Pyrilutamide combination therapy

Abstract

The present disclosure provides a method of treating hair loss in a subject in need thereof, comprising topically administering to the subject an effective amount of pyrilutamide in combination with a hair growth-stimulating compound selected from the group consisting of cortexolone-17α-propionate and minoxidil. The present disclosure further provides a topical pharmaceutical formulation comprising pyrilutamide, a hair growth-stimulating compound, and one or more pharmaceutically acceptable carriers.

Description

PYRILUTAMIDE COMBINATION THERAPYBACKGROUND

[0001] Alopecia is a group of disorders with multiple and varying etiologies that results in hair loss from the body. The most common form of alopecia is androgenetic alopecia (“AGA”). AGA is also commonly called alopecia androgenetica, male pattern baldness, or male-pattern or female-pattern hair loss. It has been reported that AGA affects roughly 50% of men over 40. This form of alopecia could eventually affect up to 80% of white men by the age of 70 and about half of all women. Hair loss is often a cause of great concern to affected subjects for cosmetic and psychological reasons, but it can also be an important sign of systemic disease.

[0002] Medical management of AGA includes surgical treatment options, including hair transplantation. This procedure has been performed successfully for decades. Hair transplantation involves harvesting intact hair follicles from within a safe donor area (SDA) of a patient’s scalp by either follicular unit strip surgery (FUSS) or follicular unit extraction (FUE). Although cosmetic results after surgery are often satisfactory, surgery can only be performed when a sufficient quantity of donor plugs (or follicles) is available to cover the balding area(s). Additionally, hair transplantation is generally reserved for patients who have experienced massive hair loss and for patients in whom AGA is not still evolving. In younger patients, for example, hair transplantation generally is not recommended because androgens, particularly dihydrotestosterone (DHT), can act on the newly transplanted follicles resulting in the same thinning and eventual hair loss that affected the originally present follicles.

[0003] In view of the deficiencies and drawbacks associated with surgical treatment options, there remains a need in the art for pharmacological therapies for treating hair loss, including alopecia and in particular, AGA.BRIEF SUMMARY

[0004] Pyrilutamide, a substituted thioimidazolidinone compound also known as 4-[3-[4- cy ano-2-fluoro-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thi oxo-1-imidazolidinyl]-2-fluoro-N-methylbenzamide or KX-826, is a selective high-affinity antagonist of the androgen receptor developed for the treatment of androgen excess disorders, such as AGA and acne vulgaris. See, e.g., U.S. Patent Nos. 8,809,550 and WO 2022 / 206742, and WO 2011 / 029392, each of which is incorporated herein by reference in its entirety.

[0005] In a phase II clinical trial, pyrilutamide was effective and had a good safety profile in male patients with AGA in various topical formulations (e.g., 0.5% applied once daily, 0.25% applied twice daily, and 0.5% applied twice daily). See e.g., To Evaluate Efficacy, Safety, and Tolerability of KX-826 in Male Subjects With Androgenetic Alopecia. NCT05218642, Updated September 27, 2022. Accessed August 28, 2023. https: / / classic.clinicaltrials.gov / ct2 / show / NCT05218642, which is incorporated herein by reference in its entirety.

[0006] Cortexolone-17a-propionate, also known as 17a-propionyloxy-21 -hydroxy - pregna-4-ene-3, 20-dione and clascoterone, is a topical antiandrogen that displaces androgenic hormones from binding with their receptors. Cortexolone-17a-propionate is known to be suitable for treating acne, alopecia, and other diseases of skin and cutaneous appendages. See, e.g., U.S. Patent Nos. 8,143,240 and 8,865,690, WO 2009 / 019138, and WO 2016 / 207778, each of which is incorporated herein by reference in its entirety. Cortexolone-17a-propionate is also known to exist in several distinct crystalline polymorphs, each having unique properties. See, e.g., U.S. Patent No. 8,785,427, the entirety of which is incorporated herein by reference.

[0007] Minoxidil, also known as 2,4-diamino-6-piperidinopyrimidine 3-oxide, is formulated as a topical drug product for treatment of AGA, typically at two strength levels - 2% (topical solution) and 5% (as a topical solution or foam). See, e.g., U.S. Patent Nos. 4,596,812 and 6,946,120, each of which is incorporated herein by reference in its entirety. To exert its effect, minoxidil needs to be transformed into its active metabolite, minoxidil sulfate, by the enzyme sulfotransferase. This enzyme is present in the outer root sheath of anagen follicles. Disadvantageously, clinical trials have shown that the topical application of a 2% minoxidil solution to patients experiencing hair loss results in stimulated dense hair regrowth in fewer than about 5% of the patients and moderate hair regrowth in only about 30% of the patients. See e.g., E. A. Olsen, et al., “Topical Minoxidil in Early Male Pattern Baldness,” J. Amer. Acad. Derm. 13, 185-192 (1985); and J. Roberts,“Androgenetic Alopecia: Treatment with Topical Minoxidil,” J. Amer. Acad. Derm. 16(3) 705-710 (1987).

[0008] It has been surprisingly discovered that hair loss, including alopecia, can be effectively treated with a combination of therapies. In some aspects, a synergistic effect can be provided by the combination such that, surprisingly, a lower effective amount of each active can be used for effective treatment. As a result of this combination therapy, an advantageous clinical result can be realized after daily topical administration for an appropriate amount of time, such as a few days, weeks, or months.

[0009] Accordingly, the present disclosure provides a method of treating hair loss in a subject in need thereof, comprising topically administering to the subject an effective amount of pyrilutamide and a hair growth-stimulating compound selected from the group consisting of minoxidil and cortexolone-17a-propionate.

[0010] In some aspects, pyrilutamide can be co-administered in an amount from at least 0.1 wt% to about 20 wt% along with an effective amount of a hair growth-stimulating compound. In some aspects, cortexolone-17a-propi onate can be co-administered in an amount from at least 1 wt% to about 20 wt% along with an effective amount of pyrilutamide. In some aspects, minoxidil can be co-administered in an amount from about 0.25 wt% to about 20 wt% along with an effective amount of pyrilutamide.

[0011] In some aspects, the pyrilutamide and hair growth-stimulating compound are coadministered sequentially. In such aspects, the pyrilutamide and hair growth-stimulating compound can be in separate pharmaceutical formulations.

[0012] In other aspects, the pyrilutamide and hair growth-stimulating compound can be coadministered simultaneously. In some aspects, the pyrilutamide and hair growthstimulating compound can be combined in the same pharmaceutical formulation. In some aspects, the pharmaceutical formulation can be a liquid or semi-solid formulation. In a further aspect, the pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, an ointment, or a foam. In further aspects, the pharmaceutical formulation is a solution. In some aspects, the pharmaceutical formulation can comprise water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or any combination thereof.

[0013] In some aspects of the method, the pharmaceutical formulation can further comprise at least one (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) additive(s) selected from the group consisting ofan acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and any combination thereof. In some aspects, the pyrilutamide is co-administered in a pharmaceutical formulation comprising less than about 5 wt% water. In some aspects, the pyrilutamide and hair growth-stimulating compound are combined in the same pharmaceutical formulation comprising less than about 5 wt% water. In some aspects, the pharmaceutical formulation is co-administered topically once or twice daily.

[0014] In some aspects of the method, the hair loss is alopecia. In some aspects, the alopecia is androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or combination of any of the foregoing. In some aspects, the alopecia areata is selected from the group consisting of diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, ophiasis, alopecia totalis, and alopecia universalis. In some particular aspects, the alopecia is androgenetic alopecia.

[0015] The present disclosure further provides a topical pharmaceutical formulation comprising pyrilutamide, a hair growth-stimulating compound selected from the group consisting of minoxidil and cortexolone-17a-propi onate, and one or more pharmaceutically acceptable carriers. In some aspects, the pyrilutamide and hair growth-stimulating compound are solubilized in the pharmaceutical formulation. In some aspects, the pharmaceutical formulation comprises pyrilutamide at a concentration from about 0.1 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation comprises minoxidil at a concentration from about 0.25 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation comprises cortexolone-17a-propi onate at a concentration from about 1 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation comprises a combination of pyrilutamide and a hair growth-stimulating compound, each of them at a concentration from about 0.1 wt% to about 20 wt%, including from about 1 wt% to about 18 wt%, from about 2 wt% to about 15 wt%, from about 3 wt% to about 10 wt%, or from about 4 wt% to about 7.5 wt%.

[0016] In some aspects, the pharmaceutical formulation is a liquid or semi-solid formulation. In some aspects, the pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, an ointment, or a foam. In some aspects, the pharmaceutical formulation is a solution. In some of these aspects, the solution comprises water, saline, a buffered saline solution, or any combination thereof. In someaspects, the pharmaceutical formulation comprises less than about 5 percent water by weight.

[0017] In some aspects, the one or more pharmaceutically acceptable carriers are selected from the group consisting of a polyol, a polyol ether, a C1-C7 alcohol, and any combination thereof. In some aspects, the C1-C7 alcohol is ethanol, isopropanol, or any combination thereof. In some aspects, the C1-C7 alcohol is ethanol. In some aspects, the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerol, hexanetriol, and any combination thereof. In some aspects, the polyol is propylene glycol. In some aspects, the polyol ether is selected from the group consisting of polypropylene glycol, polyethylene glycol, a polyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether, and any combination thereof. In some aspects, the polyol ether is diethylene glycol monoethyl ether. In some aspects, the pharmaceutical formulation comprises propylene glycol, diethylene glycol monoethyl ether, and ethanol.

[0018] In some aspects, the pharmaceutical formulation further comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) additive(s) selected from an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and any combination thereof. In some aspects, the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol, propyl gallate, 2,4,5-trihydroxybutyrophenone, 4- hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, pharmaceutically acceptable salts, esters thereof, and any combination thereof. In some aspects, the antioxidant is BHT, ascorbyl palmitate, or a combination of BHT and ascorbyl palmitate. In some aspects, the emulsifier is selected from the group consisting of PEG-15 hydroxystearate (polyoxyl-15- hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, a polysorbate (e.g., polysorbate 20, polysorbate 60, polysorbate 80), PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, a propylene glycol ester of a fatty acid, a polyglycerol ester of a fatty acid, polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, caprylocapryl polyoxyl-8 glycerides, caprylocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoyl polyoxylglycerides, and any combination thereof. In some aspects, the emulsifier is a polysorbate, such as polysorbate60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80. In some aspects, the penetration enhancer is selected from the group consisting of a diol, a polyol, a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or any combination thereof), a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and any combination thereof. In some aspects, the moisturizer is selected from the group consisting of a fatty alcohol, a fatty acid, a fatty acid ester, an oil, a polyethylene glycol, glycerol, an alpha hydroxy acid, and any combination thereof. In some aspects, the moisturizer is cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or any combination thereof. In some aspects, the buffer is a phosphate buffer, citrate buffer, lactate buffer, or any combination thereof.

[0019] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof the topical pharmaceutical formulation described herein, wherein the topical administration of the pharmaceutical formulation for at least six months achieves a weighted average Hair Growth Assessment (HGA) score of about 0.30 in comparison with vehicle.

[0020] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein the topical administration of the pharmaceutical formulation for at least six months achieves a weighted average Investigator’s Global Assessment (IGA) score of about 0.43 in comparison with vehicle.

[0021] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein the topical administration of the pharmaceutical formulation for at least six months is free from systemic anti androgenic side-effects.

[0022] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein the topical administration of the pharmaceutical formulation provides:

[0023] a) a mean change from baseline in Target Area Hair Count equal to or higher than 9 hairs / cm2after 6 months of daily or BID application; or

[0024] b) a mean change from baseline in Target Area Hair Count equal to or higher than 10 hairs / cm2after 6 months of daily or BID application; or

[0025] c) a mean change from baseline in Target Area Hair Count equal to or higher than 11 hairs / cm2after 6 months of daily or BID application; or

[0026] d) a mean change from baseline in Target Area Hair Count equal to or higher than 12 hairs / cm2after 6 months of daily or BID application; or

[0027] e) a weighted average HGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0028] f) a weighted average HGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0029] g) a weighted average HGA score equal to or higher than 0.40 after 6 months of daily or BID application; or

[0030] h) a weighted average IGA score equal to or higher than 0.10 after 6 months of daily or BID application; or

[0031] i) a weighted average IGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0032] j) a weighted average IGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0033] k) a favorable (positive) HGA score in at least about 10 % of subjects after 6 months of daily or BID application; or

[0034] 1) a favorable (positive) HGA score in at least about 20 % of subjects after 6 months of daily or BID application; or

[0035] m) a favorable (positive) HGA score in at least about 30 % of subjects after 6 months of daily or BID application; or

[0036] n) a favorable (positive) IGA score in at least about 10 % of subjects after 6 months of daily or BID application; or

[0037] o) a favorable (positive) IGA score in at least about 20 % of subjects after 6 months of daily or BID application; or

[0038] p) a favorable (positive) IGA score in at least about 30 % of subjects after 6 months of daily or BID application; or

[0039] q) a favorable (positive) IGA score in at least about 40 % of subjects after 6 months of daily or BID application.DETAILED DESCRIPTION

[0040] The articles “a,” “an,” and “the” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0041] As used herein, the term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to ±10% (e.g., up to ±5%, up to ±1%) of a given value.

[0042] As used herein, the phrase “active agent” refers to either pyrilutamide, cortexolone- 17a-propi onate, or minoxidil.

[0043] The term “alopecia” as used herein refers to, collectively, or individually as specified, androgenetic alopecia (AGA), alopecia areata (including diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, ophiasis, alopecia totalis, and alopecia universalis), telogen effluvium, anagen effluvium, and traction alopecia.

[0044] As used herein, the term “anhydrous” means substantially free of water, i.e., having less than about 5 wt% water, and, in certain aspects as specified herein, less than about 3 wt% water, or less than about 1 wt% water.

[0045] As used herein, the term “at least” prior to a number or series of numbers is understood to include the number associated with the term “at least,” and all subsequent numbers or integers that could logically be included, as clear from context. When at least is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range. For example, “at least 3” means at least 3, at least 4, at least 5, etc. When at least is present before a component in a method step, then that component is included in the step, whereas additional components are optional.

[0046] As used herein, the term “Bis In Die” or “BID” means “twice a day.”

[0047] As used herein, the term “buffer” refers to a compound or group of compounds (e.g., a weak conjugate acid-base pair, such as a weak acid and its conjugate base or a weak base and its conjugate acid) that controls the pH of a solution within a desired range. Insome aspects, the conjugate base can be added as a Group I or Group II salt. Examples of a buffer include, e.g., a phosphate buffer, citrate buffer, lactate buffer, or any combination thereof.

[0048] As used herein, the phrase “C1-C7 alcohol” refers to an alcohol having 1, 2, 3, 4, 5, 6, or 7 carbons that is suitable for use in a topical pharmaceutical formulation. Examples of such C1-C7 alcohols include, but are not limited to, methanol, ethanol, isopropanol, n- butanol, n-propanol, benzyl alcohol, and the like. Without wishing to be bound by any particular theory, it is believed that C1-C7 alcohols, and particularly short chain C1-C7 alcohols, like C2-C3 alcohols (e.g., ethanol, n-propanol, or isopropyl alcohol), contribute to the spreadability of the pharmaceutical formulations described herein.

[0049] As used herein, the term “chelating agent” refers to a compound that can bind metal ions or metallic compounds. In some aspects, a chelating agent can stabilize the formulation by preventing, e.g., oxidation or precipitation. Suitable chelating agents include, e.g., citric acid, phytic acid, sodium phytate, clioquinol, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, or any combination thereof.

[0050] As used herein, the term “co-administration” means concurrent or sequential administration of two different active agents, i.e., pyrilutamide and either cortexolone- 17 a- propionate or minoxidil. In some aspects, the active agents are administered close enough in time to each other that the first and second therapeutic agents are simultaneously present in subjects receiving the co-administration.

[0051] As used herein the term “cortexolone” (also known as “11-deoxy corti sol” or “Reichstein’s substance”) refers to the compound having the structure:

[0052] As used herein, the term “cortexolone- 17a-propi onate” refers to the compound 17a- propionyloxy-21-hydroxy-pregna-4-ene-3, 20-dione, which is also known as clascoterone and is equivalent to the chemical structure:

[0053] As used herein, the term “degradation product” refers to those compounds that result from the in vitro degradation of cortexolone-17a-propi onate. Exemplary known cortexolone-17a-propi onate degradation products include, but are not limited to, cortexol one-21 -propionate and cortexolone.

[0054] As used herein, the term “ester” refers to esterified organic solvents including, but not limited to, ethyl acetate and ethyl lactate.

[0055] As used herein, the term “ethanol,” refers to ethyl alcohol, i.e., CH3CH2OH, and includes pure (absolute) ethanol and 96% ethanol, the latter being ethanol containing water in an amount typically ranging from about 4% to about 5.1% by volume. In some aspects, the ethanol is denatured alcohol, such as specially denatured (SD) alcohol, which includes a denaturing agent to prevent consumption.

[0056] As used herein, the term “fatty” refers to an aliphatic carbon chain that is either saturated or unsaturated. The chain is any suitable length, such as C4-C28 (e.g., C4, C5, Ce, C7, c8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, and C24), including more specifically C10-C24, C10-C20, C12-C22, and C12-C18 chain lengths.

[0057] As used herein, the term “gelling agent” refers to a pharmaceutically acceptable compound that can turn a water or oil phase into a gel. A gelling agent acts as a thickening agent, typically without imparting stiffness. The gelling agent can be an inorganic gelling agent, an organic gelling agent, a hydrogel, an organogel, or any combination thereof.

[0058] As used herein, the term “hair growth-stimulating compound” refers to cortexolone- 17a-propi onate or minoxidil.

[0059] As used herein, the term “minoxidil” refers to the compound 2,4-diamino-6- piperidinopyrimidine 3-oxide, which is equivalent to the chemical structure:In some aspects, the minoxidil is present in the form of a salt. The salt can be, e.g., acetate, citrate, succinate, benzoate, hydrochloride, sulfate, phosphate, or lactate. In some aspects, an acetate or lactate salt of minoxidil is used.

[0060] As used herein, the term “metabolite” refers to those compounds that result from the in vivo metabolism or degradation of an active agent, such as pyrilutamide, cortexolone- 17a-propi onate, or minoxidil. Exemplary known metabolites of pyrilutamide (KX-826) include, but are not limited to, KX-982 (which is described at https: / / folliclethought.com / kintor-pharmaceutical-kx-826-phase-2-results-with-poster / , the entirety of which is incorporated herein by reference). Exemplary known metabolites of cortexolone-17a-propi onate include, but are not limited to, cortexolone and tetrahydrocortexolone. Exemplary known metabolites of minoxidil include, but are not limited to, minoxidil sulfate.

[0061] As used herein, the term “moisturizer” refers to those compounds that impart moisture to skin, soften skin, or both. Exemplary moisturizers are emollients that include, e.g., a fatty alcohol, a fatty acid, a fatty acid ester, an oil, a polyethylene glycol, glycerol, an alpha hydroxy acid (e.g., lactic acid, glycolic acid, malic acid, citric acid, or tartaric acid), and any combination thereof. Specific examples of a moisturizer include, e.g., cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, and any combination thereof.

[0062] As used herein the phrase “natural oil” refers to those oils isolable from natural sources. Exemplary natural oils include, but are not limited to, olive oil, jojoba oil, coconut oil, almond oil, cottonseed oil, safflower oil, sunflower oil, sesame oil, soybean oil, castor oil, calendula oil, and the like.

[0063] As used herein, the phrase “penetration enhancer” refers to those pharmaceutically acceptable compounds that increase penetration of the active agent through the dermis. Exemplary penetration enhancers include, e.g., hydroxypropyl P- cyclodextrin, polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide, pyrrolidone, N- methyl-2-pyrrolidone, diethylene glycol monoethyl ether (e.g., TRANSCUTOL™, Gattefosse, France), dimethyl isosorbide, diethyl sebacate, azone, menthol, nerol, camphor, methyl salicylate, polysorbate 80 (e.g., TWEEN™ 80, Sigma-Aldrich, St. Louis, MO),SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (e.g., CREMOPHOR™ RH40, KOLLIPHOR™ RH40, BASF, Germany), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB), fatty acids esters (e.g., isopropyl myristate, isopropyl palmitate), fatty acids (e.g., oleic acid, palmitic acid, linoleic acid, and salts thereof), fatty alcohols (e.g., oleyl alcohol, myristyl alcohol, stearyl alcohol), mediumchain triglycerides, and a combination of any of the foregoing.

[0064] As used herein, and unless clear from the context in which it is used that it means otherwise, the term “pH” should be considered an “apparent pH” to acknowledge the fact that the behavior of a pH electrode in a complex multicomponent dermatological vehicle which is not totally aqueous in nature cannot be considered a “pH” in the strictest sense.

[0065] As used herein, the term “polyol” refers to organic molecules containing two or more hydroxyl groups (e.g., a diol, a triol, or higher). Exemplary polyols include, but are not limited to, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, glycerol, 1,3-butylene glycol, 1,4-butylene glycol, l-(l-butoxy-2-propoxy)-2-propanol, 2- methyl-2,4-pentanediol, 1,5-pentanediol, 1,6-hexanediol, glycerol, hexanetri ol, and the like.

[0066] As used herein, the term “polyol ether” refers to a polyol ether suitable for use in a topical pharmaceutical formulation. Exemplary polyol ethers include, but are not limited to, diethylene glycol monobutyl ether, dipropylene glycol monobutyl ether, polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymers, dipropylene glycol, diethylene glycol monoethyl ether, and the like.

[0067] As used herein, the term “preservative” refers to a compound with antimicrobial activity, such as an antibacterial or antifungal. Suitable preservatives include, e.g., a paraben (e.g., methyl paraben, ethyl paraben, propyl paraben, butyl paraben), a benzoate (e.g., sodium benzoate), a sorbate (e.g., potassium sorbate), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an alcohol (e.g., chlorobutanol, benzyl alcohol, ethanol, phenol, m-cresol, chlorocresol), sodium metabisulfite, imidazolidinyl urea, glycerol, propylene glycol, or any combination thereof.

[0068] As used herein, the term “pyrilutamide” refers to the compound 4-[3-[4-cyano-2- fluoro-3-(tri fluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thi oxo-1 -imidazolidinyl]-2- fluoro-N-methylbenzamide or KX-826, which is equivalent to the chemical structure:

[0069] As used herein, the term “solvent” means one or a mixture of more than one pharmaceutically acceptable solvents suitable for topical application, including without limitation, the scalp, that is used to solubilize pyrilutamide and either cortexolone-17a- propionate or minoxidil in a formulation described herein.

[0070] The phrase “substantially free of’ means that a composition contains little to no specified ingredient / component, such as less than about 5 wt%, less than about 4 wt%, less than about 3 wt%, less than about 2 wt%, less than about 1 wt%, less than about 0.5 wt%, less than about 0.3 wt%, less than about 0.2 wt%, less than about 0.1 wt%, or about 0 wt% of the specified ingredient.

[0071] As used herein “tetrahydrocortexolone” refers to the compound having the Chemical Abstract Service (CAS) Registry Number 68-60-0.

[0072] As used herein, the terms “treat,” “treating,” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, disease, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of one or more symptoms or making the injury, disease, or condition more tolerable to the subject; slowing in the rate of degeneration or decline; or improving a subject’s physical or mental wellbeing. The treatment or amelioration of symptoms can be based on objective or subject parameters, including the results of a physical examination, neuropsychiatric examinations, or psychiatric evaluation.

[0073] As used herein, the term “preventing” refers to keeping from happening or existing, or alternatively delaying the onset or recurrence of a disease, disorder, or condition to which such term applies, or of one or more symptoms associated with a disease, disorder, or condition. The term “preventing” also refers to reducing the incidence of a disease, disorder, or condition. The term “prevention” refers to the act of preventing.

[0074] As used herein, the term “sequentially” means that a first active agent is coadministered to a subject in a first period of time followed by an administration of a second active agent in a second period of time. In other words the term “sequentially” includes a first therapy in a first period of time followed by a second therapy in a second period oftime. The first and second time periods can be separated on the order of seconds, minutes, hours, or days, as needed. In some aspects, the first and second time periods are separated by seconds (e.g., about 60 seconds or less, about 30 seconds or less).

[0075] As used herein, the term “subject” typically is directed to a mammal. In some aspects, the subject to be treated is a human.

[0076] As used herein, the phrase “wt%” is intended to encompass and disclose aspects wherein the wt% is percentage of weight by total weight (w / w) for a given value, unless otherwise specified.

[0077] As used herein, the terms “comprises,” “comprising,” “having,” “including,” “containing,” and the like are open-ended terms meaning “including, but not limited to.” To the extent a given aspect disclosed herein “comprises” certain elements, it should be understood that present disclosure also specifically contemplates and discloses aspects that “consist essentially of’ those elements and that “consist of’ those elements.

[0078] As used herein the terms “consists essentially of,” “consisting essentially of,” and the like are to be construed as a semi-closed terms, meaning that no other ingredients which materially affect the basic and novel characteristics of an aspect are included.

[0079] As used herein, the terms “consists of,” “consisting of,” and the like are to be construed as closed terms, such that an aspect “consisting of’ a particular set of elements excludes any element, step, or ingredient not specified in the aspect.

[0080] As used herein, the terms “Target Area Hair Count” or “TAHC” refer to the change, from baseline, in the number of non-vellus hairs in a target area of the scalp. The target area can be, for example, 1 cm2or a circle of a diameter of 1 inch (5.1 cm2).

[0081] As used herein, the terms “Hair Growth Assessment” or “HGA” refer to a score given by the subject comparing the baseline standardized global photo of the subject’s scalp with a “real time” standardized global photo.

[0082] As used herein, the terms “Investigator’s Global Assessment” or “IGA” refer to a score given by an evaluator comparing the baseline standardized global photo of the subject’s scalp with a “real time” standardized global photo.The Method

[0083] The present disclosure provides a method of treating hair loss, such as alopecia, in a subject in need thereof, comprising topically administering to the subject an effective amount of pyrilutamide and an effective amount of a hair growth-stimulating compoundselected from the group consisting of cortexolone-17a-propi onate and minoxidil. Topical administration comprises application of pyrilutamide and a hair growth-stimulating compound to the skin and / or the scalp of the subject, as described herein.

[0084] In some aspects, the subject can be a mammal, such as a human.

[0085] In some aspects, the hair loss can be associated with alopecia. Alopecia can include, e.g., androgenetic alopecia (AGA), alopecia areata (including diffuse alopecia areata, alopecia areata monol ocularis, alopecia areata multilocularis, ophiasis, alopecia totalis and alopecia universalis), telogen effluvium, anagen effluvium, and traction alopecia. In some aspects, the alopecia to be treated can be AGA.

[0086] In some aspects, the pyrilutamide and hair growth-stimulating compound are coadministered sequentially in that a first active agent can be administered to the subject in a first period of time followed by an administration of the second active agent in a second period of time. The particular order of administration is not limited. In some aspects, the pyrilutamide can be administered first, and the hair growth-stimulating compound can be administered second. In other aspects, the hair growth-stimulating compound can be administered first, and the pyrilutamide can be administered second. The time period between the two administering steps can be separated on the order of seconds, minutes, hours, or days, as needed. In some aspects, the first and second administering steps can be separated by seconds (e.g., about 60 seconds or less, about 30 seconds or less).

[0087] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein the topical administration of the pharmaceutical formulation for at least six months achieves a weighted average Hair Growth Assessment (HGA) score of about 0.30 in comparison with vehicle.

[0088] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein the topical administration of the pharmaceutical formulation for at least six months achieves a weighted average Investigator’s Global Assessment (IGA) score of about 0.43 in comparison with vehicle.

[0089] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein the topical administration of thepharmaceutical formulation for at least six months does not result in systemic anti- androgenic side-effects in the subject.

[0090] In certain aspects, the present disclosure provides a method of treating alopecia, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein the topical administration of the pharmaceutical formulation provides:

[0091] a) a mean change from baseline in Target Area Hair Count equal to or higher than 9 hairs / cm2after 6 months of daily or BID application; or

[0092] b) a mean change from baseline in Target Area Hair Count equal to or higher than 10 hairs / cm2after 6 months of daily or BID application; or

[0093] c) a mean change from baseline in Target Area Hair Count equal to or higher than 11 hairs / cm2after 6 months of daily or BID application; or

[0094] d) a mean change from baseline in Target Area Hair Count equal to or higher than 12 hairs / cm2after 6 months of daily or BID application; or

[0095] e) a weighted average HGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0096] f) a weighted average HGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0097] g) a weighted average HGA score equal to or higher than 0.40 after 6 months of daily or BID application; or

[0098] h) a weighted average IGA score equal to or higher than 0.10 after 6 months of daily or BID application; or

[0099] i) a weighted average IGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0100] j) a weighted average IGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0101] k) a favorable (positive) HGA score in at least about 10 % of subjects after 6 months of daily or BID application; or

[0102] 1) a favorable (positive) HGA score in at least about 20 % of subjects after 6 months of daily or BID application; or

[0103] m) a favorable (positive) HGA score in at least about 30 % of subjects after 6 months of daily or BID application; or

[0104] n) a favorable (positive) IGA score in at least about 10 % of subjects after 6 months of daily or BID application; or

[0105] o) a favorable (positive) IGA score in at least about 20 % of subjects after 6 months of daily or BID application; or

[0106] p) a favorable (positive) IGA score in at least about 30 % of subjects after 6 months of daily or BID application; or

[0107] q) a favorable (positive) IGA score in at least about 40 % of subjects after 6 months of daily or BID application.Pharmaceutical Formulations

[0108] In some aspects, the pyrilutamide and hair growth-stimulating compound can be coadministered sequentially as described above. In such aspects, the pyrilutamide and hair growth-stimulating compound can be provided in separate pharmaceutical formulations. Each pharmaceutical formulation can be as described herein.

[0109] In other aspects, the pyrilutamide and hair growth-stimulating compound can be coadministered simultaneously (i.e., concomitantly), either in the same or different formulations. In some aspects, the pyrilutamide and hair growth-stimulating compound can be provided in the same pharmaceutical formulation (e.g., a combination formulation).

[0110] In some aspects, the pyrilutamide and the hair growth-stimulating compound can be formulated individually in any of the pharmaceutical formulation described below. In other aspects, the pyrilutamide and the hair growth-stimulating compound can be formulated together in the pharmaceutical formulation described below.[OHl] The pharmaceutical formulation, regardless of whether it contains just pyrilutamide, just the hair growth-stimulating compound, or both, can be in any form suitable for topical administration. In some aspects, the pharmaceutical formulation can be a liquid or semi-solid formulation depending on the carriers and excipients that can be present, as described herein. Examples of the liquid or semi-solid formulation include, e.g., a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, an ointment, or a foam. In some aspects, the pharmaceutical formulation can be a solution.

[0112] In some aspects, the formulation can be a cream. In some aspects, the cream can comprise equal parts oil and water in the form of an emulsion.

[0113] In some aspects, the formulation can be a paste. In some aspects, the paste can comprise a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleicacid, linoleic acid, linolenic acid, or any combination thereof), an oil, or any combination thereof.

[0114] In some aspects, the formulation can be a gel that includes at least one gelling agent. The gelling agent can be, e.g., an inorganic gelling agent (e.g., aluminum hydroxide gel, bentonite magma), an organic gelling agent (e.g., a carbomer polymer, tragacanth), a hydrogel (e.g., an organic hydrogel, a natural or synthetic gum, or an inorganic hydrogel), an organogel (e.g., a hydrocarbon type, a vegetable fat, a soap based grease, or a hydrophilic organogel), or any combination thereof. The organic hydrogel can include, e.g., pectin paste and tragacanth jelly. The natural or synthetic gum can include, e.g., methylcellulose, sodium carboxymethyl cellulose, and pol oxamer. The inorganic hydrogel can include, e.g., bentonite gel, smectite (e.g., VEEGUM™, Vanderbilt Minerals, LLC, Norwalk, CT), or silica. The hydrocarbon type organogel can include, e.g., petrolatum and mineral oil / poly ethylene gel. The vegetable fat type organogel can include, e.g., cocoa butter. The soap based grease type organogel can include, e.g., aluminum stearate with heavy mineral oil gel. The hydrophilic organogels can include, e.g., carbowax bases, such as polyethylene glycol (PEG) ointment.

[0115] In some aspects, the gelling agent can be a carbomer polymer. The term “carbomer” is a generic name for high molecular weight polymer of acrylic acid lightly crosslinked with allyl ethers of polyalcohols (e.g., allyl sucrose, allyl pentaerythritol). The term also can be used to describe CARBOPOL™ polymers (Lubrizol Corp., Wickliffe, OH).

[0116] In some aspects, the formulation can be an ointment. In some aspects, the ointment can comprise a hydrocarbon (e.g., paraffin, petrolatum), lanolin, beeswax, a macrogol, a polyethylene glycol, an emulsifying wax, an alklytrimethylammonium bromide (e.g., a cetrimide), a vegetable oil (e.g., olive oil, jojoba oil, coconut oil, almond oil, cottonseed oil, safflower oil, sunflower oil, sesame oil, soybean oil, castor oil, or calendula oil), or any combination thereof. In some aspects, the ointment can comprise about 20 wt% or less (e.g., about 15 wt% or less, about 10 wt% or less, about 8 wt% or less, about 5 wt% or less, about 2 wt% or less, about 1 wt% or less, or substantially free) of water.

[0117] In some aspects, the formulation can be a foam. A foam formulation can be used in combination with one or more acceptable propellants, such as propane, butane, isobutene, nitrogen, and the like.The Solvent

[0118] In some aspects, the pharmaceutical formulation described herein, regardless of whether it contains just pyrilutamide, just the hair growth-stimulating compound, or both, can be a solution. The pharmaceutical formulation can comprise water, saline (e.g., a sodium chloride salt solution), a buffered saline solution (e.g., a phosphate-buffered saline solution), or any combination thereof.

[0119] In some aspects, the pharmaceutical formulation can be considered anhydrous and can contain less than about 5 percent by weight (wt%) (e.g., less than about 4 wt%, less than about 3 wt%, less than about 2 wt%, or less than about 1 wt%) of water.

[0120] In some aspects, particularly in aspects that contain less than about 5 wt% water, the pyrilutamide can be solubilized in the pharmaceutical formulation. The topical pharmaceutical formulation can comprise one or more pharmaceutically acceptable carriers (e.g., solvents) in addition to or in place of water, such as a polyol, a polyol ether, a C1-C7 alcohol, and any combination thereof.

[0121] In some aspects, the pharmaceutical formulation can comprise a solvent selected from the group comprising or the group consisting of: water, a C1-C7 alcohol, a polyol ether, a polyol, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), a natural oil, an ester, tricaprylin (2,3-di(octanoyloxy)propyl octanoate), a medium-chain triglyceride, capryl ocaproyl polyoxyl-8 glycerides, and a combination of any of the foregoing. In some aspects, the one or more pharmaceutically acceptable carriers are selected from the group consisting of a polyol, a polyol ether, a C1-C7 alcohol, and any combination thereof.

[0122] In some aspects, the pharmaceutical formulation can comprise at least about 50 wt% solvent (e.g., water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or any combination thereof). In other aspects, the pharmaceutical formulation can comprise at least about 60 wt% solvent. In other aspects, the pharmaceutical formulation can comprise at least about 70 wt% solvent. In other aspects, the pharmaceutical formulation can comprise at least about 80 wt% solvent. In other aspects, the pharmaceutical formulation can comprise at least about 85 wt% solvent, at least about 90 wt% solvent, at least about 91 wt% solvent, at least about 92 wt% solvent; at least about 93 wt% solvent; at least about 94 wt% solvent; or at least about 95 wt% solvent.

[0123] In some aspects, the solvent can comprise a mixture of a C1-C7 alcohol, a polyol ether, and a polyol. In such aspects, the pharmaceutical formulation can comprise fromabout 10 to about 50 wt% of the polyol ether; from about 5 wt% to about 55 wt% of the polyol; and about 5 to about 50 wt% of the C1-C7 alcohol. In some aspects, the mixture of the C1-C7 alcohol, the polyol ether, and the polyol can be present at about a 1 : 1 : 1 ratio on a w / w / w basis. In some aspects, each of the C1-C7 alcohol, the polyol ether, and the polyol can be present at about 30 wt%.

[0124] In some aspects, the pharmaceutical formulation can comprise from about 15 to about 45 wt% of the polyol ether; from about 20 to about 40 wt% of the polyol ether; from about 25 to about 35 wt% of the polyol ether; or from about 30 to about 35 wt% of the polyol ether. In some aspects, the pharmaceutical formulation can comprise about 30 wt% of the polyol ether. In other aspects, the pharmaceutical formulation can comprise about 32 wt% of the polyol ether.

[0125] In some aspects, the polyol ether can be selected from the group comprising or the group consisting of: polyethylene glycol, polypropylene glycol, polyethylenepolypropylene triblock copolymers, dipropylene glycol, diethylene glycol monoethyl ether (TRANSCUTOL™, Gattefosse, France), and any combination thereof.

[0126] When the polyol ether can be a polyethylene glycol (PEG), the PEG can have a number average molecular weight (Mn) that can be about 200 g / mol to about 6,000 g / mol. In some aspects, the PEG can be selected from the group comprising or the group consisting of: PEG 200, PEG 300, PEG 400, PEG 540, and PEG 600. In some aspects, the polyol ether can be PEG 200. In other aspects, the polyol ether can be PEG 400. In still other aspects, the polyol ether can be diethylene glycol monoethyl ether.

[0127] In some aspects, the polyol (e.g., a diol, a triol, or higher) can be selected from the group comprising or the group consisting of: diethylene glycol, triethylene glycol, propylene glycol, ethylene glycol, glycerol, 1,3-butylene glycol, 1,4-butylene glycol, 1-(1- butoxy-2-propoxy)-2-propanol, 2-methyl-2,4-pentanediol, 1,5-pentanediol, 1,6- hexanediol, glycerol, hexanetriol, and any combination thereof. In some aspects, the polyol can be glycerol. In other aspects, the polyol can be propylene glycol.

[0128] In some aspects, the polyol can be present in an amount ranging from about 5 wt% to about 55 wt% of the total formulation; from about 10 wt% to about 50 wt% of the total formulation; from about 20 wt% to about 45 wt% of the total formulation; and In some aspects, from about 25 wt% to about 40 wt%. In a particular aspect, the polyol can compriseabout 30 wt% of the total formulation. In a further aspect, the polyol comprising about 30 wt% of the total formulation can be propylene glycol.

[0129] In some aspects, the pharmaceutical formulation can comprise from about 5 to about 50 wt% of the C1-C7 alcohol. In some aspects, the pharmaceutical formulation can comprise from about 15 to about 45 wt% of the C1-C7 alcohol; from about 20 to about 40 wt% of the C1-C7 alcohol; or from about 25 to about 35 wt% of the C1-C7 alcohol. In some aspects, the pharmaceutical formulation can comprise about 30 wt% of the C1-C7 alcohol. In still further aspects, the pharmaceutical formulation can comprise the C1-C7 alcohol in an amount ranging from about 10 wt% to about 40 wt%, or from about 15 wt% to about 35 wt%.

[0130] In some aspects, the C1-C7 alcohol can be selected from the group comprising or the group consisting of: ethanol, isopropanol, n-butanol, n-propanol, and benzyl alcohol. In some aspects, the C1-C7 alcohol can be ethanol. In some aspects, the ethanol comprises about 30 wt% of the total formulation. In other aspects, the C1-C7 alcohol can be isopropanol.

[0131] In some aspects, the C1-C7 alcohol can contain a small water fraction, generally in the range of from about 4 percent to about 5.1 percent by volume. In aspects wherein the pharmaceutical formulation can be anhydrous, the C1-C7 alcohol having from about 4 percent to about 5.1 percent water by volume can be present in the pharmaceutical formulation in an amount such that the water content in the finished formulation itself can be less than about 5 wt% or less than about 3 wt%.

[0132] In some aspects, the solvent can comprise a polyol, a polyol ether, and a C1-C7 alcohol. In some aspects, the solvent can comprise ethanol as the C1-C7 alcohol, diethylene glycol monomethyl ether as the polyol ether, and propylene glycol as the polyol. These solvents can be present in any acceptable ratio, but typically are present such that each is about 25 to about 35 wt% of the pharmaceutical formulation.Other Components

[0133] In some aspects, the pharmaceutical formulation described herein, regardless of whether it contains just pyrilutamide, just the hair growth-stimulating compound, or both, can further comprise at least one additive selected from an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and any combination thereof.

[0134] In some aspects, the pharmaceutical formulation can comprise from about 0.1 wt% to about 50 wt% of each additive (e.g., an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent) relative to the total weight of the composition (i.e., making up 100 wt%). For example, each additive can be present in the pharmaceutical formulation in an amount from about 0.1 wt% to about 45 wt%, about 0.1 wt% to about 40 wt%, about 0.1 wt% to about 35 wt%, about 0.1 wt% to about 30 wt%, about 0.1 wt% to about 25 wt%, about 0.1 wt% to about 20 wt%, about 0.1 wt% to about 15 wt%, about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 2 wt%, about 0.5 wt% to about 50 wt%, about 0.5 wt% to about 45 wt%, about 0.5 wt% to about 40 wt%, about 0.5 wt% to about 35 wt%, about 0.5 wt% to about 30 wt%, about 0.5 wt% to about 25 wt%, about 0.5 wt% to about 20 wt%, about 0.5 wt% to about 15 wt%, about 0.5 wt% to about 10 wt%, about 0.5 wt% to about 5 wt%, about 0.5 wt% to about 2 wt%, about 1 wt% to about 50 wt%, about 1 wt% to about 45 wt%, about 1 wt% to about 40 wt%, about 1 wt% to about 35 wt%, about 1 wt% to about 30 wt%, about 1 wt% to about 25 wt%, about 1 wt% to about 20 wt%, about 1 wt% to about15 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 5 wt%, about 1 wt% to about 2 wt%, about 50 wt%, about 48 wt%, about 46 wt%, about 44 wt%, about 42 wt%, about 40 wt%, about 38 wt %, about 36 wt%, about 34 wt%, about 2 wt%, about 30 wt%, about 28 wt%, about 26 wt%, about 24 wt%, about 22 wt%, about 20 wt%, about 18 wt%, about16 wt%, about 14 wt%, about 12 wt%, about 10 wt%, about 8 wt%, about 6 wt%, about 5 wt%, about 4 wt%, about 3 wt%, about 2 wt%, about 1 wt%, about 0.9 wt%, about 0.8 wt%, about 0.7 wt%, about 0.6 wt%, about 0.5 wt%, about 0.4 wt%, about 0.3 wt%, about 0.2 wt%, or about 0.1 wt% of the total weight of the composition.

[0135] In some aspects, the pharmaceutical formulation can include an acid to help solubilize one or both of the active agents, to maintain a desired pH, or both. Any suitable acid can be used, such as a mineral acid (e.g., hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid), an organic acid (e.g., citric acid, acetic acid, succinic acid, or maleic acid), or mixtures thereof. Examples of suitable acid additives include, e.g., 1 -hydroxyl- naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxy ethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; L-ascorbic acid; L-aspartic acid; benzenesulfonic acid; benzoic acid; (+)-camphoric acid; (+)-camphor-10- sulfonic acid; capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid(octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-l,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; D-glucoheptonic acid; D-gluconic acid; D-glucuronic acid; glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid; lactobionic acid; lauric acid; maleic acid; L- malic acid; malonic acid; mandelic acid; methanesulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; L-pyroglutamic acid; salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; L-tartaric acid; thiocyanic acid; p-toluenesulfonic acid; and undecylenic acid. In a particular aspect, acetic acid, citric acid, or lactic acid can be added to the pharmaceutical formulation.

[0136] In some aspects, the acid can be added in a sufficient amount so that the pH of the pharmaceutical formulation can be about 7.0 or less (e.g., about 4 to about 7.0, about 4 to about 6.5, about 4 to about 6, about 4 to about 5.5, about 4 to about 5, about 4.5 to about 7.0, about 4.5 to about 6.5, about 4.5 to about 6, about 4.5 to about 5.5, about 4.5 to about 5, about 5 to about 7.0, about 5 to about 6.5, about 5 to about 6, about 5 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6, about 6 to about 7.0, or about 6 to about 6.5).

[0137] In some aspects, the pharmaceutical formulation can include a buffer to help maintain the pH of the formulation within a desired range. In some aspects, the buffer can be a phosphate buffer, citrate buffer, lactate buffer, or any combination thereof. In a particular aspect, the formulation can comprise phosphoric acid, citric acid, lactic acid, or any combination thereof.

[0138] Because oxidation can result in degradation of an active agent, in some aspects, the pharmaceutical formulation can include an antioxidant. In some aspects, the antioxidant can be, e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol, propyl gallate, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, pharmaceutically acceptable salts or esters thereof, and any combination thereof. In a particular aspect, the antioxidant can be ascorbyl palmitate, BHA, BHT, or any combination thereof. In a particular aspect, theantioxidant can be BHT, ascorbyl palmitate, or a combination of BHT and ascorbyl palmitate.

[0139] In some aspects, the pharmaceutical formulation can include up to about 5 wt% (e.g., up to about 4 wt%, up to about 3 wt%, up to about 2 wt%, or up to about 1 wt% an antioxidant). In some aspects, the pharmaceutical formulation can include up to about 0.5 wt% of an antioxidant or include about 0.5 wt% antioxidant.

[0140] In some aspects, the pharmaceutical formulation can include an emulsifier, particularly to provide a solution, a suspension, an emulsion, or a microemulsion. Without wishing to be bound to any particular theory, it is believed that emulsifiers, when present, assist or facilitate dissolution of any solid substances, such as an active agent, in the pharmaceutical formulation. In other aspects, however, the emulsifier can be present to facilitate incorporation of two non-miscible liquids into each other (e.g., to form an emulsion or microemulsion).

[0141] In other aspects, and without wishing to be bound by any particular theory, an emulsifier can increase product spreadability. For example, and without wishing to be bound to a particular theory, when the pharmaceutical formulation is a liquid solution, the presence of a suitable amount of an emulsifier is believed to decrease the surface tension between the pharmaceutical formulation and the lipid environment of the superficial layer of the skin and / or scalp. This makes it easier to spread the pharmaceutical formulation and is believed to assist penetration of the active agent(s) into skin (including the scalp), hair follicles, or both.

[0142] In some aspects, the emulsifier can be selected from the group comprising or the group consisting of: polyethylene glycol (PEG)-fatty acid monoesters such as PEG-15 hydroxystearate (also known as polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate and the like; polyoxyethylene sorbitan fatty acid esters (polysorbates) such as polysorbate 20, polysorbate 60, polysorbate 80, and the like; polyoxyethylene alkyl ethers such as PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000 and the like; sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, and the like; a propylene glycol ester of a fatty acid; a polyglycerol ester of a fatty acid; polyoxyethylene castor oil derivatives such as polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil and the like; caprylocapryl polyoxyl-8 glycerides;polyoxylglycerides such as capryl ocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoyl polyoxylglycerides, and the like; along with a combination of any of the foreoging. In some aspects, the emulsifier can be polyoxyl 40 hydrogenated castor oil, polyoxyl-15- hydroxystearate, polysorbate 60, polysorbate 80, or any combination thereof. In a particular aspect, the emulsifier can be a polysorbate, such as polysorbate 60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80.

[0143] In some aspects, the pharmaceutical formulation can include the emulsifier in an amount of up to about 5 wt% of the total formulation (e.g., up to about 4 wt%, up to about 3 wt%, up to about 2 wt%). In some aspects, the emulsifier can be present in an amount ranging from 0.05 to 5 wt% (e.g., from about 0.05 wt% to about 4 wt%, from about 0.05 wt% to about 3 wt%, from about 0.05 wt% to about 2 wt%). In some aspects, the pharmaceutical formulation can include the emulsifier in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, or about 5 wt%. In still further aspects, the pharmaceutical formulation can include the emulsifier in an amount up to about 0.1 wt% or it can include about 0.1 wt% emulsifier. In still further aspects, the emulsifier can be present in the pharmaceutical formulation at about 0.1 wt%.

[0144] In some aspects, the pharmaceutical formulation can include one or more penetration enhancers. Without wishing to be bound by a particular theory, penetration enhancers are believed to beneficially affect delivery of the active agent(s) into the skin (including the scalp) and / or the hair follicles. Advantageously, and in some aspects, the solvent or some component s) of the solvent act as a penetration enhancer. For example, in aspects wherein the pharmaceutical formulation comprises ethanol and / or diethylene glycol monoethyl ether, these solvents can also act to enhance penetration of the active agent into the skin (including the scalp), the hair follicles, or both. The presence of ethanol and / or diethylene glycol monoethyl ether notwithstanding, the pharmaceutical formulations described herein can further include additional penetration enhancers.

[0145] In some aspects, the penetration enhancer can be selected from the group consisting of hydroxypropyl P- cyclodextrin, a diol, a polyol, a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or any combination thereof), a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and anycombination thereof. Examples of further penetration enhancer that can be incorporated into formulations described herein include, but are not limited to, polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether (e.g., TRANSCUTOL™, Gattefosse, France), dimethyl isosorbide, diethyl sebacate, azone, menthol, nerol, camphor, methyl salicylate, polysorbate 80 (e.g., TWEEN™ 80, Sigma-Aldrich, St. Louis, MO), SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (e.g., CREMOPHOR™ RH40, KOLLIPHOR™ RH40, BASF, Germany), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB), fatty acids esters (e.g., isopropyl myristate, isopropyl palmitate), fatty acids (e.g., oleic acid, palmitic acid, linoleic acid, and salts thereof), fatty alcohols (e.g., oleyl alcohol, myristyl alcohol, and stearyl alcohol), mediumchain triglycerides, and any combination thereof.

[0146] In a particular aspect, the penetration enhancer can be dimethyl isosorbide. In other aspects, the penetration enhancer can be a mixture comprising dimethyl isosorbide and diethylene glycol monoethyl ether. In a particularaspect, the penetration enhancer can be dimethyl sulfoxide.

[0147] In some aspects, the penetration enhancer can be present in an amount ranging from about 1 wt% to about 50 wt% with respect to the total weight of the pharmaceutical formulation. In other aspects, the penetration enhancer can be present from about 2 wt% to about 40 wt% with respect to the total weight of the pharmaceutical formulation; or from about 5 wt% to about 35 wt% with respect to the total weight of the pharmaceutical formulation. According to some aspects, the penetration enhancer can be present in the pharmaceutical formulation described herein in an amount of about 1% wt%, about 2 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% with respect to the total weight of the pharmaceutical formulation.

[0148] In some aspects, the pharmaceutical formulation can include one or more moisturizers. Without wishing to be bound by a particular theory, a moisturizer is believed to impart moisture and / or softness into the skin (including the scalp), particularly when a component known to dry the skin, such as an alcohol, are also present in the formulation. In some aspects, the moisturizer can be a fatty alcohol, a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or anycombination thereof), a fatty acid ester, an oil, a polyethylene glycol, glycerol, an alpha hydroxy acid, or any combination thereof. In some aspects, the moisturizer can be cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or any combination thereof. In a particular aspect, the moisturizer can be cetyl alcohol, stearyl alcohol, or a combination of cetyl alcohol and stearyl alcohol.

[0149] In some aspects, the pharmaceutical formulation can include one or more preservatives (e.g., an antibacterial, an antifungal). Suitable preservatives include, e.g., a paraben (e.g., methyl paraben, ethyl paraben, propyl paraben, butyl paraben), a benzoate (e.g., sodium benzoate), a sorbate (e.g., potassium sorbate), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an alcohol (e.g., chlorobutanol, benzyl alcohol, ethanol, phenol, m-cresol, chloro cresol), sodium metabisulfite, imidazolidinyl urea, glycerol, propylene glycol, or any combination thereof.

[0150] In some aspects, the pharmaceutical formulation can include one or more chelating agents. Suitable chelating agents include, e.g., citric acid, phytic acid, sodium phytate, clioquinol, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, any salt thereof, or any combination thereof. In a particular aspect, the chelating agent can be EDTA or a salt thereof.Modes of Administration

[0151] The pharmaceutical formulations described herein, regardless of whether it contains just pyrilutamide, just the hair growth-stimulating compound, or both, can be administered according to varying schedules. In some aspects, the pyrilutamide and the hair growthstimulating compound can be administered in the same pharmaceutical formulation (e.g., a combination formulation). In some aspects, the pharmaceutical formulations described herein can be co-administered as separate pharmaceutical formulations. In one aspect, the mode of administration of the pharmaceutical formulation(s) can be continuous. For example, the pharmaceutical formulations can be applied topically once a day, twice daily, three times a day, four times a day, or more, as specified by a physician. In some aspects, a formulation described herein can be applied topically once a day or twice daily. According to a particular aspect, the pharmaceutical formulation(s) described herein can beapplied topically once a day. According to another aspect, the pharmaceutical formulation(s) described herein can be applied topically twice daily.

[0152] In some aspects, a dosing regimen can be tapered. That is, the pharmaceutical formulation(s) can be applied once a day for a first period of time, twice daily thereafter for a second period of time, three times a day thereafter for a third period of time, and so on. In a particular aspect, the pharmaceutical formulation(s) can be applied once a day on the first day, and twice daily thereafter, with the appropriate duration of treatment determined by a subject’s physician. In an alternative aspect, tapered administration can comprise administering the pharmaceutical formulation(s) in a reducing schedule starting from multiple administrations per day for an appropriate period of time and reducing the number of administrations over an appropriate period of time until a maintenance scheduled can be achieved. It is within the skill of a physician of ordinary skill in the art armed with the present disclosure to determine the appropriate starting point, reducing taper, and maintenance schedule.

[0153] In some aspects, the pharmaceutical formulation(s) can be applied over the course of a period of days, weeks, or months. For example, the pharmaceutical formulation can be applied one, two, three, four, or five times a day for up to: 1, 2, 3, 4, 5, 6, or 7 days (i.e., about 1 week); about 2 weeks, about 3 weeks, or about 4 weeks; about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about a year (i.e., about 12 months), about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months. According to a particular aspect, the pharmaceutical formulation(s) can be applied once on the first day and twice daily thereafter for about 4 weeks.

[0154] In another aspects, the pharmaceutical formulation(s) can be topically applied to the scalp once a day for 1 month, once a day for 2 months, once a day for 3 months, once a day for 4 months, once a day 5 months, once a day for 6 months, once a day for 8 months, once a day for 12 months, once a day for 14 months, once a day for 16 months, once a day for 18 months, once a day for 20 months, once a day for 22 months, or once a day for 24 months. In some aspects, the pharmaceutical formulation(s) can be topically applied to thescalp once daily for 6 months. In some aspects, the pharmaceutical formulation(s) can be topically applied to the scalp once daily for 12 months.

[0155] In other aspects, the pharmaceutical formulation can be topically applied to the scalp twice daily for: about 1 month; for about 2 months; for about 3 months; for about 4 months; for about 5 months; for about 6 months, for about 8 months, for about 12 months, for about 14 months, for about 16 months, for about 18 months, for about 20 months, for about 22 months, or for about 24 months. In some aspects, the pharmaceutical formulation(s) can be topically applied to the scalp twice daily for 6 months. In some aspects, the pharmaceutical formulation can be topically applied to the scalp twice daily for 12 months.

[0156] In other aspects, the pharmaceutical formulation can be applied more than twice daily (i.e., 3 times a day (TID), 4 times a day (QID), etc.) for: about 1 month; for about 2 months; for about 3 months; for about 4 months; for about 5 months; for about 6 months, for about 8 months, for about 12 months, for about 14 months, for about 16 months, for about 18 months, for about 20 months, for about 22 months, or for about 24 months. In some aspects, the pharmaceutical formulation(s) can be topically applied to the scalp more than twice daily (i.e., TID, QID, etc.) for 6 months. In some aspects, the pharmaceutical formulation(s) can be topically applied to the scalp more than twice daily (i.e., TID, QID, etc.) for 12 months.

[0157] In another aspect, the mode of administration of the pharmaceutical formulations can be cyclic. For example, the pharmaceutical formulation(s) can first be applied in a continuous way as described above for a desired period of time, the application can then be discontinued for a period of time, such as a few days, and then the application of the pharmaceutical formulations can be started again, as described above. The treatment period can include one or more cycles which can be the same or different. In some aspects, the treatment period can be as follows: a) the pharmaceutical formulation(s) can be topically applied to the scalp for a period of time, such as 4 months, by continuous administration, b) the application can be discontinued for a few days (e.g., 2 to 5 days), and 3) the topical application can be continued for an additional period of time, such as 6 months.

[0158] In some aspects, the mode of administration can be cyclic in that pyrilutamide and the hair growth-stimulating compound can be co-administered sequentially. For example, a pharmaceutical formulation comprising pyrilutamide can be administered first for a firstperiod of time, and a pharmaceutical formulation comprising the hair growth-stimulating compound can be administered second for a second period of time. In other aspects, a pharmaceutical formulation comprising the hair growth-stimulating compound can be administered first and a pharmaceutical formulation comprising pyrilutamide can be administered second. The time period between when the first pharmaceutical formulation can be administered, and the second pharmaceutical formulation can be administered, can be any suitable time period. For example, the time between each administration can be on the order of seconds, minutes, hours, or days, as needed. In some aspects, administration of the first and second pharmaceutical formulations can be separated by seconds (e.g., about 60 seconds or less, about 30 seconds or less). In some aspects, administration of the first and second pharmaceutical formulations can be separated by hours (e.g., about 1 hour or less, about 2 hours or less, about 3 hours or less, about 5 hours or less, about 8 hours or less, about 12 hours or less, about 24 hours or less). In some aspects, administration of the first and second pharmaceutical formulations can be separated by days (e.g., about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days). In some aspects, administration of the first and second pharmaceutical formulations can be separated by weeks (e.g., about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks).

[0159] In some aspects, a first pharmaceutical formulation comprising either pyrilutamide or the hair growth-stimulating compound can be administered for a first period of time, in which the first time period can be on the order of days or weeks. During the first period of time, the first pharmaceutical formulation can be administered multiple times to the skin or scalp, as described herein, before a second pharmaceutical formulation comprising the other active agent can be administered in a second period of time. Similar to the first period of time, the second time period can be on the order of days or weeks. For example, a first pharmaceutical formulation comprising pyrilutamide can be administered for a first period of time (e.g., about 1 day or more, about 2 days or more, about 7 days or more, about 2 weeks or more, about 3 weeks or more, or about 4 weeks or more). A second pharmaceutical formulation comprising the hair growth-stimulating compound can be administered for a second period of time (e.g., about 1 day or more, about 2 days or more, about 7 days or more, about 2 weeks or more, about 3 weeks or more, or about 4 weeks or more). In some aspects, a subject can alternate (e.g., cycle between) administration between the first and second pharmaceutical formulations for a given time period to effect treatment.

[0160] The “effective amount” of each active agent is an amount that provides a desired outcome (e.g., to induce hair growth and / or regrowth). In some aspects, the pharmaceutical formulation can comprise pyrilutamide and the hair growth-stimulating compound, or both active agents at a concentration of from about 0.1 wt% to about 20 wt%. For example, the pharmaceutical formulation can comprise pyrilutamide and the hair growth-stimulating compound, or both active agents at a concentration of about 0.1 wt% or more (e.g., about 0.2 wt% or more, about 0.3 wt% or more, about 0.4 wt% or more, about 0.5 wt% or more, about 0.6 wt% or more, about 0.7 wt% or more, about 0.8 wt% or more, about 0.9 wt% or more, about 1 wt% or more, about 1.2 wt% or more, about 1.4 wt% or more, about 1.6 wt% or more, about 1.8 wt% or more, about 2 wt% or more, about 2.2 wt% or more, about 2.4 wt% or more, about 2.6 wt% or more, about 2.8 wt% or more, about 3 wt% or more, about 3.2 wt% or more, about 3.4 wt% or more, about 3.6 wt% or more, about 3.8 wt% or more, about 4 wt% or more, about 4.2 wt% or more, about 4.4 wt% or more, about 4.6 wt% or more, about 4.8 wt% or more, about 5 wt% or more, about 5.2 wt% or more, about 5.4 wt% or more, about 5.6 wt% or more, about 5.8 wt% or more, about 6 wt% or more, about 6.2 wt% or more, about 6.4 wt% or more, about 6.6 wt% or more, about 6.8 wt% or more, about 7 wt% or more, about 7.2 wt% or more, about 7.4 wt% or more, about 7.6 wt% or more, about 7.8 wt% or more, about 8 wt% or more, about 8.2 wt% or more, about 8.4 wt% or more, about 8.6 wt% or more, about 8.8 wt% or more, about 9 wt% or more, about 9.2 wt% or more, about 9.4 wt% or more, about 9.6 wt% or more, about 9.8 wt% or more, about 10 wt% or more, about 10.5 wt% or more, about 11 wt% or more, about 11.5 wt% or more, about 12 wt% or more, about 12.5 wt% or more, about 13 wt% or more, about 13.5 wt% or more, about 14 wt% or more, about 14.5 wt% or more, about 15 wt% or more, about 15.5 wt% or more, about 16 wt% or more, about 16.5 wt% or more, about 17 wt% or more, about 17.5 wt% or more, about 18 wt% or more, about 18.5 wt% or more, about 19 wt% or more, or about 19.5 wt% or more) to about 20 wt% or less (e.g., about 19.5 wt% or less, about 19 wt% or less, about 18.5 wt% or less, about 18 wt% or less, about 17.5 wt% or less, about 17 wt% or less, about 16.5 wt% or less, about 16 wt% or less, about 15.5 wt% or less, about 15 wt% or less, about 14.5 wt% or less, about 14 wt% or less, about 13.5 wt% or less, about 13 wt% or less, about 12.5 wt% or less, about 12 wt% or less, about 11.5 wt% or less, about 11 wt% or less, about 10.5 wt% or less, about 10 wt% or less, about 9.5 wt% or less, about 9 wt% or less, about 8.5 wt% or less, about 8 wt% or less, about 7.5 wt% orless, about 7 wt% or less, about 6.5 wt% or less, about 6 wt% or less, about 5.8 wt% or less, about 5.6 wt% or less, about 5.4 wt% or less, about 5.2 wt% or less, about 5 wt% or less, about 4.8 wt% or less, about 4.6 wt% or less, about 4.4 wt% or less, about 4.2 wt% or less, about 4 wt% or less, about 3.8 wt% or less, about 3.6 wt% or less, about 3.4 wt% or less, about 3.2 wt% or less, about 3 wt% or less, about 2.8 wt% or less, about 2.6 wt% or less, about 2.4 wt% or less, about 2.2 wt% or less, about 2 wt% or less, about 1.8 wt% or less, about 1.6 wt% or less, about 1.4 wt% or less, about 1.2 wt% or less, about 1 wt% or less, about 0.9 wt% or less, about 0.8 wt% or less, about 0.7 wt% or less, about 0.6 wt% or less, about 0.5 wt% or less, about 0.4 wt% or less, about 0.3 wt% or less, or about 0.2 wt% or less). In some aspects, the pharmaceutical formulation can comprise pyrilutamide and the hair growth-stimulating compound, or both active agents at a concentration of from about 0.5 wt% to about 18 wt% or about 1 wt% to about 15 wt% or about 1.5 wt% to about 15 wt% or about 2 wt% to about 12 wt% or about 2.5 wt% to about 10 wt% or about 2.5 wt% to about 8 wt% or about 3 wt% to about 7 wt%.

[0161] In some aspects, the pharmaceutical formulation can comprise pyrilutamide at a concentration from about 0.1 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a-propi onate at a concentration from about 1 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation can comprise minoxidil at a concentration from about 0.25 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation can be a solution that can comprise pyrilutamide at a concentration from about 0.1 wt% to about 20 wt% and minoxidil at a concentration from about 0.25 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation can be a solution that can comprise pyrilutamide at a concentration from about 0.1 wt% to about 20 wt% and cortexolone-17a-propi onate at a concentration from about 1 wt% to about 20 wt%. In some aspects, the pharmaceutical formulation can be a solution that can comprise about 5 wt% pyrilutamide and about 5 wt% minoxidil. In some aspects, the pharmaceutical formulation can be a solution that can comprise about 5 wt% pyrilutamide and about 5 wt% cortexol one- 17 a-propi onate .

[0162] In some aspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 100 mg. In other aspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 90 mg. In other aspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 80 mg. In otheraspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 70 mg. In some aspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 60 mg. In other aspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 50 mg. In other aspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 40 mg. In some aspects, the amount of pyrilutamide in a single application can range from about 2 mg to about 30 mg. In some aspects, the amount of pyrilutamide in a single application can be about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg. In another aspect, the amount of pyrilutamide in a single application can be about 2.5 mg. In another aspect, the amount of pyrilutamide in a single application can be about 5 mg. In yet another aspect, the amount of pyrilutamide in a single application can be about 10 mg. In yet another aspect, the amount of pyrilutamide in a single application can be about 25 mg. In other aspects, the amount of pyrilutamide in a single application can be about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

[0163] In some aspects, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 400 mg. In other aspects, the amount of cortexolone- 17a-propi onate in a single application can range from about 20 mg to about 350 mg. In other aspects, the amount of cortexolone-17a-propi onate in a single application can range from about 20 mg to about 300 mg. In other aspects, the amount of cortexolone-17a- propionate in a single application can range from about 20 mg to about 250 mg. In some aspects, the amount of cortexolone-17a-propi onate in a single application can range from about 20 mg to about 200 mg. In other aspects, the amount of cortexolone-17a-propi onate in a single application can range from about 20 mg to about 170 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 150 mg. In some aspects, the amount of cortexolone-17a-propi onate in a single application can range from about 20 mg to about 100 mg. In some aspects, the amount of cortexolone-17a-propi onate in a single application can be about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg, about240 mg, about 260 mg, about 280 mg, about 300 mg, about 330 mg, about 360 mg, about390 mg, or about 400 mg. In another aspect, the amount of cortexolone-17a-propi onate in a single application can be about 25 mg. In another aspect, the amount of cortexolone-17a- propionate in a single application can be about 30 mg. In yet another aspect, the amount of cortexolone-17a-propi onate in a single application can be about 50 mg. In yet another aspect, the amount of cortexolone-17a-propionate in a single application can be about 75 mg. In yet another aspect, the amount of cortexolone-17a-propi onate in a single application can be about 80 mg. In yet another aspect, the amount of cortexolone-17a-propi onate in a single application can be about 100 mg. In other aspects, the amount of cortexolone-17a- propionate in a single application can be about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, or about 200 mg. In yet another aspect, the amount of cortexolone-17a-propionate in a single application can be about 150 mg.

[0164] In some aspects, the amount of minoxidil in a single application can range from about 2 mg to about 20 mg. In other aspects, the amount of minoxidil in a single application can range from about 2 mg to about 15 mg. In other aspects, the amount of minoxidil in a single application can range from about 2 mg to about 10 mg. In other aspects, the amount of minoxidil in a single application can range from about 2 mg to about 5 mg.

[0165] In some aspects, the pharmaceutical formulation can be self-administered by the subject once a day or twice daily. In some aspects, when the pharmaceutical formulation can be in liquid form having a pyrilutamide concentration of about 5 wt% and a hair growthstimulating compound concentration of about 5 wt%, the pharmaceutical formulation can be self-administered once a day or twice daily at a dose ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in further aspects at about 1 mL or about 1.5 mL.

[0166] In some aspects, when the pharmaceutical formulation can be in liquid form having a pyrilutamide concentration of about 2.5 wt% and a hair growth-stimulating compound concentration of about 2.5 wt%, the pharmaceutical formulation can be self-administered once a day or twice daily at a dose ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in further aspects at about 1 mL or about 1.5 mL.

[0167] In some aspects, when the pharmaceutical formulation can be in liquid form having a pyrilutamide concentration of about 2.5 wt% and a hair growth-stimulating compound concentration of about 5 wt%, the pharmaceutical formulation can be self-administered once a day or twice daily at a dose ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in further aspects at about 1 mL or about 1.5 mL.

[0168] In some aspects, when the pharmaceutical formulation can be in liquid form having a pyrilutamide concentration of about 5 wt% and a hair growth-stimulating compound concentration of about 1.5 wt%, the pharmaceutical formulation can be self-administered once a day or twice daily at a dose ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in further aspects at about 1 mL or about 1.5 mL.

[0169] The pharmaceutical formulation described herein can be applied to any body surface in need of treatment, such as a skin region susceptible to induction of hair growth. Suitable skin regions include e.g., scalp, face (e.g., the eyebrow, eyelashes, upper lip, lower lip, chin, cheeks, beard area, or mustache area), arms, armpits, legs, chest, abdomen, or a combination of any of the foregoing. In some aspects, treatment is not delivered to the face. In other aspects, the pharmaceutical formulation can be applied to the scalp.Kit

[0170] The present disclosure further provides a kit comprising one or more topical pharmaceutical formulations in various forms, as described herein. In an aspect, the kit can contain one or more liquid or semi-solid formulations suitable for administration. The kit can further comprise a device for administration, such as a dropper or a pipette, for use by a person skilled in the art. The kit can further include instructions for preparing and administering the one or more pharmaceutical formulations. The instruction can be in various formats, such as a printed matter, magnetic disk, magnetic tape, compact disc, flash memory, or other media suitable for conveying the appropriate information.

[0171] In some aspects, the kit can comprise a pharmaceutical formulation comprising pyrilutamide as a first component and a pharmaceutical formulation comprising the hair growth-stimulating compound as a second component. The kit can further comprise instructions for use of the first and second components. In some aspects, the first component and the second component can be combined just before use (e.g., within 1 hour before use, within 45 min before use, within 30 min before use, within 20 min before use, within 15 min before use, within 10 min before use, or within 5 min before use) and applied to theskin or scalp as a single combined formulation. In some aspects, both the first and second components can be solutions. In some aspects, one or both of the first and second components can be a gel. In some aspects, one or both of the first and second components can be a cream. In some aspects, one or both of the first and second components can be a foam.

[0172] In some aspects, the kit can comprise pyrilutamide in solid form as a first component and a pharmaceutical formulation comprising the hair growth-stimulating compound as a second component. The kit can further comprise instructions for using the first and second components. In some aspects, the pyrilutamide in solid form can be a powder, a fast-disintegrating tablet, a granule, a granulate, and the like. In some aspects, the pyrilutamide in solid form can be stored separately from the container containing the pharmaceutical formulation comprising minoxidil. In such aspects, pyrilutamide in solid form can be stored within a capped vial or closed bottle.

[0173] In some aspects, the pyrilutamide in solid form can be stored within the same container containing the pharmaceutical formulation comprising the hair growthstimulating compound. According to such aspects, the pyrilutamide in solid form can be stored in a constituent part of the container containing the pharmaceutical formulation comprising the hair growth-stimulating compound, which is designed to prevent contact between the two active agents. In some aspects, the constituent part of the container, which is designed to prevent the contact between the pyrilutamide in solid form and the pharmaceutical formulation comprising the hair growth-stimulating compound, can be a cap containing a storage chamber for a solid substance (e.g., a reservoir cap), or a chamber separated from the main chamber containing the pharmaceutical formulation comprising the hair growth-stimulating compound. In some aspects, the container containing the pharmaceutical formulation comprising the hair growth-stimulating compound can be capped with a reservoir cap containing pyrilutamide in solid form, which is equipped with a cutting device activated by the subject pushing, twisting, or pulling the cap itself. According to such aspect, activating the cutting device in the reservoir cap allows pyrilutamide in solid form to come into contact with the pharmaceutical formulation comprising the hair growth-stimulating compound.

[0174] In some aspects, the first component and the second component can be combined just before use (e.g., within 1 hour before use, within 45 min before use, within 30 minbefore use, within 20 min before use, within 15 min before use, within 10 min before use, or within 5 min before use) and applied to the skin or scalp as a single combined formulation. In some aspects, the first component can be in solid form and the second component can be a solution. In some aspects, the first component can be in solid form and the second component can be a gel. In some aspects, the first component can be in solid form and second component can be a cream. In some aspects, the first component can be in solid form and the second component can be a foam.

[0175] In some aspects, the kit can comprise the hair growth-stimulating compound in solid form as a first component and a pharmaceutical formulation comprising pyrilutamide as a second component. The kit can further comprise instructions for using the first and second components. In some aspects, the hair growth-stimulating compound in solid form can be a powder, a fast-disintegrating tablet, a granule, a granulate, and the like. In some aspects, the hair growth-stimulating compound in solid form can be stored separately from the container containing the pharmaceutical formulation comprising pyrilutamide. In such aspects, the hair growth-stimulating compound in solid form can be stored within a capped vial or closed bottle.

[0176] In some aspects, the hair growth-stimulating compound in solid form can be stored within the same container containing the pharmaceutical formulation comprising pyrilutamide. According to such aspects, the hair growth-stimulating compound in solid form can be stored in a constituent part of the container containing the pharmaceutical formulation comprising pyrilutamide, which is designed to prevent the contact between the two. In some aspects, the constituent part of the container, which is designed to prevent the contact between the hair growth-stimulating compound in solid form and the pharmaceutical formulation comprising pyrilutamide, can be a cap containing a storage chamber for a solid substance (e.g., a reservoir cap), or a chamber separated from the main chamber containing the pharmaceutical formulation comprising pyrilutamide. In some aspects, the container containing the pharmaceutical formulation comprising pyrilutamide can be capped with a reservoir cap containing the hair growth-stimulating compound in solid form, which is equipped with a cutting device activated by the subject pushing, twisting, or pulling the cap itself. According to such aspect, activating the cutting device in the reservoir cap allows the hair growth-stimulating compound in solid form to come into contact with the pharmaceutical formulation comprising pyrilutamide. In some aspects, thefirst component and the second component can be combined just before use (e.g., within 1 hour before use, within 45 min before use, within 30 min before use, within 20 min before use, within 15 min before use, within 10 min before use, or within 5 min before use) and applied to the skin or scalp as a single combined formulation. In some aspects, the first component can be in solid form and the second component can be a solution. In some aspects, the first component can be in solid form and the second component can be a gel. In some aspects, the first component can be in solid form and the second component can be a cream. In some aspects, the first component can be in solid form and the second component can be a foam.Storage Stability

[0177] Storage stability is an important metric for pharmaceutical products. In general, greater stability means that a given formulation is both easier to transport and store, increasing the likelihood that it will be stocked by pharmacies and that subjects will not have to be concerned with special storage instructions. In some aspects, the pharmaceutical formulation described herein can have a desirable stability profile allowing for storage of the final formulation for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about two years - each at room (about 20 °C) or refrigerated temperatures (e.g., about 4 °C).

[0178] For example, one of the main degradation pathways of cortexolone-17a-propi onate is transesterification to cortexol one-21 -propionate (17a-hydroxy-21-propionyloxy-pregna- 4-ene-3 ,20-dione) :

[0179] In some aspects, maintaining the pharmaceutical formulations disclosed herein at an acidic pH, including a pH of less than 7.0 (e.g., less than about 6.5, less than about 6, less than about 5.5, less than about 5, less than about 4.5, between about 4 and about 7, between about 4 and about 6.5, between about 4 and about 6, between about 4 and 5.5,between about 4 and 5, between about 4 and about 4.5, or at about 6.5, about 6, about 5.5, about 5, about 4.5, or about 4), can slow this degradation process. In some aspects, the pH can be about 4. The appropriate pH can be obtained via addition of a suitable amount of a pH modifier, such as the acids described herein.

[0180] In some aspects, the pharmaceutical formulations described herein can, at room (about 20 °C) or refrigerated (e.g., about 4 °C) temperatures, have less than about 5 wt% cortexol one-21 -propionate or other degradation products after storage for a period of about 24 months.EXAMPLES

[0181] The pharmaceutical formulations described herein are now further detailed with reference to the following examples. These examples are provided for the purpose of illustration only and the aspects described herein should in no way be construed as being limited to these examples. Rather, the aspects should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.Example 1: Anhydrous 5% w / w Solution of Pyrilutamide

[0182] A 5 wt% (w / w) solution of pyrilutamide having the components shown in Table 1 can be prepared.q.s.: quantum satisExample 2: Anhydrous 5% w / w Solution of Cortexolone-17a-propionate

[0183] A 5 wt% (w / w) solution of cortexolone-17a-propionate having the components shown in Table 2, below, was prepared by solubilizing the active agent in the mixture of solvents followed by the addition of the emulsifier (polysorbate 80).Table 2

[0184] This formulation provided the stability profile (40 °C and 75% relative humidity (RH)) shown in Table 3.Table 3*Cortexol one-21 -propionate contents calculated as (% (w / w) of cortexol one- 21 -propionate) / (% (w / w) of cortexolone-17a-propionate x 100)Example 3: 5% w / w Foam of Minoxidil

[0185] A 5 wt% (w / w) foam of minoxidil having the components shown in Table 4 can be prepared.Table 4q.s.: quantum satisExample 4: 5% w / w Solution of Minoxidil

[0186] A 5 wt% (w / w) solution of minoxidil having the components shown in Table 5 can be prepared.Table 5q.s.: quantum satis

[0187] Ethanol and propylene glycol are mixed and heated to 60-70 °C; once the temperature is within the above range (60-70 °C), minoxidil is added and the mixture is kept under stirring until minoxidil is completely solubilized. Thereafter, water is added slowly to the mixture under stirring and keeping the temperature in the range 60-70 °C, until final weight is reached. Thereafter, the mixture is slowly cooled to room temperature under stirring.Example 5: Solution of Pyrilutamide (2.5% w / w) and Cortexolone-17a-propionate (2.5% w / w)

[0188] A 2.5 wt% (w / w) solution of pyrilutamide having the components shown in Table 6 can be prepared.Table 6q.s.: quantum satisExample 6: Solution of Pyrilutamide (2.5% w / w) and Minoxidil (2.5% w / w)

[0189] A 2.5 wt% (w / w) solution of pyrilutamide having the components shown in Table 7 can be prepared.Table 7q.s.: quantum satisExample 7: Kit containing a Solution of Pyrilutamide (5.0% w / w) and Cortexolone-17a-propionate in Solid Form

[0190] A 5 wt% (w / w) solution of pyrilutamide having the components shown in Table 8 can be prepared.Table 8q.s.: quantum satis

[0191] Ethanol and propylene glycol is mixed and heated to 60-70 °C; once the temperature is within the above range (60-70 °C), pyrilutamide is added and the mixture is kept under stirring until complete pyilutamide is completely solubilized. Thereafter, water is added slowly to the mixture under stirring and keeping the temperature in the range 60-70 °C, until final weight is reached. Thereafter, the mixture is slowly cooled to room temperature under stirring. The solution containing pyrilutamide is then filled in 60 mL glass bottles. Cortexolone-17a-propionate in powder form is filled into the storage container of reservoir caps (about 3 g per cap). The 60 mL bottles containing the pyrilutamide solution are then capped with the reservoir caps filled in with cortexolone-17a-propionate powder.Example 8: Kit containing a Solution of Pyrilutamide (5.0% w / w) and Minoxidil in Solid Form

[0192] A 5 wt% (w / w) solution of pyrilutamide having the components shown in Table 9 can be prepared.Table 9q.s.: quantum satis

[0193] Ethanol and propylene glycol is mixed and heated to 60-70 °C; once the temperature is within the above range (60-70 °C), pyrilutamide is added and the mixture is kept under stirring until complete pyilutamide is completely solubilized. Thereafter, water is added slowly to the mixture under stirring and keeping the temperature in the range 60-70 °C, until final weight is reached. Thereafter, the mixture is slowly cooled to room temperature under stirring. The solution containing pyrilutamide is then filled in 60 mL glass bottles. Minoxidil in powder form is filled into the storage container of reservoir caps (about 3 g per cap). The 60 mL bottles containing the pyrilutamide solution are then capped with the reservoir caps filled in with minoxidil powder.Example 9: Kit containing a Solution of Cortexolone-17a-propionate (5.0% w / w) and Pyrilutamide in Solid Form

[0194] A 5 wt% (w / w) solution of cortexolone-17a-propionate having the components shown in Table 10 can be prepared.Table 10

[0195] A 5 wt% (w / w) solution of cortexolone-17a-propionate having the components shown in Table 10 is prepared by solubilizing the active agent in the mixture of solvents followed by the addition of the emulsifier (polysorbate 80). The solution containing cortexolone-17a-propi onate is then filled in 60 mL glass bottles. Pyrilutamide in powder form is filled into the storage container of reservoir caps (about 3 g per cap). The 60 mLbottles containing the cortexolone-17a-propionate solution are then capped with the reservoir caps filled in with pyrilutamide powder.Example 10: Kit containing a Solution of Minoxidil (5.0% w / w) and Pyrilutamide in Solid Form

[0196] A 5 wt% (w / w) solution of minoxidil having the components shown in Table 11 can be prepared.Table 11q.s.: quantum satis

[0197] Ethanol and propylene glycol are mixed and heated to 60-70 °C; once the temperature is within the above range (60-70 °C), minoxidil is added and the mixture is kept under stirring until complete minoxidil is completely solubilized. Thereafter, water is added slowly to the mixture under stirring and keeping the temperature in the range 60-70 °C, until final weight is reached. Thereafter, the mixture is slowly cooled to room temperature under stirring. The solution containing minoxidil is then filled in 60 mL glass bottles. Pyrilutamide in powder form is filled into the storage container of reservoir caps (about 3 g per cap). The 60 mL bottles containing the minoxidil solution are then capped with the reservoir caps filled in with pyrilutamide powder.

[0198] The phraseology or terminology herein is for the purpose of description and not of limitation. As such, the terminology and / or phraseology of the present specification should be interpreted by the skilled artisan in light of the teachings and guidance herein.

[0199] The breadth and scope of the present invention should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

[0200] All patents, patent applications, and other references noted or referenced in this application are hereby incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of treating hair loss in a subject in need thereof, comprising topically administering to the subject an effective amount of: a) pyrilutamide; and b) a hair growth-stimulating compound, selected from the group consisting of minoxidil and cortexolone-17a-propionate.

2. The method of claim 1, wherein pyrilutamide is co-administered in an amount from about 0.1 weight percent to about 20 weight percent along with an effective amount of the hair growth-stimulating compound.

3. The method of claim 1, wherein minoxidil is co-administered in an amount from about 0.25 weight percent to about 20 weight percent along with an effective amount of the hair growth-stimulating compound.

4. The method of claim 1, wherein cortexolone-17a-propi onate is co-administered in an amount from at least 1 weight percent to about 20 weight percent along with an effective amount of the hair growth-stimulating compound.

5. The method of any one of claims 1-4, wherein the pyrilutamide and the hair growthstimulating compound are administered sequentially.

6. The method of claim 5, wherein the pyrilutamide and the hair growth-stimulating compound are in separate pharmaceutical formulations.

7. The method of any one of claims 1-4, wherein the pyrilutamide and the hair growthstimulating compound are co-administered simultaneously.

8. The method of claim 7, wherein the pyrilutamide and the hair growth-stimulating compound are in the same pharmaceutical formulation.

9. The method of claim 8, wherein the pharmaceutical formulation is a liquid or semi-solid formulation.

10. The method of claim 8 or 9, wherein the pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, a foam, or an ointment.

11. The method of any one of claims 8-10, wherein the pharmaceutical formulation is a solution.

12. The method of any one of claims 8-11, wherein the pharmaceutical formulation comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or any combination thereof.

13. The method of any one of claims 8-12, wherein the pharmaceutical formulation further comprises at least one additive selected from an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and any combination thereof.

14. The method of any one of claims 1-13, wherein the pyrilutamide is co-administered in a pharmaceutical formulation comprising less than about 5 weight percent water.

15. The method of any one of claims 8-14, wherein the pharmaceutical formulation is coadministered topically once or twice daily.

16. The method of any one of claims 1-15, wherein the hair loss is alopecia.

17. The method of claim 16, wherein the alopecia is androgenetic alopecia, alopecia areata telogen effluvium, anagen effluvium, traction alopecia, or a combination of any of the foregoing.

18. The method of claim 17, wherein the alopecia areata is selected from the group consisting of diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, ophiasis, alopecia totalis, and alopecia universalis.

19. The method of claim 17, wherein the alopecia is androgenetic alopecia.

20. A topical pharmaceutical formulation comprising: a) pyrilutamide; b) a hair growth-stimulating compound selected from the group consisting of minoxidil and cortexolone-17a-propionate; and c) one or more pharmaceutically acceptable carriers.

21. The topical pharmaceutical formulation of claim 20, wherein the pyrilutamide and the hair growth-stimulating compound are solubilized in the formulation.

22. The topical pharmaceutical formulation of claim 20 or 21, wherein the formulation comprises pyrilutamide at a concentration from about 0.1 weight percent to about 20 weight percent.

23. The topical pharmaceutical formulation of any one of claims 20-22, wherein the pharmaceutical formulation comprises minoxidil at a concentration from about 0.25 weight percent to about 20 weight percent.

24. The topical pharmaceutical formulation of any one of claims 20-22, wherein the formulation comprises cortexolone-17a-propi onate at a concentration from 1 weight percent to about 20 weight percent.

25. The topical pharmaceutical formulation of any one of claims 20-24, wherein the pharmaceutical formulation is a liquid or semi-solid formulation.

26. The topical pharmaceutical formulation of claim 25, wherein the liquid or semi-solid formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, a foam, or an ointment.

27. The topical pharmaceutical formulation of claim 26, wherein the pharmaceutical formulation is a solution.

28. The topical pharmaceutical formulation of claim 26 or 27, wherein the solution comprises water, saline, a buffered saline solution, or any combination thereof.

29. The topical pharmaceutical formulation of any one of claims 20-28, wherein the pharmaceutical formulation comprises less than about 5 percent water by weight.

30. The topical pharmaceutical formulation of any one of claims 20-29, wherein the one or more pharmaceutically acceptable carriers are selected from the group consisting of a polyol, a polyol ether, a C1-C7 alcohol, and any combination thereof.

31. The topical pharmaceutical formulation of claim 30, wherein the C1-C7 alcohol is ethanol, isopropanol, or any combination thereof.

32. The topical pharmaceutical formulation of claim 31, wherein the C1-C7 alcohol is ethanol.

33. The topical pharmaceutical formulation of any one of claims 30-32, wherein the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerol, hexanetriol, and any combination thereof.

34. The topical pharmaceutical formulation of claim 33, wherein the polyol is propylene glycol.

35. The topical pharmaceutical formulation of any one of claims 30-34, wherein the polyol ether is selected from the group consisting of polypropylene glycol, polyethylene glycol, apolyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether, and any combination thereof.

36. The topical pharmaceutical formulation of any one of claims 20-35, wherein the pharmaceutical formulation further comprises at least one additive selected from the group consisting of an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and any combination thereof.

37. The topical pharmaceutical formulation of claim 36, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol, propyl gallate, 2,4,5- trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, pharmaceutically acceptable salts thereof, esters thereof, and any combination thereof.

38. The topical pharmaceutical formulation of claim 37, wherein the antioxidant is BHT, ascorbyl palmitate, or a combination of BHT and ascorbyl palmitate.

39. The topical pharmaceutical formulation of any one of claims 36-38, wherein the emulsifier is selected from the group consisting of PEG-15 hydroxystearate (polyoxyl-15- hydroxy stearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbate 20, polysorbate 60, polysorbate 80, PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate a propylene glycol ester of a fatty acid, a polyglycerol ester of a fatty acid, polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, caprylocapryl polyoxyl-8 glycerides, capryl ocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoyl polyoxylglycerides, and any combination thereof.

40. The topical pharmaceutical formulation of claim 39, wherein the emulsifier is polysorbate 60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80.

41. The topical pharmaceutical formulation of any one of claims 36-40, wherein the penetration enhancer is selected from the group consisting of a diol, a polyol, a fatty acid, a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and any combination thereof.

42. The topical pharmaceutical formulation of any one of claims 36-41, wherein the moisturizer is selected from the group consisting of a fatty alcohol, a fatty acid, a fatty acid ester, an oil, a polyethylene glycol, glycerol, an alpha hydroxyl acid, and any combination thereof.

43. The topical pharmaceutical formulation of claim 42, wherein the moisturizer is cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or any combination thereof.

44. The topical pharmaceutical formulation of any one of claims 36-43, wherein the buffer is a phosphate buffer, citrate buffer, lactate buffer, or any combination thereof.

45. A method of treating alopecia, the method comprising topically administering to a subject in need thereof the topical pharmaceutical formulation of any one of claims 20-44, wherein the topical administration of the formulation for at least six months achieves a weighted average Hair Growth Assessment (HGA) score of about 0.30 in comparison with vehicle.

46. A method of treating alopecia, the method comprising topically administering to a subject in need thereof the topical pharmaceutical formulation of any one of claims 20-44, wherein the topical administration of the formulation for at least six months achieves a weighted average Investigator’s Global Assessment (IGA) score of about 0.43 in comparison with vehicle.

47. A method of treating alopecia, the method comprising topically administering to a subject in need thereof the topical pharmaceutical formulation of any one of claims 20-44, wherein the topical administration of the formulation for at least six months is free from systemic anti androgenic side-effects.

8. A method of treating alopecia, the method comprising topically administering to a subject in need thereof the topical pharmaceutical formulation of any one of claims 20-44, wherein the topical administration of the formulation provides a) a mean change from baseline in Target Area Hair Count equal to or higher than 9 hairs / cm2after 6 months of daily or BID application; or b) a mean change from baseline in Target Area Hair Count equal to or higher than 10 hairs / cm2after 6 months of daily or BID application; or c) a mean change from baseline in Target Area Hair Count equal to or higher than 11 hairs / cm2after 6 months of daily or BID application; or d) a mean change from baseline in Target Area Hair Count equal to or higher than 12 hairs / cm2after 6 months of daily or BID application; or e) a weighted average HGA score equal to or higher than 0.20 after 6 months of daily or BID application; or f) a weighted average HGA score equal to or higher than 0.30 after 6 months of daily or BID application; or g) a weighted average HGA score equal to or higher than 0.40 after 6 months of daily or BID application; or h) a weighted average IGA score equal to or higher than 0.10 after 6 months of daily or BID application; or i) a weighted average IGA score equal to or higher than 0.20 after 6 months of daily or BID application; or j) a weighted average IGA score equal to or higher than 0.30 after 6 months of daily or BID application; or k) a favorable (positive) HGA score in at least about 10 % of subjects after 6 months of daily or BID application; or l) a favorable (positive) HGA score in at least about 20 % of subjects after 6 months of daily or BID application; or m) a favorable (positive) HGA score in at least about 30 % of subjects after 6 months of daily or BID application; or n) a favorable (positive) IGA score in at least about 10 % of subjects after 6 months of daily or BID application; oro) a favorable (positive) IGA score in at least about 20 % of subj ects after 6 months of daily or BID application; or p) a favorable (positive) IGA score in at least about 30 % of subj ects after 6 months of daily or BID application; or q) a favorable (positive) IGA score in at least about 40 % of subjects after 6 months of daily or BID application.

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