments, midostaurin or a topical pharmaceutical composition comprising midostaurin or a salt thereof does not cause phototoxicity. In some embodiments, the methods described herein do not cause phototoxicity in a subject.In some embodiments, midostaurin or a topical pharmaceutical composition comprising midostaurin or a salt thereof does not result in systemic exposure. In some embodiments, the methods described herein do not result in systemic exposure of the multi-targeted protein kinase inhibitor (such as midostaurin).

[0143] kit Kits for the midostaurin topical pharmaceutical compositions described herein are also described. Such kits may include a carrier, package, or container that is compartmentalized to receive one or more containers, such as bottles, vials, or tubes, each containing one of the separate components used in the methods described herein, including the midostaurin topical pharmaceutical composition, such as an ointment, cream, or gel. Suitable containers include, for example, bottles, tubes, vials, and test tubes. The containers can be formed from a variety of materials, such as glass or plastic. The containers can further include a light protection mechanism. The containers can have different sizes, such as about 12 ounces, about 10 ounces, about 8 ounces, about 4 ounces, about 3 ounces, about 2 ounces, or about 1 ounce. The containers can have a seal, such as an induction seal. In some embodiments, the kit includes a package enclosing the midostaurin topical pharmaceutical composition described herein. In some embodiments, the package is a tube.

[0144] The kit may include one or more additional containers, each containing one or more of various materials (e.g., devices) desirable from a commercial and user perspective for the midostaurin topical pharmaceutical composition described herein. Non-limiting examples of such materials include, but are not limited to, carriers, packages, containers, vials and / or tubes, labels listing the contents and / or instructions for use, and package inserts with instructions for use related to the midostaurin topical pharmaceutical composition. A set of instructions may also be included. In some embodiments, the kit includes instructions for use of the topical pharmaceutical composition described herein.

[0145] A label may be on or associated with a container, such as a tube. A label may be on a container when letters, numbers, or other special characters forming the label are attached, molded, or etched into the container itself, or it may be associated with a container when present in a receptacle or carrier that also holds the container, for example, as a package insert. A label can be used to indicate that the contents are to be used for a particular therapeutic application. A label can also indicate directions for using the contents, for example, in the methods described herein.

[0146] Manufacturing Method Preparation of the midostaurin topical pharmaceutical compositions described herein includes any known pharmaceutical method.

[0147] In one embodiment, the midostaurin topical pharmaceutical compositions described herein are prepared by mixing midostaurin or a pharmaceutically acceptable salt thereof with a carrier vehicle (e.g., purified water) and excipients (e.g., viscosity modifiers, pH stabilizers, surfactants, penetration enhancers, antioxidants, or any combination thereof), thereby forming a gel. In some embodiments, the midostaurin or a pharmaceutically acceptable salt thereof, the carrier vehicle, and the excipients can be combined in any order of addition.

[0148] In one embodiment, the midostaurin topical pharmaceutical compositions described herein are prepared by mixing midostaurin or a pharmaceutically acceptable salt thereof with a carrier vehicle and excipients (e.g., a surfactant, a penetration enhancer, an antioxidant, or any combination thereof), thereby forming an ointment. In some embodiments, the midostaurin or a pharmaceutically acceptable salt thereof, the carrier vehicle, and the excipients can be combined in any order of addition.

[0149] In one embodiment, the midostaurin topical pharmaceutical composition described herein is prepared by mixing midostaurin or a pharmaceutically acceptable salt thereof with a carrier vehicle and excipients (e.g., surfactants, penetration enhancers, humectants, viscosity modifiers, antioxidants, or any combination thereof), thereby forming a cream. In some embodiments, the midostaurin or a pharmaceutically acceptable salt thereof, carrier vehicle, and excipients can be combined in any order of addition. In some embodiments, the preparation includes preparing an oil phase and an aqueous phase. In some embodiments, the oil phase is prepared by mixing midostaurin or a pharmaceutically acceptable salt thereof with a carrier vehicle and excipients (e.g., surfactants, optionally penetration enhancers, optionally viscosity modifiers, optionally humectants) and heating to above 80°C. In some embodiments, the aqueous phase is prepared by weighing water and optionally an excipient (e.g., antioxidant) and heating to above 80°C. In some embodiments, the preparation involves gradually adding the oil phase to the water phase and stirring to form a cream.

[0150] definition Unless otherwise specified or clear from the context, as used herein, the term "about" in connection with a number or range of numbers is understood to mean the stated number and + / - 10% of that number, or 10% below the recited lower limit and 10% above the recited upper limit of the recited values ​​for a range.

[0151] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to a "surfactant" includes a reference to one or more specific surfactants, and reference to an "antioxidant" includes a reference to one or more such additives.

[0152] Use of the term "or" in the claims is used to mean "and / or," unless explicitly indicated to refer to alternatives only, or the present disclosure supports a definition that refers to alternatives only and "and / or," but the alternatives are mutually exclusive. The terms "comprise," "have," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs (such as "comprises," "comprising," "has," "having," "includes," and "including") is also open-ended. For example, any method that "comprises," "have," and "include" one or more steps is not limited to having only those one or more steps, but also encompasses other unlisted steps.

[0153] "Optional" or "optionally" means that the described structure, event, or circumstance may or may not occur, and the description may be meant to include instances where the event occurs and instances where it does not occur.

[0154] As used herein, the term "therapeutic agent" refers to an agent utilized to treat, combat, ameliorate, prevent, or improve an undesirable condition or disease in a patient. In some embodiments, a therapeutic agent, such as midostaurin, is directed to treating and / or ameliorating, reversing, or stabilizing the symptoms of adrenocortical insufficiency described herein.

[0155] The term "subject" as used herein refers to a mammal (e.g., a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig, or a non-human primate such as a monkey, chimpanzee, or baboon).

[0156] "Administration," when used in conjunction with a therapeutic means for administering a therapeutic agent systemically or locally directly into or onto a target tissue, or for administering a therapeutic agent to a patient, thereby positively impacts the targeted tissue. Thus, as used herein, the term "administration," when used in conjunction with a midostaurin formulation, can include, but is not limited to, providing a midostaurin formulation into or onto a target tissue, and providing a midostaurin formulation to a patient systemically, for example, by oral administration, whereby the therapeutic agent reaches the target tissue or cells. "Administration" of a formulation can be achieved by injection, topical administration, oral administration, alone or in combination with other known techniques, or by other methods.

[0157] In some embodiments, an error band is included. The term "total error band" is used herein to identify all causes, including sampling and sample preparation, calculated at a 95% confidence level. An example is a D50 100 μm with a total error band of + / - 5% for size. Other statistics may be used to describe particle size distribution. The most common calculations are standard deviation and variance. Standard Deviation (St Dev.). The standard deviation specification defines a diameter such that approximately 68.27% of the total population is within + / - 1 St Dev and 95.45% is within + / - 2 St Dev.

[0158] "Effective amount" and "sufficient amount" are used interchangeably and may refer to an amount of a substance that is sufficient to achieve an intended purpose or goal.

[0159] A "therapeutically effective amount," when used in connection with the pharmaceutical compositions described herein, is an amount of one or more pharmaceutically active agents sufficient to produce a therapeutic result in a subject in need thereof.

[0160] "Therapeutically equivalent" when used in connection with the pharmaceutical compositions described herein refers to the amount or quantity of a pharmaceutically acceptable salt or ester of a pharmaceutically active agent that is equivalent to a therapeutically effective amount of the free base or alcohol of the pharmaceutically active agent.

[0161] As used herein, the terms "treat," "treated," "treatment," or "treating" refer to therapeutic treatment, the purpose of which is to prevent or delay (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; lessening of the extent of the condition, disorder, or disease; stabilization (i.e., not worsening) of the condition, disorder, or disease state; delaying the onset or slowing the progression of the condition, disorder, or disease; amelioration of the condition, disorder, or disease state; reduction (partial or total) (whether detectable or undetectable), or improvement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. For example, as used herein, "treating" hyperpigmented skin includes reducing the size of abnormal skin pigmentation, reducing the intensity of abnormal skin pigmentation, removing abnormal skin pigmentation associated with melasma, and the like. [Example]

[0162] The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the disclosure, and it will be understood that by their exemplary nature, other procedures, methods, or techniques known to those skilled in the art may alternatively be used.

[0163] Example A. Solubility of midostaurin in different solvents and solubilizer / water systems. This example illustrates the process of selecting a suitable solvent for a topical formulation of midostaurin or a pharmaceutically acceptable salt thereof, according to some embodiments of the present disclosure.

[0164] Many different solvents were evaluated for their compatibility with midostaurin. The solubility measurement method involved adding excess amorphous midostaurin powder to the various solvents listed on the x-axis of Figure 1 and mixing at 600 rpm at 25°C for 24 to 72 hours to ensure equilibrium was achieved. Solubility was measured by HPLC. The HPLC method and parameters are provided in Table A-1.

[0165] [Table 1]

[0166] The results in Figure 1 show that in this study, amidostaurin showed low solubility (<10 mg / mL) in many hydrophilic solvents, such as ethanol and glycerol. Midostaurin has relatively high hydrophobicity, with a log P >5, suggesting that it may have higher solubility in lipid solvents. However, the results showed low solubility (<10 mg / mL) in most oils, such as soybean oil and corn oil. Midostaurin has good solubility (>50 mg / mL) in certain solubilizers, such as Tween 80 and Labrasol.

[0167] The solubility of midostaurin in systems combining water and solubilizers at specific ratios was also evaluated. The method involved adding excess amorphous midostaurin powder to various concentrations of solubilizer and water systems and mixing at 600 rpm at 25°C for 24 hours to ensure equilibrium was achieved. Solubility was measured by HPLC using the method provided in Table A-1. The solubilizers selected for this study included Transcutol, Labrasol, Tween 80, Cremphor EL, and Kolliphor HS15. Each solubilizer was mixed with water at 10%, 20%, and 30% v / v, respectively, to form systems in which the amorphous midostaurin powder was dissolved.

[0168] The results are summarized in Figure 2. Although Tween 80, Cremphor EL, and Kolliphor were able to significantly increase the solubility of midostaurin in water, all systems tested still exhibit low solubility (<10 mg / mL).

[0169] Example B. Excipient compatibility testing of midostaurin. This example illustrates the process of selecting suitable excipients for topical formulations of midostaurin or a pharmaceutically acceptable salt thereof, according to some embodiments of the present disclosure.

[0170] Midostaurin was mixed 1:200 (w / w) with a number of excipients used in topical formulations and stored at 60°C for 10 days before testing. Impurities in each API and excipient combination were determined by HPLC and the results are listed in Table B-1. The HPLC method and parameters are provided in Table B-2.

[0171] [Table 2]

[0172] [Table 3]

[0173] [Table 4]

[0174] The excipient compatibility results showed that midostaurin powder was very stable at 60°C for 10 days (assay content was 99.64%). However, when dissolved in a different excipient, the stability decreased, and the maximum impurity appeared at an RRT of 1.76. When an antioxidant (e.g., butylated hydroxyanisole) was added to a mixture of midostaurin and Peceol, little degradation was observed. One possibility is that midostaurin, when dissolved in oil, is more susceptible to generating oxidative impurities when exposed to high temperatures.

[0175] Example C. Skin deposition measurement method to evaluate the efficiency of various topical formulations of midostaurin to penetrate skin layers. This example describes steps to evaluate the extent to which midostaurin can penetrate the skin barrier when prepared in a particular topical formulation according to some embodiments of the present disclosure.

[0176] Melasma is clinically characterized by epidermal hyperpigmentation. Histopathological changes involve both the epidermis and dermis, as illustrated in Figure 3. Therefore, topically administered midostaurin should ideally penetrate deeper skin layers. However, the stratum corneum (SC), the outermost layer of the skin, can be a barrier to drug penetration. Skin penetration enhancers can be designed into topical formulations to help midostaurin penetrate the SC. Penetration efficiency can be evaluated using a skin deposition test.

[0177] Skin deposition or retention experiments were performed in vitro using a Franz diffusion cell as shown in Figure 4 and nude mouse skin. Skin from nude mice (approximately 6 weeks old) was carefully excised, washed, and placed on the diffusion cell with the stratum corneum facing the donor side. The tested formulation was typically added to the donor compartment and incubated with the skin at a constant temperature (32 ± 0.5°C) for a predetermined interval. At the end of the experiment, the skin was removed, washed, and the stratum corneum was removed using tape stripping. The midostaurin content in the stratum corneum and epidermis / dermis layers was determined by the HPLC method described in Table A-1.

[0178] A series of midostaurin solutions (0.1% and 1%) and hydroquinone solutions (1% and 2%) were prepared in a mixture of DMSO and propylene glycol (1:3, v / v). The deposition of midostaurin and hydroquinone in nude mouse skin was investigated. The results, summarized in Figure 5 and Table C-1, show that the skin deposition of hydroquinone at a regular concentration (2%) was greater than that of 1% midostaurin when dissolved in the same solution. Therefore, formulation strategies to enhance the permeability of midostaurin in the skin should be considered.

[0179] [Table 5]

[0180] Example D. Development of Midostaurin Gel Formulation. This example describes the process of developing a gel formulation of midostaurin according to some embodiments of the present disclosure.

[0181] Gel formulations were prepared using Transcutol, Labrasol, Tween 80, or combinations thereof, as shown in Table D-1, listing each ingredient and its weight percent.

[0182] Skin deposition in the layer and dermis of the gel formulation was determined using the method described in Example C.

[0183] [Table 6]

[0184] Skin deposition results for lots A1, A2 and A3 are listed in Figure 6. The gel formulation containing Labrasol (Lot A2) had the highest skin deposition.

[0185] Because gel formulations tend to crystallize, lots A1, A2, A3, and A4 were placed at 60°C for 7 days and examined for crystallization under a polarized light microscope. The results of crystallization under a polarized light microscope are shown in Figures 7A-7D. The micrographs show needle-like and star-like crystallization of midostaurin in the gel formulations, particularly the lot A1 gel. The gel formulations appear prone to crystallization after exposure to 60°C, regardless of whether a single solubilizer at 10% w / w or a mixed solubilizer at levels as high as 30% w / w was used. Because midostaurin has relatively low solubility in solubilizers and aqueous systems, developing a gel formulation can be challenging. Cream and ointment formulations can be considered for the next step.

[0186] Example E. Development of a midostaurin cream formulation. This example describes the process of developing a cream formulation of midostaurin according to some embodiments of the present disclosure.

[0187] A cream formulation of midostaurin cream (Lot B1) was prepared, and an appropriate amount of Maisine CC was additionally added as an oil phase (Lot B2), and an improvement in crystallization was observed. The complete formulations of Lots B1 and B2 are shown in Table E-1.

[0188] [Table 7]

[0189] The cream formulation preparation procedure involves preparing an oil phase and an aqueous phase. To prepare the oil phase, weighed amounts of API, octadecyl alcohol, white petrolatum, liquid paraffin, glyceryl monostearate, Transcutol, and / or Maisine CC are combined in the same beaker and heated to above 80°C until completely melted. To prepare the aqueous phase, weighed amounts of sodium dodecyl sulfate, propylene glycol, glycerin, and water are combined in the same beaker and heated to above 80°C. The oil phase is gradually added to the aqueous phase with continuous stirring until a cream is formed.

[0190] Both lots B1 and B2 were placed at 60 °C for further crystallization investigation under a polarized light microscope, and the results are shown in Figures 8A-8B. The micrographs show needle-like and snowflake-like crystallization of midostaurin in the cream formulation. Both creams (lots B1 and B2) were stable at room temperature for the first two weeks, with crystallization beginning in the third week. The main cause of crystallization may be insufficient solubility of midostaurin in the oil phase. To prevent midostaurin crystallization in a 1% concentration cream formulation, the oil content should be 10% or higher, according to the solubility of midostaurin in various oils shown in Figure 1.

[0191] To investigate the stability of the cream formulation, midostaurin cream (Lot B1) was exposed to 4500 Lx and 60°C for 7 days and subjected to freeze-thaw cycles (60°C, 6 hours / -20°C, 24 hours). Impurities were tested using the HPLC method described in Table B-2. The impurity results are summarized in Table E-2. The data showed that midostaurin cream (Lot B1) was sensitive to light exposure; therefore, steps to avoid light exposure or add sunscreen agents can be considered in subsequent formulation development. High temperature and freeze-thaw cycles did not significantly affect its stability.

[0192] [Table 8]

[0193] To investigate the skin deposition of midostaurin in cream formulations, 0.1% and 1% midostaurin creams and 2% hydroquinone cream were prepared according to the formulation of Lot B2. Additionally, a commercially available 2% hydroquinone cream was also tested for comparison. Skin deposition tests were conducted on the four creams according to the steps described in Example C. The results are summarized in Figure 9 and Table E-3. The data show that the 2% hydroquinone cream, both homemade and commercially available, exhibited better skin deposition than the midostaurin cream formulation, which may be due to the relatively lower log P of hydroquinone (1.09 vs. 5.27). The midostaurin cream formulations showed higher deposition of midostaurin in the stratum corneum than that of midostaurin solution (1% midostaurin: 6.16 μg / cm in cream). 2 2.74 μg / cm in solution 2 , 0.1% midostaurin: 2.01 μg / cm in cream 2 0.86 μg / cm in solution 2 However, the cream formulation showed little improvement in midostaurin deposition in the dermis compared to midostaurin solution (1% cream 1.20 μg / cm 2 Solution 1.20 μg / cm 2 , 0.1%: cream 0.47 μg / cm 2 0.23μg / cm against solution 2 ) Penetration enhancers may be thought to further increase deposition of midostaurin in the skin.

[0194] [Table 9]

[0195] Azone was used in the oil phase, and Tefose 63 and Labrafil M 1944CS were selected as co-emulsifiers. Four ternary phase diagrams were constructed, as shown in Figures 10A-10D. The designated regions in the ternary phase diagrams indicate the range of oil phase, water phase, and emulsifier that can form a cream, and each point in this region corresponds to a specific ratio of oil phase, water phase, and emulsifier, respectively. According to the results of the ternary phase diagrams, the appropriate ratios of oil phase, water phase, and emulsifier for the cream were selected. The optimal oil and co-emulsifier ratio was selected to prepare a 1% midostaurin cream. The complete formulation is listed in Table E-4.

[0196] [Table 10]

[0197] To prepare the oil phase, API, Azone, Tefose 63, and Labrafil M 1944CS were weighed and added to the same beaker and heated to over 80°C until completely melted. To prepare the aqueous phase, water was weighed into a beaker and heated to over 80°C. The oil phase was then gradually added to the aqueous phase and stirred continuously until a cream was formed. Lots B3 and B7 were subjected to stress testing at 4500 lx, 60°C, or room temperature for 7 days. The midostaurin content was measured using the HPLC method described in Table B-2, and the results are shown in Table E-5. The assay results suggest significant degradation of midostaurin in lots B3 and B7. Oxidative impurities may be generated due to conditions such as high temperature, light weight, or large amounts of oil.

[0198] [Table 11]

[0199] Lots B3, B4, B5, B6, and B7 were placed at 60°C and examined for crystallization under a polarized microscope. The results are shown in Figures 11A-11E. Micrographs of lots B3 and B7 show that the droplets are evenly distributed without needle-like or star-like crystallization. Lots B3 and B7 did not show any crystallization at 60°C for 7 days. Micrographs of lots B4 and B5 show that star-like crystallization occurred. Lots B4 and B5 showed crystallization when placed at room temperature after 3 days. Demulsification was observed in lot B6 when placed at room temperature. Micrographs of lot B6 show that the droplet distribution became broader and the droplet size became larger.

[0200] Peceol was selected as the oil phase and Gelot 64 was selected as the emulsifier, and a ternary phase diagram was constructed as shown in Figure 12. The optimal oil and co-emulsifier ratio was selected to prepare a 1% midostaurin cream. The formulation is listed in Table E-6.

[0201] [Table 12]

[0202] To prepare the oil phase, the API, Peceol, and Gelot 64 were weighed into the same beaker and heated above 80°C until completely melted. To prepare the aqueous phase, water was weighed into a beaker and heated above 80°C. The oil phase was then gradually added to the aqueous phase, which was stirred to form a cream. The cream was then placed at 4500 lx, 60°C, and room temperature for 7 days. Midostaurin impurities were measured using the HPLC method described in Table B-2, and the results are shown in Table E-7. The midostaurin cream prepared with Peceol / Gelot 64 was highly susceptible to high temperatures, which appears consistent with the hypothesis that oxidation impurities are more likely to occur under high temperatures and larger amounts of oil. Lot B8 and the blank carrier vehicle of Lot B8 were placed at 60°C for 7 days and examined for crystallization under a polarized microscope; the results are shown in Figures 13A-13B. The photomicrograph of Lot B8 was similar to that of the blank carrier vehicle, indicating a stable state. Since Lot B8 cream showed no crystallization for 7 days at 60°C, it was concluded that there was no crystalline precipitation in the midostaurin cream during the period evaluated.

[0203] [Table 13]

[0204] According to the optimized cream formulation with Peceol as the oil phase, penetration enhancers and optionally antioxidants were added to the formulation to prepare midostaurin cream.First, creams formed with different ratios of Peceol, emulsifier (Tween 80 and Span 60 combined), and water were compared, as listed in Table E-8.When the emulsifier was about 20% and the oil phase was about 10%, the cream had good stability, was smooth, and did not feel oily.

[0205] [Table 14]

[0206] To prepare the oil phase, the API, Peceol, Tween 80, Span 60, antioxidant, and one of three penetration enhancers, Plurol oleique CC 497, Transcutol, or Labrafil M 1944 CS, are weighed into the same beaker and heated to above 80°C to melt. To prepare the water phase, water is weighed into a beaker and heated to above 80°C. The oil phase is gradually added to the water phase, which is stirred to form a cream. Different penetration enhancers (all at 5% level) and different antioxidants (all at 0.02% level) were compared. The complete formulation is shown in Table E-9.

[0207] [Table 15]

[0208] Skin deposition tests were conducted on formulations using different penetration enhancers (Lots B9, B10, and B11), and the results are shown in Figure 14 and Table E-10. The above cream formulations (Lots B11, B12, B13, and B14) were subjected to stress tests at 4500 Lx, 40°C, and 60°C, or at room temperature for 7 days. Midostaurin impurities were measured using the HPLC method described in Table B-2, and the results are shown in Table E-11. Plurol oleique CC 497 provided the best penetration enhancement effect. BHT demonstrated the best antioxidant effect.

[0209] [Table 16]

[0210] [Table 17]

[0211] Example F. Development of a midostaurin ointment formulation. This example describes the process of developing an ointment formulation of midostaurin according to some embodiments of the present disclosure.

[0212] Midostaurin ointments were prepared using PEG-400 and PEG-4000 as matrices due to their higher solubility in PEG-400, and Labrasol was added as a solubilizer. The ointments were stressed at 4500 Lx, 60°C, or room temperature for 7 days. The ointment formulations are shown in Table F-1. The midostaurin content was measured using the HPLC method described in Table A-1, and the results are shown in Table F-2.

[0213] [Table 18]

[0214] [Table 19]

[0215] The results showed that the midostaurin content decreased when the midostaurin ointment was exposed to high temperatures and 4500 Lx. XRPD testing of the midostaurin ointment showed no crystalline peaks, so it was determined that there was no crystallization in the midostaurin ointment at the time evaluated.

[0216] Example G. Skin Pigmentation Reduction Efficacy Study. This example describes the process of evaluating the effectiveness of various topical formulations of midostaurin in reducing skin pigmentation, according to some embodiments of the present disclosure.

[0217] Guinea pigs approximately 12-20 weeks old were used to evaluate the effectiveness of various topical formulations of midostaurin in reducing skin pigmentation. Prior to the experiment, their backs were shaved and six areas (3.2 cm) were cut into strips as illustrated in Figure 15A. 2 The control group (N=1) that did not receive UV stimulation is shown in Figures 15B-C. Guinea pigs were anesthetized with 0.3 mL of a mixture (0.75 mL of 50 mg / mL ketamine and 0.15 mL of 100 mg / mL xylazine), and sites 1-6 were exposed to UV light (315-400 nm) for 14 minutes and 42 seconds (150 mJ / cm). 2) once a day for two consecutive weeks. The solar simulator was equipped with a 1000 W xenon arc lamp fitted with a WG 305 cutoff filter. The radiation dose was 0.17 mW / cm. 2 (or 1.7*10-4W). Midostaurin cream (0.1% and 1.0%) was prepared according to the formula of lot B2. 1% midostaurin solution and 2% hydroquinone solution were prepared using DMSO / propylene glycol (1:3, v / v). 2% hydroquinone cream was commercially available and provided by Guangdong Renrenkang Pharmaceutical Co., Ltd. At the start of modeling, the positive control (hydroquinone cream and solution) and test materials (midostaurin cream and solution) were administered at doses of 0.2 mL for the solution or 0.2 g for the cream to sites 2 to 6. An equal amount of blank cream was administered to site 1 according to Figure 16A. All treatments were administered twice daily for two weeks, starting from the day of UV stimulation. After completion of modeling, treatments were continued twice daily for two weeks, for a total of four weeks.

[0218] The level of skin pigmentation can be assessed through whole-body photography, Fontana-Masson staining, and tyrosinase activity measurement. For Fontana-Masson staining, the protocol and scoring criteria are as follows: After the experiment, skin tissues were collected, embedded in paraffin, and stained with Fontana silver nitrate solution. The Fontana-Masson-stained paraffin sections were examined under a microscope, and melanin particles in the skin tissue sections of each group were observed under a 200x lens. The scoring criteria for local pathological observations are shown in Table G-1.

[0219] [Table 20]

[0220] The protocol for measuring tyrosinase activity is as follows: Skin tissues are collected, embedded in paraffin, and subjected to immunohistochemical staining. The expression of tyrosinase in the thin sections of skin tissues is observed under a 200x lens, and the average optical density value is analyzed using ImageJ software. The average optical density value is calculated by the formula AOD (average optical density) = IOD (integrated optical density) / positive staining area in each image.

[0221] Figures 16A-16B show photographs of the back of a guinea pig after the test, where the skin color is different in six areas receiving different treatments: no drug treatment (model), 2% hydroquinone cream, 1% midostaurin cream, 0.1% midostaurin cream, 2% hydroquinone solution, and 1% midostaurin solution.

[0222] Figure 17 shows the tyrosinase activity results for seven different groups: the control group (shown in Figures 15B-15C, no UV stimulation), the model group (no active treatment following UV stimulation), and the treatment groups with 2% hydroquinone cream, 2% hydroquinone solution, 1% midostaurin cream, 0.1% midostaurin cream, and 1% midostaurin solution. Figure 18 shows the melanin distribution scores for seven different groups: the control group (shown in Figures 15B-15C, no UV stimulation), the model group (no treatment following UV stimulation), and the treatment groups with 2% hydroquinone cream, 2% hydroquinone solution, 1% midostaurin cream, 0.1% midostaurin cream, and 1% midostaurin solution.

[0223] Compared with the skin color of the model group (site 1), the five drug-treated sites were lighter, with site 3 (1% midostaurin cream) showing the lightest color. The melanin particle distribution scores of 2% hydroquinone cream, 1.0% midostaurin solution, and midostaurin cream (0.1%, 1.0%) were significantly reduced compared with the model group, demonstrating dose-dependence for midostaurin cream. Based on the results of this animal study, 1% midostaurin cream showed the best efficacy among all treatment groups, including 2% hydroquinone cream, which was used as a positive control.

[0224] Another efficacy study using the same animal model and protocol described above confirmed the dose-dependent nature of midostaurin cream, with a higher dose (1.5% midostaurin cream) being more effective than 2% hydroquinone. A control group (without UV stimulation) and six treatment groups were tested, including a model group (no treatment following UV stimulation), a 2% hydroquinone positive control (referred to as "2-1" in Figures 19A-19B), 0.01% midostaurin cream (referred to as "2-2" in Figures 19A-19B), 0.05% midostaurin cream (referred to as "2-3" in Figures 19A-19B), 0.25% midostaurin cream (referred to as "2-4" in Figures 19A-19B), and 1.5% midostaurin cream (referred to as "2-5" in Figures 19A-19B). As shown in Figures 19A-19B, both hydroquinone cream and midostaurin cream reduced tyrosinase activity and melanin distribution compared to the model group, and a positive correlation between dose and reduction in tyrosinase activity and melanin distribution was observed for midostaurin cream.

[0225] Formulation stability, including assays and impurities, of the midostaurin topical formulations described herein can be tested, for example, using the HPLC methods described in Table A-1 and Table B-2, under various conditions, at different time points, for example, after 1 month, 3 months, 6 months, 12 months, 24 months, and / or 36 months of storage under refrigerated, ambient, and / or accelerated conditions.

[0226] Example H. Skin Irritation Test Using New Zealand rabbits as a model, a skin irritation test was conducted to evaluate local skin irritation after repeated cutaneous administration of midostaurin cream for 28 days. The study consisted of two groups: a blank control group (saline) and a treatment group. Rabbits in the treatment group received 1% midostaurin cream, a positive control (2% hydroquinone cream), or a blank base of midostaurin cream, based on the amount of cream. Treatment was administered to the dorsal skin of each rabbit at a dose of 0.2 g per rabbit twice daily for 28 consecutive days. The rabbits' general condition and the condition of the administration site were observed daily. Skin irritation scores and intensity were evaluated at the following time points: before the first administration of each day, 1 hour after the final administration of each day, and 1, 24, 48, and 72 hours after the final administration on the final day. The widely accepted and standardized skin irritation scoring system established by the Chinese National Medical Products Administration was adopted for skin irritation evaluation. More specifically, skin irritation was evaluated based on 1) erythema and crusting, and 2) edema formation, according to the criteria shown in Tables H-1 and H-2.

[0227] [Table 21]

[0228] [Table 22]

[0229] The irritation score results are shown in Table H-3. The results suggest that under the conditions of this study, New Zealand White rabbits were treated transdermally with 0.2 g / rabbit twice daily for 28 consecutive days, and 1% midostaurin cream exhibited mild irritation, which is significantly better than the moderate irritation of commercially available hydroquinone cream.

[0230] [Table 23]

[0231] Example I. Phototoxicity Test The phototoxicity of midostaurin cream was tested using English guinea pigs as a model. Male guinea pigs were randomly divided into groups and received a single cutaneous administration of saline (negative control), 8-MOP (positive control), 1.0% midostaurin cream, and midostaurin cream blank matrix. The administered dose was 0.2 mL / site, and the administration site was immobilized after the treatment. 0.5 hours later, the administration site was irradiated with a solar simulator from Dr. Hoenle AG (SOL500) at a designated irradiance of 10 ± 1 J / cm. 2 The irradiance was measured using a UV radiometer equipped with a UVA F0 model from Dr. Hoenle AG. The first day of administration is designated as day 1 (day 1) of the study. After irradiation, skin irritation at the administration site was observed and scored at 1±0.5, 24, 48, and 72 hours. No animals were found to be moribund or dead during the experiment. No clinical findings or weight changes related to midostaurin cream were observed during the study. Edema and erythema were only observed at the site of the positive control substance (8-MOP, UV irradiation), but not at the site of the positive control substance not exposed to UV irradiation, the two control substances exposed to UV irradiation: midostaurin blank matrix and negative control substance (saline), or 1% midostaurin cream. Thus, after a 3-day observation period in guinea pigs, no significant differences in skin irritation scores were found between skin sites treated once with saline or midostaurin cream. Therefore, under the conditions of this study, 1% midostaurin cream is not phototoxic.

[0232] Example J. Pharmacokinetic Studies A pharmacokinetic study was conducted to evaluate the percutaneous absorption of midostaurin in Bama pigs after a single and 7-day continuous percutaneous administration of midostaurin cream.

[0233] Single transdermal administration: After shaving the backs of the piglets, a single 42 mg dose of 1% midostaurin cream (approximately 5 cm x 5 cm area) was administered transdermally near the spine. Blood samples were collected before administration and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours after administration. Skin tissue samples from the administration site were collected after the final blood collection. Midostaurin levels in plasma and skin tissue samples were detected using an LC-MS / MS method.

[0234] Seven-day continuous transdermal administration: After shaving the backs of the piglets, 42 mg of 1% midostaurin cream (approximately 5 cm x 5 cm) was administered transdermally to the spine twice daily for seven days, with two administrations 8 hours apart. Blood samples were collected before the first administration, and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after the first administration, 30 minutes after the third administration, and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours after the final administration. Skin tissue samples from the administration site were collected after the final blood collection. Midostaurin levels in plasma and skin tissue samples were detected using an LC-MS / MS method.

[0235] The results suggest that after a single transdermal administration of 1% midostaurin cream to Bama pigs, plasma midostaurin concentrations were below the lower limit of quantification or not detectable, and midostaurin concentrations in the stratum corneum, epidermis, and dermis were 34.1 ± 13.8 μg / g, 12.1 ± 3.38 μg / g, and 0.280 ± 0.141 μg / g, respectively. After 7 consecutive days of transdermal administration of 1% midostaurin cream to Bama pigs, plasma midostaurin concentrations were below the lower limit of quantification or not detectable, and midostaurin concentrations in the stratum corneum, epidermis, and dermis were 268 ± 124 μg / g, 113 ± 63.3 μg / g, and 3.61 ± 1.53 μg / g, respectively.

[0236] Thus, midostaurin distribution decreased sequentially in the stratum corneum, epidermis, and dermis of Bama pigs after single or 7 consecutive days (twice daily) transdermal administration of 1% midostaurin cream at 42 mg each time. The concentrations of midostaurin in the blood were extremely low, below the lower limit of quantification, or not detectable, suggesting that systemic exposure to midostaurin was extremely low.

[0237] It should be understood that the above listed components and methods are merely illustrative of the types of components and methods encompassed by the present disclosure, and are not limiting.

Claims

1. A method for treating a skin-related disease or disorder, the method comprising topically applying a multi-targeting protein kinase inhibitor or a salt thereof to the skin of a subject, wherein the skin is affected by a skin-related disease or disorder.

2. 10. The method of claim 1, wherein the skin-related disease or disorder is a skin pigmentation disorder.

3. A method for reducing skin pigmentation, comprising topically applying a multi-targeting protein kinase inhibitor or a salt thereof to the pigmented skin of a subject.

4. 1. A method for reducing tyrosinase activity, comprising topically applying a multi-targeting protein kinase inhibitor or a salt thereof to the skin of a subject in need thereof.

5. The method of any one of claims 1 to 4, wherein the multi-targeting protein kinase inhibitor is midostaurin.

6. The method of any one of claims 1 to 5, wherein the subject has a skin hyperpigmentation condition.

7. 7. The method of claim 6, wherein the skin hyperpigmentation condition comprises solar lentigo or age spots.

8. 7. The method of claim 6, wherein the skin hyperpigmentation condition comprises melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, macules of pregnancy, nevus of Ota, or age-related hyperpigmentation.

9. 1. A method for treating melasma, comprising topically applying a multi-targeting protein kinase inhibitor or a salt thereof to the skin of a subject in need thereof.

10. The method of any one of claims 1 to 9, wherein the skin is facial skin of the subject.

11. The method according to any one of claims 8 to 10, wherein the melasma is a chloasma.

12. 12. The method of any one of claims 8 to 11, wherein the melasma is caused or exacerbated by one or more of oral contraceptives, pregnancy, hormone therapy, stress, thyroid disease, sun exposure, inflammation, familial predisposition, or free radicals.

13. 13. The method of any one of claims 8 to 12, wherein said treating comprises reducing the size of abnormal skin pigmentation, reducing the intensity of abnormal skin pigmentation, and / or removing the abnormal skin pigmentation associated with said melasma.

14. 14. The method of any one of claims 1 to 13, wherein said treatment comprises reducing the amount of melanin in an area of ​​skin by at least 25% compared to a similar area of ​​skin in the same subject not receiving said treatment.

15. 14. The method of any one of claims 1 to 13, wherein said treatment comprises reducing the amount of melanin in an area of ​​skin by at least 1.0 according to a melanin distribution score, compared to a similar area of ​​skin in the same subject not receiving said treatment.

16. 14. The method of any one of claims 1-13, wherein said treatment comprises reducing the amount of melanin in said area of ​​skin by at least 1.0 according to the Fontana-Masson staining scoring scale, compared to a similar area of ​​skin in the same subject not receiving said treatment.

17. 17. The method of any one of claims 1 to 16, wherein the method does not cause moderate or severe skin irritation in the subject.

18. 18. The method of any one of claims 1 to 17, comprising topically applying a pharmaceutical composition, wherein the pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof.

19. The method according to any one of claims 1 to 18, wherein the therapeutically effective amount of the multi-targeted protein kinase inhibitor or a salt thereof is a dose that is 80% less than the therapeutically effective amount of hydroquinone.

20. 1. A topical pharmaceutical composition comprising: a) a multi-targeted protein kinase inhibitor (optionally midostaurin) or a pharmaceutically acceptable salt thereof in an amount of 0.001% to about 20% by weight; b) a carrier vehicle; and c) an excipient; and 1. A topical pharmaceutical composition comprising:

21. 21. The topical pharmaceutical composition of claim 20, wherein the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 2% by weight.

22. 21. The topical pharmaceutical composition of claim 20, wherein the midostaurin or pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 0.25% by weight, or about 0.25% to about 1.5% by weight.

23. The topical pharmaceutical composition according to any one of claims 20 to 22, wherein the multi-targeted protein kinase inhibitor or a pharmaceutically acceptable salt thereof is midostaurin.

24. The topical pharmaceutical composition of any one of claims 20 to 23, wherein the topical pharmaceutical composition does not contain phospholipids.

25. The topical pharmaceutical composition of any one of claims 20 to 24, wherein the carrier vehicle comprises an aqueous carrier vehicle.

26. 26. The topical pharmaceutical composition of claim 25, wherein the carrier vehicle comprises water.

27. The topical pharmaceutical composition of any one of claims 20 to 26, wherein the carrier vehicle comprises a non-aqueous carrier vehicle.

28. 28. The topical pharmaceutical composition of claim 27, wherein the carrier vehicle comprises polyethylene glycol (PEG), propylene glycol, glycerin (or glycerol), dimethyl sulfoxide (DMSO), petrolatum, mineral oil, wax, liquid paraffin, petrolatum, or a combination thereof.

29. 29. The topical pharmaceutical composition of any one of claims 20 to 28, wherein the carrier vehicle comprises water, polyethylene glycol, propylene glycol, or glycerin, or a combination thereof.

30. 30. The topical pharmaceutical composition of any one of claims 20 to 29, wherein the carrier vehicle is present in the composition in an amount of from 40% to 99% by weight.

31. 30. The topical pharmaceutical composition of any one of claims 20 to 29, wherein the carrier vehicle is present in the composition in an amount of from 70% to 90% by weight.

32. 32. The topical pharmaceutical composition of any one of claims 20 to 31, wherein the excipient comprises a surfactant, a penetration enhancer, an antioxidant, a sunscreen, a viscosity modifier, a pH stabilizer, or a humectant, or any combination thereof.

33. 33. The topical pharmaceutical composition of claim 32, wherein the excipient comprises a surfactant.

34. 34. The topical pharmaceutical composition of claim 33, wherein the surfactant comprises a non-ionic surfactant.

35. The surfactant may be glyceryl monooleate, glyceryl monolinoleate, polyethylene glycol-hydroxystearate (e.g., macrogol-15-hydroxystearate), polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80 or polysorbate 80), polyoxylglyceride (e.g., caprylocaproyl polyoxyl-8 glyceride, oleoyl polyoxyl-6 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., polyoxyl 35 hydrogenated castor oil), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol stearate), sorbitan monostearate, polyglyceryl-3 dioleate, sodium dodecyl sulfate (SDS), or polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2), or a combination thereof.

36. 34. The topical pharmaceutical composition of claim 33, wherein the surfactant comprises an ionic surfactant (e.g., sodium dodecyl sulfate or SDS).

37. 34. The topical pharmaceutical composition of claim 33, wherein the surfactant comprises an emulsifier.

38. 38. The topical pharmaceutical composition of claim 37, wherein the emulsifier comprises polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol stearate), sorbitan monostearate, sodium dodecyl sulfate (SDS), oleoyl polyoxyl-6 glyceride), or polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2), or a combination thereof.

39. 39. The topical pharmaceutical composition of any one of claims 20 to 38, wherein the topical pharmaceutical composition comprises two, three, four, or more surfactants.

40. 40. The topical pharmaceutical composition of any one of claims 32 to 39, wherein the surfactant is present in the composition in an amount of about 1% to 50% by weight.

41. 39. The topical pharmaceutical composition of claim 37, wherein the emulsifier is present in the composition in an amount of about 1% to 50% by weight.

42. 42. A topical pharmaceutical composition according to any one of claims 20 to 41, comprising a penetration enhancer.

43. 43. The topical pharmaceutical composition of claim 42, wherein the penetration enhancer comprises polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, oleoyl polyoxyl-6 glyceride), 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof.

44. 44. The topical pharmaceutical composition of claim 42 or 43, wherein the penetration enhancer is present in the composition in an amount of about 0.1% to 40% by weight.

45. 45. The topical pharmaceutical composition of any one of claims 20 to 44, wherein the topical pharmaceutical composition comprises an antioxidant.

46. 46. ​​The topical pharmaceutical composition of claim 45, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, or a tocopherol (e.g., d-α-tocopherol), or a combination thereof.

47. 47. The topical pharmaceutical composition of claim 45 or 46, wherein the antioxidant is present in the composition in an amount of about 0.001% to 5% by weight.

48. 48. The topical pharmaceutical composition of any one of claims 20 to 47, wherein the topical pharmaceutical composition comprises a sunscreen.

49. 49. The topical pharmaceutical composition of claim 48, wherein the sunscreen comprises avobenzone, bemotrizinol, benzophenone-3 (BZ-3, oxybenzone), bisoctisol, homosalate, octinoxate, octisalate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof.

50. 50. The topical pharmaceutical composition of claim 48 or 49, wherein the sunscreen agent is present in the composition in an amount of about 0.001% to 2% by weight.

51. 51. The topical pharmaceutical composition of any one of claims 20 to 50, wherein the topical pharmaceutical composition comprises a viscosity modifier.

52. 52. The topical pharmaceutical composition of claim 51, wherein the viscosity modifier comprises aluminum monostearate, bentonite, polyacrylic acid (or PAA) (e.g., cross-linked polyacrylic acid), octadecyl alcohol, glyceryl behenate, or a combination thereof.

53. 53. The topical pharmaceutical composition of any one of claims 20 to 52, wherein the topical pharmaceutical composition comprises a pH stabilizer.

54. 54. The topical pharmaceutical composition of claim 53, wherein the pH stabilizer comprises citric acid, glycolic acid, lactic acid, sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof.

55. 54. The topical pharmaceutical composition of claim 53, wherein the pH stabilizer comprises a pH buffering agent.

56. 56. The topical pharmaceutical composition of any one of claims 20 to 55, wherein the topical pharmaceutical composition has a pH of about 5 to 8.

57. 56. The topical pharmaceutical composition of any one of claims 20 to 55, wherein the topical pharmaceutical composition has a pH ranging from about 6.5 to about 7.

5.

58. 58. The topical pharmaceutical composition of any one of claims 20 to 57, wherein the topical pharmaceutical composition comprises a moisturizer.

59. 59. The topical pharmaceutical composition of claim 58, wherein the moisturizer comprises petrolatum, mineral oil, wax, liquid paraffin, petrolatum (e.g., white petrolatum), glycerol (or glycerin), propylene glycol, or a combination thereof.

60. 60. The topical pharmaceutical composition of any one of claims 20 to 59, wherein the topical pharmaceutical composition comprises a multifunctional excipient, which is simultaneously two or more of a surfactant, a penetration enhancer, a viscosity modifier, a carrier vehicle, and a humectant.

61. 61. The topical pharmaceutical composition of claim 60, wherein the multifunctional excipient is simultaneously a surfactant and a penetration enhancer.

62. 62. The topical pharmaceutical composition of claim 61, wherein the multifunctional excipient is oleoyl polyoxyl-6 glyceride or polyglyceryl-3 dioleate.

63. 61. The topical pharmaceutical composition of claim 60, wherein the multifunctional excipient is simultaneously a moisturizer and a carrier vehicle.

64. 64. The topical pharmaceutical composition of claim 63, wherein the multifunctional excipient is petrolatum, mineral oil, wax, liquid paraffin, petrolatum, propylene glycol, or glycerol.

65. 65. The topical pharmaceutical composition of any one of claims 20 to 64, wherein the topical pharmaceutical composition is in a form selected from an ointment, a gel, a cream, a lotion, a solution, an emulsion, a paste, a patch, a wipe, a swab, and a pad.

66. 66. The topical pharmaceutical composition of claim 65, wherein the topical pharmaceutical composition is an ointment.

67. The topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight; b) a surfactant in an amount of about 5% to about 20% by weight; c) a penetration enhancer in an amount of about 0.05% to about 20% by weight; d) a carrier vehicle in an amount of about 70% to about 90% by weight; e) a humectant in an amount of about 5% to about 25% by weight; e) an antioxidant in an amount of about 0.001% to 5% by weight.

68. The topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 2% by weight; b) a surfactant comprising glyceryl monolinoleate, glyceryl monooleate, polyoxylglyceride (e.g., caprylocaproyl polyoxyl-8 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., ricinoleate 35), polyethylene glycol hydroxystearate (e.g., macrogol-15-hydroxystearate), or a combination thereof; c) a penetration enhancer comprising polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone), or a combination thereof; d) a carrier vehicle comprising polyethylene glycol (PEG), mineral oil, or a combination thereof; e) a humectant comprising glycerol or propylene glycol, or a combination thereof; f) an antioxidant comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

69. 66. The topical pharmaceutical composition of claim 65, wherein the topical pharmaceutical composition is a gel.

70. The topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight; b) a surfactant in an amount of about 5% to about 50% by weight; c) optionally, a penetration enhancer in an amount of about 1% to about 30% by weight; d) a carrier vehicle in an amount of about 60% to about 95% by weight; e) a viscosity modifier in an amount of about 0.01% to about 5% by weight; f) optionally a pH stabilizer; and g) an antioxidant in an amount of about 0.001% to 5% by weight.

71. The topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 2% by weight; b) a surfactant comprising glyceryl monolinoleate, glyceryl monooleate, polyoxylglyceride (e.g., caprylocaproyl polyoxyl-8 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., macrogolglycerol ricinoleate 35), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), or a combination thereof; c) optionally, a penetration enhancer comprising polyglyceryl-3 dioleate, oleoyl polyoxyl-6 glyceride diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone); d) a viscosity modifier comprising polyacrylic acid; e) optionally a pH stabilizer comprising sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof; f) a carrier vehicle comprising water; g) an antioxidant comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

72. 66. The topical pharmaceutical composition of claim 65, wherein the topical pharmaceutical composition is a cream.

73. The topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight; b) a carrier vehicle in an amount of about 30% to about 70% by weight; c) a surfactant in an amount of about 5% to about 50% by weight; d) optionally a humectant in an amount of about 5% to about 30% by weight; e) optionally, a penetration enhancer in an amount of about 1% to about 40% by weight; f) optionally a viscosity modifier in an amount of about 0.01% to about 5% by weight; g) an antioxidant in an amount of about 0.001% to 5% by weight.

74. The topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% to about 5% by weight; b) a carrier vehicle comprising water and optionally polyethylene glycol (PEG), propylene glycol, liquid paraffin, or petrolatum (e.g., white petrolatum), or a combination thereof; c) a surfactant comprising glyceryl monooleate, glyceryl monolinoleate, polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or macrogol stearate), sorbitan monostearate, sodium dodecyl sulfate (SDS), polyoxyethylene alkyl ether (e.g., steareth-20, steareth-2), or a combination thereof; d) optionally a humectant comprising glycerol or propylene glycol, or a combination thereof; e) optionally a penetration enhancer comprising oleoyl polyoxyl-6 glyceride, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof; f) an antioxidant comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

75. The topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 2% by weight; b) a surfactant in an amount of about 5% to about 50% by weight, said surfactant comprising glyceryl monolinoleate, glyceryl monooleate, PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate, polyoxyethylene stearate (e.g., macrogol-75 stearate), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), sorbitan monostearate, sodium dodecyl sulfate, or a combination thereof; c) optionally, a penetration enhancer in an amount of about 1% to about 35% by weight, said penetration enhancer comprising oleoyl polyoxyl-6 glyceride, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone), or a combination thereof; d) optionally a humectant in an amount of about 5% to about 25% by weight, said humectant comprising glycerol (glycerin), propylene glycol, or a combination thereof; e) an antioxidant in an amount of about 0.01% to about 2% by weight, said antioxidant comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, alpha-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof; f) a carrier vehicle in an amount of about 30% to about 70% by weight, said carrier vehicle comprising water and optionally liquid paraffin, or white petrolatum.

76. 76. The topical pharmaceutical composition of any one of claims 65 to 75, wherein the topical pharmaceutical composition further comprises a sunscreen.

77. 77. The topical pharmaceutical composition of any one of claims 20-76, wherein the topical pharmaceutical composition reduces the amount of melanin in an area of ​​skin by at least 25% compared to a similar area of ​​skin in the same subject not receiving any treatment, wherein the amount of melanin is measured by a melanin distribution score using a guinea pig as a model.

78. 78. The topical pharmaceutical composition of any one of claims 20-77, wherein the reduction in the amount of melanin in an area of ​​skin treated with the topical pharmaceutical composition is at least 100% relative to the amount of melanin in a similar area of ​​skin of the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, and wherein the topical pharmaceutical composition is administered at a dose lower than the dose of the reference topical pharmaceutical composition.

79. 78. The topical pharmaceutical composition of any one of claims 20-77, wherein the topical pharmaceutical composition reduces tyrosinase activity in an area of ​​skin by at least 25% compared to a similar area of ​​skin in the same subject not receiving any treatment, wherein the tyrosinase activity is measured per gram of tissue using a guinea pig as a model.

80. 80. The topical pharmaceutical composition of any one of claims 20-79, wherein the reduction in tyrosinase activity in an area of ​​skin treated with the topical pharmaceutical composition is at least about 100% relative to the tyrosinase activity in a similar area of ​​skin of the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, and wherein the topical pharmaceutical composition is administered at a dose lower than the dose of the reference topical pharmaceutical composition.

81. 81. The topical pharmaceutical composition of any one of claims 20-80, wherein the level of skin irritation in the skin area treated with the topical pharmaceutical composition is minimal, and wherein the topical pharmaceutical composition comprises up to 1.0% by weight of midostaurin.

82. 82. The topical pharmaceutical composition of any one of claims 20-81, wherein the skin irritation score in an area of ​​skin treated with the topical pharmaceutical composition is at most about 50% of the skin irritation score in a similar area of ​​skin of the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, and wherein the topical pharmaceutical composition is administered at a dose lower than the dose of the reference topical pharmaceutical composition.

83. 83. The topical pharmaceutical composition of any one of claims 20 to 82, wherein the topical pharmaceutical composition is chemically stable for at least 7 days when stored under conditions of 4500 lux (lx) during light exposure or at about 60°C.

84. 81. The topical pharmaceutical composition of any one of claims 20 to 80, wherein the topical pharmaceutical composition retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof when stored under conditions of 4500 lux (lx) of light exposure and a temperature of about 15°C to about 25°C for 7 days.

85. 85. The topical pharmaceutical composition of any one of claims 20-84, wherein the topical pharmaceutical composition retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof when stored at about 60°C for 7 days.

86. 86. The topical pharmaceutical composition of any one of claims 20-85, wherein the topical pharmaceutical composition retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after at least one freeze-thaw cycle.

87. 87. The topical pharmaceutical composition of any one of claims 20-86, wherein the topical pharmaceutical composition retains at least 90% by weight of the midostaurin or pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 3, 6, 9, 12, or 24 months.

88. 88. The topical pharmaceutical composition of any one of claims 84 to 87, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is determined according to a high performance liquid chromatography (HPLC) assay (e.g., as described in Table A-1).

89. 89. The topical pharmaceutical composition of any one of claims 20-88, wherein the topical pharmaceutical composition contains 5% by weight or less of total impurities after storage at ambient conditions for at least 3, 6, 9, 12, or 24 months.

90. 90. The topical pharmaceutical composition of claim 89, wherein the amount of total impurities is determined according to high performance liquid chromatography (HPLC) impurity analysis (e.g., as described in Table B-2).

91. 1. A method for treating a skin-related disease or disorder, comprising topically applying a topical pharmaceutical composition to the skin of a subject in need thereof, wherein the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof.

92. 1. A method for reducing skin pigmentation, comprising topically applying a topical pharmaceutical composition to the skin of a subject in need thereof, wherein the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof.

93. 1. A method for reducing tyrosinase activity, comprising topically applying a topical pharmaceutical composition to the skin of a subject in need thereof, wherein the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof.

94. 94. The method of any one of claims 91 to 93, comprising topically applying the topical pharmaceutical composition of any one of claims 20 to 90 to the skin of a subject in need thereof.

95. 95. The method of any one of claims 92 to 94, wherein the subject has a skin-related disorder.

96. 96. The method of claim 95, wherein the skin-related disorder comprises a skin pigmentation disorder.

97. A kit comprising a package enclosing the topical pharmaceutical composition of any one of claims 20 to 90.

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