Clascoterone and minoxidil combination therapy for use in treating hair loss

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 cortexolone-17α-propionate and an effective amount of minoxidil. The present disclosure further provides a topical pharmaceutical formulation comprising cortexolone-17α-propionate, minoxidil, and one or more pharmaceutically acceptable carriers.

Description

CLASCOTERONE AND MINOXIDIL 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] 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 wt% (topical solution) and 5 wt% (as a topical solution or foam). See, e.g., U.S. Patent Nos. 4,596,812 and6,946,120, 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 wt% minoxidil solution to patients experiencing hair loss results in stimulated dense hair regrowth in fewer than about 5 wt% 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).

[0005] 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. The compound is also known to exist in several distinct crystalline polymorphs, each having unique properties. See, e.g., U.S. Patent No. 8,785,427. Each of these patents is incorporated herein by reference in its entirety.

[0006] It has been surprisingly discovered that hair loss, including alopecia, can be effectively treated with a combination of cortexolone-17a-propionate and minoxidil. In some embodiments, 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.

[0007] It has been further surprisingly discovered that concurrently treating a subject suffering from hair loss with 5 wt% solutions of both cortexolone-17a-propionate and minoxidil synergistically affects versican expression in dermal papilla Accordingly, the present disclosure also provides a method of increasing expression of versican in dermal papilla of a subject suffering from hair loss, comprising co-administering to the subject a 5 wt% cortexolone-17a-propionate solution and a 5 wt% minoxidil solution, wherein versican expression in dermal papilla coadministered the 5 wt% cortexolone-17a-propionate and minoxidil solutions is at least about 25%greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0008] In some embodiments, versican expression in dermal papilla of a subject coadministered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil is at least about 25% to about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression in dermal papilla of a subject co-administered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil is about 50% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0009] In some embodiments, versican expression is increased in hair follicles in anagen phase, catagen phase, telogen phase, or any combination thereof, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression is increased in hair follicles in the anagen phase, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propi onate alone or a 5 wt% solution of minoxidil alone.

[0010] In some embodiments, versican expression is increased in terminal hair follicles, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propi onate alone or a 5 wt% solution of minoxidil alone.

[0011] In some embodiments, increased versican expression in dermal papilla of subjects coadministered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil increases dermal papilla inductivity, relative to subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone.

[0012] In some embodiments, the 5 wt% solutions of cortexolone-17a-propionate and minoxidil are administered sequentially. In some embodiments, the 5 wt% solution of cortexolone-17a-propionate is administered in a first treatment and the 5 wt% solution of minoxidil is administered in a second treatment. In some embodiments, the first treatment and the second treatment are spaced apart by about 1 to about 9 hours. In some embodiments, the first treatment and the second treatment are spaced apart by about 4 hours. In some embodiments, thefirst treatment is applied in the morning. In some embodiments, the second treatment is applied in the afternoon.

[0013] In some embodiments, the 5 wt% solutions of cortexolone-17a-propionate and minoxidil are each administered to the subject once every two days.

[0014] In some embodiments, the hair loss is alopecia. In some embodiments, the alopecia is androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or a combination of any of the foregoing. In some embodiments, 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 embodiments, the alopecia is androgenetic alopecia and female pattern hair loss.

[0015] In some embodiments, the 5 wt% cortexolone-17a-propionate solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof. In some embodiments, the solution 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 combinations thereof.

[0016] In some embodiments, the 5 wt% minoxidil solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof. In some embodiments, the solution 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 combinations thereof.

[0017] A further embodiment is a cosmetic non therapeutic method of increasing expression of versican in dermal papilla of a subject suffering from hair loss, comprising co-administering to the subject a 5 wt% cortexolone-17a-propionate solution and a 5 wt% minoxidil solution, wherein versican expression in dermal papilla co-administered the 5 wt% cortexolone-17a-propionate and minoxidil solutions is at least about 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0018] In a further embodiment the co-administration to a subject of a 5 wt% cortexolone- 17a-propi onate solution and of a 5 wt% minoxidil solution increasing expression of versican in dermal papilla of a subject is for use in the treatment of hair loss, wherein hair loss is alopecia andwherein versican expression in dermal papilla co-administered the 5 wt% cortexolone-17a- propionate and minoxidil solutions is at least about 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone.BRIEF DESCRIPTION OF THE DRAWINGS / FIGURES

[0019] FIG. 1 shows a patient overview table for Patients 1-4.

[0020] FIGs. 2A-2C show the workflow for setting up an ex vivo skin culture. FIG. 2A depicts4 mm punch collection and transportation at 4 °C. FIG. 2B depicts the punch being cut in half. FIG. 2C depicts starting an Air-Liquid Interphase (ALI) culture.

[0021] FIG. 3 depicts a schematic of the experimental workflow for Patients 1-4.

[0022] FIGs. 4A-4C show representative brightfield images of terminal and intermediate hair follicles after: microdissection (FIG. 4A); in scalp skin (FIG. 4B); and follicular unit extraction (FIG. 4C).

[0023] FIG. 5 shows representative images of terminal and intermediate hair follicles in anagen phase (left) and catagen phase (right).

[0024] FIG. 6 shows representative images from Patient 3 of the 4 mm biopsy halves on treatment day before application of the first topical treatment (z.e., on day 1 and day 3) and before closing the culture on day 5.

[0025] FIG. 7 shows representative images from Patient 3 of the 4 mm biopsy halves at the beginning of the culture and at the end of the culture.

[0026] FIG. 8 provides representative images from Patient 3 of microscopic sample sections acquired while cutting the halves of the 4 mm biopsies from each indicated treatment group.

[0027] FIG. 9A is a graph depicting of the percentage of hair follicles (mean + / - SEM) in each hair cycle stage following treatment of Patient 3.

[0028] FIG. 9B is a graph depicting the percentage of terminal hair follicles (mean + / - SEM) in telogen, late catagen, mid catagen, early catagen, and anagen stages V-VI following treatment of Patient 3.

[0029] FIG. 9C is a graph depicting the percentage of intermediate hair follicles (mean + / - SEM) in catagen / telgen phase or anagen phase following treatment of Patient 3.

[0030] FIG. 10A is a graph of pooled data from Patients 1-3 depicting of the percentage of hair follicles (mean + / - SEM) in each hair cycle stage following treatment.

[0031] FIG. 10B is a graph of pooled data from Patients 1-3 depicting the percentage of terminal hair follicles (mean + / - SEM) in telogen, late catagen, mid catagen, early catagen, and anagen stages V-VI following treatment.

[0032] FIG. 10C is a graph of pooled data from Patients 1-3 depicting the percentage of intermediate hair follicles (mean + / - SEM) in catagen / telgen phase or anagen phase following treatment.

[0033] FIGs. 11A-11B depict graphs of alkaline phosphatase activity in Patient 3 in all hair follicles following treatment (FIG. 11 A) and in all anagen hair follicles following treatment (FIG. 11B).

[0034] FIGs. 12A-12C depict graphs of alkaline phosphatase activity in Patient 3 of all terminal hair follicles following treatment (FIG. 12 A); in all terminal anagen hair follicles following treatment (FIG. 12B); and in all intermediate hair follicles following treatment (FIG. 12C).

[0035] FIGs. 13 A-13B depict graphs of pooled data from Patients 1-3 of alkaline phosphatase activity in all terminal hair follicles following treatment (FIG. 13 A) and in all anagen hair follicles (FIG. 13B).

[0036] FIGs. 14A-14C depict graphs of pooled data from Patients 1-3 of alkaline phosphatase activity in all terminal hair follicles following treatment (FIG. 14 A); in all terminal anagen hair follicles following treatment (FIG. 14B); and in all intermediate hair follicles following treatment (FIG. 14C).

[0037] FIGs. 15A-15B depict graphs of versican expression in Patient 3 in all hair follicles following treatment (FIG. 15 A) and in all anagen hair follicles following treatment (FIG. 15B).

[0038] FIG. 16 includes images showing versican expression in Patient 3 in intermediate and terminal hair follicles.

[0039] FIGs. 17A-17C depict graphs of versican expression in Patient 3 in all terminal hair follicles following treatment (FIG. 17 A); in all terminal anagen hair follicles following treatment (FIG. 17B); and in all intermediate hair follicles following treatment (FIG. 17C).

[0040] FIGs. 18A-18B depict graphs of pooled data from Patients 1-3 of versican expression in all hair follicles following treatment (FIG. 18 A) and in all anagen hair follicles following treatment (FIG. 18B).

[0041] FIGs. 19A-19C depict graphs of pooled data from Patients 1-3 of versican expression in all terminal hair follicles following treatment (FIG. 19 A); in all terminal anagen hair follicles following treatment (FIG. 19B); and in all intermediate hair follicles following treatment (FIG. 19C).DETAILED DESCRIPTION

[0042] 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.

[0043] 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 within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 10% (e.g., up to 5%, up to 1%) of a given value.

[0044] As used herein, the phrase “active agent” refers to either cortexolone-17a-propionate or minoxidil.

[0045] The term “alopecia” as used herein refers to, collectively, or individually as specified, androgenetic alopecia (AGA), female pattern hair loss, 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.

[0046] As used herein, the term “anhydrous” means substantially free of water, i.e., having less than about 5 wt% water, and, in certain embodiments as specified herein, less than about 3 wt% water.

[0047] 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 ispresent before a component in a method step, then that component is included in the step, whereas additional components are optional.

[0048] As used herein, the term “Bis In Die” or “BID” means “twice a day.”

[0049] 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. In some embodiments, 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 a combination thereof.

[0050] 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.

[0051] As used herein, the term “chelating agent” refers to a compound that can bind metal ions or metallic compounds. In some embodiments, 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 a combination thereof.

[0052] As used herein, the term “co-administration” or “co-administering” means concurrent or sequential administration of two different active agents, i.e., cortexolone-17a-propionate and minoxidil. In some embodiments, 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.

[0053] As used herein the term “cortexolone” (also known as “11-deoxy corti sol” or “Reichstein’s substance”) refers to the compound having the structure:

[0054] 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:

[0055] As used herein, the term “degradation product” refers to those compounds that result from the in vitro degradation of cortexolone-17a-propionate. Exemplary known cortexolone- 17a-propi onate degradation products include, but are not limited to, cortexol one-21 -propionate and cortexol one.

[0056] As used herein, the term “ester” refers to esterified organic solvents including, but not limited to, ethyl acetate and ethyl lactate.

[0057] 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 embodiments, the ethanol is denatured alcohol, such as specially denatured (SD) alcohol, which includes a denaturing agent to prevent consumption.

[0058] 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, including more specifically C10-C20, C12-C22, and C12-C18 chain lengths.

[0059] 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 a combination thereof.

[0060] 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 embodiments, 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 embodiments, an acetate or lactate salt of minoxidil is used.

[0061] 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 cortexolone-17a-propionate or minoxidil. Exemplary known metabolites of cortexolone-17a-propionate include, but are not limited to, cortexolone and tetrahydrocortexolone. Exemplary known metabolites of minoxidil include, but are not limited to, minoxidil sulfate.

[0062] 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, glycerin, an alpha hydroxy acid (e.g., lactic acid, glycolic acid, malic acid, citric acid, or tartaric acid), and combinations 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, glycerin, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or a combination thereof.

[0063] As used herein the phrase “natural oil” refers to those oils i sol able 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.

[0064] 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), medium-chain triglycerides, and combinations of any of the foregoing.

[0065] 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.

[0066] As used herein, the term “polyol” refers to organic molecules containing two or more hydroxyl groups. Exemplary polyols include, but are not limited to, ethylene glycol, propylene glycol, glycerol, hexanetriol, and the like.

[0067] 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, polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymers, dipropylene glycol, diethylene glycol monoethyl ether, and the like.

[0068] 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, glycerin, propylene glycol, or a combination thereof.

[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 cortexolone-17a-propionate and / or minoxidil in a formulation described herein.

[0070] As used herein “tetrahydrocortexolone” refers to the compound having the Chemical Abstract Service (CAS) Registry Number 68-60-0.

[0071] 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 well-being. The treatment or amelioration of symptoms can be based on obj ective or subj ect parameters, including the results of a physical examination, neuropsychiatric examinations, or psychiatric evaluation.

[0072] 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.

[0073] As used herein, the term “sequential” or “sequentially” refers to the administration of two or more active agents (e.g., cortexolone-17a-propionate and minoxidil, as disclosed herein), to a subject at different time points that are separated by seconds, minutes, hours, or days, as needed. In other words the term “sequentially” includes administration of a first active agent in a first period of time followed by administration of a second active agent in a second period of time. The first and second time periods can be separated on the order of seconds, minutes, hours, or days, as needed. In some embodiments, the first and second time periods are separated by hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or longer).

[0074] As used herein, the term “subject” typically is directed to a mammal. In some embodiments, the subject to be treated is a human.

[0075] As used herein, the phrase “wt%” is intended to encompass and disclose embodiments wherein the wt% is wt% by volume (w / v) and percentage of weight by total weight (w / w) for a given value. By way of example, an embodiment comprising 10 wt% of element “X” discloses embodiments comprising both 10 wt% “X” (w / v) and 10 wt% “X” (w / w). Similarly, and again by way of example, an embodiment comprising 10 wt% “X,” 20 wt% “Y,” and 60 wt% “Z,” discloses embodiments comprising: a) 10 wt% “X” (w / v), 20 wt% “Y” (w / v), and 60 wt% “Z” (w / v); and b) 10 wt% “X” (w / w), 20 wt% “Y” (w / w), and 60 wt% “Z” (w / w). The foregoing notwithstanding, in some embodiments, a value will be marked specifically “(w / w)” or “(w / v).” In those instances, the value should be interpreted as disclosing only the labeled value, i.e. only (w / w) or only (w / v) - but not both.

[0076] 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 embodiment disclosed herein “comprises” certain elements, it should be understood that present disclosure also specifically contemplates and discloses embodiments that “consist essentially of’ those elements and that “consist of’ those elements.

[0077] 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 embodiment are included.

[0078] As used herein, the terms “consists of,” “consisting of,” and the like are to be construed as closed terms, such that an embodiment “consisting of’ a particular set of elements excludes any element, step, or ingredient not specified in the embodiment.

[0079] 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).

[0080] 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.

[0081] 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

[0082] Versican, a large chondroitin sulfate proteoglycan molecule, is expressed in the dermal papilla in anagen hair follicles and diminishes in catagen hair follicles (Yang, J Dermatol Sci 2010). A loss of versican expression in vellus-like hair follicles affected by male pattern hair loss (MPHL) suggests its importance for maintaining normal growing phase of hair follicles (Soma et al., J Dermatol Sci. 2005). It has been surprisingly discovered that versican expression in hair follicles can be effectively increased in a synergistic fashion by treating a subject in need thereof with a combination of cortexolone-17a-propionate and minoxidil.

[0083] Accordingly, the present disclosure provides a method of increasing expression of versican in dermal papilla of a subject suffering from hair loss, comprising co-administering to the subject a 5 wt% cortexolone-17a-propionate solution and a 5 wt% minoxidil solution, wherein versican expression in dermal papilla co-administered the 5 wt% cortexolone-17a-propionate and minoxidil solutions is at least about 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0084] In such embodiments, the cortexolone-17a-propionate and minoxidil can be coadministered sequentially. In some embodiments, the cortexolone-17a-propionate and minoxidil can be co-administered simultaneously (i.e., concomitantly). In some embodiments, the cortexolone-17a-propionate and minoxidil can be provided in the same pharmaceutical formulation (e.g., a combination formulation).

[0085] In some embodiments, versican expression in dermal papilla of a subject coadministered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil is at least about 25% to about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. For example, versican expression in dermal papilla of a subject co-administered the 5 wt% solutions of cortexolone-17a-propi onate and minoxidil is at least about 25% to about 75% greater (e.g., about 25% to about 70%, about 25% to about 65%, about 25% to about 60%, about 25% to about 55%, about 25% to about 50%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 25% to about 30%, about 30% to about 75%, about 35% to about 75%, about 40% to about 75%, about 45% to about 75%, about 50% to about 75%, about 55% to about75%, about 60% to about 75%, about 65% to about 75%, or about 70% to about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression in dermal papilla of a subject co-administered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil is about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression in dermal papilla of a subject co-administered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil is about 50% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone.

[0086] In some embodiments, versican expression is increased in hair follicles in anagen phase, catagen phase, telogen phase, or any combination thereof, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression is increased in hair follicles in the anagen phase, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propi onate alone or a 5 wt% solution of minoxidil alone.

[0087] In some embodiments, versican expression is increased in terminal hair follicles, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propi onate alone or a 5 wt% solution of minoxidil alone.

[0088] Versican expression correlates with hair inductive properties (Yang, J Dermatol Sci 2010). Accordingly, in some embodiments, increased versican expression in dermal papilla of subjects co-administered the 5 wt% solutions of cortexol one- 17a-propi onate and minoxidil increases dermal papilla inductivity, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0089] The present disclosure further provides a method of increasing expression of versican in dermal papilla of a subject suffering from hair loss, comprising administering to the subject a combination formulation comprising 5 wt% cortexolone-17a-propionate and 5 wt% minoxidil, wherein versican expression in dermal papilla administered the combination formulation is at leastabout 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0090] In some embodiments, versican expression in dermal papilla of a subject administered the combination formulation is at least about 25% to about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone. For example, versican expression in dermal papilla of a subject administered the combination formulation is at least about 25% to about 75% greater (e.g., about 25% to about 70%, about 25% to about 65%, about 25% to about 60%, about 25% to about 55%, about 25% to about 50%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 25% to about 30%, about 30% to about 75%, about 35% to about 75%, about 40% to about 75%, about 45% to about 75%, about 50% to about 75%, about 55% to about 75%, about 60% to about 75%, about 65% to about 75%, or about 70% to about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression in dermal papilla of a subject administered the combination formulation is about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression in dermal papilla of a subject administered the combination formulation is about 50% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0091] In some embodiments, versican expression is increased in hair follicles in anagen phase, catagen phase, telogen phase, or any combination thereof, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. In some embodiments, versican expression is increased in hair follicles in the anagen phase, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propi onate alone or a 5 wt% solution of minoxidil alone.

[0092] In some embodiments, versican expression is increased in terminal hair follicles, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propi onate alone or a 5 wt% solution of minoxidil alone.

[0093] In some embodiments, increased versican expression in dermal papilla of subjects administered the combination formulation increases dermal papilla inductivity, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0094] The present disclosure further 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 cortexolone-17a-propionate and an effective amount of minoxidil. Topical administration comprises application of cortexolone-17a-propionate and minoxidil to the skin and / or the scalp of the subject, as described herein.

[0095] In some embodiments, the subject can be a mammal, such as a human.

[0096] In some embodiments, the hair loss can be associated with alopecia. Alopecia can include, e.g., androgenetic alopecia (AGA), female pattern hair loss, 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. In some embodiments, the alopecia to be treated can be AGA.

[0097] In some embodiments, the cortexolone-17a-propionate and minoxidil 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 embodiments, the cortexolone-17a- propionate can be administered first, and the minoxidil can be administered second. In other embodiments, the minoxidil can be administered first, and the cortexolone-17a-propi onate 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 embodiments, the first and second administering steps can be separated by seconds, minutes, hours, or days (e.g., about 12 hours or less, about 6 hours or less).

[0098] In some embodiments, the first treatment and the second treatment are spaced apart by about 1 to about 9 hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, or about 9 hours). In some embodiments, the first treatment and the second treatment are spaced apart by about 4 hours.

[0099] In some embodiments, the cortexolone-17a-propionate can be administered first. In some embodiments, the minoxidil can be administered second, about 4 hours after administering the cortexolone-17a-propionate.

[0100] In some embodiments, the minoxidil can be administered first. In some embodiments, the cortexolone-17a-propionate can be administered second, about 4 hours after administering the minoxidil. In still further embodiments, the cortexolone-17a-propionate can be administered at substantially the same time as the minoxidil. In some embodiments, the cortexolone-17a- propionate and minoxidil can be co-administered simultaneously (i.e., concomitantly). In some embodiments, the cortexolone-17a-propionate and minoxidil can be provided in the same pharmaceutical formulation (e.g., a combination formulation).

[0101] The time of day of administration is not limited. In some embodiments, the first treatment is applied in the morning. In some embodiments, the first treatment is applied in the afternoon. In some embodiments, the first treatment is applied in the evening. In some embodiments, the second treatment is applied in the morning. In some embodiments, the second treatment is applied in the afternoon. In some embodiments, the second treatment is applied in the evening.

[0102] In some embodiments, the cortexolone-17a-propionate can be administered in the morning. In some embodiments, the minoxidil can be administered in the afternoon, about 4 hours after administering the cortexolone-17a-propi onate.

[0103] In some embodiments, the minoxidil can be administered in the morning. In some embodiments, the cortexolone-17a-propionate can be administered in the afternoon, about 4 hours after administering the minoxidil.

[0104] In certain embodiments, 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.

[0105] In certain embodiments, 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.

[0106] In certain embodiments, 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 does not result in systemic anti androgenic sideeffects in the subject.

[0107] In certain embodiments, 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:

[0108] a) a mean change from baseline in Target Area Hair Count equal to or higher than9 hairs / cm2after 6 months of daily or BID application; or

[0109] b) a mean change from baseline in Target Area Hair Count equal to or higher than10 hairs / cm2after 6 months of daily or BID application; or

[0110] c) a mean change from baseline in Target Area Hair Count equal to or higher than11 hairs / cm2after 6 months of daily or BID application; or

[0111] 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

[0112] e) a weighted average HGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0113] f) a weighted average HGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0114] g) a weighted average HGA score equal to or higher than 0.40 after 6 months of daily or BID application; or

[0115] h) a weighted average IGA score equal to or higher than 0.10 after 6 months of daily or BID application; or

[0116] i) a weighted average IGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0117] j) a weighted average IGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0118] k) a favorable (positive) HGA score in at least about 10 % of subjects after 6 months of daily or BID application; or

[0119] 1) a favorable (positive) HGA score in at least about 20 % of subjects after 6 months of daily or BID application; or

[0120] m) a favorable (positive) HGA score in at least about 30 % of subjects after 6 months of daily or BID application; or

[0121] n) a favorable (positive) IGA score in at least about 10 % of subjects after 6 months of daily or BID application; or

[0122] o) a favorable (positive) IGA score in at least about 20 % of subjects after 6 months of daily or BID application; or

[0123] p) a favorable (positive) IGA score in at least about 30 % of subjects after 6 months of daily or BID application; or

[0124] q) a favorable (positive) IGA score in at least about 40 % of subjects after 6 months of daily or BID application.Pharmaceutical Formulations

[0125] In some embodiments, the cortexolone-17a-propionate and minoxidil can be coadministered sequentially. In such embodiments, the cortexolone-17a-propionate and minoxidil can be provided in separate pharmaceutical formulations. Each pharmaceutical formulation can be as described herein.

[0126] For example, and in some embodiments, the cortexolone-17a-propi onate can be provided dissolved in a solution. In some embodiments, the solution can comprise from 3 wt% to 7.5 wt% by weight, cortexolone-17a-propionate. In some embodiments, the solution can comprise about 5 wt% weight cortexolone-17a-propionate. In some embodiments, the 5 wt% cortexolone-17a-propionate solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof. In some embodiments, the 5 wt%cortexolone-17a-propionate solution 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 combinations thereof.

[0127] Similarly, and in some embodiments, minoxidil can be provided in any known commercially available formulation, e.g. as a foam, shampoo, or solution. In some embodiments, the minoxidil is provided in a solution comprising from about 1 wt% to about 10 wt% minoxidil by weight. In particular embodiments, the minoxidil is provided as a 5 wt% solution. In some embodiments, the 5 wt% minoxidil solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof. In some embodiments, the 5 wt% minoxidil solution 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 combinations thereof.

[0128] As discussed elsewhere herein, the 5 wt% solution of cortexolone-17a-propionate and the 5 wt% solution of minoxidil described above, i.e. the 5 wt% cortexolone-17a-propionate solution comprising water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof, and optionally, 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 combinations thereof, and the 5 wt% solution of minoxidil comprising water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof, and optionally further comprising 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 combinations thereof, can be co-administered.

[0129] In other embodiments, the cortexolone-17a-propionate and minoxidil can be coadministered simultaneously (i.e., concomitantly).

[0130] In some embodiments, the cortexolone-17a-propionate and minoxidil can be provided in the same pharmaceutical formulation (e.g., a combination formulation).

[0131] For example, and in some embodiments, the cortexolone-17a-propionate and the minoxidil can be provided in any known commercially available formulation, e.g. as a foam, shampoo, or solution. In some embodiments, the solution can comprise from 3 wt% to 7.5 wt% by weight, cortexolone-17a-propi onate and from about 1 wt% to about 10 wt% minoxidil byweight. In some embodiments, the solution can comprise about 5 wt% weight cortexolone-17a- propionate and about 5 wt% weight minoxidil.

[0132] In some embodiments, the 5 wt% cortexolone-17a-propionate and 5 wt% minoxidil solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof. In some embodiments, the 5 wt% cortexolone-17a-propionate and 5 wt% minoxidil solution 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 combinations thereof.

[0133] The pharmaceutical formulation can be in any form suitable for topical administration. In some embodiments, 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 embodiments, the pharmaceutical formulation can be a solution.

[0134] In some embodiments, the formulation can be a cream. In some embodiments, the cream can comprise equal parts oil and water in the form of an emulsion.

[0135] In some embodiments, the formulation can be a paste. In some embodiments, the paste can comprise a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof), an oil, or a combination thereof.

[0136] In some embodiments, 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 a 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 poloxamer. 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 / polyethylene 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.

[0137] In some embodiments, 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).

[0138] In some embodiments, the formulation can be an ointment. In some embodiments, 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 a combination thereof. In some embodiments, the ointment can comprise about 20 wt% or less of water.

[0139] In some embodiments, 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

[0140] In some embodiments of when the pharmaceutical formulation 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 a combination thereof.

[0141] In some embodiments, 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.

[0142] In some embodiments, particularly in embodiments that contain less than about 5 wt% water, the cortexolone-17a-propionate can be fully 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 Ci- C7 alcohol, and combinations thereof.

[0143] In some embodiments, 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, apolyol, 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 combinations of any of the foregoing. In some embodiments, the one or more pharmaceutically acceptable carriers are selected from the group consisting of a polyol, a polyol ether, a C1-C7 alcohol, and combinations thereof.

[0144] In some embodiments, 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 a combination thereof). In other embodiments, the pharmaceutical formulation can comprise at least about 60 wt% solvent. In other embodiments, the pharmaceutical formulation can comprise at least about 70 wt% solvent. In other embodiments, the pharmaceutical formulation can comprise at least about 80 wt% solvent. In other embodiments, 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.

[0145] In some embodiments, the solvent can comprise a mixture of a C1-C7 alcohol, a polyol ether, and a polyol. In such embodiments, the pharmaceutical formulation can comprise from about 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 embodiments, the mixture of the Ci- 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 embodiments, each of the C1-C7 alcohol, the polyol ether, and the polyol can be present at about 30 wt%.

[0146] In some embodiments, 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 embodiments, the pharmaceutical formulation can comprise about 30 wt% of the polyol ether. In other embodiments, the pharmaceutical formulation can comprise about 32 wt% of the polyol ether.

[0147] In some embodiments, the polyol ether can be selected from the group comprising or the group consisting of: polyethylene glycol, polypropylene glycol, polyethylene-polypropylenetriblock copolymers, dipropylene glycol, di ethylene glycol monoethyl ether (TRANSCUTOL™, Gattefosse, France), and combinations thereof.

[0148] 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 embodiments, 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 embodiments, the polyol ether can be PEG 200. In other embodiments, the polyol ether can be PEG 400. In still other embodiments, the polyol ether can be diethylene glycol monoethyl ether.

[0149] In some embodiments, the polyol can be selected from the group comprising or the group consisting of: propylene glycol, ethylene glycol, glycerol, hexanetriol, and combinations thereof. In some embodiments, the polyol can be glycerol. In other embodiments, the polyol can be propylene glycol.

[0150] In some embodiments, 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 embodiments, from about 25 wt% to about 40 wt%. In a particular embodiment, the polyol can comprise about 30 wt% of the total formulation. In a further embodiment, the polyol comprising about 30 wt% of the total formulation can be propylene glycol.

[0151] In some embodiments, the pharmaceutical formulation can comprise from about 5 to about 50 wt% of the C1-C7 alcohol. In some embodiments, 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 embodiments, the pharmaceutical formulation can comprise about 30 wt% of the C1-C7 alcohol. In still further embodiments, 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%.

[0152] In some embodiments, the C1-C7 alcohol can be selected from the group comprising or the group consisting of: methanol, ethanol, isopropanol, n-butanol, n-propanol, and benzyl alcohol. In some embodiments, the C1-C7 alcohol can be ethanol. In some embodiments, the ethanol comprises about 30 wt% of the total formulation. In other embodiments, the C1-C7 alcohol can be isopropanol.

[0153] In some embodiments, 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 embodiments 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%.

[0154] In some embodiments, the solvent can comprise a polyol, a polyol ether, and a C1-C7 alcohol. In some embodiments, 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

[0155] In some embodiments, the pharmaceutical formulation 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 combinations thereof.

[0156] In some embodiments, 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 about 15wt%, 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%, about 16 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.

[0157] In some embodiments, 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., l-hydroxy-2-naphthoic acid; 2,2- di chloroacetic acid; 2-hydroxyethanesulfonic 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; naphthal ene- 1,5 -di sulfonic 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 some embodiments, acetic acid, citric acid, or lactic acid can be added to the pharmaceutical formulation.

[0158] In some embodiments, 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).

[0159] In some embodiments, the pharmaceutical formulation can include a buffer to help maintain the pH of the formulation within a desired range. In some embodiments, the buffer can be a phosphate buffer, citrate buffer, lactate buffer, or a combination thereof. In some embodiments, the formulation can comprise phosphoric acid, citric acid, lactic acid, or a combination thereof.

[0160] Because oxidation can result in degradation of the active agent, in some embodiments, the pharmaceutical formulation can include of an antioxidant. In some embodiments, 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 combinations thereof. In some embodiments, the antioxidant can be ascorbyl palmitate, BHA, BHT, or a combination thereof. In some embodiments, the antioxidant can be BHT, ascorbyl palmitate, or a combination of BHT and ascorbyl palmitate.

[0161] In some embodiments, the pharmaceutical formulation can include up to about 1 wt% an antioxidant. In some embodiments, the pharmaceutical formulation can include up to about 0.5 wt% of an antioxidant or include about 0.5 wt% antioxidant.

[0162] In some embodiments, 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 embodiments, 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).

[0163] In other embodiments, and without wishing to be bound by any particular theory, an emulsifier can increase product spreadability. For example, and without wishing to be bound toa 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.

[0164] In some embodiments, 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; propylene glycol esters of fatty acids; polyglycerol esters of fatty acids; 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 polyoxyil-8 glycerides; polyoxylglycerides such as capryl ocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoyl polyoxylglycerides, and the like; along with combinations of any of the foreoging. In some embodiments, the emulsifier can be polyoxyl 40 hydrogenated castor oil, polyoxyl- 15- hydroxystearate, polysorbate 60, polysorbate 80, or a combination thereof. In some embodiments, the emulsifier can be a polysorbate, such as polysorbate 60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80.

[0165] In some embodiments, 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 embodiments, 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 embodiments, 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 embodiments, the pharmaceuticalformulation 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 embodiments, the emulsifier can be present in the pharmaceutical formulation at about 0.1 wt%.

[0166] In some embodiments, 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 embodiments, the solvent or some component(s) of the solvent act as a penetration enhancer. For example, in embodiments 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.

[0167] In some embodiments, 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 a combination thereof), a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and combinations 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), medium-chain triglycerides, and combinations of any of the foregoing.

[0168] In some embodiments, the penetration enhancer can be dimethyl isosorbide. In other embodiments, the penetration enhancer can be a mixture comprising dimethyl isosorbide anddiethylene glycol monoethyl ether. In other embodiments, the penetration enhancer can be dimethyl sulfoxide.

[0169] In some embodiments, 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 embodiments, 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 embodiments, 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.

[0170] In some embodiments, 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 embodiments, 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 a combination thereof), a fatty acid ester, an oil, a polyethylene glycol, glycerin, an alpha hydroxy acid, or a combination thereof. In some embodiments, 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, glycerin, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or a combination thereof. In some embodiments, the moisturizer can be cetyl alcohol, stearyl alcohol, or a combination of cetyl alcohol and stearyl alcohol.

[0171] In some embodiments, 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, glycerin, propylene glycol, or a combination thereof.

[0172] In some embodiments, 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, or a combination thereof.Modes of Administration

[0173] The pharmaceutical formulations described herein can be co-administered according to varying schedules. In one embodiment, the mode of administration of the pharmaceutical formulation can be continuous. For example, the pharmaceutical formulations can each be applied topically once a week, twice a week, once every three days, once every two days, once a day, twice daily, three times a day, four times a day, or more, as specified by a physician. In some embodiments, a formulation described herein can each be applied topically once every two days. In some embodiments, a formulation described herein can be applied topically once a day or twice daily.

[0174] For example, in some embodiments, the 5 wt% cortexolone-17a-propionate solution can be applied topically once a week, twice a week, once every three days, once every two days, once a day, twice daily, three times a day, four times a day, or more, as specified by a physician. In some embodiments, the 5 wt% cortexolone-17a-propionate solution can be applied topically once every two days. In some embodiments, the 5 wt% cortexolone-17a-propionate solution can be applied topically once a day.

[0175] Similarly, and in some embodiments, the 5 wt% minoxidil solution can be applied topically once a week, twice a week, once every three days, once every two days, once a day, twice daily, three times a day, four times a day, or more, as specified by a physician. In some embodiments, the 5 wt% minoxidil solution is administered to the subject once every two days. In some embodiments, the 5 wt% minoxidil solution is administered to the subject once a day.

[0176] As discussed elsewhere herein, the 5 wt% solutions of cortexolone-17a-propionate and minoxidil can be co-administered topically once a week, twice a week, once every three days,once every two days, once a day, twice daily, three times a day, four times a day, or more, as specified by a physician. In some embodiments, the 5 wt% solutions of cortexolone-17a- propionate and minoxidil can be co-administered to the subject once every two days. In some embodiments, the 5 wt% solutions of cortexolone-17a-propionate and minoxidil can be coadministered to the subject once a day.

[0177] As discussed elsewhere herein, the cortexolone-17a-propionate and minoxidil can be provided in the same pharmaceutical formulation (e.g., a combination formulation). In some embodiments, the 5 wt% cortexolone-17a-propi onate and 5 wt% minoxidil combination formulation can be administered topically once a week, twice a week, once every three days, once every two days, once a day, twice daily, three times a day, four times a day, or more, as specified by a physician. In some embodiments, the 5 wt% cortexolone-17a-propionate and 5 wt% minoxidil combination formulation can be administered to the subject once every two days. In some embodiments, the 5 wt% cortexolone-17a-propionate and 5 wt% minoxidil combination formulation can be administered to the subject once a day.

[0178] According to a particular embodiment, the pharmaceutical formulation described herein can be applied topically once a day. According to another embodiment, the pharmaceutical formulation described herein can be applied topically twice daily.

[0179] In some embodiments, a dosing regimen can be tapered. That is, the pharmaceutical formulation 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 embodiment, the pharmaceutical formulation 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 embodiment, tapered administration can comprise administering the pharmaceutical formulation 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.

[0180] In some embodiments, the pharmaceutical formulation can be applied over the course of a period of days, weeks, or months. For example, the pharmaceutical formulation can beapplied 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 embodiment, the pharmaceutical formulation can be applied once on the first day and twice daily thereafter for about 4 weeks.

[0181] In another embodiments, the pharmaceutical formulation 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 embodiments, the pharmaceutical formulation can be topically applied to the scalp once daily for 6 months. In some embodiments, the pharmaceutical formulation can be topically applied to the scalp once daily for 12 months.

[0182] In other embodiments, 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 embodiments, the pharmaceutical formulation can be topically applied to the scalp twice daily for 6 months. In some embodiments, the pharmaceutical formulation can be topically applied to the scalp twice daily for 12 months.

[0183] In other embodiments, 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 embodiments, the pharmaceutical formulation can be topically applied to the scalp more than twice daily (i.e., TID,QID, etc.) for 6 months. In some embodiments, the pharmaceutical formulation can be topically applied to the scalp more than twice daily (i.e., TID, QID, etc.) for 12 months.

[0184] In another embodiment, the mode of administration of the pharmaceutical formulations can be cyclic. For example, the pharmaceutical formulation 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 embodiments, the treatment period can be as follows: a) the pharmaceutical formulation 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.

[0185] In some embodiments, the mode of administration can be cyclic in that cortexolone- 17a-propi onate and minoxidil can be co-administered sequentially. For example, a pharmaceutical formulation comprising cortexolone-17a-propionate can be administered first for a first period of time, and a pharmaceutical composition comprising minoxidil can be administered second for a second period of time. In other embodiments, a pharmaceutical composition comprising minoxidil can be administered first and a pharmaceutical composition comprising cortexolone-17a-propionate can be administered second. The time period between when the first pharmaceutical composition can be administered, and the second pharmaceutical composition 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 embodiments, administration of the first and second pharmaceutical compositions can be separated by seconds (e.g., about 60 seconds or less, about 30 seconds or less). In some embodiments, administration of the first and second pharmaceutical compositions 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 embodiments, administration of the first and second pharmaceutical compositions 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 embodiments, administration of the first and secondpharmaceutical compositions can be separated by weeks (e.g., about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks).

[0186] In some embodiments, a first pharmaceutical formulation comprising either cortexolone-17a-propionate or minoxidil 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 cortexolone-17a-propionate 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 minoxidil 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 embodiments, a subject can alternate (e.g., cycle between) administration between the first and second pharmaceutical formulations for a given time period to effect treatment.

[0187] 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 embodiments, the pharmaceutical formulation can comprise cortexolone-17a-propionate, minoxidil, or both active agents at a concentration of from about 0.1 wt% to about 20 wt%. For example, the pharmaceutical formulation can comprise cortexolone-17a-propionate, minoxidil, 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% or less, 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 embodiments, the pharmaceutical formulation can comprise cortexolone-17a-propionate, minoxidil, 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%.

[0188] In some embodiments, the pharmaceutical formulation can comprise cortexolone-17a- propionate at a concentration from about 1 wt% to about 20 wt%. In some embodiments, the pharmaceutical formulation can comprise minoxidil at a concentration from about 0.1 wt% to about 20 wt%. In some embodiments, the pharmaceutical formulation can be a solution that can comprise cortexolone-17a-propionate at a concentration from about 1 wt% to about 20 wt% and minoxidil at a concentration from about 0.1 wt% to about 20 wt%. In some embodiments, the pharmaceutical formulation can be a solution that can comprise about 5 wt% cortexolone-17a- propionate and about 5 wt% minoxidil.

[0189] In some embodiments, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 400 mg. In other embodiments, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 350 mg. In other embodiments, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 300 mg. In other embodiments, the amount of cortexolone-17a- propionate in a single application can range from about 20 mg to about 250 mg.

[0190] In some embodiments, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 200 mg. In other embodiments, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 170 mg. In other embodiments, the amount of cortexolone-17a-propionate in a single application can range from about 20 mg to about 150 mg. In some embodiments, the amount of cortexolone-17a- propionate in a single application can range from about 20 mg to about 100 mg. In some embodiments, 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 75 mg, about 80 mg, about 85 mg, about 90 mg, or about 100 mg. In another embodiment, the amount of cortexolone-17a-propi onate in a single application can be about 25 mg. In another embodiment, the amount of cortexolone-17a-propionate in a single application can be about 30 mg. In yet another embodiment, the amount of cortexolone-17a- propionate in a single application can be about 50 mg. In yet another embodiment, the amount of cortexolone-17a-propionate in a single application can be about 75 mg. In yet another embodiment, the amount of cortexolone-17a-propionate in a single application can be about 80 mg. In yet another embodiment, the amount of cortexolone-17a-propionate in a single applicationcan be about 100 mg. In other embodiments, 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 embodiment, the amount of cortexolone-17a-propi onate in a single application can be about 150 mg.

[0191] In some embodiments, the amount of minoxidil in a single application can range from about 2 mg to about 20 mg. In other embodiments, the amount of minoxidil in a single application can range from about 2 mg to about 15 mg. In other embodiments, the amount of minoxidil in a single application can range from about 2 mg to about 10 mg. In other embodiments, the amount of minoxidil in a single application can range from about 2 mg to about 5 mg.

[0192] In some embodiments, the pharmaceutical formulation can be self-administered by the subject once a day or twice daily. In some embodiments, when the pharmaceutical formulation can be in liquid form having a cortexolone-17a-propionate concentration of about 5 wt% and a minoxidil 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 embodiments at about 1 mL or about 1.5 mL.

[0193] In some embodiments, when the pharmaceutical formulation can be in liquid form having a cortexolone-17a-propionate concentration of about 2.5 wt% and a minoxidil concentration of about 2 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 embodiments at about 1 mL or about 1.5 mL.

[0194] In some embodiments, when the pharmaceutical formulation can be in liquid form having a cortexolone-17a-propionate concentration of about 3 wt% and a minoxidil concentration of about 3 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 embodiments at about 1 mL or about 1.5 mL.

[0195] In some embodiments, when the pharmaceutical formulation can be in liquid form having a cortexolone-17a-propionate concentration of about 7.5 wt% and a minoxidil concentration of about 1.5 wt%, the pharmaceutical formulation can be self-administered once aday 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 embodiments at about 1 mL or about 1.5 mL.

[0196] 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 any combination of the foregoing. In some embodiments, treatment is not delivered to the face. In other embodiments, the pharmaceutical formulation can be applied to the scalp.Kit

[0197] The present disclosure further provides a kit comprising one or more topical pharmaceutical formulations in various forms, as described herein. 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, a pipette, or an injection device (e.g., manual or electronic driven), 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.

[0198] In some embodiments, the kit can comprise a pharmaceutical formulation comprising cortexolone-17a-propionate as a first component and a pharmaceutical formulation comprising minoxidil as a second component. The kit can further comprise instructions for use of the first and second components. In some embodiments, 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 the skin or scalp as a single combined formulation. In some embodiments, both the first and second components are solutions. In some embodiments, one or both of the first and second components can be a gel. In some embodiments, one or both of the first and second components can be a cream. In some embodiments, one or both of the first and second components can be a foam.

[0199] In some embodiments, the kit can comprise cortexolone-17a-propionate in solid form as a first component and a pharmaceutical formulation comprising minoxidil as a second component. The kit can further comprise instructions for using the first and second components. In some embodiments, the cortexolone-17a-propionate in solid form can be a powder, a fastdisintegrating tablet, a granule, a granulate, and the like. In some embodiments, the cortexolone- 17a-propi onate in solid form can be stored separately from the container containing the pharmaceutical formulation comprising minoxidil. In such embodiments, cortexolone-17a- propionate in solid form can be stored within a capped vial or closed bottle.

[0200] In some embodiments, the cortexolone-17a-propionate in solid form can be stored within the same container containing the pharmaceutical formulation comprising minoxidil. According to such embodiments, the cortexolone-17a-propionate in solid form can be stored in a constituent part of the container containing the pharmaceutical formulation comprising minoxidil, which is designed to prevent contact between the two active agents. In some embodiments, the constituent part of the container, which is designed to prevent the contact between the cortexolone-17a-propionate in solid form and the pharmaceutical formulation comprising minoxidil, 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 minoxidil. In some embodiments, the container containing the pharmaceutical formulation comprising minoxidil can be capped with a reservoir cap containing cortexolone-17a- propionate in solid form, which is equipped with a cutting device activated by the subject pushing, twisting, or pulling the cap itself. According to such embodiment, activating the cutting device in the reservoir cap allows cortexolone-17a-propionate in solid form to come into contact with the pharmaceutical formulation comprising minoxidil.

[0201] In some embodiments, 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 the skin or scalp as a single combined formulation. In some embodiments, the first component can be in solid form and the second component can be a solution. In some embodiments, the first component can be in solid form and the second component can be a gel. In some embodiments, the first component can be in solid form andsecond component can be a cream. In some embodiments, the first component can be in solid form and the second component can be a foam.

[0202] In some embodiments, the kit can comprise minoxidil in solid form as a first component and a pharmaceutical formulation comprising cortexolone-17a-propionate as a second component. The kit can further comprise instructions for using the first and second components. In some embodiments, the minoxidil in solid form can be a powder, a fast-disintegrating tablet, a granule, a granulate, and the like. In some embodiments, the minoxidil in solid form can be stored separately from the container containing the pharmaceutical formulation comprising cortexolone- 17a-propi onate. In such embodiments, minoxidil in solid form can be stored within a capped vial or closed bottle.

[0203] In some embodiments, the minoxidil in solid form can be stored within the same container containing the pharmaceutical formulation comprising cortexolone-17a-propionate. According to such embodiments, the minoxidil in solid form can be stored in a constituent part of the container containing the pharmaceutical formulation comprising cortexolone-17a-propionate, which is designed to prevent the contact between the two. In some embodiments, the constituent part of the container, which is designed to prevent the contact between the minoxidil in solid form and the pharmaceutical formulation comprising cortexolone-17a-propionate, 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 cortexolone-17a- propionate. In some embodiments, the container containing the pharmaceutical formulation comprising cortexolone-17a-propionate can be capped with a reservoir cap containing minoxidil in solid form, which is equipped with a cutting device activated by the subject pushing, twisting, or pulling the cap itself. According to such embodiment, activating the cutting device in the reservoir cap allows minoxidil in solid form to come into contact with the pharmaceutical formulation comprising cortexolone-17a-propi onate. In some embodiments, 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 the skin or scalp as a single combined formulation. In some embodiments, the first component can be in solid form and the second component can be a solution. In some embodiments, the first component can be in solidform and the second component can be a gel. In some embodiments, the first component can be in solid form and the second component can be a cream. In some embodiments, the first component can be in solid form and the second component can be a foam.Storage Stability

[0204] 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 embodiments, 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).

[0205] For example, one of the main degradation pathway of cortexolone-17a-propionate is transesterification to cortexol one-21 -propionate (17a-hydroxy-21-propionyloxy-pregna-4-ene- 3, 20-dione):

[0206] In some embodiments, 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 embodiments, 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.

[0207] In some embodiments, 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

[0208] 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 embodiments described herein should in no way be construed as being limited to these examples. Rather, the embodiments should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0209] Example 1: Anhydrous 5% w / w Solution of Cortexolone-17a-propionate

[0210] A 5 wt% (w / w) solution of cortexolone-17a-propionate having the components shown in Table 1, below, was prepared by solubilizing the active agent in the mixture of solvents followed by the addition of the emulsifier (polysorbate 80).Table 1

[0211] This formulation provided the stability profile (40 °C and 75% relative humidity (RH)) shown in Table 2.Table 2*Cortexolone-21 -propionate contents calculated as (% (w / w) of cortexolone-21- propionate) / (% (w / w) of cortexolone-17a-propionate x 100)

[0212] Example 2: 5% w / w Foam of Minoxidil

[0213] A 5 wt% (w / w) foam of minoxidil having the components shown in Table 3 is prepared.Table 3q.s.: quantum satis

[0214] Example 3: 5% w / w Solution of Minoxidil

[0215] A 5 wt% (w / w) solution of minoxidil having the components shown in Table 4 was prepared by solubilizing the active agent in the mixture of solvents.Table 4

[0216] Example 4: Solution of Minoxidil (2.5% w / w) and of cortexolone-17a-propionate (2.5% w / w)

[0217] A solution of 2.5 wt% minoxidil and 2.5 wt% cortexolone-17a-propi onate having the components shown in Table 5 is prepared.Table 5

[0218] 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. Then, cortexolone-17a-propionate 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.

[0219] Example 5: Kit containing a Solution of Minoxidil (5.0% w / w) and Cortexolone- 17a-propionate in Solid Form

[0220] A 5 wt% (w / w) solution of minoxidil having the components shown in Table 4, above, was prepared by solubilizing the active agent in the mixture of solvents.

[0221] The solution containing minoxidil is then filled in 60 mL glass bottles. Cortexolone- 17a-propi onate in powder form is filled into the storage container of reservoir caps (about 3 g percap). The 60 mL bottles containing the minoxidil solution are then capped with the reservoir caps filled in with cortexolone-17a-propionate powder.

[0222] Example 6: Kit containing a Solution of Cortexolone-17a-propionate (5.0% w / w) and Minoxidil in Solid Form

[0223] A 5 wt% (w / w) solution of cortexolone-17a-propionate having the components shown in Table 6 is prepared by solubilizing the active agent in the mixture of solvents followed by the addition of the emulsifier (polysorbate 80).Table 6

[0224] The solution containing cortexolone-17a-propionate 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 cortexolone-17a-propionate solution are then capped with the reservoir caps filled in with minoxidil powder.

[0225] Example 7: Investigation of cortexolone-17a-propionate solution on blocking androgen receptor (AR) signaling and ameliorating androgenetic alopecia (AGA) phenotype in affected skin organ culture

[0226] Model: Ex vivo skin culture (liquid-air interface). 2x 4 mm scalp skin biopsies from affected skin from male AGA patients were split in two. Each 4 mm scalp skin biopsy half was subjected to systemic testosterone treatment to stimulate androgen receptor signaling. An overview of patient details for Patients 1-4, including disease stage and biopsy collection area, is provided in FIG. 1.

[0227] Experimental Conditions:

[0228] A 5 wt% (w / w) solution of cortexolone-17a-propionate having the components shown in Table 1, above, was prepared by solubilizing the active agent in the mixture of solvents followed by the addition of the emulsifier (polysorbate 80).

[0229] A 5 wt% (w / w) solution of minoxidil having the components shown in Table 4, above, was prepared.

[0230] Experimental groups and treatments were as follows:

[0231] 1. 1sttreatment: placebo; 2ndtreatment: minoxidil vehicle

[0232] 2. 1sttreatment: 5 wt% cortexolone-17a-propionate solution (Breezula); 2ndtreatment: minoxidil vehicle

[0233] 3. 1sttreatment: placebo; 2ndtreatment: 5 wt% minoxidil solution

[0234] 4. 1sttreatment: 5 wt% cortexolone-17a-propionate solution (Breezula); 2ndtreatment: minoxidil vehicle

[0235] Methods and Read-outs:

[0236] 1. Sample collection and ex vivo skin culture:

[0237] Two 4 mm punches from affected scalp skin from the vertex or frontal region of an AGA patient were obtained. Skin specimens were transported at 4 °C to retard tissue degeneration. After carefully examining the hair growth orientation (FIG. 2A), each biopsy was cut in half, partially dipped in Williams Complete Media (WCM) and placed individually in 3.5 cm2wells inside a holder (FIG. 2B), and WCM complete media supplemented with 30nM testosterone was added to establish an Air-Liquid Interphase (ALI) culture (FIG. 2C) (Bertolini et al., Int J Cosmet Sci 2020, Edelkamp et al., Molec Dermatol 2020). A workflow of ex vivo culture, treatment, and in situ analysis is provided in FIG. 3. The cultures / punches were maintained under normoxic (37 °C, 50% CO2) conditions. After a 24 hour resting period, topical treatments were performed once every two days (i.e., day 1 and day 3). The punches were embedded in Optimal Cutting Temperature (OCT) compound on day 5 of ex vivo culture and cryosectioned (7 pm sections).

[0238] Topical application volume of each treatment was 0.8 pL, and the duration of each treatment was 4 hours. First treatment was applied in the morning, and second treatment was applied in the afternoon. At the end of the application period of each treatment, liquid from the skin surface was removed using sterilized filter paper strips.

[0239] The identification of intermediate versus terminal hair follicles were made following the qualitative and quantitative criteria shown in FIGs. 4A-4C and listed in Table 7 below based on Miranda et al., Br J Dermatol 2010 (originally described in female hair follicles). The miniaturization of hair follicles in male pattern hair loss (MPHL) is a progressive and unsynchronized process leading to a gradual replacement of terminal hairs by intermediate hairs and then miniaturized hairs.Table 7

[0240] 2. Microscopic hair cycle staging (samples of skin with hair from MPHL patients):

[0241] Hair cycle staging was performed at the end of the culture. The hair cycle stage of each hair follicle was determined according to several established microscopic parameters (Oh et al., J Invest Dermatol 2016). See FIG. 5 and Tables 8-9 below. Hair cycle stage was determined using Ki-67 / TUNEL immunohistology and Masson Fontana (MF) histochemistry. These criteria were applied for terminal hair follicles, while intermediate hair follicles were only differentiated for anagen and catagen phases.Table 8Table 9

[0242] 3. Dermal papilla inductivity

[0243] Dermal papilla inductivity was assessed using biomarkers expressed in dermal papilla. Versican expression was analyzed using immunofluorescence staining, and versican intensity was analyzed in the dermal papilla. Alkaline phosphatase (AP) in situ activity was measured in the dermal papilla.

[0244] Versican expression and AP activity were analyzed in all terminal hair follicles (anagen I- VI, EC, MC, LC), and intermediate hair follicles (anagen and catagen). To investigate the overall difference in expression of versican and AP, all of the hair follicles used in the study were considered. Considering versican and AP are primarily expressed in anagen, all the hair follicles in the anagen stage were also considered. To determine whether there was a difference in expression between terminal and intermediate hair follicles, as well as hair follicles in anagen stage, they were separately analyzed.

[0245] Results:

[0246] To confirm that culture and treatment conditions were not negatively impacting hair growth, hair follicles were assessed on a macroscopic level. For Patients 1-4, brightfield imaging showed no significant skin damage throughout the culture. However, cutting revealed some epidermal and hair follicle infundibulum damage in all groups, suggesting tissue fragility caused by consecutive topical application, as it was also observed in vehicle group. However, hair follicles bulbs were not impacted and were fully analyzable. Moreover, no cytotoxic effects were observed as neither dystrophy nor significant catagen induction was noted. Representative images of scalp skin biopsies from Patient 3 are depicted in FIGs. 6-8.

[0247] For the following experiments, only Patients 1-3 were evaluated.

[0248] To investigate the effect of the combination therapy on hair cycle staging, the percentage of hair follicles in each hair cycle stage were measured. For Patients 1 and 2, no major change in cycle stage was observed after application of either 5 wt% cortexolone-17a-propi onate solution alone, 5 wt% Minoxidil solution alone, or their combination, in both intermediate and terminal hair follicles. For Patient 3, 5 wt% cortexolone-17a-propionate and 5 wt% Minoxidil combination resulted in more anagen V+VI and fewer catagen hair follicles compared to vehicle.In contrast, individual treatments with 5 wt% cortexolone-17a-propionate and 5 wt% Minoxidil each resulted in similar percentages of both anagen and catagen hair follicles (FIGs. 9A-9C). Upon pooling the data from Patients 1-3, no major change in cycle stage was observed after either application of 5 wt% cortexolone-17a-propionate or 5 wt% Minoxidil alone, or after applying both, in both intermediate and terminal hair follicles (Table 10, below, and FIGs. 10A-10C).Table 10 - Number of terminal and intermediate hair follicles obtained in halves of 4mm scalp skin biopies from three analyzed AGA patients

[0249] Next, the impact of the treatment on dermal papilla (DP) inductivity was studied using alkaline phosphatase (AP) in situ activity. For Patients 1 and 2, no clear modulation of AP activity was seen with application of either 5 wt% cortexolone-17a-propi onate alone or 5 wt% Minoxidil alone, or upon application of both, due to inter-individual variation observed between the two analyzed patients. Only a slight increase was observed in anagen hair follicles after topical application of 5 wt% Minoxidil. Treatment with 5 wt% cortexolone-17a-propi onate increased AP activity in Patient 2 while AP activity in Patient 1 was decreased. For Patient 3, application of 5 wt% cortexolone-17a-propionate alone as well as 5 wt% Minoxidil alone and their combination increased AP activity. This result was also observed when only anagen hair follicles were analyzed (FIGs. 11A-11B). Application of 5 wt% cortexolone-17a-propi onate alone and 5 wt% Minoxidil alone increased AP activity in the dermal papilla of terminal hair follicles.

[0250] Similarly, the result was also observed when only anagen hair follicles were analyzed (FIGs. 12A-12B). No clear modulation was observed in intermediate hair follicles (FIG. 12C). When data from Patients 1-3 was pooled, application of 5 wt% cortexolone-17a-propi onate alonesignificantly increased AP activity, and 5 wt% Minoxidil increased AP activity when compared to placebo and vehicle group. This results was also observed in anagen hair follicles (FIGs. 13A- 13B). Application of 5 wt% Minoxidil alone increased AP activity in terminal anagen hair follicles while 5 wt% cortexolone-17a-propionate alone and in combination with 5 wt% Minoxidil did not exert clear effect in both terminal and intermediate hair follicles (FIGs. 14A-14C).

[0251] The impact of the treatment on dermal papilla (DP) inductivity was also assessed using versican expression. For Patients 1 and 2, application of combination of 5 wt% cortexolone-17a- propionate solution and 5 wt% Minoxidil solution as described elsewhere herein significantly boosted versican expression in the DP, also when only anagen hair follicles were analyzed. The same significant effect was observed in terminal (anagen) hair follicles while only a minor increase was observed in intermediate hair follicles.

[0252] Application of 5 wt% cortexolone-17a-propi onate solution alone increased versican expression while 5 wt% Minoxidil exerted no effect. For Patient 3, treatment with 5 wt% cortexolone-17a-propionate and 5 wt% Minoxidil combination increased versican expression, while 5 wt% Minoxidil alone reduced versican expression, and 5 wt% cortexolone-17a- propionate alone did not exert a clear effect (FIGs. 15A-15B, 16). Treatment with 5 wt% cortexolone-17a-propionate and 5 wt% Minoxidil combination increased the expression of versican in the dermal papilla of terminal hair follicles while 5 wt% Minoxidil alone reduced expression of versican in the dermal papilla of terminal hair follicles, also when only anagen hair follicles were analyzed (FIGs. 17A-17C). When data from Patients 1-3 was pooled, application of 5 wt% cortexolone-17a-propionate and 5 wt% Minoxidil in combination significantly increased the expression of versican in the dermal papilla, also when only anagen hair follicles were analyzed (FIGs. 18A-18B). Application of 5 wt% cortexolone-17a-propionate in combination with 5 wt% Minoxidil significantly increased expression of versican in the dermal papilla of terminal hair follicles, also when only anagen hair follicles were analyzed (FIGs. 19A- 19B). A slight increase was observed in intermediate hair follicles after application of the combination (FIG. 19C).

[0253] Example 8: Solutions of Minoxidil (5% w / w) and cortexolone-17a-propionate (5% w / w)

[0254] Cortexolone-17a-propionate and Minoxidil can be provided in separate pharmaceutical formulations as described herein.

[0255] A 5 wt% (w / w) solution of cortexolone-17a-propionate having the components shown in Table 1, above, is prepared by solubilizing the active agent in the mixture of solvents followed by the addition of the emulsifier (polysorbate 80).

[0256] A 5 wt% (w / w) solution of minoxidil having the components shown in Table 4 is prepared by solubilizing the active agent in the mixture of solvents.

[0257] The 5 wt% cortexolone-17a-propi onate solution and the 5 wt% minoxidil solution are administered to a subject in need thereof at substantially the same time. Topical administration of the 5 wt% solutions of cortexolone-17a-propionate and minoxidil to the scalp of a subject suffering from hair loss has the results described in Example 7, above. That is, co-administering to the subject a 5 wt% cortexolone-17a-propionate solution and a 5 wt% minoxidil solution increases expression of versican in dermal papilla of the subject suffering from hair loss. The amount of versican expression is at least about 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone.

[0258] Example 9: Solution of Minoxidil (5% w / w) and cortexolone-17a-propionate (5% w / w)

[0259] Cortexolone-17a-propionate and minoxidil can be provided in the same pharmaceutical formulation (e.g., a combination formulation).

[0260] A combination formulation comprising 5 wt% minoxidil and 5 wt% cortexolone-17a- propionate having the components shown in Table 11 is prepared.Table 11

[0261] 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. Then, cortexolone-17a-propionate is added and the mixture is kept under stirring until cortexolone-17a-propionate 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.

[0262] Topical administration of the 5 wt% cortexolone-17a-propionate and 5 wt% minoxidil combination formulation to the scalp of a subject suffering from hair loss has the results described in Example 7, above. That is, administering to the subject a 5 wt% cortexolone-17a-propionate and 5 wt% minoxidil combination formulation increases expression of versican in dermal papilla of the subject suffering from hair loss. The amount of versican expression is at least about 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

[0263] 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.

[0264] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0265] 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 increasing expression of versican in dermal papilla of a subject suffering from hair loss, comprising co-administering to the subject a 5 wt% cortexolone-17a-propionate solution and a 5 wt% minoxidil solution, wherein versican expression in dermal papilla coadministered the 5 wt% cortexolone-17a-propionate and minoxidil solutions is at least about 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. The method of claim 1, wherein versican expression in dermal papilla of a subject coadministered the 5 wt% solutions of cortexolone-17a-propi onate and minoxidil is at least about 25% to about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.3 The method of claim 2, wherein versican expression in dermal papilla of a subject coadministered the 5 wt% solutions of cortexolone-17a-propi onate and minoxidil is about 50% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone. The method of any one of claims 1-3, wherein versican expression is increased in hair follicles in anagen phase, catagen phase, telogen phase, or any combination thereof, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.5 The method of claim 4, wherein versican expression is increased in hair follicles in the anagen phase, relative to subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone.6 The method of any one of claims 1-5, wherein versican expression is increased in terminal hair follicles, relative to subjects treated with either a 5 wt% solution of cortexolone-17a- propionate alone or a 5 wt% solution of minoxidil alone.

7. The method of claim 1, wherein increased versican expression in dermal papilla of subjects co-administered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil increases dermal papilla inductivity, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

8. The method of any one of claims 1-7, wherein the 5 wt% solutions of cortexolone-17a- propionate and minoxidil are administered sequentially.9 The method of claim 8, wherein the 5 wt% solution of cortexolone-17a-propionate is administered in a first treatment and the 5 wt% solution of minoxidil is administered in a second treatment.10 The method of claim 9, wherein the first treatment and the second treatment are spaced apart by about 1 to about 9 hours.11 The method of claim 10, wherein the first treatment and the second treatment are spaced apart by about 4 hours.12 The method of claim 9, wherein the first treatment is applied in the morning.13 The method of claim 9, wherein the second treatment is applied in the afternoon.14 The method of any one of claims 1-13, wherein the 5 wt% solutions of cortexolone-17a- propionate and minoxidil are each administered to the subject once every two days.15 The method of any one of claims 1-14, wherein the hair loss is alopecia.16 The method of claim 15, wherein the alopecia is androgenetic alopecia, female pattern hair loss, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or a combination of any of the foregoing.17 The method of claim 16, 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.

18. The method of claim 15, wherein the alopecia is androgenetic alopecia.

19. The method of any one of claims 1-18, wherein the 5 wt% cortexolone-17a-propi onate solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof.

20. The method of claim 19, wherein the solution 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 combinations thereof.

21. The method of any one of claims 1-18, wherein the 5 wt% minoxidil solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof.

22. The method of claim 21, wherein the solution 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 combinations thereof.

23. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil increasing the expression of versican in dermal papilla of a subject for use in the treatment of hair loss, wherein versican expression in dermal papilla co-administered the 5 wt% cortexolone-17a- propionate and minoxidil solutions is at least about 25% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone- 17a-propi onate alone or a 5 wt% solution of minoxidil alone and characterized in that they are co-administered to a subject.

24. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 23, wherein versican expression in dermal papilla of a subject co-administered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil is at least about 25% to about 75% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

25. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 24, wherein versican expression in dermal papilla of a subject co-administered the 5 wt% solutions of cortexolone-17a-propionate and minoxidil is about 50% greater than the amounts of versican expression observed in subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

26. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to any of claims 23-25, wherein versican expression is increased in hair follicles in anagen phase, catagen phase, telogen phase, or any combination thereof, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

27. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 26, wherein versican expression is increased in hair follicles in the anagen phase, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

28. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to any of claims 23-27, wherein versican expression is increased in terminal hair follicles, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

29. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 23, wherein increased versican expression in dermal papilla of subjects coadministered the 5 wt% solutions of cortexolone-17a-propi onate and minoxidil increases dermal papilla inductivity, relative to subjects treated with either a 5 wt% solution of cortexolone-17a-propionate alone or a 5 wt% solution of minoxidil alone.

30. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to any of claims 23-29, wherein the 5 wt% solutions of cortexolone-17a-propionate and minoxidil are administered sequentially.

31. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 30, wherein the 5 wt% solution of cortexolone-17a-propionate is administered in a first treatment and the 5 wt% solution of minoxidil is administered in a second treatment.

32. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 31, wherein the first treatment and the second treatment are spaced apart by about 1 to about 9 hours.

33. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 32, wherein the first treatment and the second treatment are spaced apart by about 4 hours.

34. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 31, wherein the first treatment is applied in the morning.

35. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 31, wherein the second treatment is applied in the afternoon.

36. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to any of claims 23-35, wherein the 5 wt% solutions of cortexolone-17a-propionate and minoxidil are each administered to the subject once every two days.

37. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to any of claims 23-36, wherein the hair loss is alopecia.

38. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 37, wherein the alopecia is androgenetic alopecia, female pattern hair loss, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or a combination of any of the foregoing.

39. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 38, wherein the alopecia areata is selected from the group consisting of diffusealopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, ophiasis, alopecia totalis, and alopecia universalis.

40. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 37, wherein the alopecia is androgenic alopecia.

41. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to any of claims 23-40, wherein the 5 wt% cortexolone-17a-propionate solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof.

42. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 41, wherein the solution 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 combinations thereof.

43. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to any of claims 23-42, wherein the 5 wt% minoxidil solution comprises water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or a combination thereof.

44. A solution of 5 wt% cortexolone-17a-propi onate and of 5 wt% minoxidil for use according to claim 43, wherein the solution 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 combinations thereof.

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