Topical pharmaceutical compositions and uses thereof

Abstract

Provided herein are methods of treating skin-related diseases or conditions, such as black spot. Also provided are pharmaceutical compositions of miindopturine, or a pharmaceutically acceptable salt thereof, which are formulated for topical administration. Further described are methods for preparing such topical pharmaceutical compositions and methods of treating subjects using the topical pharmaceutical compositions.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of patent application No. PCT / CN2022 / 139952, filed on December 19, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Hyperpigmentation of the skin is characterized by an overall or localized darkening of the individual's normal skin color. Hyperpigmentation of the skin includes melasma, post-inflammatory hyperpigmentation, post-traumatic pigmentation, discoid lupus erythematosus, freckles, senile pigmentation, lentigo, nevus of Ota, etc. Hyperpigmentation may occur on all parts of the body. Currently, therapies for hyperpigmentation of the skin use non-selective toxins that reduce tyrosinase activity, including hydroquinone, azelaic acid, and kojic acid. These therapies are only partially effective and toxic, sometimes resulting in loss of skin pigmentation or ochronosis. Thus, there is a need for novel methods or products for treating hyperpigmentation conditions and limiting serious side effects.

[0004] Incorporated by Reference

[0005] 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

[0006] In one aspect, disclosed herein is a method for treating a skin-related disease or condition, comprising topically applying a multi-targeted protein kinase inhibitor (e.g., midostaurin) or a salt thereof to the skin of a subject, wherein the skin is associated with a skin-related disease or condition. In some embodiments, the skin-related disease or condition is a skin pigmentation condition. In one aspect, disclosed herein is a method for reducing skin pigmentation, comprising topically applying a multi-targeted 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 for reducing tyrosinase activity, comprising topically applying a multi-targeted protein kinase inhibitor (e.g., midostaurin) or a salt thereof to the skin of a subject in need thereof. In some embodiments, the subject suffers from a skin hyperpigmentation condition. In some embodiments, the skin hyperpigmentation condition comprises sun spots or age spots. In some embodiments, the skin hyperpigmentation condition comprises melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, lentigo, nevus of Ota, or senile pigmentation. In one aspect, disclosed herein is a method for treating melasma, comprising topically applying a multi-targeted 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 on the face of the subject. In some embodiments, the melasma is chloasma. In some embodiments, the melasma is caused or exacerbated by one or more of the following: birth control pills, pregnancy, hormone therapy, stress, thyroid disease, sun exposure, inflammation, family susceptibility, or free radicals. In some embodiments, the treatment comprises reducing the size of abnormal skin pigmentation, reducing the intensity of abnormal skin pigmentation, and / or eliminating abnormal skin pigmentation associated with the 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 a similar skin area by at least 25% compared to the amount of melanin in the skin area of ​​the same subject not undergoing the treatment. In some embodiments, the treatment comprises reducing the amount of melanin in a similar skin area by at least 1.0 according to the Melanin Distribution Score, compared to the amount of melanin in the skin area of ​​the same subject not undergoing the treatment. In some embodiments, the treatment comprises reducing the amount of melanin in a similar skin area by at least 1.0 according to the Fontana-Masson staining scoring standard, compared to the amount of melanin in the skin area of ​​the same subject not undergoing the treatment.In some embodiments, the multi-targeted protein kinase inhibitor or salt thereof is midostaurin or a salt thereof. In some embodiments, the midostaurin or a salt thereof is administered in a therapeutically effective amount. In some embodiments, the therapeutically effective amount of the multi-targeted protein kinase inhibitor or a salt thereof is a dose that is 80% less than the dose of hydroquinone.

[0007] 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, a carrier vehicle, and an excipient in an amount of 0.001% wt to about 20% wt, wherein the topical pharmaceutical composition is formulated for topical administration. In some embodiments, the midostaurin or its pharmaceutically acceptable salt is present in the composition in an amount of about 0.01 wt % to about 2 wt %. In some embodiments, the midostaurin or its pharmaceutically acceptable salt is present in the composition in an amount of about 0.01 wt % to about 0.25 wt %. In some embodiments, the midostaurin or its pharmaceutically acceptable salt is present in the composition in an amount of about 0.25 wt % to about 1.5 wt %. In some embodiments, the midostaurin or its pharmaceutically acceptable salt is present in the composition in an amount of about 1.5 wt % to about 2.5 wt %. In some embodiments, the midostaurin or its pharmaceutically acceptable salt is present in the composition in an amount of about 1.0 wt %. In some embodiments, the multi-targeted protein kinase inhibitor or its pharmaceutically acceptable salt is midostaurin. In some embodiments, the topical pharmaceutical composition does not contain a phospholipid. In some embodiments, the topical pharmaceutical composition contains a phospholipid. 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 comprises polyethylene glycol (PEG), propylene glycol, glycerin (glycerin or glycerol), dimethyl sulfoxide (DMSO), petrolatum, mineral oil, wax, liquid paraffin, petroleum jelly, or a combination thereof. In some embodiments, the carrier vehicle comprises 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 wt % to 99 wt %. In some embodiments, the carrier vehicle is present in the composition in an amount of 70 wt % to 90 wt %. 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 nonionic surfactant.In some embodiments, the surfactant comprises glyceryl monooleate, glyceryl monolinoleate, macrogol-hydroxystearate (e.g., macrogol-15-hydroxystearate), polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), polyoxylglyceride (e.g., caprylocaproyl polyoxyethylene-8 glyceride, oleoyl polyoxyethylene-6 glyceride), glyceryl macrogol ricinoleate (e.g., polyoxyethylene 35 hydrogenated castor oil), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), glycol palmitostearate, glycerol monostearate or glyceryl stearate. In some embodiments, the surfactant comprises an ionic surfactant (e.g., sodium lauryl 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), glycol palmitostearate, glycerol monostearate (glycerol monostearate or glyceryl monostearate, GMS), polyoxyethylene stearate (or polyethylene glycol stearate), sorbitan monostearate, sodium lauryl sulfate (SDS), oleoyl polyoxyethylene-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 wt % to 50 wt %. In some embodiments, the emulsifier is present in the composition in an amount of about 1 wt % to 50 wt %. 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 polyoxyethylene-6 glyceride, 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof.In certain embodiments, the penetration enhancer is present in the composition in an amount of about 0.1wt% to 40wt%. In certain embodiments, the topical pharmaceutical composition comprises an antioxidant. In certain embodiments, the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, thiourea or tocopherol (for example, da-tocopherol) or its combination. In certain embodiments, the antioxidant is present in the composition in an amount of about 0.001wt% to 5wt%. In certain embodiments, the topical pharmaceutical composition comprises a sunscreen. In some embodiments, the sunscreen comprises avobenzone, bemotrizinol, benzophenone-3 (BZ-3, oxybenzone), oxotriazole, homosalate, octinoxate, octisalate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof. In some embodiments, the sunscreen is present in the composition in an amount of about 0.001 wt % to 2 wt %. 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), stearyl 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 pH of the topical pharmaceutical composition is about 5 to 8. In some embodiments, the pH of the topical pharmaceutical composition is in the range of about 6.5 to about 7.5. In some embodiments, the pH of the topical pharmaceutical composition is about 7.0. In some embodiments, the topical pharmaceutical composition comprises the wetting agent. In some embodiments, the wetting agent comprises petrolatum, mineral oil, wax, liquid paraffin, petroleum jelly (e.g., white petrolatum), glycerol (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 the following: a surfactant, a penetration enhancer, a viscosity modifier, a carrier medium and a wetting agent.In certain embodiments, the multifunctional excipient is a surfactant and a penetration enhancer simultaneously. In certain embodiments, the multifunctional excipient is oleoyl polyoxyethylene-6 glyceride or polyglyceryl-3 dioleate. In certain embodiments, the multifunctional excipient is a wetting agent and a carrier medium simultaneously. In certain embodiments, the multifunctional excipient is petrolatum, mineral oil, wax, liquid paraffin, petroleum jelly, propylene glycol or glycerol. In certain embodiments, the topical pharmaceutical composition is in a form selected from the group consisting of ointment, gel, cream, lotion, solution, emulsion, paste, patch, wipe, cotton swab and protective pad. In certain 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% wt to about 5% wt, b) a surfactant in an amount of about 5% wt to about 20% wt, c) a penetration enhancer in an amount of about 0.05% wt to about 20% wt, d) a carrier vehicle in an amount of about 70% wt to about 90% wt, e) a moisturizer in an amount of about 5% wt to about 25% wt, and e) an antioxidant in an amount of about 0.001% wt to 5% wt. 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 carrier vehicle, and a moisturizer. In some embodiments, the topical pharmaceutical composition is an ointment comprising: midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is 0.05% wt to about 2% wt; a surfactant, wherein the surfactant comprises glyceryl monolinoleate, glyceryl monooleate, polyoxyethylene glycerides (e.g., caprylocaproyl polyoxyethylene-8 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., ricinoleate 35), polyethylene glycol-hydroxystearate (e.g., polyethylene glycol-15-hydroxystearate), or a combination thereof; a penetration enhancer, wherein the penetration enhancer comprises polyglycerol -3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone), or a combination thereof; a carrier vehicle, wherein the carrier vehicle comprises polyethylene glycol (PEG), mineral oil, or a combination thereof; a humectant, wherein the humectant comprises glycerol or propylene glycol, or a combination thereof; and an antioxidant, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, 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, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is about 0.5% wt to about 1.5% wt; a surfactant, wherein the amount of the surfactant is about 7% wt to about 15% wt, wherein the surfactant comprises caprylocaproyl polyoxyethylene-8 glyceride; a penetration enhancer, wherein the amount of the penetration enhancer is about 0.5% wt to about 3% wt, wherein the penetration enhancer comprises 1-dodecylazacycloheptan-2-one; and a carrier vehicle, wherein the amount of the carrier vehicle is about 70% wt to about 80% wt, wherein the carrier vehicle comprises a polyoxyethylene glycol having a number average molecular weight of about 300 g / L. The topical pharmaceutical composition can be a composition comprising: a polyethylene glycol having a molecular weight of about 1000 g / mol to about 500 g / mol, a polyethylene glycol having a number average molecular weight of about 3000 g / mol to about 5000 g / mol, or a combination thereof; a moisturizer in an amount of about 10% wt to about 15% wt, wherein the moisturizer comprises glycerol; and an antioxidant in an amount of about 0.001% wt to about 1% wt, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, 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% wt to about 5% wt; a surfactant in an amount of about 5% wt to about 50% wt; optionally, a penetration enhancer in an amount of about 1% wt to about 30% wt; a carrier vehicle in an amount of about 60% wt to about 95% wt; a viscosity modifier in an amount of about 0.01% wt to about 5% wt; optionally, a pH stabilizer; and an antioxidant in an amount of about 0.001% wt to 5% wt. In some embodiments, the topical pharmaceutical composition comprises a multifunctional excipient, wherein the multifunctional excipient is both a surfactant and a penetration enhancer. In some embodiments, the topical pharmaceutical composition is a gel comprising:

[0008] a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is 0.05% wt to about 2% wt;

[0009] b) a surfactant, wherein the surfactant comprises glyceryl monolinoleate, glyceryl monooleate, polyoxyethylene glyceryl ester (e.g., caprylocaproyl polyoxyethylene-8 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., polyethylene glycol glyceryl ricinoleate 35), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), or a combination thereof; c) optionally, a penetration enhancer, wherein the penetration enhancer comprises polyglyceryl-3 dioleate, oleoyl polyoxyethylene-6 glyceride, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone); d) a viscosity adjuster. e) optionally, a pH stabilizer, wherein the pH stabilizer comprises sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof; f) a carrier vehicle, wherein the carrier vehicle comprises water; and g) an antioxidant, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, 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, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is from about 0.05% wt to about 1.5% wt; b) a surfactant, wherein the amount of the surfactant is from about 5% wt to about 20% wt, wherein the surfactant comprises caprylocaproyl polyoxyethylene-8 glyceride, polysorbate 80, or a combination thereof; c) optionally, a penetration enhancer, wherein the amount of the penetration enhancer is from about 5% wt to about 25% wt, wherein the penetration enhancer comprises diethylene glycol monoethyl ether; d) a viscosity modifier, The amount of the viscosity modifier is from about 0.1% wt to about 2% wt, wherein the viscosity modifier comprises cross-linked polyacrylic acid; e) optionally, a pH stabilizer, wherein the pH stabilizer comprises triethanolamine; f) an aqueous carrier vehicle, the amount of the aqueous carrier vehicle is from about 70% wt to about 90% wt, wherein the aqueous carrier vehicle comprises water; and g) an antioxidant, the amount of the antioxidant is from about 0.001% wt to 2% wt, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof. In some embodiments, the pH of the topical pharmaceutical composition is from about 6.5 to about 7.5. In some embodiments, the pH of the topical pharmaceutical composition is 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, said midostaurin or a pharmaceutically acceptable salt thereof, in an amount of about 0.01% wt to about 5% wt; a carrier vehicle, said carrier vehicle in an amount of about 30% wt to about 70% wt; a surfactant, said surfactant in an amount of about 5% wt to about 50% wt; optionally, a moisturizer, said moisturizer in an amount of about 5% wt to about 30% wt; optionally, a penetration enhancer, said penetration enhancer in an amount of about 1% wt to about 40% wt; optionally, a viscosity modifier, said viscosity modifier in an amount of about 0.01% wt to about 5% wt; and an antioxidant, said antioxidant in an amount of about 0.001% wt to 5% wt. In some embodiments, the topical pharmaceutical composition comprises: midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is 0.05% wt to about 5% wt; a carrier vehicle comprising water and optionally polyethylene glycol (PEG), propylene glycol, liquid paraffin or petroleum jelly (e.g., white petrolatum) or a combination thereof; a surfactant, wherein the surfactant comprises 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 stearate. monostearate (GMS), polyoxyethylene stearate (or polyethylene glycol stearate), sorbitan monostearate, sodium lauryl sulfate (SDS), polyoxyethylene alkyl ether (e.g., Steareth-20, Steareth-2), or a combination thereof; optionally, a moisturizer comprising glycerol or propylene glycol, or a combination thereof; optionally, a penetration enhancer, wherein the penetration enhancer comprises oleoyl polyoxyethylene-6 glyceride, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof; and an antioxidant, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, 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, said midostaurin or a pharmaceutically acceptable salt thereof being present in an amount of about 0.1% wt to about 2% wt; a surfactant being present in an amount of about 5% wt to about 50% wt, wherein the surfactant comprises glyceryl monolinoleate, glyceryl monooleate, PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), glycol palmitostearate, glyceryl monostearate, polyoxyethylene stearate (e.g., polyethylene glycol-75 stearate), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), sorbitan monostearate, sodium lauryl sulfate, or a combination thereof; and optionally, a penetration enhancer being present in an amount of about 1% wt to about 35% wt, wherein the penetration enhancer comprises oleoylpolyoxyethylene- 6 glycerides, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone) or a combination thereof; optionally, a moisturizer, the moisturizer in an amount of about 5% wt to about 25% wt, wherein the moisturizer comprises glycerol (glycerol / glycerin), propylene glycol or a combination thereof; an antioxidant, the antioxidant in an amount of about 0.01% wt to about 2% wt, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride or a combination thereof; and a carrier vehicle in an amount of about 30% wt to about 70% wt, wherein the carrier vehicle comprises water and optionally liquid paraffin or white petrolatum.In some embodiments, the topical pharmaceutical composition comprises: midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is about 0.5% wt to about 2% wt; a surfactant, wherein the amount of the surfactant is about 5% wt to about 35% wt, wherein the surfactant comprises glyceryl monolinoleate or glyceryl monooleate, PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), glycol palmitostearate, glyceryl monostearate, polyoxyethylene stearate (e.g., polyethylene glycol-75 stearate), polyoxyethylene sorbitan monooleate (e.g., polysorbate 60), polysorbate 70, polysorbate 80, polysorbate 90, polysorbate 10 ... Ester 80), sorbitan monostearate or a combination thereof; a penetration enhancer in an amount of about 1% wt to about 35% wt, wherein the penetration enhancer comprises 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% wt to about 0.1% wt, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate or a combination thereof; and a carrier vehicle in an amount of about 60% wt to about 70% wt, wherein the carrier vehicle comprises water. In some embodiments, the topical pharmaceutical composition comprises: midostaurin or a pharmaceutically acceptable salt thereof, said midostaurin or a pharmaceutically acceptable salt thereof being present in an amount of about 1% wt; glyceryl monooleate, said glyceryl monooleate being present in an amount of about 10% wt; polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), said polyoxyethylene sorbitan monooleate being present in an amount of about 5% wt to about 14% wt; sorbitan monostearate, said sorbitan monostearate being present in an amount of about 3.5% wt; polyglyceryl-3 dioleate, said polyglyceryl-3 dioleate being present in an amount of about 5%; an antioxidant, said antioxidant being present in an amount of about 0.06% wt, wherein said antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbyl palmitate; and water, said water being present in an amount of about 66.5% wt. In some embodiments, the topical pharmaceutical composition further comprises a sunscreen. In some embodiments, the sunscreen comprises avobenzone, betrizinol, benzophenone-3 (BZ-3, oxybenzone), and octotriazole, homosalate, octinoxate, octalate, 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 similar skin area by at least 25% compared to the amount of melanin in the same skin area of ​​the subject without any treatment, wherein the amount of melanin is measured by a melanin distribution score using a guinea pig as a model.In some embodiments, the amount of melanin in the area of ​​skin treated with the topical pharmaceutical composition is reduced by at least 100% of the amount of melanin in a similar area of ​​skin of the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, wherein the topical pharmaceutical composition is administered at a dose lower than the dose of the reference topical pharmaceutical composition. In some embodiments, the topical pharmaceutical composition reduces tyrosinase activity in a similar area of ​​skin by at least 25% compared to tyrosinase activity in an area of ​​skin of the same subject that has not undergone any treatment, wherein the tyrosinase activity is measured per gram of tissue using a guinea pig as a model. In some embodiments, the reduction in tyrosinase activity in the area of ​​skin treated with the topical pharmaceutical composition is at least about 100% of the tyrosinase activity in a similar area of ​​skin of the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, wherein the topical pharmaceutical composition is administered at a dose lower than the dose of the reference topical pharmaceutical composition. In some embodiments, the level of skin irritation in the area of ​​skin treated with the topical pharmaceutical composition is mild at best, and wherein the topical pharmaceutical composition comprises at most 1.0 wt % midostaurin. In some embodiments, the skin irritation score in the 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, wherein the topical pharmaceutical composition is administered at a dose lower than the dose of the reference topical pharmaceutical composition. In some embodiments, the topical pharmaceutical composition is chemically stable for at least 7 days under conditions of 4500 lux (lx) light exposure or when stored at about 60°C. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or its pharmaceutically acceptable salt when stored for 7 days under conditions of 4500 lux (lx) 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 its pharmaceutically acceptable salt when stored at about 60°C for 7 days. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or its pharmaceutically acceptable salt after at least one freeze-thaw cycle. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or said pharmaceutically acceptable salt thereof after storage under refrigeration for at least 3 months, 6 months, 9 months, 12 months, 24 months, or 36 months. In some embodiments, the topical pharmaceutical composition retains at least 95% by weight of midostaurin or said pharmaceutically acceptable salt thereof after storage under refrigeration for at least 3 months, 6 months, 9 months, 12 months, 24 months, or 36 months.In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or its pharmaceutically acceptable salt after storage at ambient conditions for at least 3 months, 6 months, 9 months, 12 months, or 24 months. In some embodiments, the topical pharmaceutical composition retains at least 95% by weight of midostaurin or its pharmaceutically acceptable salt after storage at ambient conditions for at least 3 months, 6 months, 9 months, 12 months, or 24 months. In some embodiments, the topical pharmaceutical composition retains at least 90% by weight of midostaurin or its pharmaceutically acceptable salt after storage at about 40° C. for at least 1 month, 3 months, or 6 months. In some embodiments, the topical pharmaceutical composition retains at least 95% by weight of midostaurin or its pharmaceutically acceptable salt after storage at about 40° C. for at least 1 month, 3 months, or 6 months. In some embodiments, the amount of midostaurin or its pharmaceutically acceptable salt 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 no more than 5 wt% total impurities after storage under refrigerated conditions for at least 3 months, 6 months, 9 months, 12 months, 24 months, or 36 months. In some embodiments, the topical pharmaceutical composition contains no more than 2 wt% total impurities after storage under refrigerated conditions for at least 3 months, 6 months, 9 months, 12 months, 24 months, or 36 months. In some embodiments, the topical pharmaceutical composition contains no more than 5 wt% total impurities after storage under ambient conditions for at least 3 months, 6 months, 9 months, 12 months, or 24 months. In some embodiments, the topical pharmaceutical composition contains no more than 2 wt% total impurities after storage under ambient conditions for at least 3 months, 6 months, 9 months, 12 months, or 24 months. In some embodiments, the topical pharmaceutical composition contains no more than 5 wt% total impurities after storage at about 40°C for at least 1 month, 3 months, or 6 months. In some embodiments, the topical pharmaceutical composition contains no more than 2 wt% total impurities after storage at about 40°C for at least 1 month, 3 months, or 6 months. In some embodiments, the amount of total impurities is determined according to a high performance liquid chromatography (HPLC) impurity analysis (e.g., as described in Table B-2).

[0010] Disclosed herein is a method of treating a skin-related disease or condition, 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 condition 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.

[0011] Disclosed herein is a method of reducing skin pigmentation, the method 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.

[0012] Disclosed herein is a method for reducing tyrosinase activity, the method 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.

[0013] Disclosed herein is a kit comprising a package enclosing a topical pharmaceutical composition described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] 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 referring to the following detailed description of illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings, in which:

[0015] Figure 1 The equilibrium solubility of midostaurin in different solvents is shown.

[0016] Figure 2 The solubility of midostaurin in various solubilizer-water mixture systems is shown.

[0017] Figure 3 The different layers of human skin are shown.

[0018] Figure 4 Shown is a Franz diffusion cells system used to perform skin deposition testing.

[0019] Figure 5 Shown are the results for skin deposition of midostaurin and hydroquinone when prepared at various concentrations in a mixture of DMSO and propylene glycol.

[0020] Figure 6 Results for skin deposition of midostaurin in gel formulations with different excipients are shown.

[0021] Figures 7A-7DThe crystals of midostaurin gel formulations batch A1, batch A2, batch A3 and batch A4 are shown under polarized microscopy. The micrographs show needle-shaped crystals and star-shaped crystals of midostaurin in the gel formulations (particularly in batch A1 gel).

[0022] Figure 8A and 8B The crystals of midostaurin cream formulations Batch B1 and B2 are shown under a polarized microscope. The micrographs show needle-shaped crystals and snowflake-shaped crystals of midostaurin in the cream formulation.

[0023] Figure 9 Results are shown for skin deposition of 1% and 0.1% midostaurin creams and a 2% hydroquinone cream, a commercially available 2% hydroquinone cream, and all other formulations were prepared according to the components of batch B2.

[0024] Figures 10A-10D Four ternary phase diagrams are depicted, each showing the phase behavior of a system consisting of a certain ratio of Azone, water, and a mixture of Tefose 63 and Labrafil M 1944CS.

[0025] Figures 11A-11E Polarized microscopic images of crystals from midostaurin cream formulations Batch B3, Batch B4, Batch B5, Batch B6, and B7 are shown. Micrographs of Batch B3 and B7 show uniform droplet distribution, with no needle- or star-shaped crystals. Micrographs of Batch B4 and B5 show the presence of star-shaped crystals. Micrographs of Batch B6 show a wider droplet distribution and larger droplet diameters.

[0026] Figure 12 A ternary phase diagram showing the phase behavior of a system consisting of Peceol, water and Gelot 64 is depicted.

[0027] Figures 13A-13B Crystallization of midostaurin cream formulation batch B8 and the blank carrier vehicle of batch B8 are shown under polarized microscopy. The micrograph of batch B8 is similar to that of the blank carrier vehicle, indicating that the batch is in a stable state.

[0028] Figure 14 Shown are midostaurin deposition results for batches B9, B10, B11 and cream batch B2 used for pharmacodynamic (PD) efficacy experiments, which compare the effects of different penetration enhancers on the skin deposition of midostaurin in cream formulations.

[0029] Figure 15A Shown is a picture of a guinea pig whose back is shaved and divided into six areas.

[0030] Figure 15B -C shows a picture of a control group of guinea pigs (N=1) without UV stimulation.

[0031] Figures 16A-16B Two pictures of the back of a guinea pig are shown, in which the skin color varies at six areas that received different treatments: (i) upper left area, no treatment (model); (ii) upper right area, 2% hydroquinone cream; (iii) lower left area, 2% hydroquinone solution; (iv) middle left area, 1% midostaurin cream; (v) middle right area, 0.1% midostaurin cream; and (vi) lower right area, 1% midostaurin solution. Treatment type Figure 16A Notes.

[0032] Figure 17 Tyrosinase activities of seven different groups are shown: control group (no UV stimulation), model group (UV stimulation followed by no treatment), 2% hydroquinone cream-treated group, 2% hydroquinone solution-treated group, 1% midostaurin cream-treated group, 0.1% midostaurin cream-treated group, and 1% midostaurin solution-treated group.

[0033] Figure 18 Melanin distribution scores of seven different groups are shown: control group (no UV stimulation), model group (UV stimulation followed by no treatment), 2% hydroquinone cream-treated group, 2% hydroquinone solution-treated group, 1% midostaurin cream-treated group, 0.1% midostaurin cream-treated group, and 1% midostaurin solution-treated group.

[0034] Figure 19A Melanin distribution scores for seven different groups are shown: control group (no UV stimulation), model group (UV stimulation followed by no treatment), 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").

[0035] Figure 19B Tyrosinase activity of seven different groups is shown: control group (no UV stimulation), model group (UV stimulation followed by no treatment), 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

[0036] The present disclosure generally relates to topical pharmaceutical compositions and methods of use and preparation thereof, comprising a multi-targeted protein kinase inhibitor (e.g., midostaurin) or a pharmaceutically acceptable salt thereof. The multi-targeted protein kinase inhibitor can target at least two protein kinases. The multi-targeted protein kinase inhibitor can inhibit two or more protein kinases selected from the group consisting of PKCα / β / γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ, and VEGFR1 / 2. In some cases, the multi-targeted protein kinase inhibitor inhibits PKCα, PKCβ, and PKCγ. In some cases, the multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and Syk. In some cases, the multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and Akt. In some cases, the multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and PKA. In some cases, the multi-targeted protein kinase targets PKCα / β / γ and c-Kit. In some cases, a multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and c-Fgr. In some cases, a multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and c-Src. In some cases, a multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and FLT3. In some cases, a multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and PDFRβ. In some cases, a multi-targeted protein kinase inhibitor inhibits PKCα / β / γ and VEGFR1 / 2. In some cases, a multi-targeted 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-targeted protein kinase inhibitor is midostaurin.

[0037] The topical pharmaceutical composition comprising a multi-targeted protein kinase inhibitor (eg, midostaurin) or a pharmaceutically acceptable salt thereof can comprise midostaurin or a salt thereof. Midostaurin (midostaurin) was approved by the FDA in 2017 for the treatment of AML (acute myeloid leukemia) and ASM (aggressive systemic mastocytosis). Midostaurin is a multikinase inhibitor for oral use. In one aspect, the present disclosure discloses that topical administration of midostaurin can reduce skin hyperpigmentation in a UV-induced guinea pig model in a dose-dependent manner. Without being bound by theory, it was found that midostaurin is more effective when topically applied and has a better safety profile (e.g., better skin tolerance) compared to other treatments for skin hyperpigmentation currently on the market.

[0038] Midostaurin is a small molecule kinase inhibitor currently available for oral use. The molecular formula of midostaurin is C 35 H30 N4O4. The molecular weight is 570.65 g / mol. The structural formula of midostaurin is as follows:

[0039]

[0040] Midostaurin has a high log P value of 5.8 and is very difficult to dissolve in aqueous solutions. Furthermore, midostaurin is unstable under many conditions, such as acid, alkali, oxidation, heat, and photolytic degradation, making its development even more challenging. Consequently, developing an appropriate topical formulation for midostaurin can be very challenging. Different excipients used in the composition of a topical formulation can affect the amount of midostaurin delivered to different skin layers.

[0041] In one aspect, provided herein are pharmaceutical compositions of midostaurin for topical administration. Midostaurin topical formulations can be used as therapeutic agents to alleviate, reduce, or eliminate one or more skin-related conditions in a subject in need thereof, as further described herein. In some embodiments, skin-related conditions include hyperpigmentation conditions of the skin, such as melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, lentigo, lentigo of pregnancy, nevus of Ota, age-related hyperpigmentation, and the like.

[0042] In one aspect, embodiments of the present invention provide novel methods or products for treating hyperpigmentation conditions of the skin. In some embodiments, midostaurin used in the topical pharmaceutical compositions described herein is midostaurin free base. In some embodiments, midostaurin used in the formulations described herein is a midostaurin salt.

[0043] 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,

[0044]

[0045] Midostaurin topical pharmaceutical composition

[0046] In one aspect, disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof. Topical formulations of the present invention may include, but are not limited to, ointments, gels, creams, lotions, solutions, emulsions, pastes, patches, wipes, cotton swabs, pads, and any other form suitable for topical delivery of midostaurin or its pharmaceutically acceptable salt. It is contemplated that where some of the components described herein are in the form of a cream and other components are in the form of a gel or ointment, lotions, solutions, emulsions, and pastes are also contemplated.

[0047] In some embodiments, the topical pharmaceutical composition further comprises a carrier vehicle. In some embodiments, the topical pharmaceutical composition further comprises an excipient. In some embodiments, the topical pharmaceutical composition is formulated for topical administration.

[0048] In some embodiments, midostaurin is present in the pharmaceutical composition as 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, potassium, and lithium salts; alkaline earth metals such as calcium and magnesium salts; organic amine salts such as triethylamine, pyridinium, picoline, ethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine salts; inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, and phosphates; organic acid salts such as formates, acetates, trifluoroacetates, maleates, and tartrates; sulfonates such as methanesulfonates, benzenesulfonates, and p-toluenesulfonates; and amino acid salts such as arginine, aspartate, and glutamate. Pharmaceutically acceptable salts include bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate, pentafluoropropionate, hydrobromide, mucate, oleate, dihydrogen phosphate, dihydrogen 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, clavulariate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fiunarate, fumarate, glucoheptonate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinate, hydrazine ( Pharmaceutically acceptable salts include, but are not limited to, hydroxybenzoate ... In some embodiments, the topical pharmaceutical composition comprises midostaurin.

[0049] Disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001 wt % to about 30 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.001 wt % to about 0.01 wt %, about 0.01 wt % to about 0.1 wt %, about 0.1 wt % to about 0.5 wt %, about 0.5 wt % to about 1 wt %, about 1 wt % to about 2 wt %, about 2 wt % to about 5 wt %, about 5 wt % to about 10 wt %, about 10 wt % to about 20 wt %, or about 20 wt % to about 30 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.001 wt % to about 0.01 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01 wt % to about 0.1 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.1 wt % to about 0.5 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.5 wt % to about 1 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1 wt % to about 2 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 2 wt % to about 5 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 5 wt % to about 10 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 10 wt % to about 20 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 20 wt % to about 30 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.001 wt % to about 1.0 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01 wt % to about 1.0 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01 wt % to about 2 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.01 wt % to about 0.25 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.25 wt % to about 1.5 wt %.In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.1 wt % to about 1.0 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.25 wt % to about 0.75 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.5 wt % to about 1.25 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.8 wt % to about 1.2 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.5 wt % to about 2.5 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.75 wt % to about 2.25 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.8 wt % to about 2.2 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.1 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.2 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.25 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.3 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.4 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.5 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.75 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.25 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 1.5 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 2 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 2.5 wt %. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is midostaurin.

[0050] Disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and an excipient. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof is present in the topical pharmaceutical composition in an amount of about 0.001 wt % to about 20 wt %. In some embodiments, the topical pharmaceutical composition does not contain 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 humectant, 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 humectant.

[0051] 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% wt to about 5% wt. In some embodiments, the topical pharmaceutical compositions comprise a surfactant in an amount of about 5% wt to about 20% wt. In some embodiments, the topical pharmaceutical compositions comprise a penetration enhancer in an amount of about 0.05% wt to about 20% wt. In some embodiments, the topical pharmaceutical compositions comprise a penetration enhancer in an amount of about 0.05% wt to about 5% wt. In some embodiments, the topical pharmaceutical compositions comprise a carrier vehicle in an amount of about 70% wt to about 90% wt. In some embodiments, the topical pharmaceutical compositions comprise a moisturizer in an amount of about 5% wt to about 25% wt. In some embodiments, the topical pharmaceutical compositions comprise an antioxidant in an amount of about 0.001% wt to 5% wt. 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.

[0052] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% wt to about 2% wt. In some embodiments, the topical pharmaceutical composition comprises a surfactant, such as glyceryl monolinoleate, glyceryl monooleate, polyoxyethylene glycerides, 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 moisturizer, such as glycerol, propylene glycol, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises an antioxidant comprising, for example, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

[0053] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.1% wt to about 1.0% wt, a surfactant (e.g., caprylocaproyl polyoxyethylene-8 glyceride) in an amount of about 7% wt to about 15% wt, a penetration enhancer (e.g., 1-dodecylazacycloheptan-2-one or Azone) in an amount of about 0.5% wt to about 3% wt, a carrier vehicle (e.g., polyethylene glycol pr PEG) in an amount of about 70% wt to about 80% wt, a humectant (e.g., glycerin) in an amount of about 10% wt to about 15% wt, and an antioxidant in an amount of about 0.001% wt to 1% wt. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.5% wt to about 1.5% wt, a surfactant (e.g., caprylocaproyl polyoxyethylene-8 glyceride) in an amount of about 7% wt to about 15% wt, a penetration enhancer (e.g., 1-dodecylazacycloheptan-2-one or Azone) in an amount of about 0.5% wt to about 3% wt, a carrier vehicle (e.g., polyethylene glycol prPEG) in an amount of about 70% wt to about 80% wt, a humectant (e.g., glycerin) in an amount of about 10% wt to about 15% wt, and an antioxidant in an amount of about 0.001% wt to 1% wt. In some embodiments, the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof. In some embodiments, the carrier medium comprises a polyethylene glycol having a number average molecular weight of about 100 g / mol to 800 g / mol or a polyethylene glycol having a number average molecular weight of about 2000 g / mol to 6000 g / mol, or a combination thereof. In some embodiments, the carrier medium comprises a polyethylene glycol having a number average molecular weight of about 200 g / mol to 600 g / mol or a polyethylene glycol having a number average molecular weight of about 3000 g / mol to 5000 g / mol, or a combination thereof. In some embodiments, the carrier medium comprises a polyethylene glycol having a number average molecular weight of about 300 g / mol to 500 g / mol or a polyethylene glycol having a number average molecular weight of about 3500 g / mol to 4500 g / mol, or a combination thereof.

[0054] In some embodiments, the topical pharmaceutical compositions described herein are gels. In some embodiments, the topical pharmaceutical compositions comprise midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.05%wt to about 5%wt. In some embodiments, the topical pharmaceutical compositions comprise a surfactant in an amount of about 5%wt to about 50%wt. In some embodiments, the topical pharmaceutical compositions comprise, optionally, a penetration enhancer in an amount of about 1%wt to about 30%wt. In some embodiments, the topical pharmaceutical compositions comprise a carrier vehicle in an amount of about 60%wt to about 95%wt. In some embodiments, the topical pharmaceutical compositions comprise a viscosity modifier in an amount of about 0.01%wt to about 5%wt. In some embodiments, the topical pharmaceutical compositions comprise a pH stabilizer. In some embodiments, the topical pharmaceutical compositions comprise an antioxidant in an amount of about 0.001%wt to 5%wt. In some embodiments, the topical pharmaceutical compositions comprise a multifunctional excipient. In some embodiments, the multifunctional excipient is both a surfactant and a penetration enhancer.

[0055] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% wt to about 2% wt. In some embodiments, the topical pharmaceutical composition comprises a surfactant, such as monolinolein, monoolein, polyoxyethylene glycerol, glyceryl polyethylene glycol ricinoleate, polyoxyethylene sorbitan monooleate, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises optionally a penetration enhancer, such as polyglyceryl-3 dioleate, oleoyl polyoxyethylene-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 comprising, for example, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

[0056] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% wt to about 1.5% wt. In some embodiments, the topical pharmaceutical composition comprises a surfactant (e.g., caprylocaproyl polyoxyethylene-8 glyceride or polysorbate 80) in an amount of about 5% wt to about 20% wt. In some embodiments, the topical pharmaceutical composition comprises a penetration enhancer (e.g., diethylene glycol monoethyl ether) optionally in an amount of about 15% wt to about 25% wt. 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% wt to about 2% wt. 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% wt to about 90% wt. 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% wt to 2% wt.

[0057] In some embodiments, the topical pharmaceutical compositions described herein are creams. In some embodiments, the topical pharmaceutical compositions comprise midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.01%wt to about 5%wt. In some embodiments, the topical pharmaceutical compositions comprise a carrier vehicle in an amount of about 30%wt to about 70%wt. In some embodiments, the topical pharmaceutical compositions comprise a surfactant in an amount of about 5%wt to about 50%wt. In some embodiments, the topical pharmaceutical compositions comprise a penetration enhancer optionally in an amount of about 1%wt to about 40%wt. In some embodiments, the topical pharmaceutical compositions comprise a viscosity modifier in an amount of about 0.01%wt to about 5%wt. In some embodiments, the topical pharmaceutical compositions comprise a moisturizer optionally in an amount of about 5%wt to about 30%wt. In some embodiments, the topical pharmaceutical compositions comprise a viscosity enhancer optionally in an amount of about 0.01%wt to about 5%wt. In some embodiments, the topical pharmaceutical compositions comprise an antioxidant in an amount of about 0.001%wt to 5%wt.

[0058] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.05% wt to about 5% wt. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle comprising water and optionally polyethylene glycol (PEG), propylene glycol, or liquid paraffin, or petroleum jelly (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), glycol palmitostearate, glycerol monostearate or glyceryl monostearate, GMS), polyoxyethylene stearate (or polyethylene glycol-75 stearate), sorbitan monostearate, sodium lauryl sulfate (SDS), polyoxyethylene alkyl ether (e.g., Steareth-20, Steareth-2), or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises optionally a humectant such as glycerol or propylene glycol, or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises an optional penetration enhancer, such as oleoyl polyoxyethylene-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-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

[0059] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.1% wt to about 2% wt. In some embodiments, the topical pharmaceutical composition comprises a surfactant in an amount of about 5% wt to about 50% wt. 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), glycol palmitostearate, glyceryl monostearate, polyoxyethylene stearate (or polyethylene glycol-75 stearate), sorbitan monostearate, sodium lauryl sulfate (SDS), or a combination thereof. In some embodiments, the topical pharmaceutical composition comprises, optionally, a penetration enhancer (e.g., oleoyl polyoxyethylene-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% wt to about 35% wt. In some embodiments, the topical pharmaceutical composition comprises a moisturizer (e.g., glycerol / glycerin or propylene glycol or a combination thereof) in an amount of about 5% wt to about 25% wt. 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% wt to about 2% wt. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle (e.g., water and optionally liquid paraffin or white petrolatum) in an amount of about 30% wt to about 70% wt.

[0060] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of 0.5% wt to about 2% wt. 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, polyethylene glycol-75 stearate, or a combination thereof) in an amount of about 5% wt to about 35% wt. 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% wt to about 35% wt. 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% wt to about 0.1% wt. In some embodiments, the topical pharmaceutical composition comprises a carrier vehicle (eg, water) in an amount of about 60% wt to about 70% wt.

[0061] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 1%wt. In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof in an amount of about 0.5%wt. In some embodiments, the topical pharmaceutical composition comprises glyceryl monooleate in an amount of about 10%wt. In some embodiments, the topical pharmaceutical composition comprises polyoxyethylene sorbitan monooleate (e.g., polysorbate 80) in an amount of about 5%wt to about 14%wt. In some embodiments, the topical pharmaceutical composition comprises sorbitan monostearate in an amount of about 3.5%wt. In some embodiments, the topical pharmaceutical composition comprises polyglyceryl-3 dioleate in an amount of about 5%. 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%wt. In some embodiments, the topical pharmaceutical composition comprises water in an amount of about 66.5%wt.

[0062] In some embodiments, the topical pharmaceutical compositions described herein further comprise a sunscreen. In some embodiments, the sunscreen comprises avobenzone, betrizinol, benzophenone-3 (BZ-3, oxybenzone), oxalotriazole, homosalate, octinoxate, octalolate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof.

[0063] In some embodiments, the topical pharmaceutical composition comprises midostaurin or a pharmaceutically acceptable salt thereof. In some embodiments, the pH of the topical pharmaceutical composition is from about 5.0 to about 8.0, from about 5.5 to about 7.5, from about 6.0 to about 7.5, from about 6.5 to about 7.5, from about 6.8 to about 7.2, or from about 6.9 to about 7.1. In some embodiments, the pH of the topical pharmaceutical composition is from about 5.0 to about 8.0. In some embodiments, the pH of the topical pharmaceutical composition is from about 5.5 to about 7.5. In some embodiments, the pH of the topical pharmaceutical composition is from about 6.0 to about 7.5. In some embodiments, the pH of the topical pharmaceutical composition is from about 6.5 to about 7.5. In some embodiments, the pH of the topical pharmaceutical composition is from about 6.8 to about 7.2. In some embodiments, the pH of the topical pharmaceutical composition is about 7.0.

[0064] In some embodiments, the excipients in the topical pharmaceutical compositions described herein can have more than one function in the composition, i.e., multifunctional excipients. In some embodiments, the multifunctional excipients can function as two or more of a surfactant, a penetration enhancer, a viscosity modifier, a carrier vehicle, and a humectant. In some embodiments, the multifunctional excipients can function as both a surfactant and a penetration enhancer, such as oleoyl polyoxyethylene-6 glycerides (e.g., sold under the trademark GLUTAMATE®). M 1944CS), polyglyceryl-3 dioleate (e.g., sold under the trademark Oleique CC 497). In some embodiments, a multifunctional excipient can function as both a humectant and a carrier vehicle, such as propylene glycol or glycerin.

[0065] Carrier medium

[0066] In one aspect, disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof and a carrier vehicle. The carrier vehicle can be any suitable carrier vehicle that can deliver midostaurin or a pharmaceutically acceptable salt thereof in the topical pharmaceutical composition. The carrier vehicle can be any suitable carrier vehicle that can deliver midostaurin or a pharmaceutically acceptable salt thereof and a suitable excipient. The carrier vehicle can be any suitable carrier vehicle that can dissolve midostaurin or a pharmaceutically acceptable salt thereof and can form a mixture that can maintain 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. The non-aqueous carrier can include an oil (e.g., an edible vegetable oil or a synthetic edible oil), propylene glycol, glycerol, polypropylene glycol, polyethylene glycol (PEG), an alcohol (e.g., ethanol) or any combination thereof. In some embodiments, the carrier medium comprises polyethylene glycol (PEG), propylene glycol, glycerin (glycerin or glycerol), dimethyl sulfoxide (DMSO), petrolatum, mineral oil, wax, liquid paraffin, petroleum jelly, or a combination thereof. In some embodiments, the carrier medium comprises water, polyethylene glycol, propylene glycol, or glycerin, or a combination thereof. In some embodiments, the carrier medium comprises water. In some embodiments, the carrier medium comprises water, liquid paraffin, petroleum jelly, or a combination thereof.

[0067] In some embodiments, the carrier vehicle comprises propylene glycol. In some embodiments, the carrier vehicle comprises glycerol. In some embodiments, the carrier vehicle comprises PEG. In some embodiments, the average molecular weight of PEG is from about 100 g / mol to about 10,000 g / mol. In some embodiments, the average molecular weight of PEG is from about 100 g / mol to about 500 g / mol, from about 500 g / mol to about 1000 g / mol, from about 1000 g / mol to about 5000 g / mol, from about 5000 g / mol to about 10,000 g / mol. In some embodiments, the average molecular weight of PEG is from about 200 g / mol to about 500 g / mol. In some embodiments, the average molecular weight of PEG is from about 300 g / mol to about 500 g / mol. In some embodiments, the average molecular weight of PEG is from about 350 g / mol to about 450 g / mol. In some embodiments, the average molecular weight of PEG is about 400 g / mol. In some embodiments, PEG is PEG 400.

[0068] In some embodiments, the carrier vehicle comprises PEG. In some embodiments, the number average molecular weight of PEG is from about 200 g / mol to about 20,000 g / mol. In some embodiments, the number average molecular weight of PEG is from about 200 g / mol to about 500 g / mol, from about 500 g / mol to about 1000 g / mol, from about 1000 g / mol to about 8000 g / mol, from about 8000 g / mol to about 12,000 g / mol, or from about 12,000 g / mol to about 20,000 g / mol. In some embodiments, the number average molecular weight of PEG is from about 1000 g / mol to about 8000 g / mol, from about 2000 g / mol to about 7000 g / mol, from about 3000 g / mol to about 6000 g / mol, from about 3500 g / mol to about 5500 g / mol, from about 3500 g / mol to about 5000 g / mol, from about 3700 g / mol to about 4500 g / mol, from about 3800 g / mol to about 4200 g / mol. In some embodiments, the number average molecular weight of PEG is from about 1000 g / mol to about 8000 g / mol. In some embodiments, the number average molecular weight of PEG is from about 2000 g / mol to about 7000 g / mol. In some embodiments, the number average molecular weight of PEG is from about 3000 g / mol to about 6000 g / mol. In some embodiments, the number average molecular weight of PEG is from about 3500 g / mol to about 5500 g / mol. In some embodiments, the number average molecular weight of PEG is from about 3500 g / mol to about 5000 g / mol. In some embodiments, the number average molecular weight of PEG is from about 3700 g / mol to about 4500 g / mol. In some embodiments, the number average molecular weight of PEG is from about 3800 g / mol to about 4200 g / mol. In some embodiments, the number average molecular weight of PEG is about 4000 g / mol. In some embodiments, PEG is PEG 4000.

[0069] In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition described herein in an amount of about 35wt% to about 99wt%. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition described herein in an amount of about 35wt% to about 40wt%, about 40wt% to about 45wt%, about 45wt% to about 50wt%, about 50wt% to about 55wt%, about 55wt% to about 60wt%, about 60wt% to about 65wt%, about 65wt% to about 70wt%, about 70wt% to about 75wt%, about 75wt% to about 80wt%, about 80wt% to about 85wt%, about 85wt% to about 90wt%, about 90wt% to about 93wt%, about 93wt% to about 96wt% or about 96wt% to about 99wt%. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 35wt% to about 40wt%. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 40wt% to about 45wt%. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 45 wt % to about 50 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 50 wt % to about 55 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 55 wt % to about 60 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 60 wt % to about 65 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 65 wt % to about 70 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 70 wt % to about 75 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 75 wt % to about 80 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 80 wt % to about 85 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 85 wt % to about 90 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 70 wt % to about 95 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 90 wt % to about 99 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 90 wt % to about 93 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 93 wt % to about 96 wt %. In some embodiments, the carrier vehicle is present in the topical pharmaceutical composition in an amount of about 96 wt % to about 99 wt %. 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 glycerol. In some embodiments, the carrier vehicle comprises PEG 400, PEG 4000, and glycerol. In some embodiments, the carrier vehicle comprises propylene glycol. In some embodiments, the carrier vehicle comprises water and propylene glycol.

[0070] In some embodiments, the carrier medium comprises water. In some embodiments, water is present in the topical pharmaceutical composition described herein in an amount of about 35wt% to about 95wt%. In some embodiments, water is present in the topical pharmaceutical composition described herein in an amount of about 35wt% to about 40wt%, about 40wt% to about 45wt%, about 45wt% to about 50wt%, about 50wt% to about 55wt%, about 55wt% to about 60wt%, about 60wt% to about 65wt%, about 65wt% to about 70wt%, about 70wt% to about 75wt%, about 75wt% to about 80wt%, about 80wt% to about 85wt%, about 85wt% to about 90wt% or about 90wt% to about 95wt%. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 35wt% to about 40wt%. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 40wt% to about 45wt%. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 45wt% to about 50wt%. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 50 wt % to about 55 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 55 wt % to about 60 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 60 wt % to about 65 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 65 wt % to about 70 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 70 wt % to about 75 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 75 wt % to about 80 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 80 wt % to about 85 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 85 wt % to about 90 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 90 wt % to about 95 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 40 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 50 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 60 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 65 wt %. In some embodiments, water is present in the topical pharmaceutical composition in an amount of about 67.5 wt %.

[0071] In some embodiments, the carrier vehicle comprises water, propylene glycol, and glycerol. In some embodiments, the carrier vehicle comprises propylene glycol and glycerol in a weight ratio of about 1:1 to about 5:1, about 2:1 to about 4:1, about 2.5:1 to about 3.5:1. In some embodiments, the carrier vehicle comprises propylene glycol and glycerol in a weight ratio of about 2.5:1 to about 3.5:1. In some embodiments, the carrier vehicle comprises propylene glycol and glycerol 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, 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.

[0072] In some embodiments, the carrier medium comprises water, liquid paraffin and petroleum jelly (e.g., white petrolatum). In some embodiments, the carrier medium comprises liquid paraffin and petroleum jelly (e.g., white petrolatum) in a weight ratio of about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1. In some embodiments, the carrier medium comprises liquid paraffin and petroleum jelly (e.g., white petrolatum) in a weight ratio of about 1:1 to about 3:1. In some embodiments, the carrier medium comprises liquid paraffin and petroleum jelly (e.g., white petrolatum) in a weight ratio of about 5:3. In some embodiments, the carrier medium comprises water and liquid paraffin in a weight ratio of about 20:1 to about 5:1, about 15:1 to about 6:1, about 12:1 to about 8:1. In some embodiments, the carrier medium comprises water and liquid paraffin in a weight ratio of about 12:1 to about 8:1. In some embodiments, the carrier medium comprises water and liquid paraffin in a weight ratio of about 11:1 to about 9:1. In some embodiments, the carrier medium comprises water and liquid paraffin in a weight ratio of about 10:1.

[0073] 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, PEG is present in the topical pharmaceutical composition in an amount of about 60 wt % to about 85 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 60 wt % to about 65 wt %, about 65 wt % to about 70 wt %, about 70 wt % to about 75 wt %, about 75 wt % to about 80 wt %, or about 80 wt % to about 85 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 35 wt % to about 40 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 40 wt % to about 45 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 45 wt % to about 50 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 50 wt % to about 55 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 55 wt % to about 60 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 60 wt % to about 65 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 65 wt % to about 70 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 70 wt % to about 75 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 75 wt % to about 80 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 70 wt % to about 75 wt %. In some embodiments, PEG is present in the topical pharmaceutical composition in an amount of about 75 wt %.

[0074] surfactants

[0075] In one aspect, disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and an excipient (eg, comprising a surfactant).

[0076] In certain embodiments, topical pharmaceutical compositions as described herein include surfactants. In certain embodiments, surfactants are compounds or mixtures of compounds comprising a hydrophobic group (typically a hydrocarbon chain) and a hydrophilic group. In certain embodiments, surfactants may include emulsifiers. Surfactants may play one or more roles, including solubility enhancers, bioavailability enhancers, penetration enhancers, and emulsifiers. Examples of surfactants include, but are not limited to, Kolliphor series (RH40), sorbitan oleate, SDS, Solutal, Soluplus, sucrose fatty acid esters, polyoxyethylene stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor, polyethylene glycol glyceryl 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 lauryl sulfate, lauromacrogol arlasolve, poloxamer, Labrafil, Labrasol, Tween 80, tocopheryl polyethylene glycol 1000 succinate (abbreviated as TPGS or vitamin E TPGS), and the like.

[0077] The surfactant used in the present disclosure can include one or more nonionic surfactants, one or more ionic surfactants, one or more zwitterionic surfactants or their mixtures. In certain embodiments, the nonionic surfactant does not have a charged group in its head. Exemplary nonionic surfactants include but are not limited to fatty alcohol, cetyl alcohol, stearyl alcohol, cetearyl alcohol and oleyl alcohol. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (e.g., octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (e.g., decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ether (e.g., Triton X-100), polyethylene glycol alkylphenyl ether (e.g., nonenol-9), glyceryl alkyl esters (e.g., glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (e.g., polysorbates), sorbitan alkyl esters (e.g., Spans), cocamide MEA, cocamide DEA, block copolymers of polyethylene glycol and polypropylene glycol (e.g., poloxamer), polyethoxylated tallow amine (POEA), and tocopheryl polyethylene glycol 1000 succinate (abbreviated as TPGS or vitamin E TPGS). In some embodiments, the nonionic surfactant comprises one or more of a fatty alcohol (e.g., cetyl alcohol, stearyl alcohol, cetearyl alcohol, and oleyl alcohol). In some embodiments, the nonionic surfactant comprises C9-C 30 In some embodiments, the nonionic surfactant comprises C 12 -C 24 In some embodiments, the nonionic surfactant comprises C 12 -C 18 Fatty alcohols or fatty acids. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (e.g., octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (e.g., decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ether (e.g., Triton X-100), polyethylene glycol alkylphenyl ether (e.g., nonenol-9), glycerol alkyl esters (e.g., glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (e.g., polysorbates), sorbitan alkyl esters (e.g., Spans), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (e.g., poloxamer), polyethoxylated tallow amine (POEA), and tocopheryl polyethylene glycol 1000 succinate (abbreviated as TPGS or vitamin E TPGS).

[0078] 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.

[0079] In some embodiments, the surfactant comprises glyceryl monooleate (e.g., sold under the trademark Peceol TM In some embodiments, the surfactant comprises glyceryl monolinoleate (e.g., sold under the trademark In some embodiments, the surfactant comprises polyethylene glycol-hydroxystearate, such as polyethylene glycol-15-hydroxystearate (e.g., sold under the trademark HS15). In some embodiments, the surfactant comprises a polyoxyethylene sorbitan monooleate, such as polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80. In some embodiments, the surfactant comprises a polyoxyethylene glyceride, such as caprylocaproyl polyoxyethylene-8 glyceride (e.g., sold under the trademark In some embodiments, the surfactant comprises oleoyl polyoxyethylene-6 glyceride (e.g., sold under the trademark In some embodiments, the surfactant comprises glyceryl polyethylene glycol ricinoleate, such as polyoxyethylene 35 hydrogenated castor oil (e.g., sold under the trademark 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 63). In some embodiments, the surfactant comprises glycerol monostearate or glyceryl monostearate (GMS). In some embodiments, the surfactant comprises polyoxyethylene stearate and polyethylene glycol stearate (e.g., a mixture of glyceryl monostearate and polyethylene glycol-75 stearate sold under the trademark Geot TM 64). In some embodiments, the surfactant comprises sorbitan monostearate (e.g., sold under the trademark 60). In some embodiments, the surfactant comprises polyglyceryl-3 dioleate (e.g., sold under the trade name Oleique CC 497). In some embodiments, the surfactant comprises sodium lauryl sulfate (SDS). In some embodiments, the surfactant comprises a polyoxyethylene alkyl ether (e.g., Steareth-20, Steareth-2).

[0080] 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), glycol palmitostearate, glycerol monostearate (glycerol monostearate or glycerylmonostearate, GMS), polyoxyethylene stearate (or polyethylene glycol stearate), sorbitan monostearate, sodium lauryl sulfate (SDS), oleoyl polyoxyethylene-6 glyceride, or polyoxyethylene alkyl ether (e.g., Steareth-20, Steareth-2), or a combination thereof.

[0081] In some embodiments, the surfactant comprises fatty acids, sphingolipids, glycolipids, polyketides, sterol lipids, isoprenoid lipids, etc. In some embodiments, the surfactant does not comprise a phospholipid.

[0082] In some embodiments, the surfactant comprises a nonionic surfactant. In some embodiments, the nonionic surfactant comprises a block copolymer of vitamin E, polyethylene glycol and polypropylene glycol, or any combination thereof. In some embodiments, the surfactant comprises two or more repeating units, such as a polyoxyalkylene unit. 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.

[0083] In some embodiments, the surfactant comprises an ionic surfactant. An ionic surfactant may have a charged group in its head. An ionic surfactant has an anionic head group or a cationic head group. In some embodiments, exemplary ionic surfactants include sodium lauryl sulfate (SLS), sodium lauryl sulfate, calcium oleate, triethanolamine oleate, docusate sodium (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.

[0084] In some embodiments, the number average molecular weight of the nonionic surfactant is about 1000Da to about 100,000Da, 2000Da to about 20,000Da, about 4000Da to about 15,000Da, about 6000Da to about 12,000Da, or about 7000Da to about 10,000Da. In some embodiments, the number average molecular weight of the nonionic surfactant is about 7000Da to about 10,000Da. In some embodiments, the ethylene glycol content of the nonionic surfactant is about 30wt% to about 99wt%, about 50wt% to about 95wt%, about 60wt% to about 95wt%, about 75wt% to about 90wt%, or about 80wt% to about 85wt%. In some embodiments, the ethylene glycol content of the nonionic surfactant is about 80wt% to about 85wt%.

[0085] In some embodiments, surfactant is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 55wt%. In some embodiments, surfactant is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 1wt%, about 1wt% to about 5wt%, about 5wt% to about 10wt%, about 10wt% to about 15wt%, about 15wt% to about 20wt%, about 20wt% to about 25wt%, about 25wt% to about 30wt%, about 30wt% to about 40wt%, about 40wt% to about 45wt%, about 45wt% to about 50wt% or about 50wt% to about 55wt%. In some embodiments, surfactant is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 1wt%. In some embodiments, surfactant is present in the topical pharmaceutical composition in an amount of about 1wt% to about 5wt%. In some embodiments, surfactant is present in the topical pharmaceutical composition in an amount of about 5wt% to about 10wt%. In some embodiments, surfactant is present in the topical pharmaceutical composition in an amount of about 10wt% to about 15wt%. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 20 wt % to about 25 wt %. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 25 wt % to about 30 wt %. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 30 wt % to about 35 wt %. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 35 wt % to about 40 wt %. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 40 wt % to about 45 wt %. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 45 wt % to about 50 wt %. In some embodiments, the surfactant is present in the topical pharmaceutical composition in an amount of about 50 wt % to about 55 wt %. In some embodiments, the surfactant comprises polyoxyethylene glyceride (e.g., caprylocaproyl polyoxyethylene-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 polyoxyethylene-6 glyceride. In some embodiments, the surfactant comprises PEG-6 palmitostearate, PEG-32 palmitostearate, and glycol palmitostearate (e.g., 63). In some embodiments, the surfactant comprises polyoxyethylene stearate or polyethylene glycol stearate (e.g., Gelot TM 64). In some embodiments, the surfactant comprises sorbitan monostearate (e.g., 60). In some embodiments, the surfactant comprises polyglyceryl-3 dioleate (e.g., Oleique CC 497). In some embodiments, the surfactant comprises sodium lauryl sulfate (SDS). In some embodiments, the surfactant comprises glyceryl monooleate (e.g., Peceol TM ).

[0086] In some embodiments, glyceryl monooleate (e.g., Peceol TM ) is present in the topical pharmaceutical composition in an amount of about 1 wt % to about 20 wt %. In some embodiments, glyceryl monooleate (e.g., Peceol TM ) is present in the topical pharmaceutical composition in an amount of about 1 wt % to about 5 wt %, about 5 wt % to about 10 wt %, about 10 wt % to about 15 wt %, or about 15 wt % to about 20 wt %. In some embodiments, glyceryl monooleate (e.g., Peceol TM ) is present in the topical pharmaceutical composition in an amount of about 1 wt % to about 5 wt %. In some embodiments, glyceryl monooleate (e.g., Peceol TM ) is present in the topical pharmaceutical composition in an amount of about 5 wt % to about 10 wt %. In some embodiments, glyceryl monooleate (e.g., Peceol TM ) is present in the topical pharmaceutical composition in an amount of about 10 wt % to about 15 wt %. In some embodiments, glyceryl monooleate (e.g., Peceol TM ) is present in the topical pharmaceutical composition in an amount of about 15 wt % to about 20 wt %. In some embodiments, glyceryl monooleate (e.g., Peceol TM ) is present in the topical pharmaceutical composition in an amount of about 10 wt %.

[0087] In some embodiments, 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 wt% to about 25 wt%. In some embodiments, 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 wt% to about 5 wt%, about 5 wt% to about 10 wt%, about 10 wt% to about 15 wt%, about 15 wt% to about 20 wt%, or about 20 wt% to about 25 wt%. In some embodiments, 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 wt% to about 5 wt%. In some embodiments, 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 wt% to about 10 wt%. In some embodiments, 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 wt% to about 15 wt%. In some embodiments, 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 wt% to about 20 wt%. In some embodiments, 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 wt% to about 25 wt%. In some embodiments, 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 wt%.

[0088] In some embodiments, sorbitan monostearate (e.g., 60) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 10 wt%. In some embodiments, sorbitan monostearate (e.g., 60) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 2 wt%, about 2 wt% to about 5 wt%, about 5 wt% to about 7 wt%, or about 7 wt% to about 10 wt%. In some embodiments, sorbitan monostearate (e.g., 60) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 2 wt%. In some embodiments, sorbitan monostearate (e.g., 60) is present in the topical pharmaceutical composition in an amount of about 2 wt% to about 5 wt%. In some embodiments, sorbitan monostearate (e.g., 60) is present in the topical pharmaceutical composition in an amount of about 5 wt% to about 7 wt%. In some embodiments, sorbitan monostearate (e.g., 60) is present in the topical pharmaceutical composition in an amount of about 7 wt% to about 10 wt%. In some embodiments, sorbitan monostearate (e.g., 60) is present in the topical pharmaceutical composition in an amount of about 3.5 wt%.

[0089] In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 10 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 2 wt%, about 2 wt% to about 5 wt%, about 5 wt% to about 7 wt%, or about 7 wt% to about 10 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 2 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 2 wt% to about 5 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5 wt% to about 7 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 7 wt% to about 10 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5 wt%.

[0090] penetration enhancers

[0091] In one aspect, disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and excipients (eg, including a penetration enhancer).

[0092] In some embodiments, the topical pharmaceutical compositions described herein include a penetration enhancer. A penetration enhancer can penetrate the skin, interact with skin components, reduce skin barrier resistance, and promote the flux of the drug (e.g., midostaurin or a pharmaceutically acceptable salt thereof) in the topical pharmaceutical compositions described herein. In some embodiments, a penetration enhancer can have one or more functions simultaneously, including surfactants, solubility enhancers, bioavailability enhancers, and emulsifiers. Other terms in the field of penetration enhancers include penetration-enhancing agents, penetrants, adsorption accelerators, accelerators, and the like. 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 (e.g., 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.

[0093] In some embodiments, the penetration enhancer comprises polyglyceryl-3 dioleate (e.g., Oleique CC497), diethylene glycol monoethyl ether (e.g., P sold), oleoyl polyoxyethylene-6 glycerides (e.g., M 1944CS) or 1-dodecylazacycloheptan-2-one (or Azone) or a combination thereof.

[0094] In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 45wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 1wt%, about 1wt% to about 5wt%, about 5wt% to about 10wt%, about 10wt% to about 15wt%, about 15wt% to about 20wt%, about 20wt% to about 25wt%, about 25wt% to about 30wt%, about 30wt% to about 40wt% or about 40wt% to about 45wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 1wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 1wt% to about 5wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 5wt% to about 10wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 10wt% to about 15wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 20wt% to about 25wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 25wt% to about 30wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 30wt% to about 35wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 35wt% to about 40wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 40wt% to about 45wt%. In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 45wt% to about 50wt%. In some embodiments, the penetration enhancer comprises polyglyceryl-3 dioleate (e.g., Oleique CC 497). In some embodiments, the penetration enhancer comprises diethylene glycol monoethyl ether (e.g., P). In some embodiments, the penetration enhancer comprises oleoyl polyoxyethylene-6 glyceride (e.g., M 1944CS). In some embodiments, the penetration enhancer comprises 1-dodecylazacycloheptan-2-one (or Azone). In some embodiments, the penetration enhancer comprises oleoyl polyoxyethylene-6 glyceride (e.g., M 1944CS) and 1-dodecylazacycloheptan-2-one (or Azone).

[0095] In some embodiments, the penetration enhancer is present in the topical pharmaceutical composition in an amount of about 5 wt % to about 10 wt %. In some embodiments, the penetration enhancer comprises polyglyceryl-3 dioleate (e.g., Oleique CC497). In some embodiments, the penetration enhancer comprises diethylene glycol monoethyl ether (e.g., P). In some embodiments, the penetration enhancer comprises oleoyl polyoxyethylene-6 glyceride (e.g., M 1944CS).

[0096] In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 15 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 2 wt%, about 2 wt% to about 5 wt%, about 5 wt% to about 7 wt%, about 7 wt% to about 10 wt%, or about 10 wt% to about 15 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 1 wt% to about 2 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 2 wt% to about 5 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5 wt% to about 7 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 7 wt% to about 10 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 10 wt% to about 15 wt%. In some embodiments, polyglyceryl-3 dioleate (e.g., Oleique CC 497) is present in the topical pharmaceutical composition in an amount of about 5 wt%.

[0097] pH stabilizers

[0098] In one aspect, disclosed herein are topical pharmaceutical compositions comprising midostaurin or a pharmaceutically acceptable salt thereof, a carrier vehicle, and excipients (eg, including a pH stabilizer).

[0099] In some embodiments, the topical pharmaceutical compositions described herein comprise a pH stabilizer. In some embodiments, the gel topical pharmaceutical compositions described herein comprise a pH stabilizer. In some embodiments, the topical pharmaceutical compositions described herein comprise means for maintaining pH. In some embodiments, the means for maintaining pH are 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.

[0100] 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.

[0101] In certain embodiments, the pH stabilizer comprises 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. Other 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, a mixture of aluminum glycinate and a buffer, a mixture of an amino acid acid salt and a buffer, and a mixture of an amino acid alkali salt and a buffer. In certain embodiments, the pH stabilizer comprises citric acid. In certain embodiments, the topical pharmaceutical composition is a cream formulation.

[0102] In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein 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 suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 5.0 to about 8.0. In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 5.5 to about 7.5. In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 6.0 to about 7.5. In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 6.5 to about 7.5. In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 6.7 to about 7.3. In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 6.8 to about 7.2. In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 6.9 to about 7.1. In some embodiments, a suitable amount of a pH stabilizer is present in the topical pharmaceutical compositions described herein to maintain the pH of the composition at about 7.0. In some embodiments, the pH stabilizer is triethanolamine.

[0103] antioxidants

[0104] In one aspect, topical pharmaceutical compositions as described herein comprise midostaurin or a pharmaceutically acceptable salt thereof, a carrier medium and an excipient (e.g., a preservative, including an antioxidant). In certain embodiments, topical pharmaceutical compositions as described herein comprise a preservative. Preservatives may include antimicrobial agents, antioxidants, and agents that enhance sterility or reduce oxidation. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, citric acid, EDTA and its salt, isoascorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium pyrosulfite, sodium sulfite, parahydroxybenzoates (such as methylparaben, ethylparaben, propylparaben, butylparaben and its salt), benzoic acid, sodium benzoate, potassium sorbate, vanillin, etc.

[0105] In certain embodiments, topical pharmaceutical compositions as herein described include antioxidants. In certain embodiments, topical pharmaceutical compositions as herein described include two or more antioxidants. In certain embodiments, antioxidants include α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, BHA, BHT, cysteine, cysteine ​​hydrochloride, da-tocopherol (natural or synthetic), dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea or tocopherol (for example, da-tocopherol) or its combination.

[0106] In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.0001 wt % to about 15 wt %. In some embodiments, the antioxidant is present in an amount of about 0.0001 wt % to about 0.001 wt %, about 0.0001 wt % to about 0.01 wt %, about 0.0001 wt % to about 0.1 wt %, about 0.0001 wt % to about 1 wt %, about 0.0001 wt % to about 2 wt %, about 0.0001 wt % to about 5 wt %, about 0.0001 wt % to about 7 wt %, about 0.0001 wt % to about 10 wt %, about 0.0001 wt % to about 15 wt %, 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 wt% to about 7 wt%, about 0.001 wt% to about 10 wt%, about 0.001 wt% to about 15 wt%, about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 5 wt%, about 0.01 wt% to about 7 wt%, about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 15 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 2 wt%, about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 7 wt%, about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 15 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 5 wt%, about % to about 10 wt %, about 7 wt % to about 15 wt %, about 10 wt % to about 15 wt %, about 2 wt % to about 5 wt %, about 2 wt % to about 7 wt %, about 2 wt % to about 10 wt %, about 2 wt % to about 15 wt %, about 5 wt % to about 7 wt %, about 5 wt % to about 10 wt %, about 5 wt % to about 15 wt %, about 7 wt % to about 10 wt %, about 7 wt % to about 15 wt %, or about 10 wt % to about 15 wt %. In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.0001 wt %, about 0.001 wt %, about 0.01 wt %, about 0.1 wt %, about 1 wt %, about 2 wt %, about 5 wt %, about 7 wt %, about 10 wt % or about 15 wt %. In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of at least about 0.0001 wt%, about 0.001 wt%, about 0.01 wt%, about 0.1 wt%, about 1 wt%, about 2 wt%, about 5 wt%, about 7 wt%, or about 10 wt% by weight.

[0107] In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.01 wt % to about 0.1 wt %. In some embodiments, the antioxidant is present in the topical pharmaceutical composition in an amount of about 0.06 wt %. In some embodiments, the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbyl palmitate.

[0108] Viscosity regulator

[0109] Viscosity modifiers are agents that can increase or decrease the viscosity of a pharmaceutical composition or change its texture. Viscosity modifiers can include rheology modifiers or other names known in the art. Viscosity modifiers can include viscosity enhancers (viscosity enhancer / viscosity-enhancing agent), thickeners or other names known in the art. Viscosity modifiers can also include viscosity reducers (viscosity-reducing agent) 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 trade name Carbomer), stearyl alcohol, glyceryl behenate (e.g., sold under the trademark 888ATO), white petrolatum, silicone compounds (e.g., a mixture of cyclopentasiloxane, dimethicone, and phenyltrimethylsilane sold under the trademark sell).

[0110] In some embodiments, the midostaurin topical pharmaceutical compositions described herein comprise a viscosity modifier. In some embodiments, the viscosity modifier comprises aluminum monostearate, bentonite, polyacrylic acid (or PAA) (e.g., cross-linked polyacrylic acid sold under the trade name Carbomer), stearyl alcohol, glyceryl behenate (e.g., 888ATO), white petrolatum, or a combination thereof.

[0111] In some embodiments, the viscosity modifier is present in the topical pharmaceutical composition in an amount of about 0.01 wt % to about 15 wt %. In some embodiments, the viscosity modifier is present in the topical pharmaceutical composition in an amount of about 0.01 wt % to about 0.1 wt %, about 0.01 wt % to about 1 wt %, about 0.01 wt % to about 2 wt %, about 0.01 wt % to about 5 wt %, about 0.01 wt % to about 7 wt %, about 0.01 wt % to about 10 wt %, about 0.01 wt % to about 15 wt %, about 0.1 wt % to about 0.5 wt %, about 0.1 wt % to about 1 wt %, about 0.1 wt % to about 2 wt %, about 0.1 wt % to about 5 wt %, about 0.1 wt % to about 7 wt %, about 0.1 wt % to about 10 wt %, about 0.1 wt % to about 15 wt %, about 0.5 wt % to about 1 wt %, about 0.5 wt % to about 2 wt %, about 0.5 % to about 15 wt %, about 2 wt % to about 5 wt %, about 2 wt % to about 7 wt %, about 2 wt % to about 10 wt %, about 2 wt % to about 15 wt %, about 5 wt % to about 7 wt %, about 5 wt % to about 10 wt %, about 5 wt % to about 15 wt %, about 7 wt % to about 10 wt %, about 7 wt % to about 15 wt %, or about 10 wt % to about 15 wt %. 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), stearyl alcohol, petroleum jelly (e.g., white petrolatum), or a combination thereof.

[0112] In some embodiments, the cross-linked polyacrylic acid (or carbomer) is present in the topical pharmaceutical composition in an amount of about 0.1 wt % to about 1 wt %. In some embodiments, the cross-linked polyacrylic acid (or carbomer) is present in the topical pharmaceutical composition in an amount of about 0.25 wt % to about 0.75 wt %. In some embodiments, the cross-linked polyacrylic acid (or carbomer) is present in the topical pharmaceutical composition in an amount of about 0.5 wt %.

[0113] In some embodiments, stearyl alcohol is present in the topical pharmaceutical composition in an amount of about 1 wt % to about 5 wt %. In some embodiments, stearyl alcohol is present in the topical pharmaceutical composition in an amount of about 2 wt % to about 4 wt %. In some embodiments, stearyl alcohol is present in the topical pharmaceutical composition in an amount of about 3.5 wt %.

[0114] moisturizer

[0115] Wetting agent is the medicament that makes water or moisture be combined with skin or moisture is retained in the skin.Wetting agent can include wetting agent, and described wetting agent can make water or moisture be combined with skin.Wetting agent can include sealing agent, and described sealing agent can produce the protective barrier that moisture is retained in skin and prevents water loss.Wetting agent can include emollient, and described emollient keeps skin hydrated and smooth.The example of wetting agent includes but is not limited to petrolatum, mineral oil, wax, liquid paraffin, petroleum jelly (for example, white vaseline), glycerol (glycerol or glycerin), propylene glycol, polyethylene glycol (PEG), hexylene glycol and sorbitol.(referring to for example U.S. publication No. US2004 / 0191276, described U.S. publication is incorporated by reference at this).

[0116] In some embodiments, the midostaurin topical pharmaceutical compositions described herein comprise a moisturizer. In some embodiments, the midostaurin topical pharmaceutical compositions described herein comprise two or more moisturizers. In some embodiments, the moisturizer comprises petrolatum, mineral oil, wax, liquid paraffin, petroleum jelly, glycerol (glycerin), propylene glycol, hexylene glycol, or a combination thereof.

[0117] In some embodiments, the wetting agent is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 35wt%. In some embodiments, the wetting agent is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 1wt%, about 1wt% to about 5wt%, about 5wt% to about 10wt%, about 10wt% to about 15wt%, about 15wt% to about 20wt%, about 20wt% to about 25wt%, about 25wt% to about 30wt%, or about 30wt% to about 35wt%. In some embodiments, the wetting agent is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 1wt%. In some embodiments, the wetting agent is present in the topical pharmaceutical composition in an amount of about 1wt% to about 5wt%. In some embodiments, the wetting agent is present in the topical pharmaceutical composition in an amount of about 5wt% to about 10wt%. In some embodiments, the wetting agent is present in the topical pharmaceutical composition in an amount of about 10wt% to about 15wt%. In some embodiments, the wetting agent is present in the topical pharmaceutical composition in an amount of about 20wt% to about 25wt%. In some embodiments, the moisturizing agent is present in the topical pharmaceutical composition in an amount of about 25 wt % to about 30 wt %. In some embodiments, the moisturizing agent is present in the topical pharmaceutical composition in an amount of about 30 wt % to about 35 wt %. In some embodiments, the moisturizing agent comprises liquid paraffin, petroleum jelly (e.g., white petrolatum), glycerol (glycerin), propylene glycol, or a combination thereof.

[0118] In some embodiments, the humectant comprises glycerin. In some embodiments, glycerin is present in the topical pharmaceutical composition in an amount of about 5 wt % to about 10 wt %. In some embodiments, glycerin is present in the topical pharmaceutical composition in an amount of about 10 wt % to about 15 wt %. In some embodiments, glycerin is present in the topical pharmaceutical composition in an amount of about 5 wt %. In some embodiments, glycerin is present in the topical pharmaceutical composition in an amount of about 13 wt %.

[0119] In some embodiments, the humectant comprises glycerol (glycerol or glycerin) and propylene glycol. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 10wt% to about 30wt%. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 15wt% to about 25wt%. In some embodiments, the humectant is present in the topical pharmaceutical composition in an amount of about 20wt%.

[0120] sunscreen

[0121] Sunscreen is an agent that can protect the skin from ultraviolet (UV) radiation. Sunscreen can absorb UV and visible sunlight. Sunscreen can also reflect, scatter or block UV and visible sunlight. Sunscreen can include physical sunscreens. Sunscreen can include chemical sunscreens. Other terms in this area include sunscreen (sun-screening agent / sunscreen), sunscreen isolation cream, etc. Non-limiting examples of sunscreen include avobenzone, betrizinol, benzophenone-3 (BZ-3, oxybenzone), and octotriazole, homosalate, octinoxate, octocrylene, oxybenzone, titanium dioxide or zinc oxide or a combination 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, which is incorporated herein by reference.

[0122] In some embodiments, the midostaurin topical pharmaceutical compositions described herein comprise a sunscreen. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.0001 wt% to about 5 wt%. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.0001 wt% to about 0.001 wt%, about 0.0001 wt% to about 0.01 wt%, about 0.0001 wt% to about 0.1 wt%, about 0.0001 wt% to about 1 wt%, about 0.0001 wt% to about 2 wt%, about 0.0001 wt% to about 5 wt%, 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 0.0001 wt% to about 5 wt%, 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 About 2wt%, about 0.001wt% to about 5wt%, about 0.01wt% to about 0.1wt%, about 0.01wt% to about 1wt%, about 0.01wt% to about 2wt%, about 0.01wt% to about 5wt%, about 0.1wt% to about 1wt%, about 0.1wt% to about 2wt%, about 0.1wt% to about 5wt%, about 1wt% to about 2wt%, about 1wt% to about 5wt%, about 2wt% to about 5wt% or about 3wt% to about 5wt% is present in the topical pharmaceutical composition. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.001wt% to about 0.01wt%. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.01wt% to about 0.1wt%. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.1wt% to about 0.5wt%. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 0.5 wt % to about 1 wt %. In some embodiments, the sunscreen is present in the topical pharmaceutical composition in an amount of about 1 wt % to about 2 wt %. In some embodiments, the sunscreen comprises avobenzone, betrizinol, benzophenone-3 (BZ-3, oxybenzone), oxalotriazole, homosalate, octinoxate, octocrylene, oxybenzone, titanium dioxide, or zinc oxide, or a combination thereof.

[0123] Other additives

[0124] The excipients described herein can be used alone or in combination. In some embodiments, other additives conventionally mixed with pharmaceutical compositions can include topical pharmaceutical compositions. Additives include, but are not limited to, suspending agents (e.g., cellulose ethers), defoaming agents (e.g., hydrophobic silica), or any suitable agent that can improve general skin condition, such as alpha hydroxy acids (e.g., glycolic acid and lactic acid).

[0125] Additives can also be materials such as proteins (e.g., collagen, gelatin, zein, gluten, mussel proteins, 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, shellac such as shellac based on sugars (e.g., lactose, sucrose, dextrose) or starch, polysaccharide-based polymers (e.g., maltodextrin and maltodextrin derivatives, dextran, cyclodextrin and cyclodextrin derivatives).

[0014] Examples of the present invention include, but are not limited to, cellulose derivatives, cellulose-based polymers (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxypropyl cellulose, cellulose acetate, nitrocellulose, cellulose acetate butyrate, cellulose acetate, trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose phthalate), inorganics (e.g., dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc, and titanium dioxide), polyols (e.g., mannitol, xylitol, and sorbitan polyethylene glycol esters), and polymers (e.g., alginates, poly(lactide-co-glycolide), gelatin, cross-linked gelatin, and agar). In some embodiments, the protein comprises an amino acid, such as an acidic salt of glutamic acid, aspartic acid, or glycine, alanine, or serine.

[0126] stability

[0127] In some embodiments, the topical pharmaceutical compositions described herein are stable under various storage conditions, including refrigerated conditions, ambient conditions, room temperature, and accelerated conditions. In some embodiments, a stable midostaurin composition, as used herein, refers to a midostaurin topical pharmaceutical composition having about 95% or more of the initial amount of midostaurin and about 5% or less of total impurities or related substances by weight at the end of a given storage period. In some embodiments, a stable midostaurin composition, as used herein, refers to a midostaurin topical pharmaceutical composition having about 90% or more of the initial amount of midostaurin and about 10% or less of total impurities or related substances by weight at the end of a given storage period.

[0128] The percentage of impurities can be calculated based on the amount of the impurity relative to the amount of midostaurin. The percentage of impurities can be assessed by high performance liquid chromatography (HPLC), such as using the method described in Table B-2 or any other known test method. In some embodiments, the stable midostaurin topical pharmaceutical composition contains no more than about 10 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2.5 wt%, about 2 wt%, about 1.5 wt%, about 1 wt%, or about 0.5 wt% of total impurities or related substances. In other embodiments, the stable midostaurin topical pharmaceutical composition contains no more than about 10 wt% of total impurities or related substances. In other embodiments, the stable midostaurin topical pharmaceutical composition contains no more than about 5 wt% of total impurities or related substances. In yet other embodiments, the stable midostaurin topical pharmaceutical composition contains no more than about 4 wt% of total impurities or related substances. In yet other embodiments, the stable midostaurin topical pharmaceutical composition contains no more than about 3 wt% of total impurities or related substances. In yet other embodiments, the stable midostaurin topical pharmaceutical composition contains no more than about 2 wt % of total impurities or related substances. In yet other embodiments, the stable midostaurin topical pharmaceutical composition contains no more than about 1 wt % of total impurities or related substances.

[0129] The percentage of midostaurin retained in the composition can be calculated based on the amount of midostaurin in the composition at a certain time point relative to the initial amount of midostaurin. The amount or midostaurin content can be assessed by HPLC, such as using the methods described in Table A-1 or any other known test method. In some embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 90 wt%, about 91 wt%, about 92 wt%, about 93 wt%, about 94 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, about 99 wt%, about 99.5 wt%, or about 99.9 wt% of the initial amount of midostaurin. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 90 wt% of the initial amount of midostaurin. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 91 wt% of the initial amount of midostaurin. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 92 wt% of the initial amount of midostaurin. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 93% by weight of the initial midostaurin amount. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 94% by weight of the initial midostaurin amount. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 95% by weight of the initial midostaurin amount. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 96% by weight of the initial midostaurin amount. In yet other embodiments, the stable midostaurin topical pharmaceutical composition retains at least about 97% by weight of the initial midostaurin amount. In yet other embodiments, the 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. In 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 midostaurin amount.

[0130] In some embodiments, the midostaurin topical pharmaceutical compositions described herein are stable under conditions of 4500 lux (1x) light exposure for at least 1 day, 3 days, 7 days, 14 days, 21 days, or 30 days. In some embodiments, the midostaurin topical pharmaceutical compositions are stable under conditions of 4500 lux (1x) light exposure for at least 1 day. In some embodiments, the midostaurin topical pharmaceutical compositions are stable under conditions of 4500 lux (1x) light exposure for at least 3 days. In some embodiments, the midostaurin topical pharmaceutical compositions are stable under conditions of 4500 lux (1x) light exposure for at least 7 days. In some embodiments, the midostaurin topical pharmaceutical compositions are stable under conditions of 4500 lux (1x) light exposure for at least 21 days. In some embodiments, the midostaurin topical pharmaceutical compositions are stable under conditions of 4500 lux (1x) light exposure for at least 30 days.

[0131] 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 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 compositions are stable for at least 1 day 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 compositions are stable for at least 3 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 compositions are stable for at least 7 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 compositions are 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.

[0132] 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 compositions are stable for at least 1 day when stored at about 60°C. In some embodiments, the midostaurin topical pharmaceutical compositions are stable for at least 3 days when stored at about 60°C. In some embodiments, the midostaurin topical pharmaceutical compositions are stable for at least 7 days when stored at about 60°C. In some embodiments, the midostaurin topical pharmaceutical compositions are stable for at least 21 days when stored at about 60°C.

[0133] 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, the stable topical pharmaceutical compositions are 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 compositions are stable for at least 1 day after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical compositions are stable for at least 3 days after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical compositions are stable for at least 7 days after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical compositions are stable for at least 21 days after at least one freeze-thaw cycle. In some embodiments, the midostaurin topical pharmaceutical compositions are stable for at least 30 days after at least one freeze-thaw cycle.

[0134] 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 refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 1 month when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 3 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 6 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 9 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 12 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 15 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 18 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 24 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 30 months when stored under refrigeration. In some embodiments, the midostaurin topical formulations described herein are stable for at least 36 months when stored under refrigeration.

[0135] 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 under refrigeration 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 formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 1 month. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 3 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 24 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 30 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 36 months.

[0136] In some embodiments, the midostaurin topical formulations described herein contain no more than 5% by weight of total impurities after storage under refrigeration 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 formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 1 month. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 3 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 6 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 9 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 12 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 15 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 18 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 24 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 30 months. In some embodiments, the midostaurin topical formulation contains no more than 5% by weight of total impurities after storage under refrigeration for at least 36 months.

[0137] In some embodiments, the midostaurin topical formulations described herein retain at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration 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 formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 1 month. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 3 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 24 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 30 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage under refrigeration for at least 36 months.

[0138] In some embodiments, the midostaurin topical formulations described herein contain no more than 2% by weight of total impurities after storage under refrigeration 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 formulation contains no more than 2% by weight of total impurities after storage under refrigeration for at least 1 month. In some embodiments, the midostaurin topical formulation contains no more than 2% by weight of total impurities after storage under refrigeration for at least 3 months. In some embodiments, the midostaurin topical formulation contains no more than 2% by weight of total impurities after storage under refrigeration for at least 6 months. In some embodiments, the midostaurin topical formulation contains no more than 2% by weight of total impurities after storage under refrigeration for at least 9 months. In some embodiments, the midostaurin topical formulation contains no more than 2% by weight of total impurities after storage under refrigeration for at least 12 months. In some embodiments, the midostaurin topical formulation contains no more than 2% by weight of total impurities after storage under refrigeration for at least 15 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under refrigeration for at least 18 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under refrigeration for at least 24 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under refrigeration for at least 30 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under refrigeration for at least 36 months.

[0139] 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, or at least 24 months when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 1 month when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 3 months when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 6 months when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 9 months when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 12 months when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 15 months when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 18 months when stored at ambient conditions. In some embodiments, the midostaurin topical formulations described herein are stable for at least 24 months when stored under ambient conditions.

[0140] 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 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 formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin, or a pharmaceutically acceptable salt thereof, after storage at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin, or a pharmaceutically acceptable salt thereof, after storage at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin, or a pharmaceutically acceptable salt thereof, after storage at ambient conditions for at least 24 months.

[0141] In some embodiments, the midostaurin topical formulations described herein contain no more than 5 wt% 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 formulation contains no more than 5 wt% total impurities after storage at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulation contains no more than 5 wt% total impurities after storage at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulation contains no more than 5 wt% total impurities after storage at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulation contains no more than 5 wt% total impurities after storage at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulation contains no more than 5 wt% total impurities after storage at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation contains no more than 5 wt% total impurities after storage at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation contains no more than 5 wt% total impurities after storage at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation contains no more than 5 wt % total impurities after storage at ambient conditions for at least 24 months.

[0142] In some embodiments, the midostaurin topical formulations described herein retain at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof 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 formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin, or a pharmaceutically acceptable salt thereof, after storage at ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin, or a pharmaceutically acceptable salt thereof, after storage at ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin, or a pharmaceutically acceptable salt thereof, after storage at ambient conditions for at least 24 months.

[0143] In some embodiments, the midostaurin topical formulations described herein contain no more than 2 wt% total impurities after storage under 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 formulation contains no more than 2 wt% total impurities after storage under ambient conditions for at least 1 month. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under ambient conditions for at least 3 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under ambient conditions for at least 6 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under ambient conditions for at least 9 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under ambient conditions for at least 12 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under ambient conditions for at least 15 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt% total impurities after storage under ambient conditions for at least 18 months. In some embodiments, the midostaurin topical formulation contains no more than 2 wt % total impurities after storage at ambient conditions for at least 24 months.

[0144] In some embodiments, the midostaurin topical formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, or at least 6 months when stored at about 40°C. In some embodiments, the midostaurin topical formulations described herein are stable for at least 1 month when stored at about 40°C. In some embodiments, the midostaurin topical formulations described herein are stable for at least 2 months when stored at about 40°C. In some embodiments, the midostaurin topical formulations described herein are stable for at least 3 months when stored at about 40°C. In some embodiments, the midostaurin topical formulations described herein are stable for at least 6 months when stored at about 40°C.

[0145] 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 1 month, at least 2 months, at least 3 months, or at least 6 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulation retains at least 90% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 6 months.

[0146] In some embodiments, the midostaurin topical formulations described herein contain no more than 5% 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 no more than 5% by weight of total impurities after storage at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulations contain no more than 5% by weight of total impurities after storage at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulations contain no more than 5% by weight of total impurities after storage at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulations contain no more than 5% by weight of total impurities after storage at about 40° C. for at least 6 months.

[0147] In some embodiments, the midostaurin topical formulations described herein retain at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof 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 formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 1 month. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 2 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 3 months. In some embodiments, the midostaurin topical formulation retains at least 95% by weight of midostaurin or a pharmaceutically acceptable salt thereof after storage at about 40° C. for at least 6 months.

[0148] In some embodiments, the midostaurin topical formulations described herein contain no more than 2 wt% 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 no more than 2 wt% total impurities after storage at about 40°C for at least 1 month. In some embodiments, the midostaurin topical formulations contain no more than 2 wt% total impurities after storage at about 40°C for at least 2 months. In some embodiments, the midostaurin topical formulations contain no more than 2 wt% total impurities after storage at about 40°C for at least 3 months. In some embodiments, the midostaurin topical formulations contain no more than 2 wt% total impurities after storage at about 40°C for at least 6 months.

[0149] The refrigerated temperature as defined by USP is between 2 degrees Celsius and 8 degrees Celsius, and is sometimes represented by a nominal value of 5 degrees Celsius. In some embodiments, the refrigerated temperature can be defined as 5 ± 3 ° C. Refrigerated conditions include the temperature and / or relative humidity (RH) in a typical refrigeration unit (e.g., 5 ± 3 ° C). In some instances, the refrigerated condition is 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 refrigerated condition is about 2 ° C to about 8 ° C.

[0150] 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 comprise a temperature 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 instances, 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 instances, ambient conditions are about 55% RH, about 60% RH, or about 65% RH.

[0151] The accelerated conditions for the midostaurin topical pharmaceutical formulations described herein include temperatures and / or relative humidity (RH) at or above ambient levels 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 above 55% RH, about 65% RH, about 70% RH, about 75% RH, or about 80% RH. In further examples, the accelerated conditions are about 40°C ± 2°C or 60°C at ambient humidity. In yet other examples, the accelerated conditions are about 40°C ± 2°C at 75 ± 5% RH.

[0152] Freeze-thaw studies can include subjecting the pharmaceutical composition to a series of extreme temperature changes, which are referred to as freeze-thaw cycles (freeze-thaw cycle or freeze thaw cycle). An example of a freeze-thaw cycle is exposing the pharmaceutical composition to freezing temperatures (e.g., about -15°C to about -25°C) for 24 hours, and then storing the pharmaceutical composition at a higher temperature (e.g., about 25°C) for 24 hours. In some embodiments, a freeze-thaw cycle refers to placing the 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.

[0153] Drug administration

[0154] The pharmaceutical compositions described herein are administered for the treatment or prevention of disease. When used to treat or prevent a disease or condition, the pharmaceutical compositions are administered or applied alone or in combination with other pharmaceutical 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 a topical pharmaceutical composition 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.

[0155] In some embodiments, the pharmaceutical composition is topically administered. In some embodiments, the pharmaceutical composition is administered in the form of a topical dosage form. In some embodiments, the pharmaceutical composition is administered in the form of an ointment, gel, cream, lotion, solution, emulsion, paste, patch, wipe, cotton swab, and pad, or any suitable form. In some embodiments, the pharmaceutical composition is administered in the form of a gel. In some embodiments, the pharmaceutical composition is administered in the form of a cream. In some embodiments, the pharmaceutical composition is administered in the form of an ointment.

[0156] 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.

[0157] The dosage of the described midostaurin topical pharmaceutical composition can be determined by any suitable method. The maximum tolerated dose (MTD) and maximum response dose (MRD) of midostaurin can be determined by established animal and human experimental protocols and can be determined in the examples described herein. For example, the toxicity and therapeutic efficacy of midostaurin can be determined in cell cultures or experimental animals by standard pharmaceutical procedures, including but not limited to, for determining the LD 50 (a dose lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as LD 50 With ED 50 Doses of midostaurin that exhibit a high therapeutic index are of interest. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages expressed as a percentage of the maximal response or the maximum tolerated dose are readily achieved by the regimen.

[0158] In some embodiments, the amount of a given midostaurin topical pharmaceutical composition corresponding to such an amount varies depending on factors such as the particular midostaurin salt or form, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., weight, sex), etc. However, the amount can still be determined based on the specific circumstances surrounding the case, including, for example, the specific agent being administered, the type of liquid composition, the disease condition being treated, and the subject or host being treated. In some instances, if a lack of a satisfactory response is noted, the midostaurin topical pharmaceutical composition can be discontinued.

[0159] In some embodiments, the midostaurin topical pharmaceutical compositions described herein are provided in dosages of about 0.001 mg to 300 mg, about 0.01 mg to about 200 mg, about 0.1 mg to about 20 mg, about 0.2 mg to about 10 mg of midostaurin per day. In certain embodiments, the midostaurin topical pharmaceutical compositions described herein are administered in an amount of about 0.001 mg to about 0.005 mg, about 0.005 mg to about 0.05 mg, about 0.05 mg to about 0.1 mg, about 0.1 mg to about 0.15 mg, about 0.15 mg to about 0.2 mg, about 0.2 mg to about 0.25 mg, about 0.25 mg to about 0.3 mg, about 0.3 mg to about 0.35 mg, about 0.35 mg to about 0.4 mg, about 0.4 mg to about 0.45 mg, about 0.45 mg to about 0.5 mg, about 0.5 mg to about 0.6 mg, about 0.6 mg to about 0.7 mg, about 0.7 mg to about 0.8 mg, or about 0.8 mg. In some instances, the midostaurin topical pharmaceutical compositions described herein are provided in a daily dose of 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 some instances, the midostaurin topical pharmaceutical compositions described herein are provided in a dose of about 0.1 mg per day. In some instances, the midostaurin topical pharmaceutical compositions described herein are provided in a dose of about 0.15 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.2 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.25 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.3 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.35 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.4 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.5 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.6 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.7 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.8 mg per day.In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 0.9 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 1 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 2 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 3 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 4 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 5 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 6 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 7 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 8 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 9 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 10 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 11 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 12 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 13 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 14 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 15 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 16 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 17 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 18 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dose of about 19 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 20 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 25 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 30 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 60 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 90 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 120 mg per day. In certain instances, the midostaurin topical pharmaceutical compositions described herein are provided at a dosage of about 200 mg per day.In certain examples, the midostaurin topical pharmaceutical compositions described herein are provided in a dosage of about 300 mg per day. The daily dosages described herein can be administered once daily or multiple times per day in the form of subdoses administered twice a day (bid), three times a day (tid), four times a day (qid), etc., wherein the number of subdoses is equal to the daily dosage.

[0160] 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 from about 10% to about 90% of the maximum tolerated dose (MTD), from about 25% to about 75% of the MTD, or about 50% of the MTD. In specific embodiments, the amount of the midostaurin topical pharmaceutical composition administered is from about 5% to about 10%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 99%, or more of the MTD of midostaurin or a pharmaceutically acceptable salt thereof.

[0161] The topical pharmaceutical compositions described herein can be administered at a dose lower than the dose of a commercially available topical pharmaceutical composition (e.g., 2% hydroquinone cream) used to treat the same indication to achieve the same therapeutic effect. In some embodiments, the therapeutically effective amount of the multi-targeted protein kinase inhibitor or its salt (e.g., midostaurin) is a dose that is 80% less than the dose of hydroquinone. In some embodiments, the therapeutically effective amount of the topical pharmaceutical composition comprising the multi-targeted protein kinase inhibitor or its salt (e.g., midostaurin) is a dose that is 80% less than the dose of 2% hydroquinone cream. In some embodiments, the therapeutically effective amount of the topical pharmaceutical composition comprising the multi-targeted protein kinase inhibitor or its salt (e.g., midostaurin) is a dose that is 70% less than the dose of 2% hydroquinone cream. In some embodiments, the therapeutically effective amount of the topical pharmaceutical composition comprising the multi-targeted protein kinase inhibitor or its salt (e.g., midostaurin) is a dose that is 50% less than the dose of 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition comprising midostaurin is administered at a dose that is 80% less than the dose of 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition comprising midostaurin is administered at a dose that is 60% lower than the dose of 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition comprising midostaurin is administered at a dose that is 50% lower than the dose of 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition comprising midostaurin is administered at a dose that is 30% lower than the dose of 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition comprises up to 1.0% wt midostaurin and is administered at a dose that is up to 80% of the dose required to achieve the same therapeutic effect as 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition comprises 0.5% wt midostaurin and is administered at a dose that is up to 50% of the dose required to achieve the same therapeutic effect as 2% hydroquinone cream. In some embodiments, the topical pharmaceutical composition comprises 0.5% wt midostaurin and is administered at a dose that is up to 30% of the dose required to achieve the same therapeutic effect as 2% hydroquinone cream.

[0162] Treatment

[0163] In one aspect, disclosed herein is a method for treating a skin-related disease or condition, comprising topically applying midostaurin or a salt thereof to the skin of a subject, wherein the skin is associated with a skin-related disease or condition. In one aspect, described herein is a method for treating a disease or condition by topically applying a composition (e.g., a cosmetic composition or a pharmaceutical composition) comprising midostaurin or a salt thereof to a subject in need thereof. In one aspect, described herein is a method for treating a disease or condition by topically applying a pharmaceutical composition comprising midostaurin or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the skin-related disease or condition is a skin pigmentation condition. In some embodiments, the subject suffers from a skin hyperpigmentation condition. In one aspect, the midostaurin topical pharmaceutical composition described herein is used to treat a skin-related disease or condition. 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 condition comprises skin hyperpigmentation. In some embodiments, skin hyperpigmentation is characterized by an overall darkening of the individual's normal skin color. In some embodiments, skin hyperpigmentation is characterized by a localized darkening of an individual's normal skin color. Hyperpigmentation conditions can include, for example, melasma, post-inflammatory hyperpigmentation, post-traumatic hyperpigmentation, discoid lupus erythematosus, freckles, lentigo of pregnancy, nevus of Ota, senile hyperpigmentation, and the like. In some embodiments, the hyperpigmentation condition comprises sun spots or age spots. Hyperpigmentation of the skin can occur on any or all parts of the body. In one aspect, disclosed herein is a method for 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 chloasma. In some embodiments, the treatment comprises reducing the size of the abnormal skin pigmentation, reducing the intensity of the abnormal skin pigmentation, and / or eliminating the abnormal skin pigmentation associated with the 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 a salt thereof is administered in a therapeutically effective amount.

[0164] In some embodiments, the methods described herein comprise applying midostaurin or a salt thereof, or a pharmaceutical composition or cosmetic composition comprising said midostaurin or a salt thereof, to the skin of a subject. In some embodiments, the skin is on the face, cheeks, bridge of the nose, forehead, chin, and above the upper lip of the subject. In some embodiments, the skin is on the face of the subject. In some embodiments, midostaurin or a salt thereof is applied in the form of a composition (e.g., an ointment, gel, cream, lotion, solution, emulsion, paste, patch, wipe, cotton swab, and pad, and any other form suitable for topical delivery). In some embodiments, midostaurin or a salt thereof is applied in the form of a transdermal composition. In some embodiments, midostaurin or a salt thereof is applied in the form of a pharmaceutical composition. In some embodiments, midostaurin or a salt thereof is applied in the form of a cosmetic composition.

[0165] In one aspect, disclosed herein is a method for reducing skin pigmentation, comprising topically applying midostaurin or a salt thereof to pigmented skin of a subject. In one aspect, the 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 suffers from 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, lentigo, nevus of Ota, senile hyperpigmentation, and the like. In some embodiments, midostaurin or a salt thereof, or a pharmaceutical composition comprising midostaurin or a salt thereof, is applied to the pigmented skin. The pigmented skin may be a pigmented birthmark, macular degeneration, hemangioma, or port wine stain. The pigmented skin may be a sun spot. The pigmented skin may be a dark spot. The pigmented skin may be age spots. The pigmented skin may be associated with a skin-related disease or condition. In some embodiments, the skin-related disease or condition is melasma or post-inflammatory hyperpigmentation.

[0166] 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 suffers from 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, lentigo, lentigo of pregnancy, nevus of Ota, age-related pigmentation, and the like.

[0167] Melasma is a common skin problem that causes skin pigmentation problems such as brown to gray-brown patches, which are usually on the face, cheeks, bridge of the nose, forehead, chin, and above the upper lip. Melasma is believed to be caused or aggravated by one or more of the following: birth control pills, pregnancy and hormone therapy, stress, thyroid disease, sun exposure, inflammation, family susceptibility, or free radicals. In some embodiments, melasma is caused or aggravated by one or more of the following: birth control pills, hormone therapy, sun exposure, or family susceptibility. It is believed that sun exposure can cause melasma due to ultraviolet rays affecting the cells that control pigments (melanocytes). UV radiation may cause lipid peroxidation in the cell membranes, thereby generating free radicals that may stimulate melanocytes to produce excess melanin.

[0168] 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, midostaurin or a salt thereof is formulated as a cosmetic composition.

[0169] 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 one year old. In some embodiments, the subject is less than one year old. In some embodiments, the subject is between 1 and 12 years old. In some embodiments, the subject is between 1 and 18 years old. In some embodiments, the subject is between 12 and 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 between 1 and 90 years old. In some embodiments, the subject has received or is currently receiving hormone therapy. In some embodiments, the subject has received or is currently receiving birth control pills. In some embodiments, the subject has a familial predisposition to hyperpigmentation or melasma.

[0170] 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 therapeutic agent can act additively, or more preferably synergistically. In some embodiments, the pharmaceutical composition is administered concurrently with the administration of another therapeutic agent. In some embodiments, the pharmaceutical composition is administered before or after the administration of another therapeutic agent.

[0171] In one aspect, midostaurin or a salt thereof reduces the amount of melanin in an area of ​​skin. 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. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar area of ​​skin by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the amount of melanin in the same area of ​​skin in a subject that has not received any treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar area of ​​skin by at least 25% compared to the amount of melanin in the same area of ​​skin in a subject that has not received any treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar area of ​​skin by at least 50% compared to the amount of melanin in the same area of ​​skin in a subject that has not received any treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 75%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 10%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 15%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 20%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 25%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 30%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 35%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 40%, compared to the amount of melanin in the same skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 45%, compared to the amount of melanin in the same skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 50%, compared to the amount of melanin in the same skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 60%, compared to the amount of melanin in the same skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 70%, compared to the amount of melanin in the same skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 80%, compared to the amount of melanin in the same skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 90%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 95%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 99%, compared to the amount of melanin in the skin area of ​​the same subject that has not received any treatment. In some embodiments, the amount of melanin is measured by a melanin profile score, such as the method described in Example G. In some embodiments, the amount of melanin is measured by a melanin profile score using a guinea pig model.

[0172] In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the amount of melanin in the same skin area of ​​the subject treated with a corresponding composition comprising hydroquinone. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 25% compared to the amount of melanin in the same skin area of ​​the subject treated with a corresponding composition comprising hydroquinone. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 50% compared to the amount of melanin in the same skin area of ​​the subject treated with a corresponding composition comprising hydroquinone. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 75% compared to the amount of melanin in the same skin area of ​​the subject treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a comparable skin area by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a comparable skin area by at least 10% compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a comparable skin area by at least 20% compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a comparable skin area by at least 30% compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 40%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 50%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 60%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 70%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 80%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 90%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 95%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce the amount of melanin in a similar skin area by at least 99%, compared to the amount of melanin in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the amount of melanin is measured by a melanin profile score, such as that described in Example G. In some embodiments, the amount of melanin is measured by melanin distribution scoring using guinea pigs as a model.

[0173] In some embodiments, a topical pharmaceutical composition comprising midostaurin or a salt thereof reduces the amount of melanin in an area of ​​skin. In some embodiments, the reduction in the amount of melanin in an area of ​​skin treated with the topical pharmaceutical composition is at least 100%, 110%, 120%, 130%, or 150% of the amount of melanin in a similar area of ​​skin of the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, wherein the topical pharmaceutical composition is administered at a dose lower than the dose 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% wt of midostaurin. In some cases, the reduction in the amount of melanin in an area of ​​skin treated with the topical pharmaceutical composition is at least 130% of the amount of melanin in a similar area of ​​skin of the same subject treated with a 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 1.5% wt of midostaurin. In some cases, the amount of melanin in an area of ​​skin treated with a topical pharmaceutical composition is reduced by at least 90% of the amount of melanin in a similar area of ​​skin of the same subject treated with 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 0.25% wt midostaurin. In some cases, the amount of melanin in an area of ​​skin treated with a topical pharmaceutical composition is reduced by at least 50% of the amount of melanin in a similar area of ​​skin of the same subject treated with 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 0.05% wt midostaurin. In some cases, the amount of melanin in an area of ​​skin treated with a topical pharmaceutical composition is reduced by at least 50% of the amount of melanin in a similar area of ​​skin of the same subject treated with 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 0.01% wt midostaurin. In some embodiments, the amount of melanin is measured by a melanin profile score, such as that described in Example G. In some embodiments, the amount of melanin is measured by a melanin profile score using a guinea pig as a model.

[0174] In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0, as compared to the amount of melanin in the skin area of ​​the same subject not undergoing said treatment, according to a melanin distribution score. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 1.0, as compared to the amount of melanin in the skin area of ​​the same subject not undergoing said treatment, according to a melanin distribution score. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 2.0, as compared to the amount of melanin in the skin area of ​​the same subject not undergoing said treatment, according to a melanin distribution score. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 1, 2, 3, or 4, as compared to the amount of melanin in the skin area of ​​the same subject not undergoing said treatment, according to a Fontana–Masson staining scale. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 1, as measured by the Fontana–Masson staining scale, compared to the amount of melanin in the skin area of ​​the same subject not undergoing the treatment. In some embodiments, midostaurin or a salt thereof reduces the amount of melanin in a similar skin area by at least 2, as measured by the Fontana–Masson staining scale, compared to the amount of melanin in the skin area of ​​the same subject not undergoing the 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.

[0175] In one aspect, midostaurin or a salt thereof reduces tyrosinase activity in an area of ​​skin. 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. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a similar area of ​​skin by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to tyrosinase activity in an area of ​​skin from the same subject that has not received any treatment. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a similar area of ​​skin by at least 25% compared to tyrosinase activity in an area of ​​skin from the same subject that has not received any treatment. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a similar area of ​​skin by at least 50% compared to tyrosinase activity in an area of ​​skin from the same subject that has not received any treatment. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a similar skin area by at least 75%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 10%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 15%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 20%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 25%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 30%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 35%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 40%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 45%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 50%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 60%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 70%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 80%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 90%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 95%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 99%, compared to tyrosinase activity in a skin area of ​​the same subject that has not received any treatment. In some embodiments, tyrosinase activity is measured per gram of tissue as described in Use Example G. In some embodiments, tyrosinase activity is measured per gram of tissue using guinea pigs as a model.

[0176] In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a comparable skin area by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. 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. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a comparable skin area by at least 25% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a comparable skin area by at least 55% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, midostaurin or a salt thereof reduces tyrosinase activity in a comparable skin area by at least 75%, compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 10%, compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 20%, compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 30%, compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 40%, compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 50%, compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a similar skin area by at least 60%, compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone.In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 70% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 80% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 90% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 95% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, the midostaurin topical pharmaceutical compositions described herein reduce tyrosinase activity in a comparable skin area by at least 99% compared to tyrosinase activity in the same subject's skin area treated with a corresponding composition comprising hydroquinone. In some embodiments, tyrosinase activity is measured per gram of tissue using the method described in Example G. In some embodiments, tyrosinase activity is measured per gram of tissue using guinea pigs as a model.

[0177] In some embodiments, midostaurin or a topical pharmaceutical composition comprising midostaurin or a salt thereof reduces tyrosinase activity in an area of ​​skin. In some embodiments, the reduction in tyrosinase activity in an area of ​​skin treated with the topical pharmaceutical composition is at least 100%, 110%, 120%, 130%, or 150% of the tyrosinase activity in a similar area of ​​skin from the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, wherein the topical pharmaceutical composition is administered at a dose lower than the dose 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 an area of ​​skin treated with the topical pharmaceutical composition is at least 120% of the tyrosinase activity in a similar area of ​​skin from the same subject treated with a 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 1.5% by weight of midostaurin. In some cases, the reduction in tyrosinase activity in an area of ​​skin treated with a topical pharmaceutical composition is at least 90% of the tyrosinase activity in a similar area of ​​skin from the same subject treated with 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 0.25% wt midostaurin. In some cases, the reduction in tyrosinase activity in an area of ​​skin treated with a topical pharmaceutical composition is at least 50% of the tyrosinase activity in a similar area of ​​skin from the same subject treated with 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 0.05% wt midostaurin. In some cases, the reduction in tyrosinase activity in an area of ​​skin treated with a topical pharmaceutical composition is at least 50% of the tyrosinase activity in a similar area of ​​skin from the same subject treated with 2% hydroquinone cream, wherein the topical pharmaceutical composition comprises 0.01% wt midostaurin. In some embodiments, tyrosinase activity is measured per gram of tissue as described in Use Example G. In some embodiments, tyrosinase activity is measured per gram of tissue using guinea pigs as a model.

[0178] 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 area of ​​skin treated with the topical pharmaceutical composition is mild at most, and wherein the topical pharmaceutical composition comprises at most 1.0 wt% midostaurin. In some embodiments, the level of skin irritation in the area of ​​skin treated with the topical pharmaceutical composition is mild, and wherein the topical pharmaceutical composition comprises at most 1.0 wt% midostaurin. In some embodiments, the level of skin irritation in the area of ​​skin treated with the topical pharmaceutical composition is mild, and wherein the topical pharmaceutical composition comprises 0.5% wt of midostaurin. In some embodiments, the level of skin irritation in the area of ​​skin treated with the topical pharmaceutical composition is non-irritating, and wherein the topical pharmaceutical composition comprises at most 0.5% wt of midostaurin. In some embodiments, the skin irritation score in the area of ​​skin treated with the topical pharmaceutical composition is at most 2.0, and wherein the topical pharmaceutical composition comprises 1.0% wt of midostaurin. In some embodiments, the skin irritation score in the area of ​​skin treated with the topical pharmaceutical composition is at most 1.5, and wherein the topical pharmaceutical composition comprises 1.0% wt of midostaurin. In some embodiments, the skin irritation score in the area of ​​skin treated with the topical pharmaceutical composition is at most 1.2, and wherein the topical pharmaceutical composition comprises 1.0% wt of midostaurin. In some embodiments, the skin irritation score in the area of ​​skin treated with the topical pharmaceutical composition is at most 1.0, and wherein the topical pharmaceutical composition comprises 0.5% wt of midostaurin. In some embodiments, the skin irritation score is evaluated using appropriate criteria 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.

[0179] In some embodiments, the 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., 2% hydroquinone cream). In some embodiments, the methods described herein do not produce any skin irritation. In some embodiments, the methods described herein do not produce any mild skin irritation. In some embodiments, the methods described herein do not produce any moderate skin irritation. In some embodiments, the methods described herein do not produce any moderate or severe skin irritation. In some cases, the skin irritation score in an area of ​​skin 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 area of ​​skin of the same subject treated with a reference topical pharmaceutical composition comprising hydroquinone, wherein the topical pharmaceutical composition is administered at a dose lower than the dose 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 the 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, wherein the topical pharmaceutical composition comprises 1.0% wt midostaurin. In some cases, the skin irritation score in the 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, wherein the topical pharmaceutical composition comprises 0.5% wt midostaurin. In some embodiments, the skin irritation score is evaluated using appropriate criteria set forth by regulatory agencies (such as the methods described in Example H). In some embodiments, the skin irritation score and irritation level are measured using rabbits as a model. In some embodiments, midostaurin or a topical pharmaceutical composition comprising midostaurin or a salt thereof does not produce phototoxicity. In some embodiments, the methods described herein do not produce 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 a multi-targeted protein kinase inhibitor (such as midostaurin).

[0180] Reagent test kit

[0181] For the midostaurin topical pharmaceutical compositions described herein, kits are also described. Such kits can include a carrier, package, or container that is separated to accommodate one or more containers (e.g., bottles, vials, tubes, etc.), each of which contains one of the individual elements to be 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 container can be formed from various materials such as glass or plastic. The container can further include a light protection mechanism. The container can have different sizes, such as about 12 oz, about 10 oz, about 8 oz, about 4 oz, about 3 oz, about 2 oz, about 1 oz. The container can have a seal, such as an induction seal. In some embodiments, the kit includes packaging that encapsulates the midostaurin topical pharmaceutical composition described herein. In some embodiments, the packaging is a tube.

[0182] The kit may include one or more additional containers, each containing one or more of the various materials (e.g., devices) required from a commercial and user perspective for the midostaurin topical pharmaceutical compositions described herein. Non-limiting examples of such materials include, but are not limited to, carriers, packaging, containers, vials, and / or tubes, labels listing the contents and / or instructions for use, and package inserts containing instructions for use associated with the midostaurin topical pharmaceutical compositions. An instruction set may also be included. In some embodiments, the kit includes instructions for use of the topical pharmaceutical compositions described herein.

[0183] The label can be on or associated with a container, such as a tube. The label can be on the container when the letters, numbers, or other characters forming the label are affixed, molded, or etched into the container itself; the label can be associated with the container when the label is present within a receptacle or carrier that also holds the container, such as as a package insert. The label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate instructions for use of the contents, such as in the methods described herein.

[0184] Manufacturing method

[0185] The midostaurin topical pharmaceutical compositions described herein may be prepared by any known pharmaceutical methods.

[0186] 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 (e.g., purified water) and excipients (e.g., a viscosity modifier, a pH stabilizer, a surfactant, a penetration enhancer, an antioxidant, or any combination thereof) to form a gel. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof, the carrier vehicle, and the excipients can be combined in any order of addition.

[0187] 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., a surfactant, a penetration enhancer, an antioxidant, or any combination thereof) to form an ointment. In some embodiments, midostaurin, or a pharmaceutically acceptable salt thereof, the carrier vehicle, and the excipients can be combined in any order of addition.

[0188] 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., a surfactant, a penetration enhancer, a humectant, a viscosity modifier, an antioxidant, or any combination thereof) to form a cream. In some embodiments, midostaurin or a pharmaceutically acceptable salt thereof, the carrier vehicle, and the excipients can be combined in any order of addition. In some embodiments, the preparation comprises 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., a surfactant, optionally a penetration enhancer, optionally a viscosity modifier, optionally a humectant) and heating to above 80°C. In some embodiments, the aqueous phase is prepared by weighing water and optional excipients (e.g., an antioxidant) and heating to above 80°C. In some embodiments, the preparation comprises gradually adding the oil phase to the aqueous phase and stirring to form a cream.

[0189] definition

[0190] Unless specifically stated or obvious from the context, as used herein, the term "about" with respect to a number or numerical range is understood to mean the stated number and + / - 10% of that number, or for a value in the listed range, 10% below the listed lower limit and 10% above the listed upper limit.

[0191] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. Thus, for example, reference to "a surfactant" includes reference to one or more of the specific surfactants, and reference to "an antioxidant" includes reference to one or more of such additives.

[0192] The use of the term "or" in the claims is used to mean "and / or" unless it is expressly stated that it refers only to alternatives or that the alternatives are mutually exclusive, but the present disclosure supports definitions that refer only to alternatives as well as to "and / or". The terms "comprises", "having" and "includes" 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" are also open-ended. For example, any method that "comprises", "has", or "includes" one or more steps is not limited to having only those one or more steps, and also encompasses other unlisted steps.

[0193] “Optional” or “optionally” can be taken to mean that the subsequently described structure, event, or circumstance can or cannot occur, and that the description includes instances where the event occurs and instances where it does not.

[0194] As used herein, the term "therapeutic agent" refers to an agent used to treat, counteract, alleviate, prevent, or improve an undesirable condition or disease in a patient. In some embodiments, therapeutic agents such as midostaurin are involved in the treatment and / or improvement, reversal, or stabilization of the symptoms of adrenal insufficiency as described herein.

[0195] As used herein, the term "subject" refers to a mammal (eg, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate such as a monkey, chimpanzee, or baboon).

[0196] When used in conjunction with a therapeutic agent, "administering" means administering the therapeutic agent systemically or locally, such as directly into or onto a target tissue, or administering the therapeutic agent to a patient whereby the therapeutic agent positively affects the tissue to which it is targeted. Thus, as used herein, the term "administering" when used in conjunction with a midostaurin formulation can include, but is not limited to, providing the midostaurin formulation into or onto a target tissue; providing the midostaurin formulation to a patient systemically, such as by oral administration, whereby the therapeutic agent reaches the target tissue or cells. "Administering" a formulation can be accomplished by injection, topical administration, and oral administration, or by other methods alone or in combination with other known techniques.

[0197] In some embodiments, an error band is included. The term "total error band" is used herein to describe all sources including sampling and sample preparation calculated at a 95% confidence level. An example is: D50 100 μm, where the total error band for size is + / - 5%. Other statistics are sometimes used to describe particle size distributions. The most common calculations are standard deviation and variance. Standard Deviation (St Dev.). The standard deviation specification defines the diameter at which approximately 68.27% of the total population lies within + / - 1 St Dev and 95.45% lies within + / - 2 St Dev.

[0198] "Effective amount" and "sufficient amount" are used interchangeably and refer to an amount of a substance sufficient to achieve the intended purpose or objective.

[0199] When used in conjunction with the pharmaceutical compositions described herein, a "therapeutically effective amount" is an amount of one or more pharmaceutically active agents sufficient to produce a therapeutic result in a subject in need thereof.

[0200] When used in connection with the pharmaceutical compositions described herein, "therapeutically equivalent" refers to an 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.

[0201] As used herein, the terms "treat," "treated," "treatment," or "treating" refer to therapeutic treatment, wherein the purpose is to prevent or slow down (mitigate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, relief of symptoms; a decrease in the extent of the condition, disorder, or disease; a stabilization of the condition, disorder, or disease state (i.e., no worsening); a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement in the condition, disorder, or disease state; and relief (whether partial or complete) of the condition, disorder, or disease, whether the condition, disorder, or disease is detectable or undetectable, or whether it is an enhancement or improvement. Treatment includes eliciting a clinically significant response without producing excessive levels of side effects. Treatment also includes prolonging survival compared to the 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, eliminating abnormal skin pigmentation associated with melasma, and the like.

[0202] Examples

[0203] The following examples are provided to further illustrate some embodiments of the present disclosure but are not intended to limit the scope of the present disclosure; by their exemplary nature it will be understood that other procedures, methods or techniques known to those skilled in the art may be used instead.

[0204] Example A. Solubility of midostaurin in different solvents and solubilizer / water systems.

[0205] 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.

[0206] A number of different solvents were evaluated for their compatibility with midostaurin. The solubility measurement method involved adding an excess of amorphous midostaurin powder to Figure 1 The various solvents listed on the x-axis were mixed at 600 rpm for 24-72 hours at 25°C to ensure equilibrium was achieved. Solubility was measured by HPLC. The HPLC method and parameters are provided in Table A-1.

[0207] Table A-1 HPLC method for measuring the content of midostaurin.

[0208]

[0209] Figure 1 Results from the current study showed that midostaurin exhibited low solubility (<10 mg / mL) in many hydrophilic solvents, such as ethanol and glycerol. Midostaurin has a 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 had good solubility (>50 mg / mL) in certain solubilizing agents, such as Tween 80 and Labrasol.

[0210] The solubility of midostaurin in systems where water and a solubilizing agent were combined at certain ratios was also evaluated. The method involved adding an excess of amorphous midostaurin powder to a system of various concentrations of solubilizing agent and water and mixing at 600 rpm for 24 hours at 25°C to ensure equilibrium was achieved. Solubility was measured by HPLC using the method provided in Table A-1. The solubilizing agents selected for this study included Transcutol, Labrasol, Tween 80, Cremphor EL, and Kolliphor HS15. Each solubilizing agent was mixed with water at 10% v / v, 20% v / v, and 30% v / v, respectively, to form systems in which amorphous midostaurin could dissolve.

[0211] The results are summarized in Figure 2Although Tween 80, Cremphor EL, and Kolliphor significantly improved the solubility of midostaurin in water, all systems tested still showed low solubility (<10 mg / mL).

[0212] Example B. Excipient compatibility study of midostaurin.

[0213] This example illustrates the process of selecting suitable excipients for a topical formulation of midostaurin or a pharmaceutically acceptable salt thereof, according to some embodiments of the present disclosure.

[0214] Midostaurin was mixed with a number of excipients used in topical formulations at a 1:200 (w / w) ratio and placed at 60°C for 10 days before testing. Impurities for each API and excipient combination were measured by HPLC, and the results are listed in Table B-1. The HPLC method and parameters are provided in Table B-2.

[0215]

[0216]

[0217] Table B-2 HPLC method for determination of midostaurin and its impurities.

[0218] column C18, 5μm, 4.6×150mm wavelength 294nm Column temperature 40℃ flow rate 0.9mL / min Injection volume 10 μL Mobile phase 40 mM ammonium formate:acetonitrile (35:65, v / v)

[0219] Excipient compatibility results showed that midostaurin powder was stable at 60°C for 10 days (assayed at 99.64%). However, when dissolved in different excipients, midostaurin powder became less stable, with the maximum impurity appearing at an RRT of 1.76. When an antioxidant (e.g., butylated hydroxyanisole) was added to the mixture of midostaurin and Peceol, less degradation was seen. One possibility is that when midostaurin is dissolved in oil, it is more susceptible to oxidized impurities when exposed to high temperatures.

[0220] Example C. Skin deposition measurement method for evaluating the efficiency of various topical formulations of midostaurin in penetrating the skin layers.

[0221] This example illustrates steps for evaluating how much midostaurin can penetrate the skin barrier when prepared in a specific topical formulation, according to some embodiments of the present disclosure.

[0222] Melasma is clinically characterized by epidermal hyperpigmentation. Histopathological changes involve both the epidermis and dermis, such as Figure 3As shown. Therefore, topically applied midostaurin should ideally penetrate into deeper skin layers. However, the outermost layer of the skin, the stratum corneum (SC), can be a barrier to drug penetration. Skin penetration enhancers can be designed into topical formulations to help midostaurin penetrate the SC. A skin deposition test can be used to evaluate penetration efficiency.

[0223] Use as Figure 4 The Franz diffusion cell and nude mouse skin shown were used for ex vivo skin deposition or retention experiments. The skin of nude mice (approximately 6 weeks old) was carefully excised, cleaned, and mounted on a diffusion cell with the stratum corneum facing the donor side. The formulation being tested 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 a tape stripping procedure. The midostaurin content in the stratum corneum and epidermis / dermis was determined by the HPLC method described in Table A-1.

[0224] 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 the skin of nude mice was studied. The results are summarized in Figure 5 The results are shown in Table C-1 and Table C-2, and show that when hydroquinone and midostaurin are dissolved in the same solution, the skin deposition of hydroquinone at a conventional concentration (2%) is greater than the skin deposition of midostaurin at 1%. Therefore, formulation strategies should consider enhancing the permeability of midostaurin in the skin.

[0225] Table C-1 Skin deposition of midostaurin solution in DMSO / propylene glycol relative to hydroquinone solution (1 / 3 v / v)

[0226]

[0227] Example D. Development of midostaurin gel formulation.

[0228] This example illustrates the process of developing a gel formulation of midostaurin according to some embodiments of the present disclosure.

[0229] Transcutol, Labrasol, Tween 80 or a combination thereof were used to prepare gel formulations as shown in Table D-1, in which each component and its weight percentage are listed.

[0230] The method described in Example C was used to determine skin deposition of the gel formulations in the stratum corneum and dermis.

[0231] Table D-1 Midostaurin gel formulation.

[0232]

[0233] The skin deposition results of batches A1, A2 and A3 were Figure 6 The gel formulation with Labrasol (Batch A2) had the greatest skin deposition.

[0234] Since the gel formulations tend to crystallize, batches A1, A2, A3 and A4 were placed at 60°C for 7 days to study their crystallization under a polarizing microscope. The crystallization results under the polarizing microscope are shown in Figures 7A-7D Micrographs show needle- and star-shaped crystals of midostaurin in gel formulations, particularly in batch A1 gel. It appears that gel formulations tend to crystallize after exposure to 60°C, regardless of whether a single solubilizer at 10% w / w or mixed solubilizer levels up to 30% w / w are used. Gel formulation development can be challenging due to the relatively low solubility of midostaurin in solubilizer-water systems. Creams and ointments may be considered as next steps.

[0235] Example E. Development of a midostaurin cream formulation.

[0236] This example illustrates the process of developing a cream formulation of midostaurin according to some embodiments of the present disclosure.

[0237] A cream formulation of midostaurin cream (Batch B1) was prepared, and an appropriate amount of Maisine CC (Batch B2) was additionally added as an oil phase to observe improvement in crystallization. The complete formulations of batches B1 and B2 are shown in Table E-1.

[0238] Table E-1 Midostaurin cream formulations - batches B1 and B2

[0239]

[0240] The preparation procedure for the cream formulation involves preparing an oil phase and an aqueous phase. To prepare the oil phase, weigh the API, stearyl alcohol, white petrolatum, liquid paraffin, glyceryl monostearate, Transcutol, and / or Maisine CC in a beaker and heat to above 80°C to completely melt. To prepare the aqueous phase, weigh sodium lauryl sulfate, propylene glycol, glycerin, and water in a beaker and heat to above 80°C. Gradually add the oil phase to the aqueous phase with continuous stirring until a cream is formed.

[0241] Both batches B1 and B2 were placed at 60°C to continuously study the crystallization under a polarizing microscope and the results are shown in Figures 8A-8BThe micrographs show needle-shaped and snowflake-shaped crystals of midostaurin in the cream formulation. Both creams (batches B1 and B2) remained stable at room temperature for the first 2 weeks and began to crystallize from the 3rd week. The main reason for the crystallization may be the insufficient solubility of midostaurin in the oil phase. To prevent the crystallization of midostaurin in the cream formulation at a concentration of 1%, the following formula was used: Figure 1 The solubility of midostaurin in various oils is shown in Table 2. The oil content should not be less than 10%.

[0242] To investigate the stability of the cream formulation, midostaurin cream (Batch B1) was exposed to 4500 Lx and 60°C for 7 days and subjected to freeze-thaw cycles (60°C for 6 hours / -20°C for 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 (Batch B1) was sensitive to light exposure, suggesting that avoiding light exposure or adding a sunscreen may be considered in subsequent formulation development. High temperatures and freeze-thaw cycles had minimal impact on its stability.

[0243] Table E-2. Impurity results of midostaurin cream (batch B1)

[0244]

[0245] To investigate the skin deposition of midostaurin in cream formulations, 0.1% and 1% midostaurin creams and a 2% hydroquinone cream were prepared according to the formulation components of batch B2. Additionally, a commercially available 2% hydroquinone cream was tested for comparison. The skin deposition tests for the four creams were performed according to the procedure described in Example C. The results are summarized in Figure 9 and Table E-3. The data indicate that both the homemade and commercially available 2% hydroquinone creams exhibited better skin deposition than the midostaurin cream formulation, which can be attributed to the relatively lower log P of hydroquinone (1.09 vs. 5.27). The midostaurin cream formulation exhibited higher deposition of midostaurin in the stratum corneum than the deposition of the midostaurin solution (1% midostaurin: 6.16 μg / cm in cream). 2 Compared to 2.74 μg / cm in solution 2 ; 0.1% midostaurin: 2.01 μg / cm in cream 2 Relative to 0.86 μg / cm in solution 2 However, the cream formulation showed little improvement in midostaurin deposition in the dermis when compared to midostaurin solution (1%: 1.20 μg / cm for cream). 2 Relative to 1.20 μg / cm for solution 2 ; 0.1%: 0.47 μg / cm for cream 2 Relative to 0.23 μg / cm for solution2 It is believed that penetration enhancers further increase the skin deposition of midostaurin.

[0246] Table E-3. Skin Deposition of Midostaurin Cream and Hydroquinone Cream

[0247]

[0248] Azone was used in the oil phase, and Tefose 63 and Labrafil M 1944CS were selected as co-emulsifiers. Four ternary phase diagrams were prepared, as shown in Figure 2. Figures 10A-10D The designated region in the ternary phase diagram represents the range of oil phase, aqueous phase, and emulsifier that allows for the formation of a cream, and each point in this region corresponds to a certain percentage of oil phase, aqueous phase, and emulsifier, respectively. Based on the results of the ternary phase diagram, the appropriate percentages of oil phase, aqueous 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.

[0249] Table E-4. Cream Formulations (Batch B3, B4, B5, B6, and B7)

[0250]

[0251] To prepare the oil phase, API, Azone, Tefose 63, and Labrafil M 1944CS were weighed and added to the same beaker and heated to above 80°C for complete melting. To prepare the aqueous phase, water was weighed into a beaker and heated to above 80°C. The oil phase was then gradually added to the aqueous phase and stirred continuously until a cream was formed. Batches B3 and B7 were placed at 4500 1x, 60°C, or room temperature for 7 days to perform a stress test. 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 showed that midostaurin in batches B3 and B7 was significantly degraded. Oxidative impurities may be produced due to conditions such as high temperature, light, or large amounts of oil.

[0252] Table E-5. Stress test of cream formulations (batches B3, B7)

[0253]

[0254] Batches B3, B4, B5, B6 and B7 were placed at 60°C to study their crystallization under a polarizing microscope. The results are shown in Figures 11A-11EMicrographs of batches B3 and B7 show that the droplets are evenly distributed, with no needle- or star-shaped crystals. Batches B3 and B7 did not show any crystallization at 60°C for 7 days. Micrographs of batches B4 and B5 show the appearance of star-shaped crystals. After 3 days at room temperature, batches B4 and B5 showed crystallization. For batch B6, demulsification was observed when it was left at room temperature. Micrographs of batch B6 show that the droplet distribution became wider and the droplet diameter became larger.

[0255] Peceol was selected as the oil phase and Gelot 64 was selected as the emulsifier. Figure 12 The ternary phase diagram was prepared as shown. The optimal oil and co-emulsifier ratio was selected to prepare a 1% midostaurin cream. The formulation is listed in Table E-6.

[0256] Table E-6. Cream Formulation (Batch B8)

[0257]

[0258] To prepare the oil phase, API, Peceol and Gelot 64 were weighed into the same beaker and heated to above 80°C to completely melt. To prepare the aqueous phase, water was weighed into a beaker and heated to above 80°C. The oil phase was then gradually added to the aqueous phase and stirred into a cream. The cream was 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. Midostaurin cream prepared with Peceol / Gelot 64 was very susceptible to high temperatures, which seems consistent with the hypothesis that oxidative impurities are more likely to appear at high temperatures and with larger amounts of oil. Batch B8 and the blank carrier vehicle of Batch B8 were placed at 60°C for 7 days to study their crystallization under a polarizing microscope, and the results are shown in Table E-7. Figures 13A-13B The micrographs of batch B8 were similar to those of the blank carrier vehicle, indicating that the batch was stable. Batch B8 cream showed no crystallization over 7 days at 60°C, leading to the conclusion that no crystalline precipitation was present in midostaurin cream over the duration evaluated.

[0259] Table E-7. Stress test of cream formulation (batch B8)

[0260]

[0261] Midostaurin cream was prepared based on an optimized cream formulation using Peceol as the oil phase, with a penetration enhancer and, optionally, an antioxidant added to the formulation. First, creams formed using different ratios of Peceol, an emulsifier (a combination of Tween 80 and Span 60), and water, as listed in Table E-8, were compared. When the emulsifier was approximately 20% and the oil phase was approximately 10%, the cream had good stability, a non-greasy feel, and a smooth texture.

[0262] Table E-8. Different ratios of Peceol, Tween 80, Span 60, and water for cream formulations.

[0263]

[0264] To prepare the oil phase, the API, Peceol, Tween 80, Span 60, an antioxidant, and one of three penetration enhancers, Plurol oleique CC 497, Transcutol, or Labrafil M 1944CS, were weighed into the same beaker and heated to above 80°C to melt. To prepare the aqueous phase, water was weighed into a beaker and heated to above 80°C. The oil phase was gradually added to the aqueous phase and stirred into a cream. Different penetration enhancers (all at a 5% level) and different antioxidants (all at a 0.02% level) were compared. The complete formulation is shown in Table E-9.

[0265] Table E-9. Cream Formulations (Batch B9, B10, B11, B12, B13, B14, and B15)

[0266]

[0267] The formulations (batches B9, B10, B11) were tested for skin deposition using different penetration enhancers and the results are shown in Figure 14 and Table E-10. The above cream formulations (batches B11, B12, B13, and B14) were exposed to 4500 Lx, 40°C, 60°C, or at room temperature for 7 days as a stress test. 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 produced the best penetration-enhancing effect. BHT exhibited the best antioxidant effect.

[0268] Table E-10. Skin Deposition of Different Penetration Enhancers

[0269]

[0270]

[0271] Example F. Development of a midostaurin ointment formulation.

[0272] This example illustrates the process of developing an ointment formulation of midostaurin according to some embodiments of the present disclosure.

[0273] Due to the high solubility of midostaurin in PEG-400, PEG-400 and PEG-4000 were used as the base for preparing the midostaurin ointment, and Labrasol was added as a solubilizer. The ointment was subjected to stress treatment 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.

[0274] Table F-1. Ointment formulation (batch C1)

[0275] Components Percentage (wt%) PEG 400 64.24 PEG 4000 10.56 glycerin 13.2 Labrasol 10 Azone 1 Midostaurin 1

[0276] Table F-2. Stress test of ointment formulations

[0277]

[0278] The results showed that the midostaurin content decreased when midostaurin ointment was exposed to high temperature and 4500 Lx. No crystal peaks were present in the XRPD analysis of midostaurin ointment, thus confirming that no crystals were present in midostaurin ointment during the time period evaluated.

[0279] Example G. Skin pigmentation reduction efficacy study.

[0280] This example illustrates a process for evaluating the efficacy of various topical formulations of midostaurin in reducing skin pigmentation, according to some embodiments of the present disclosure.

[0281] Guinea pigs, approximately 12-20 weeks old, were used to evaluate the efficacy of various topical formulations of midostaurin in reducing skin pigmentation. Prior to the experiment, the dorsum of the guinea pigs was shaved and divided into six areas (3.2 cm 2 / region), such as Figure 15A The control group without UV stimulation (N=1) is shown in Figure 15B -C. Guinea pigs were anesthetized with 0.3 mL of a mixture (50 mg / mL ketamine 0.75 mL and 100 mg / mL xylazine 0.15 ml), and sites 1-6 were exposed to UV light (315-400 nm) once a day for 14 minutes and 42 seconds (150 mJ / cm 2 ) for 2 weeks. The solar simulator contained a 1000W xenon arc lamp equipped with a WG305 cutoff filter. The radiation dose was 0.17mW / cm2 (or 1.7*10–4W). Midostaurin cream (0.1% and 1.0%) was prepared according to the formulation of batch B2, and 1% midostaurin solution and 2% hydroquinone solution were prepared using DMSO / propylene glycol (1:3, v / v). 2% hydroquinone cream is commercially available and provided by Guangdong Renrenkang Pharmaceutical Co., Ltd. At the beginning of modeling, the positive control (hydroquinone cream and solution) and the test material (midostaurin cream and solution) were applied to sites 2-6 at a dose of 0.2 mL for the solution or 0.2 g for the cream. According to Figure 16A , an equal amount of blank cream was applied to site 1. Starting from the day of UV stimulation, all treatments were applied twice a day for 2 weeks. After modeling was completed, treatments were continued twice a day for 2 weeks, and all treatments were applied for a total of 4 weeks.

[0282] The evaluation of skin pigmentation level can be completed by general photographs, Fontana-Masson staining and tyrosinase activity measurement. For Fontana-Masson staining, the protocol and scoring criteria are as follows. After the experiment, the skin tissue is extracted, embedded in paraffin, and stained with Fontana silver nitrate solution. Paraffin sections stained with Fontana-Masson were examined under a microscope, and the melanin granules in the skin tissue sections of each group were observed under a 200x lens. The scoring criteria for the local pathological observation results are shown in Table G-1.

[0283] Table G-1. Fontana-Masson staining scoring criteria for local pathological observations.

[0284]

[0285] The protocol for measuring tyrosinase activity is as follows. Skin tissue was extracted, embedded in paraffin, and immunohistochemically stained. Tyrosinase expression in skin tissue sections was observed under a 200x lens, and mean optical density (AOD) values ​​were analyzed using ImageJ software. AOD (Average Optical Density) = IOD (Integrated Optical Density) / Area of ​​Positive Staining in Each Image was calculated.

[0286] Figure 16A -B shows a picture of the back of a guinea pig after the study, in which the skin color was different at six areas that received different treatments, namely no drug treatment (model), 2% hydroquinone cream, 1% midostaurin cream, 0.1% midostaurin cream, 2% hydroquinone solution, and 1% midostaurin solution.

[0287] Figure 17 Results of tyrosinase activity of seven different groups are shown: control group (no UV stimulation, e.g. Figure 15B -C), model group (UV stimulation followed by no active treatment), 2% hydroquinone cream-treated group, 2% hydroquinone solution-treated group, 1% midostaurin cream-treated group, 0.1% midostaurin cream-treated group, and 1% midostaurin solution-treated group. Figure 18 The melanin distribution scores of seven different groups are shown: control group (no UV stimulation, e.g. Figure 15B -C), model group (UV stimulation, followed by no treatment), 2% hydroquinone cream-treated group, 2% hydroquinone solution-treated group, 1% midostaurin cream-treated group, 0.1% midostaurin cream-treated group, and 1% midostaurin solution-treated group.

[0288] Compared to 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. Compared to the model group, the melanin granule distribution score was significantly reduced with 2% hydroquinone cream, 1.0% midostaurin solution, and midostaurin cream (0.1%, 1.0%), and the effect was dose-dependent for midostaurin cream. Based on the results of this animal study, 1% midostaurin cream demonstrated the best efficacy among all treatment groups, including 2% hydroquinone cream, which served as a positive control.

[0289] Another efficacy study was conducted using the same animal model and protocol described above to confirm the dose dependency in midostaurin cream and to demonstrate that the high dose (1.5% midostaurin cream) was more effective than 2% hydroquinone. A control group (no UV stimulation) and six treatment groups were tested, including a model group (UV stimulation followed by no treatment), a 2% hydroquinone positive control (in Figures 19A-19B 2-1), 0.01% midostaurin cream (in Figures 19A-19B 2-2), 0.05% midostaurin cream (in Figures 19A-19B 2-3), 0.25% midostaurin cream (in Figures 19A-19B 2-4), 1.5% midostaurin cream (in Figures 19A-19B is referred to as "2-5" in the Figures 19A-19B As shown in , both hydroquinone and midostaurin creams decreased tyrosinase activity and melanin distribution relative to the model group, and a positive correlation between the dose and the decrease in tyrosinase activity and melanin distribution was observed in midostaurin cream.

[0290] The formulation stability (e.g., content and impurities, etc.) 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 and 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 conditions, ambient conditions, and / or accelerated conditions.

[0291] Example H. Skin irritation test

[0292] A skin irritation study was conducted to evaluate local skin irritation following repeated application of midostaurin cream to the skin for 28 days using New Zealand rabbits as a model. This study consisted of two groups: a control group (saline) and a treatment group. Rabbits in the treatment group were given 1% midostaurin cream, a positive control (2% hydroquinone cream), or a blank base of midostaurin cream, depending on the amount of cream. Treatment was administered to the dorsal skin of each rabbit at a dose of 0.2 g / rabbit twice daily for 28 consecutive days. The rabbits' general condition and the condition of the application site were observed daily. Skin irritation scores and irritation intensity were evaluated at the following time points: before the first dose of each day, one hour after the last dose of each day, and one hour, 24 hours, 48 ​​hours, and 72 hours after the last dose of the last day. Skin irritation evaluations were performed using the widely recognized and standardized skin irritation scoring system established by the Chinese National Medical Products and Administration. More specifically, skin irritation was evaluated based on 1) erythema and eschar formation and 2) edema formation based on the criteria shown in Table H-1 and Table H-2.

[0293] Table H-1. Criteria for scoring skin irritation responses.

[0294] reaction score Erythema and eschar formation No erythema 0 Mild erythema (barely visible) 1 Moderate erythema (clearly visible) 2 Severe erythema 3 Purple-red erythema to slight eschar formation 4 Edema formation No edema 0 Mild edema (barely visible) 1 Moderate edema (noticeable swelling of the skin) 2 Severe edema (skin bulge of about 1 mm with clear outlines) 3 Extremely severe edema (skin swelling ≥ 1 mm extending beyond exposed areas) 4

[0295] Table H-2. Standards for skin irritation levels.

[0296] Stimulation level score No stimulation 0-0.49 Mild irritation 0.5-2.99 Moderate stimulation 3.0-5.99 Severe stimulation 6.0-8.0

[0297] The irritation score results are shown in Table H-3. The results show that under the conditions of this test, 1% midostaurin cream showed mild irritation when transdermally treated with 0.2 g / rabbit twice a day for 28 consecutive days in New Zealand white rabbits, which was much better than the moderate irritation of the commercial hydroquinone cream.

[0298] Table H-3: Skin irritation scores of different test groups.

[0299]

[0300] Example I. Phototoxicity Test

[0301] The phototoxicity of midostaurin cream was tested using British guinea pigs as a model. Male guinea pigs were randomly divided into groups and given a single skin application of saline (negative control), 8-MOP (positive control), 1.0% midostaurin cream, and a blank midostaurin cream matrix. The dose administered was 0.2 mL / site, and after the application treatment, the application site was fixed. After 0.5 hours, the skin was treated with a 30-well gel electrophoresis kit (Holland, MA) and a 10-well gel electrophoresis kit (Holland, MA). AG) solar simulator (SOL500) irradiates the application site to achieve 10±1J / cm 2 The specified irradiation dose was measured using a UV irradiator equipped with a UVAF0 model from the Holl Group. The first day of administration was designated as Day 1 of the experiment (Day 1). After irradiation, skin irritation at the application site was observed at 1±0.5 hours, 24 hours, 48 ​​hours, and 72 hours, and the skin irritation was scored. During the experimental period, no animals were about to die or no animals were found to have died. No clinical observations or weight changes associated with midostaurin cream were seen in the experiment. Edema and erythema were only seen at the site of the positive control substance (8-MOP, UV irradiation), but were not seen at the site of the positive control substance without UV irradiation and the site of 1% midostaurin cream, two control substances that were UV irradiated: midostaurin blank matrix and negative control substance (saline). Therefore, in guinea pigs, it was found that there was no significant difference in skin irritation scores between skin sites treated once with saline or midostaurin cream after 3 days of observation. Therefore, under the conditions of this test, 1% midostaurin cream is not phototoxic.

[0302] Example J. Pharmacokinetic Studies

[0303] A pharmacokinetic study was conducted to evaluate the transdermal absorption of midostaurin in Bama pigs following single and 7-day continuous transdermal administration of midostaurin cream.

[0304] Single transdermal administration: After shaving the back of Bama pigs, a single dose of 42 mg of 1% midostaurin cream was transdermally applied near the spine (approximately 5 cm x 5 cm area). Blood was collected before 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 was collected at the application site after the last blood draw. Midostaurin levels were measured in plasma and skin tissue samples using LC-MS / MS.

[0305] Seven consecutive days of transdermal administration: After shaving the back of Bama pigs, 42 mg of 1% midostaurin cream (approximately 5 cm×5 cm area) was transdermally applied twice daily near the spine for 7 days, with an 8-hour interval between doses. Blood was collected before the first dose and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after the first dose, 30 minutes after the third dose, and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours after the last dose. Skin tissue at the application site was collected after the last blood draw. Midostaurin levels were measured in plasma and skin tissue samples using LC-MS / MS.

[0306] The results showed that after a single transdermal administration of 1% midostaurin cream to Bama pigs, the concentration of midostaurin in plasma was below the limit of quantification or undetectable, and the concentrations of midostaurin in the stratum corneum, epidermis, and dermis were 34.1±13.8μg / g, 12.1±3.38μg / g, and 0.280±0.141μg / g, respectively. After transdermal administration of 1% midostaurin cream to Bama pigs for 7 consecutive days, the concentration of midostaurin in plasma was below the limit of quantification or undetectable, and the concentrations in the stratum corneum, epidermis, and dermis were 268±124μg / g, 113±63.3μg / g, and 3.61±1.53μg / g, respectively.

[0307] Thus, after single or 7 consecutive days (twice daily) administration of 42 mg of 1% midostaurin cream, the distribution of midostaurin in Bama pigs decreased sequentially in the stratum corneum, epidermis, and dermis. Midostaurin concentrations in the blood were extremely low, below the limit of quantification or undetectable, indicating that systemic exposure to midostaurin was extremely low.

[0308] It should be understood that the above listed components and methods should be regarded as exemplary only, and not limiting of the types of components and methods encompassed by the present disclosure.

Claims

1. A method of treating a skin-related disease or condition, the method comprising topically applying a multi-targeted protein kinase inhibitor or a salt thereof to the skin of a subject, wherein the skin is associated with a skin-related disease or condition.

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

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

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

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

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

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

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

9. A method of treating melasma, comprising topically applying a multi-targeted 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 on the face of the subject.

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

12. The method of any one of claims 8 to 11, wherein the melasma is caused or exacerbated by one or more of the following: birth control pills, pregnancy, hormone therapy, stress, thyroid disease, sun exposure, inflammation, family susceptibility, or free radicals.

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

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

15. The method of any one of claims 1 to 13, wherein the treatment comprises reducing the amount of melanin in a similar skin area according to a Melanin Distribution Score by at least 1.0 compared to the amount of melanin in a similar skin area of ​​the same subject not undergoing the treatment.

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

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

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 dose of hydroquinone.

20. A topical pharmaceutical composition comprising a) a multi-targeted protein kinase inhibitor (optionally, midostaurin) or a pharmaceutically acceptable salt thereof, wherein the amount of the multi-targeted protein kinase inhibitor (optionally, midostaurin) or a pharmaceutically acceptable salt thereof is 0.001% wt to about 20% wt; b) a carrier vehicle; and c) excipients; wherein the topical pharmaceutical composition is formulated for topical administration.

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

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

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

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

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

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

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

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

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

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

34. The topical pharmaceutical composition of claim 33, wherein the surfactant comprises a nonionic surfactant.

35. The topical pharmaceutical composition of claim 33 or 34, wherein the surfactant comprises glyceryl monooleate, glyceryl monolinoleate, macrogol-hydroxystearate (e.g., macrogol-15-hydroxystearate), polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, Tween 80, or polysorbate 80), polyoxyethylene glycerides (e.g., caprylocaproyl polyoxyethylene-8 glyceride, oleoyl polyoxyethylene-6 glyceride), glyceryl macrogol ricinoleate (e.g., polyoxyethylene 35 hydrogenated castor oil), PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glycerol monostearate, or glyceryl stearate. monostearate (GMS), polyoxyethylene stearate (or polyethylene glycol stearate), sorbitan monostearate, polyglyceryl-3 dioleate, sodium lauryl sulfate (SDS) or polyoxyethylene alkyl ether (e.g., Steareth-20, Steareth-2) or a combination thereof.

36. The topical pharmaceutical composition of claim 33, wherein the surfactant comprises an ionic surfactant (eg, sodium lauryl sulfate or SDS).

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

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), glycol palmitostearate, glycerol monostearate (or glyceryl monostearate, GMS), polyoxyethylene stearate (or polyethylene glycol stearate), sorbitan monostearate, sodium lauryl sulfate (SDS), oleoyl polyoxyethylene-6 glyceride, or polyoxyethylene alkyl ether (e.g., Steareth-20, Steareth-2), or a combination thereof.

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. 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 wt% to 50 wt%.

41. The topical pharmaceutical composition of any one of claims 37 or 38, wherein the emulsifier is present in the composition in an amount of about 1 wt% to 50 wt%.

42. The topical pharmaceutical composition of any one of claims 20 to 41, wherein the topical pharmaceutical composition comprises a penetration enhancer.

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

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 wt% to 40 wt%.

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

46. ​​The topical pharmaceutical composition of claim 45, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, alpha-tocopheryl acetate, sodium bisulfite acetone, 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., da-tocopherol), or a combination thereof.

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 wt% to 5 wt%.

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

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

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

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

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

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

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. The topical pharmaceutical composition of claim 53, wherein the pH stabilizer comprises a pH buffer.

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

57. The topical pharmaceutical composition of any one of claims 20 to 55, wherein the pH of the topical pharmaceutical composition is in the range of about 6.5 to about 7.

5.

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

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

60. The topical pharmaceutical composition of any one of claims 20 to 59, wherein 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.

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

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

63. The topical pharmaceutical composition of claim 60, wherein the multifunctional excipient is both a humectant and a carrier vehicle.

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

65. The topical pharmaceutical composition of any one of claims 20 to 64, wherein the topical pharmaceutical composition is in a form selected from the group consisting of ointments, gels, creams, lotions, solutions, emulsions, pastes, patches, wipes, cotton swabs, and pads.

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

67. The topical pharmaceutical composition of claim 66, wherein the topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is from about 0.01% wt to about 5% wt; b) a surfactant in an amount of about 5% wt to about 20% wt; c) a penetration enhancer in an amount of about 0.05% wt to about 20% wt; d) a carrier vehicle, wherein the amount of the carrier vehicle is from about 70% wt to about 90% wt; e) a humectant in an amount of about 5% wt to about 25% wt; and e) an antioxidant, said antioxidant being present in an amount of about 0.001% wt to 5% wt.

68. The topical pharmaceutical composition of claim 66 or 67, wherein the topical pharmaceutical composition is an ointment comprising: a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is 0.05% wt to about 2% wt; b) a surfactant, wherein the surfactant comprises glyceryl monolinoleate, glyceryl monooleate, polyoxyethylene glycerides (e.g., caprylocaproyl polyoxyethylene-8 glyceride), glyceryl polyethylene glycol ricinoleate (e.g., ricinoleate 35), polyethylene glycol-hydroxystearate (e.g., polyethylene glycol-15-hydroxystearate), or a combination thereof; c) a penetration enhancer, wherein the penetration enhancer comprises polyglycerol-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone), or a combination thereof; d) a carrier vehicle, wherein the carrier vehicle comprises polyethylene glycol (PEG), mineral oil, or a combination thereof; e) a humectant, wherein the humectant comprises glycerin or propylene glycol or a combination thereof; and f) an antioxidant, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

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

70. The topical pharmaceutical composition of claim 69, wherein the topical pharmaceutical composition is a gel comprising: a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is from about 0.01% wt to about 5% wt; b) a surfactant in an amount of about 5% wt to about 50% wt; c) optionally, a penetration enhancer, said penetration enhancer being in an amount of about 1% wt to about 30% wt; d) a carrier vehicle, wherein the amount of the carrier vehicle is from about 60% wt to about 95% wt; e) a viscosity modifier in an amount of about 0.01% wt to about 5% wt; f) optionally, a pH stabilizer; and g) an antioxidant, said antioxidant being present in an amount of about 0.001% wt to 5% wt.

71. The topical pharmaceutical composition of claim 69 or 70, wherein the topical pharmaceutical composition is a gel comprising: a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is 0.05% wt to about 2% wt; b) a surfactant, wherein the surfactant comprises glyceryl monolinoleate, glyceryl monooleate, polyoxyethylene glycerides (e.g., caprylocaproyl polyoxyethylene-8 glyceride), glyceryl macrogol ricinoleate (e.g., macrogol glyceryl ricinoleate 35), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), or a combination thereof; c) optionally, a penetration enhancer, wherein the penetration enhancer comprises polyglyceryl-3 dioleate, oleoyl polyoxyethylene-6 glyceride, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (Azone); d) a viscosity modifier, wherein the viscosity modifier comprises polyacrylic acid; e) optionally, a pH stabilizer, wherein the pH stabilizer comprises sodium hydroxide, sodium bicarbonate, L-arginine, triethanolamine, or a combination thereof; f) a carrier vehicle, wherein the carrier vehicle comprises water; and g) an antioxidant, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

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

73. The topical pharmaceutical composition of claim 72, wherein the topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is from about 0.01% wt to about 5% wt; b) a carrier vehicle in an amount of about 30% wt to about 70% wt; c) a surfactant in an amount of about 5% wt to about 50% wt; d) optionally, a humectant, said humectant being present in an amount of about 5% wt to about 30% wt; e) optionally, a penetration enhancer in an amount of about 1% wt to about 40% wt; f) optionally, a viscosity modifier in an amount of about 0.01% wt to about 5% wt; and g) an antioxidant, said antioxidant being present in an amount of about 0.001% wt to 5% wt.

74. The topical pharmaceutical composition of claim 72 or 73, wherein the topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is 0.05% wt to about 5% wt; b) a carrier vehicle comprising water and optionally polyethylene glycol (PEG), propylene glycol, liquid paraffin, or petroleum jelly (e.g., white petrolatum), or a combination thereof; c) a surfactant, wherein the surfactant comprises 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), glycol palmitostearate, glycerol monostearate (glycerol monostearate or glyceryl monostearate, GMS), polyoxyethylene stearate (or polyethylene glycol stearate), sorbitan monostearate, sodium lauryl sulfate (SDS), polyoxyethylene alkyl ether (e.g., Steareth-20, Steareth-2) or a combination thereof; d) optionally, a humectant comprising glycerin or propylene glycol or a combination thereof; e) optionally, a penetration enhancer, wherein the penetration enhancer comprises oleoyl polyoxyethylene-6 glyceride, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether, 1-dodecylazacycloheptan-2-one (or Azone), or a combination thereof; and f) an antioxidant, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof.

75. The topical pharmaceutical composition of any one of claims 72 to 74, wherein the topical pharmaceutical composition comprises: a) midostaurin or a pharmaceutically acceptable salt thereof, wherein the amount of midostaurin or a pharmaceutically acceptable salt thereof is from about 0.1% wt to about 2% wt; b) a surfactant in an amount of about 5% wt to about 50% wt, wherein the surfactant comprises glyceryl monolinoleate, glyceryl monooleate, PEG palmitostearate (e.g., PEG-6 palmitostearate, PEG-32 palmitostearate), ethylene glycol palmitostearate, glyceryl monostearate, polyoxyethylene stearate (e.g., polyethylene glycol-75 stearate), polyoxyethylene sorbitan monooleate (e.g., polysorbate 80), sorbitan monostearate, sodium lauryl sulfate, or a combination thereof; c) optionally, a penetration enhancer, the amount of the penetration enhancer being from about 1% wt to about 35% wt, wherein the penetration enhancer comprises oleoyl polyoxyethylene-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% wt to about 25% wt, wherein the humectant comprises glycerol (glycerin), propylene glycol, or a combination thereof; e) an antioxidant in an amount of about 0.01% wt to about 2% wt, wherein the antioxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, α-tocopheryl acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, cysteine, cysteine ​​hydrochloride, or a combination thereof; and f) a carrier vehicle in an amount of about 30% wt to about 70% wt, wherein the carrier vehicle comprises water and optionally liquid paraffin or white petrolatum.

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

77. The topical pharmaceutical composition of any one of claims 20 to 76, wherein the topical pharmaceutical composition reduces the amount of melanin in a skin area by at least 25% compared to the amount of melanin in a similar skin area of ​​the same subject without any treatment, wherein the amount of melanin is measured by a melanin distribution score using a guinea pig as a model.

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

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

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

81. The topical pharmaceutical composition of any one of claims 20 to 80, wherein the level of skin irritation in the area of ​​skin treated with the topical pharmaceutical composition is mild at most, and wherein the topical pharmaceutical composition comprises at most 1.0 wt% midostaurin.

82. The topical pharmaceutical composition of any one of claims 20 to 81, wherein the skin irritation score in the 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, wherein the topical pharmaceutical composition is administered at a dose that is lower than the dose of the reference topical pharmaceutical composition.

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 under conditions of 4500 lux (lx) light exposure or when it is stored at about 60°C.

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

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

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

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

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

89. The topical pharmaceutical composition of any one of claims 20 to 88, wherein the topical pharmaceutical composition contains no more than 5 wt% total impurities after storage at ambient conditions for at least 3 months, 6 months, 9 months, 12 months, or 24 months.

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

91. A method of treating a skin-related disease or condition, the method 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. A method of reducing skin pigmentation, the method 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. A method of reducing tyrosinase activity, the method 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. 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. The method of any one of claims 92 to 94, wherein the subject suffers from a skin-related disorder.

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.

Images