Combination therapy of clastone and minodil for the treatment of hair loss

Abstract

The present disclosure provides a method of treating hair loss in a subject in need thereof, comprising administering to the surface of the subject an effective amount of picosterone-17a-propionate and an effective amount of minoxidil. The present disclosure also provides surface pharmaceutical formulations comprising picosterone-17a-propionate, minoxidil, and one or more pharmaceutically acceptable carriers.

Description

BACKGROUND

[0001] Hair loss is a group of disorders with multiple and different causes that result in the loss of hair from the body. The most common type of hair loss is androgenetic alopecia ("AGA"). AGA is also commonly referred to as androgenic alopecia, male-pattern baldness, or male- or female-pattern hair loss. AGA is reported to affect about 50% of men over the age of 40. By the age of 70, this type of hair loss can ultimately affect up to 80% of white men and about half of all women. Hair loss is often a very concerning issue for the affected subject for cosmetic and psychological reasons, but can also be an important marker of a systemic disease.

[0002] Medical management of AGA includes surgical treatment options, including hair transplantation. This surgery has been successfully performed for decades. Hair transplantation involves harvesting intact hair follicles from a safe donor area (SDA) of the patient's scalp by either follicular unit strip surgery (FUSS) or follicular unit extraction (FUE). Although the cosmetic results after surgery are often satisfactory, the surgery can only be performed if there is a sufficient number of donor grafts (plugs) (or hair follicles) available to cover the balding area. In addition, hair transplantation is typically reserved for patients who have experienced significant hair loss and for patients whose AGA is no longer progressing. For example, in younger patients, hair transplantation is often not recommended because androgens, particularly dihydrotestosterone (DHT), act on the newly transplanted hair follicles, leading to the same thinning and eventual hair loss as the original hair follicles.

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

[0004] Minoxidil (also known as 2,4-diamino-6-piperidinylpyrimidine 3-oxide) is formulated as a topical pharmaceutical product for the treatment of AGA, typically at two strength levels - 2% (as a topical solution) and 5% (as a topical solution or foam). See, e.g., U.S. Patent Nos. 4,596,812 and 6,946,120, each of which is incorporated herein by reference in its entirety. To exert its effect, minoxidil needs to be converted by the enzyme sulfotransferase to its active metabolite minoxidil sulfate. This enzyme is present in the outer root sheath of the hair follicle in the anagen phase. Unfortunately, clinical trials have shown that topical application of 2% minoxidil solution to patients experiencing hair loss results in stimulated thick hair regrowth in less than about 5% of patients, and moderate hair regrowth in only about 30% of 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] Clascoterone (also known as 17a-propionyloxy-21-hydroxy-pregna-4-ene-3,20-dione and 17a-propionyloxy-21-hydroxy-pregna-4, 6-diene-3, 20-dione) is a topical antiandrogen that displaces androgen from its receptor. Clascoterone-17a-propionate is known to be suitable for the treatment of acne, hair loss, and other skin and skin appendage diseases. 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 different crystalline polymorphs, each with 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 unexpectedly discovered that the use of a combination of epitiostanol- 17a-propionate and minoxidil can be effective in treating hair loss, including alopecia. In some embodiments, the combination can provide a synergistic effect such that unexpectedly lower effective amounts of each active can be used to effectively treat, or the same amount of each active can be used to achieve a higher combination synergy. As a result of such combination therapy, favorable clinical results can be achieved after a daily topical application for an appropriate amount of time (e.g., days, weeks, or months).

[0007] Accordingly, the present disclosure provides a method of treating hair loss in a subject in need thereof, comprising topically administering to the subject an effective amount of epitiostanol- 17a-propionate and an effective amount of minoxidil.

[0008] In some embodiments, epitiostanol- 17a-propionate can be co-administered in an amount of at least 1% to about 20% by weight with an effective amount of minoxidil. In some embodiments, minoxidil can be co-administered in an amount of about 0.1% to about 20% by weight with an effective amount of epitiostanol- 17a-propionate.

[0009] In some embodiments, epitiostanol- 17a-propionate and minoxidil are co-administered sequentially. In some such embodiments, epitiostanol- 17a-propionate and minoxidil can be in separate pharmaceutical formulations. In other embodiments, epitiostanol- 17a-propionate and minoxidil can be co-administered simultaneously. In some embodiments, epitiostanol- 17a-propionate and minoxidil can be combined in the same pharmaceutical formulation.

[0010] In some embodiments, the pharmaceutical formulation can be a liquid or semi-solid formulation. In another embodiment, the pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, an ointment, or a foam. In other embodiments, the pharmaceutical formulation is a solution. In some embodiments of a solution, the solution can comprise water, saline, a buffered saline solution, a polyol, a polyol ether, a C1-C7 alcohol, or combinations thereof.

[0011] In some embodiments of the method, the pharmaceutical formulation can further comprise at least one (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) additive selected from the group consisting of an acid, a buffering agent, an antioxidant, an emulsifying agent, a penetration enhancer, a humectant, a preservative, a chelating agent, and combinations thereof. In some embodiments, epitiostanol- 17a-propionate is co-administered in a pharmaceutical formulation comprising less than about 5% water by weight. In some embodiments, epitiostanol- 17a-propionate and minoxidil are combined in the same pharmaceutical formulation comprising less than about 5% water by weight. In some embodiments, the pharmaceutical formulation is topically co-administered once or twice daily.

[0012] In some embodiments of the methods, the hair loss is alopecia. In some embodiments, the alopecia is androgenic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination of the foregoing. In some embodiments, the alopecia areata is selected from diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, ophiasis, alopecia totalis, and alopecia universalis. In some particular embodiments, the alopecia is androgenic alopecia.

[0013] The present disclosure also provides topical pharmaceutical formulations comprising episkin-17a-propionate, minoxidil, and one or more pharmaceutically acceptable carriers. In some embodiments, the episkin-17a-propionate is completely dissolved in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises episkin-17a-propionate at a concentration of about 1% to about 20% by weight, including about 2% to about 15%, about 3% to about 10%, or about 4% to about 7.5% by weight. In some embodiments, the pharmaceutical formulation comprises episkin-17a-propionate at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 7.5%, about 8%, about 9%, or about 10% by weight. In some embodiments, the pharmaceutical formulation comprises minoxidil at a concentration of about 0.1% to about 20% by weight, including about 2% to about 15%, about 3% to about 10%, or about 4% to about 7.5% by weight. In some embodiments, the pharmaceutical formulation comprises minoxidil at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 7.5%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight. In some embodiments, the pharmaceutical formulation comprises a combination of episkin-17a-propionate and minoxidil each at a concentration of about 0.1% to about 20% by weight, including about 2% to about 15%, about 3% to about 10%, or about 4% to about 7.5% by weight.

[0014] In some embodiments, the pharmaceutical formulation is a liquid or semi-solid formulation. In some embodiments, the pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, an ointment, or a foam. In some embodiments, the pharmaceutical formulation is a solution. In some of these embodiments, the solution comprises water, saline, a buffered saline solution, or a combination thereof. In some embodiments, the pharmaceutical formulation comprises less than about 5% water by weight.

[0015] In some embodiments, the one or more pharmaceutically acceptable carriers are selected from the group consisting of a polyol, a polyol ether, and a C1-C7 alcohol. In some embodiments, the C1-C7 alcohol is ethanol, isopropyl alcohol, methanol, or a combination thereof. In some embodiments, the C1-C7 alcohol is ethanol. In some embodiments, the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerol, hexanetriol, and a combination thereof. In some embodiments, the polyol is propylene glycol. In some embodiments, the polyol ether is selected from the group consisting of polypropylene glycol, polyethylene glycol, polyethylene-polypropylene tri-block copolymer, dipropylene glycol, diethylene glycol monoethyl ether (Transcutol®), and a combination thereof. In some embodiments, the polyol ether is diethylene glycol monoethyl ether. In some embodiments, the polyol is propylene glycol, the polyol ether is diethylene glycol monoethyl ether, and the C1-C7 alcohol is ethanol.

[0016] In some embodiments, the pharmaceutical formulation further comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) additive selected from the group consisting of an acid, a buffering agent, an antioxidant, an emulsifying agent, a penetration enhancer, a humectant, a preservative, a chelating agent, and combinations thereof. In some embodiments, the buffering agent is a phosphate buffer, a citrate buffer, a lactate buffer, or combinations thereof. In some embodiments, the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol, propyl gallate, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, thiodipropionic acid, dilauryl thiodipropionate, t-butylhydroquinone, pharmaceutically acceptable salts or esters thereof, and combinations thereof. In some embodiments, the antioxidant is BHT, ascorbyl palmitate, or a combination of BHT and ascorbyl palmitate. In some embodiments, the emulsifying agent is selected from the group consisting of PEG-15 hydroxystearate (polyethylene glycol-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbates (e.g., polysorbate 20, polysorbate 60, polysorbate 80), PEG-20 cetylstearyl ether, macrogol 25 cetylstearyl ether, cetomacrogol 1000, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, propylene glycol esters of fatty acids, polyglyceryl esters of fatty acids, polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, octyldodecyl peg-8 glyceryl ether, octyldodecyl polyoxylglyceride, lauryl polyoxylglyceride, oleoyl polyoxylglyceride, and combinations thereof. In some embodiments, the emulsifying agent is a polysorbate, e.g., polysorbate 60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80. In some embodiments, the penetration enhancer is selected from the group consisting of glycols, polyols, fatty acids (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or combinations thereof), fatty alcohols, fatty acid esters, azone, surfactants, pyrrolidones, and combinations thereof. In some embodiments, the humectant is selected from the group consisting of fatty alcohols, fatty acids, fatty acid esters, oils, polyethylene glycols, glycerin, alpha hydroxy acids, and combinations thereof. In some embodiments, the humectant is cetyl alcohol, cetylstearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, silicone oil, castor oil, polyethylene glycol, glycerin, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or combinations thereof.

[0017] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation for at least six months achieves a weighted average Hair Growth Assessment (HGA) score of about 0.30 compared to placebo.

[0018] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation for at least six months achieves a weighted average Investigator’s Global Assessment (IGA) score of about 0.43 compared to placebo.

[0019] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation for at least six months is free of systemic anti-androgen side effects.

[0020] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation provides:

[0021] a) an average change in target area hair count relative to baseline equal to or higher than 9 hairs / cm after 6 months of daily or BID application 2 ; or

[0022] b) an average change in target area hair count relative to baseline equal to or higher than 10 hairs / cm after 6 months of daily or BID application 2 ; or

[0023] c) an average change in target area hair count relative to baseline equal to or higher than 11 hairs / cm after 6 months of daily or BID application 2 ; or

[0024] d) an average change in target area hair count relative to baseline equal to or higher than 12 hairs / cm after 6 months of daily or BID application 2 ; or

[0025] e) a weighted average HGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0026] f) a weighted average HGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0027] g) the weighted mean HGA score is equal to or greater than 0.40 after 6 months of daily or BID application; or

[0028] h) the weighted mean IGA score is equal to or greater than 0.10 after 6 months of daily or BID application; or

[0029] i) the weighted mean IGA score is equal to or greater than 0.20 after 6 months of daily or BID application; or

[0030] j) the weighted mean IGA score is equal to or greater than 0.30 after 6 months of daily or BID application; or

[0031] k) at least about 10% of the subjects have a good (positive) HGA score after 6 months of daily or BID application; or

[0032] l) at least about 20% of the subjects have a good (positive) HGA score after 6 months of daily or BID application; or

[0033] m) at least about 30% of the subjects have a good (positive) HGA score after 6 months of daily or BID application; or

[0034] n) at least about 10% of the subjects have a good (positive) IGA score after 6 months of daily or BID application; or

[0035] o) at least about 20% of the subjects have a good (positive) IGA score after 6 months of daily or BID application; or

[0036] p) at least about 30% of the subjects have a good (positive) IGA score after 6 months of daily or BID application; or

[0037] q) at least about 40% of the subjects have a good (positive) IGA score after 6 months of daily or BID application.

[0038] In another embodiment, the topical pharmaceutical formulation of the present application is used to treat hair loss in a subject in need thereof. DETAILED DESCRIPTION

[0039] As used herein, a noun without a quantifier refers to one or more than one (i.e., at least one). For example, "element" means one element or more than one element.

[0040] The term "about" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend 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 practices in the art. Alternatively, "about" can mean ranges such as up to 10% (e.g., up to 5%, up to 1%) of a given value.

[0041] The phrase "active agent" as used herein means alprostadil-17a-propionate or minoxidil.

[0042] The term "hair loss" as used herein means androgenetic alopecia (AGA), alopecia areata (including diffuse alopecia areata, single-focal alopecia areata, multifocal alopecia areata, ophiasic alopecia areata, totalis alopecia areata, and universalis alopecia areata), telogen effluvium, anagen effluvium, and traction alopecia, either collectively or individually, as specified.

[0043] The term "anhydrous" as used herein means substantially free of water, i.e., having less than about 5% water by weight, and in certain embodiments as specified herein, having less than about 3% water by weight.

[0044] The term "at least" as used herein, when preceding 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 can be logically included, as clear from the context. When "at least" precedes a series of numbers or a range, it is understood that "at least" can modify each number in the series or range. For example, "at least 3" means at least 3, at least 4, at least 5, etc. When "at least" precedes a component in a method step, then that component is included in the step, while additional components are optional.

[0045] The term "twice daily" or "BID" as used herein means "two times a day."

[0046] The term "buffer" as used herein means 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. Some examples of buffers include, for example, phosphate buffers, citrate buffers, lactate buffers, or combinations thereof.

[0047] The phrase "C1-C7alcohol" as used herein refers to an alcohol having 1, 2, 3, 4, 5, 6, or 7 carbons, which is suitable for use in a topical pharmaceutical formulation. Some examples of such C1-C7alcohols 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-C7alcohols, and in particular short chain C1-C7alcohols, such as C2-C3alcohols (e.g., ethanol, n-propanol, or isopropanol), contribute to the spreadability of the pharmaceutical formulations described herein.

[0048] The term "chelating agent" as used herein refers to a compound that is capable of binding to a metal ion or metal compound. In some embodiments, a chelating agent can stabilize a formulation by preventing, for example, oxidation or precipitation. Suitable chelating agents include, for example, citric acid, phytic acid, sodium phytate, chloroiodoxyquin, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronate, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, or combinations thereof.

[0049] The term "co-administration" as used herein means the simultaneous or sequential administration of two different active agents, i.e., corticosterone-17a-propionate and minoxidil. In some embodiments, the active agents are administered close enough in time to one another so that both the first and second therapeutic agents are present in the subject receiving co-administration at the same time.

[0050] The term "corticosterone" (also known as "11-deoxycortisol" or "Reichstein's substance") as used herein refers to a compound having the following structure:

[0051] .

[0052] The term "corticosterone-17a-propionate" as used herein refers to the compound 17a-propyloxy-21-hydroxy-pregna-4-ene-3,20-dione, also known as clascoterone, and which is equivalent to the chemical structure:

[0053] .

[0054] The term "degradation product" as used herein refers to those compounds produced from the in vitro degradation of corticosterone-17a-propionate. Exemplary known degradation products of corticosterone-17a-propionate include, but are not limited to, corticosterone-21-propionate and corticosterone.

[0055] The term "ester" as used herein refers to esterified organic solvents, which include, but are not limited to, ethyl acetate and ethyl lactate.

[0056] As used herein, the term "ethanol" refers to ethyl alcohol, i.e., CH3CH2OH, and includes pure (anhydrous) ethanol and 96° ethanol, which is ethanol containing water, typically in an amount of about 4% by volume to about 5.1% by volume. In some embodiments, the ethanol is denatured alcohol, e.g., specially denatured (SD) alcohol, which includes a denaturant to prevent consumption.

[0057] As used herein, the term "fatty" refers to a saturated or unsaturated aliphatic carbon chain. The chain is of any suitable length, e.g., C4-C 28 , more specifically, C 10 -C 20 , C 12 -C 22 , and C 12 -C 18 chain length.

[0058] As used herein, the term "gelling agent" refers to a pharmaceutically acceptable compound that can convert an aqueous or an oily phase into a gel. Gelling agents act as thickening agents, often without imparting rigidity. The gelling agent can be an inorganic gelling agent, an organic gelling agent, a hydrogel, an organic gel, or a combination thereof.

[0059] As used herein, the term "minoxidil" refers to the compound 2,4-diamino-6- piperidinylpyrimidine 3-oxide, which is equivalent to the following chemical structure:

[0060] .

[0061] In some embodiments, minoxidil is present in the form of a salt. The salt can be, for example, an acetate, a citrate, a succinate, a benzoate, a hydrochloride, a sulfate, a phosphate, or a lactate. In some embodiments, the acetate or lactate salt of minoxidil is used.

[0062] As used herein, the term "metabolite" refers to those compounds produced by in vivo metabolism or degradation of an active agent, e.g., epitiostanol-17a-propionate or minoxidil. Exemplary known metabolites of epitiostanol-17a-propionate include, but are not limited to, epitiostanol and tetrahydroepitiostanol. Exemplary known metabolites of minoxidil include, but are not limited to, minoxidil sulfate.

[0063] The term "humectant" as used herein refers to those compounds that impart moisture to the skin, soften the skin, or both. An exemplary humectant is an emollient, which includes, for example, fatty alcohols, fatty acids, fatty acid esters, oils, polyethylene glycols, glycerin, alpha hydroxy acids (e.g., lactic acid, glycolic acid, malic acid, citric acid, or tartaric acid), and combinations thereof. Some specific examples of humectants include, for example, cetyl alcohol, cetyl stearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, silicone oil, castor oil, polyethylene glycol, glycerin, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or combinations thereof; preferably, the humectant is selected from cetyl alcohol and stearyl alcohol.

[0064] The phrase "natural oil" as used herein refers to those oils that can be isolated from a natural source. 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.

[0065] The phrase "penetration enhancer" as used herein refers to those pharmaceutically acceptable compounds that increase the penetration of an active agent through the dermal layer. Exemplary penetration enhancers include, for example, hydroxypropyl beta-cyclodextrin, polyoxyethylene alkyl ethers, polyoxylglycerides, 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, polyethylene glycol 40 hydrogenated castor oil (e.g., CREMOPHOR™ RH40, KOLLIPHOR™ RH40, BASF, Germany), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB), fatty acid 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.

[0066] The term "pH" as used herein and unless otherwise clearly indicated by the context of its use, is to be taken as "apparent pH" to acknowledge the fact that in complex multi- component skin vehicle that is not completely aqueous in nature, the behavior of a pH electrode cannot be taken as "pH" in the strictest sense.

[0067] The term "polyol" as used herein refers to an organic molecule containing two or more hydroxyl groups. Exemplary polyols include, but are not limited to, ethylene glycol, propylene glycol, glycerol, hexanetriol, and the like, preferably propylene glycol.

[0068] The term "polyol ether" as used herein 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 tri-block copolymer, dipropylene glycol, diethylene glycol monoethyl ether, and the like.

[0069] The term "preservative" as used herein refers to a compound having antimicrobial activity, such as an antibacterial or antifungal agent. Suitable preservatives include, for example, a parahydroxybenzoic acid ester (e.g., methylparaben, ethylparaben, propylparaben, butylparaben), a benzoic acid salt (e.g., sodium benzoate), a sorbic acid salt (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.

[0070] The term "solvent" as used herein means a mixture of one or more than one pharmaceutically acceptable solvent suitable for topical application (including, but not limited to, the scalp) for dissolving the potentio- 17a-propionate and / or minoxidil in the formulations described herein.

[0071] "Tetrahydrocortisone" as used herein refers to the compound with Chemical Abstract Service (CAS) Registry Number 68-60-0.

[0072] The term "treat" and its conjugations as used herein 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 alleviation, remission, diminished severity, or number of symptoms, or making the subject more comfortable, slowing the development of a symptom or disorder, or improving a subject's physical or mental well-being. Treating or ameliorating a symptom can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, or psychiatric evaluation.

[0073] The term "prevent" as used herein refers to preventing the occurrence or presence of a disease, disorder, or condition to which the term applies, or alternatively delaying the onset or recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, to which the term applies. The term "prevent" also refers to reducing the incidence of a disease, disorder, or condition. The term "prevent" refers to the act of preventing.

[0074] The term "sequentially" as used herein means that, with respect to a subject, a first active agent is co-administered to the subject for a first period of time, followed by administration of a second active agent for a second period of time. In other words, the term "sequentially" includes a first treatment in a first period of time, followed by a second treatment in a second period of time. The first and second periods of time can be separated by amounts on the order of seconds, minutes, hours, or days, as desired. In some embodiments, the first and second periods of time are separated by seconds (e.g., about 60 seconds or less, about 30 seconds or less).

[0075] The term "subject" as used herein generally refers to a mammal. In some embodiments, the subject to be treated is a human.

[0076] The phrase "weight%" as used herein is intended to encompass and disclose embodiments in which, for a given value, the weight% is both a weight percent by volume (w / v) and a weight percent by total weight (w / w). For example, an embodiment comprising 10 weight% of an element "X" discloses embodiments comprising both 10 weight% of "X" (w / v) and 10 weight% of "X" (w / w). Similarly, and again by way of example, an embodiment comprising 10 weight% of "X", 20 weight% of "Y", and 60 weight% of "Z" discloses embodiments comprising: a) 10 weight% of "X" (w / v), 20 weight% of "Y" (w / v), and 60 weight% of "Z" (w / v); and b) 10 weight% of "X" (w / w), 20 weight% of "Y" (w / w), and 60 weight% of "Z" (w / w). Notwithstanding the foregoing provision, in some embodiments, a value will be specifically labeled as "(w / w)" or "(w / v)". In these cases, the value should be interpreted as disclosing only the labeled value, i.e., only (w / w) or only (w / v) - but not both.

[0077] The terms "comprising", "including", "containing", "having" and the like as used herein are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. As used herein, "comprising" and "comprises" are to be construed as meaning "consisting essentially of" and "consisting of", respectively, in reference to a given embodiment disclosed herein, unless otherwise noted.

[0078] The terms "consisting essentially of and variations thereof as used herein are to be construed as being a semi-closed term as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03(b)(3)(i), 112th Deletion (September 2004) ("consisting essentially of" is a recital of the numerical range using the term "consisting essentially of" to recite the range of elements that are present in the composition, formulation, or process).

[0079] The terms "consisting of and variations thereof as used herein are to be construed as a closed term meaning that the implementation comprises only the specified elements of which they are specified, and no other elements.

[0080] As used herein, the term "target area hair count" or "TAHC" refers to the change in the number of non-vellus hairs in a target area of the scalp from baseline. The target area can be, for example, 1 cm 2 or a circle 1 inch in diameter (5.1 cm 2 ).

[0081] As used herein, the term "hair growth assessment" or "HGA" refers to the score given by a subject comparing a baseline standardized global photograph of the subject's scalp to a "real-time" standardized global photograph.

[0082] As used herein, the term "investigator global assessment" or "IGA" refers to the score given by an evaluator comparing a baseline standardized global photograph of the subject's scalp to a "real-time" standardized global photograph.

[0083] Methods

[0084] The present disclosure provides methods of treating hair loss, e.g., alopecia, in a subject in need thereof, comprising topically administering to the subject an effective amount of

[0085] In some preferred embodiments, the subject can be a mammal, e.g., a human.

[0086] In some embodiments, the hair loss can be associated with alopecia. Alopecia can include, for example, androgenetic alopecia (AGA), alopecia areata (including diffuse alopecia areata, single-focal alopecia areata, multifocal alopecia areata, ophiasic alopecia areata, alopecia totalis, and alopecia universalis), telogen effluvium, anagen effluvium, and traction alopecia. In some embodiments, the alopecia to be treated can be AGA.

[0087] In some embodiments, the epitiostanol-17a-propionate and minoxidil are coadministered sequentially, wherein the first active agent can be administered to the subject for a first period of time, followed by administration of the second active agent for a second period of time. The specific order of administration is not limited. In some embodiments, the epitiostanol-17a-propionate can be administered first, and the minoxidil can then be administered. In other embodiments, the minoxidil can be administered first, and the epitiostanol-17a-propionate can then be administered. The period of time between the two administration steps can be separated by seconds, minutes, hours, or days, as desired. In some embodiments, the first and second administration steps can be separated by seconds (e.g., about 60 seconds or less, about 30 seconds or less).

[0088] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation for at least six months achieves a weighted average Hair Growth Assessment (HGA) score of about 0.30 compared to placebo.

[0089] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation for at least six months achieves a weighted average Investigator’s Global Assessment (IGA) score of about 0.43 compared to placebo.

[0090] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation for at least six months does not result in systemic anti-androgen side effects in the subject.

[0091] In certain embodiments, the present disclosure provides a method of treating hair loss, the method comprising topically administering to a subject in need thereof a topical pharmaceutical formulation described herein, wherein topically administering the pharmaceutical formulation provides:

[0092] a) an average change in target area hair count relative to baseline equal to or higher than 9 hairs / cm after 6 months of daily or BID application 2 ; or

[0093] b) an average change in target area hair count relative to baseline equal to or higher than 10 hairs / cm after 6 months of daily or BID application 2 ; or

[0094] c) an average change in target area hair count relative to baseline equal to or higher than 11 hairs / cm after 6 months of daily or BID application 2 ; or

[0095] d) an average change in target area hair count relative to baseline equal to or higher than 12 hairs / cm after 6 months of daily or BID application 2 ; or

[0096] e) a weighted average HGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0097] f) a weighted average HGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0098] g) a weighted mean HGA score equal to or higher than 0.40 after 6 months of daily or BID application; or

[0099] h) a weighted mean IGA score equal to or higher than 0.10 after 6 months of daily or BID application; or

[0100] i) a weighted mean IGA score equal to or higher than 0.20 after 6 months of daily or BID application; or

[0101] j) a weighted mean IGA score equal to or higher than 0.30 after 6 months of daily or BID application; or

[0102] k) at least about 10% of subjects have a good (positive) HGA score after 6 months of daily or BID application; or

[0103] l) at least about 20% of subjects have a good (positive) HGA score after 6 months of daily or BID application; or

[0104] m) at least about 30% of subjects have a good (positive) HGA score after 6 months of daily or BID application; or

[0105] n) at least about 10% of subjects have a good (positive) IGA score after 6 months of daily or BID application; or

[0106] o) at least about 20% of subjects have a good (positive) IGA score after 6 months of daily or BID application; or

[0107] p) at least about 30% of subjects have a good (positive) IGA score after 6 months of daily or BID application; or

[0108] q) at least about 40% of subjects have a good (positive) IGA score after 6 months of daily or BID application.

[0109] Pharmaceutical formulations

[0110] In some embodiments, the phytosterone-17a-propionate and minoxidil can be coadministered sequentially. In some such embodiments, the phytosterone-17a-propionate and minoxidil can be provided in separate pharmaceutical formulations. Each pharmaceutical formulation can be as described herein.

[0111] In other embodiments, the phytosterone-17a-propionate and minoxidil can be coadministered simultaneously (i.e., concomitantly). In some embodiments, the phytosterone-17a-propionate and minoxidil can be provided in the same pharmaceutical formulation (e.g., a combination formulation).

[0112] The pharmaceutical preparation can be in any form suitable for topical administration. In some embodiments, the pharmaceutical preparation can be a liquid or semi-solid preparation, depending on the carriers and excipients described herein that can be present. Some examples of liquid or semi-solid preparations include, for example, solutions, suspensions, emulsions, microemulsions, creams, pastes, gels, ointments, or foams. In some preferred embodiments, the pharmaceutical preparation can be a solution.

[0113] In some embodiments, the preparation can be a cream. In some embodiments, the cream can comprise equal parts of an oil and water in the form of an emulsion.

[0114] In some embodiments, the preparation 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 combinations thereof), an oil, or combinations thereof.

[0115] In some embodiments, the preparation can be a gel comprising at least one gelling agent. The gelling agent can be, for example, an inorganic gelling agent (e.g., aluminum hydroxide gel, bentonite slurry), an organic gelling agent (e.g., carbomer polymer, tragacanth), a hydrogel (e.g., an organic hydrogel, a natural or synthetic gum, or an inorganic hydrogel), an organic gel (e.g., a hydrocarbon type, a vegetable fat, a soap base oil, or a hydrophilic organic gel), or combinations thereof. The organic hydrogel can include, for example, xanthan gum and tragacanth. The natural or synthetic gum can include, for example, methylcellulose, sodium carboxymethylcellulose, and poloxamer. The inorganic hydrogel can include, for example, bentonite gel, montmorillonite (e.g., VEEGUM™, Vanderbilt Minerals, LLC, Norwalk, CT), or silica. The hydrocarbon type organic gel can include, for example, mineral ester and mineral oil / polyethylene gel. The vegetable fat type organic gel can include, for example, cocoa butter. The soap base oil type organic gel can include, for example, aluminum stearate with heavy mineral oil gel. The hydrophilic organic gel can include, for example, a carbon wax base, such as a polyethylene glycol (PEG) ointment.

[0116] In some embodiments, the gelling agent can be a carbomer polymer. The term "carbomer" is a generic name for high molecular weight acrylic acid polymers lightly crosslinked with allyl ethers of polyols (e.g., allyl sucrose, allyl pentaerythritol). The term can also be used to describe CARBOPOL™ polymers (Lubrizol Corp., Wickliffe, OH).

[0117] In some embodiments, the formulation can be an ointment. In some embodiments, the ointment can comprise a hydrocarbon (e.g., paraffin, petrolatum), lanolin, beeswax, macrogol, polyethylene glycol, emulsifying wax, alkyltrimethylammonium bromide (e.g., cetrimide), 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% or less water by weight.

[0118] In some embodiments, the formulation can be a foam. The foam formulation can be used in combination with one or more acceptable propellants (e.g., propane, butane, isobutylene, nitrogen, propellant P75, etc.).

[0119] Solvent

[0120] In some embodiments where the pharmaceutical formulation can be a solution, the pharmaceutical formulation can comprise water, saline (e.g., sodium chloride salt solution), buffered saline (e.g., phosphate buffered saline solution), or a combination thereof.

[0121] In some embodiments, the pharmaceutical formulation can be considered anhydrous, and can comprise less than about 5% (w / w) (e.g., less than about 4% w / w, less than about 3% w / w, less than about 2% w / w, or less than about 1% w / w) water.

[0122] In some embodiments, particularly in some embodiments where the water comprises less than about 5% w / w, the corticosterone-17a-propionate can be completely dissolved in the pharmaceutical formulation. The topical pharmaceutical formulation can comprise one or more pharmaceutically acceptable carriers (e.g., solvents) other than or instead of water, such as a polyol, a polyol ether, a C1-C7 alcohol, and combinations thereof.

[0123] In some embodiments, the pharmaceutical formulation can comprise a solvent selected from the group comprising or selected from the following: water, a C1-C7 alcohol, a polyol ether, a polyol, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), a natural oil, an ester, tricaprylin (2,3-di(octanoyloxy)propanoic acid propyl ester), a medium-chain triglyceride, caprylocaproyl macrogol-8 glycerides, and any combination of the foregoing. In some preferred embodiments, the one or more pharmaceutically acceptable carriers are selected from the group comprising a polyol, a polyol ether, a C1-C7 alcohol, and combinations thereof.

[0124] In some embodiments, the pharmaceutical formulation can comprise at least about 50% by weight of a 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% by weight of a solvent. In other embodiments, the pharmaceutical formulation can comprise at least about 70% by weight of a solvent. In other embodiments, the pharmaceutical formulation can comprise at least about 80% by weight of a solvent. In other embodiments, the pharmaceutical formulation can comprise at least about 85% by weight of a solvent, at least about 90% by weight of a solvent, at least about 91% by weight of a solvent, at least about 92% by weight of a solvent; at least about 93% by weight of a solvent; at least about 94% by weight of a solvent; or at least about 95% by weight of a solvent.

[0125] In some embodiments, the solvent can comprise a mixture of a C1-C7 alcohol, a polyol ether, and a polyol. In some such embodiments, the pharmaceutical formulation can comprise about 10% to about 50% by weight of a polyol ether; about 5% to about 55% by weight of a polyol; and about 5% to about 50% by weight of a C1-C7 alcohol. In some embodiments, the mixture of a C1-C7 alcohol, a polyol ether, and a polyol can be present in a ratio of about 1 : 1 : 1 by w / w / w weight. In some embodiments, each of the C1-C7 alcohol, the polyol ether, and the polyol can be present in about 30% by weight.

[0126] In some embodiments, the pharmaceutical formulation can comprise about 15% to about 45% by weight of a polyol ether; about 20% to about 40% by weight of a polyol ether; about 25% to about 35% by weight of a polyol ether; or about 30% to about 35% by weight of a polyol ether. In some embodiments, the pharmaceutical formulation can comprise about 30% by weight of a polyol ether. In other embodiments, the pharmaceutical formulation can comprise about 32% by weight of a polyol ether.

[0127] In some embodiments, the polyol ether can be selected from the group comprising or selected from the following: polyethylene glycol, polypropylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether (TRANSCUTOL™, Gattefosse, France), and combinations thereof.

[0128] 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 have a number average molecular weight (Mn) that is about 200 g / mol to about 2,000 g / mol. In other embodiments, the PEG can have a number average molecular weight (Mn) that is about 200 g / mol to about 1,000 g / mol. In other embodiments, the PEG can have a number average molecular weight (Mn) that is about 200 g / mol to about 500 g / mol. In other embodiments, the PEG can have a number average molecular weight (Mn) that is about 200 g / mol to about 300 g / mol. In other embodiments, the PEG can have a number average molecular weight (Mn) that is about 200 g / mol to about 250 g / mol. n). In some embodiments, the PEG can be selected from the group comprising or selected from the following: 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.

[0129] In some embodiments, the polyol can be selected from the group comprising or selected from the following: propylene glycol, ethylene glycol, glycerol, hexanetriol, and combinations thereof. In some embodiments, the polyol can be glycerol. In some preferred embodiments, the polyol can be propylene glycol.

[0130] In some embodiments, the polyol can be present in an amount of about 5% to about 55% by weight of the total formulation, about 10% to about 50% by weight of the total formulation, about 20% to about 45% by weight of the total formulation; and in some embodiments, about 25% to about 40% by weight. In one particular embodiment, the polyol can comprise about 30% by weight of the total formulation. In another embodiment, the polyol comprising about 30% by weight of the total formulation can be propylene glycol.

[0131] In some embodiments, the pharmaceutical formulation can comprise about 5% to about 50% by weight of a C1-C7 alcohol. In some embodiments, the pharmaceutical formulation can comprise about 15% to about 45% by weight of a C1-C7 alcohol; about 20% to about 40% by weight of a C1-C7 alcohol; or about 25% to about 35% by weight of a C1-C7 alcohol. In some embodiments, the pharmaceutical formulation can comprise about 30% by weight of a C1-C7 alcohol. In some further embodiments, the pharmaceutical formulation can comprise a C1-C7 alcohol in an amount of about 10% to about 40% by weight, or about 15% to about 35% by weight.

[0132] In some embodiments, the C1-C7 alcohol can be selected from the group comprising or selected from the following: methanol, ethanol, isopropyl alcohol, n-butyl alcohol, n-propyl alcohol, and benzyl alcohol. In some preferred embodiments, the C1-C7 alcohol can be ethanol. In some embodiments, the ethanol comprises about 30% by weight of the total formulation. In other embodiments, the C1-C7 alcohol can be isopropyl alcohol.

[0133] In some embodiments, the C1-C7 alcohol can comprise a small portion of water, typically in the range of about 4% to about 5.1% by volume. In some embodiments where the pharmaceutical formulation can be anhydrous, the C1-C7 alcohol having about 4% to about 5.1% by volume of water can be present in the pharmaceutical formulation in an amount such that the water content in the final formulation itself can be less than about 5% by weight or less than about 3% by weight.

[0134] In some embodiments, the solvent can include a polyol, a polyol ether, and a C1-C7 alcohol. In some embodiments, the solvent can include 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 are typically present in a ratio of each comprising about 25% to about 35% by weight of the pharmaceutical formulation.

[0135] Other Components

[0136] In some embodiments, the pharmaceutical formulation can further include at least one additive selected from the group consisting of an acid, a buffering agent, an antioxidant, an emulsifying agent, a penetration enhancer, a humectant, a preservative, a chelating agent, and combinations thereof.

[0137] In some embodiments, the pharmaceutical formulation can include about 0.1 wt% to about 50 wt% of each additive (e.g., acid, buffer, antioxidant, emulsifying agent, penetration enhancer, humectant, preservative, chelating agent) relative to the total weight of the composition (i.e., 100 wt%). For example, each additive can be present in the pharmaceutical formulation in an amount of 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 15 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 5 wt%, about 1 wt% to about 2 wt%, about 50 wt%, about 48 wt%, about 46 wt%, about 44 wt%, about 42 wt%, about 40 wt%, about 38 wt%, about 36 wt%, about 34 wt%, about 2 wt%, about 30 wt%, about 28 wt%, about 26 wt%, about 24 wt%, about 22 wt%, about 20 wt%, about 18 wt%, 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.

[0138] In some embodiments, the pharmaceutical formulation can include an acid to aid in dissolving one or both of the active agents, to maintain a desired pH, or both. Any suitable acid can be used, such as an inorganic 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 a mixture thereof. Some examples of suitable acid additives include, for example, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic 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, caproic acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic 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.

[0139] In some embodiments, the acid can be added in an amount sufficient such 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).

[0140] In some embodiments, the pharmaceutical formulation can include a buffer to aid in maintaining the pH of the formulation within a desired range. In some embodiments, the buffer can be a phosphate buffer, a citrate buffer, a lactate buffer, or a combination thereof. In some embodiments, the formulation can include phosphoric acid, citric acid, lactic acid, or a combination thereof.

[0141] Because oxidation can lead to degradation of the active agent, in some embodiments, the pharmaceutical formulation can include an antioxidant. In some embodiments, the antioxidant can be, for example, 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, t-butylhydroquinone, pharmaceutically acceptable salts or esters thereof, and combinations thereof. In some embodiments, the antioxidant can be ascorbyl palmitate, BHA, BHT, or combinations thereof. In some embodiments, the antioxidant can be BHT, ascorbyl palmitate, or a combination of BHT and ascorbyl palmitate.

[0142] In some embodiments, the pharmaceutical formulation can include up to about 1% by weight of an antioxidant. In some embodiments, the pharmaceutical formulation can include up to about 0.5% by weight of an antioxidant or about 0.5% by weight of an antioxidant.

[0143] In some embodiments, the pharmaceutical formulation can include an emulsifier, particularly to provide a solution, suspension, emulsion, or microemulsion. Without wishing to be bound by any particular theory, it is believed that the emulsifier, when present, aids or facilitates the dissolution of any solid material, such as the active agent, in the pharmaceutical formulation. However, in other embodiments, the emulsifier can be present to facilitate the intermingling of two immiscible liquids with each other (e.g., to form an emulsion or microemulsion).

[0144] In other embodiments, and without wishing to be bound by any particular theory, the emulsifier can improve the spreadability of the product. For example, and without wishing to be bound by a particular theory, when the pharmaceutical formulation is a liquid solution, it is believed that the presence of an appropriate amount of emulsifier reduces the surface tension between the pharmaceutical formulation and the lipid environment of the superficial layer of the skin and / or scalp. This makes the pharmaceutical formulation more easily spreadable, and it is believed to aid in the penetration of the active agent into the skin (including the scalp), hair follicle, or both.

[0145] In some embodiments, the emulsifier can be selected from the group comprising or selected from the following: polyethylene glycol (PEG)-fatty acid monoesters, such as PEG-15 hydroxystearate (also known as polyethylene glycol-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 cetylstearyl ether, polyoxyl 25 cetylstearyl ether, poloxyl 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; polyglyceryl 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; octanoyl octanoyl polyoxyl-8 glycerides; polyoxylglycerides, such as octanoyl hexanoyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoyl polyoxylglycerides, and the like; polyoxyethylene lauryl alcohol; and combinations of any of the foregoing. In some embodiments, the emulsifier can be polyoxyl 40 hydrogenated castor oil, polyethylene glycol-15-hydroxystearate, polysorbate 60, polysorbate 80, or combinations thereof. In some preferred embodiments, the emulsifier can be a polysorbate, such as polysorbate 60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80.

[0146] In some embodiments, the pharmaceutical formulation can comprise an emulsifier in an amount of up to about 5% by weight of the total formulation (e.g., up to about 4% by weight, up to about 3% by weight, up to about 2% by weight). In some embodiments, the emulsifier can be present in an amount of 0.05% to 5% by weight (e.g., about 0.05% to about 4% by weight, about 0.05% to about 3% by weight, about 0.05% to about 2% by weight). In some preferred embodiments, the pharmaceutical formulation can comprise an emulsifier in an amount of about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight, or about 5% by weight. In some further embodiments, the pharmaceutical formulation can comprise an emulsifier in an amount of up to about 0.1% by weight, or it can comprise about 0.1% by weight of an emulsifier. In some further embodiments, the emulsifier can be present in the pharmaceutical formulation in an amount of about 0.1% by weight.

[0147] In some embodiments, the pharmaceutical formulation can include one or more penetration enhancers. Without wishing to be bound by a particular theory, it is believed that penetration enhancers beneficially affect the delivery of the active agent into the skin (including the scalp) and / or hair follicle. Advantageously, and in some embodiments, the solvent or some component of the solvent acts as a penetration enhancer. For example, in some embodiments in which the pharmaceutical formulation includes ethanol and / or diethylene glycol monoethyl ether, these solvents can also serve to enhance the penetration of the active agent into the skin (including the scalp), hair follicle, or both. Despite the presence of ethanol and / or diethylene glycol monoethyl ether, the pharmaceutical formulations described herein can also include additional penetration enhancers.

[0148] In some embodiments, the penetration enhancer can be selected from the group consisting of hydroxypropyl beta-cyclodextrin, glycols, polyols, fatty acids (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or combinations thereof), fatty alcohols, fatty acid esters, surfactants, pyrrolidones, and combinations thereof. Some examples of additional penetration enhancers that can be incorporated into the formulations described herein include, but are not limited to, polyoxymethylene alkyl ethers, polyoxylglycerides, dimethyl sulfoxide, pyrrolidones, 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, polyethylene glycol 40 hydrogenated castor oil (e.g., CREMOPHOR™ RH40, KOLLIPHOR™ RH40, BASF, Germany), didecyldimethylammonium bromide (DDAB), didecyldimethylammonium bromide (DTAB), fatty acid 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.

[0149] In some embodiments, the penetration enhancer can be dimethyl isosorbide. In other embodiments, the penetration enhancer can be a mixture including dimethyl isosorbide and diethylene glycol monoethyl ether. In other embodiments, the penetration enhancer can be dimethyl sulfoxide.

[0150] In some embodiments, the penetration enhancer can be present in an amount of about 1% to about 50% by weight relative to the total weight of the pharmaceutical formulation. In other embodiments, the penetration enhancer can be present in an amount of about 2% to about 40% by weight relative to the total weight of the pharmaceutical formulation, or about 5% to about 35% by weight relative to the total weight of the pharmaceutical formulation. According to some embodiments, the penetration enhancer can be present in the pharmaceutical formulations described herein in an amount of about 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight relative to the total weight of the pharmaceutical formulation.

[0151] In some embodiments, the pharmaceutical formulation can include one or more humectants. Without wishing to be bound by a particular theory, it is believed that humectants impart moisture and / or softness to the skin, including the scalp, particularly when components known to dry the skin, such as alcohols, are also present in the formulation. In some embodiments, the humectant 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 combinations thereof), a fatty acid ester, an oil, a polyethylene glycol, glycerin, an alpha-hydroxy acid, or combinations thereof. In some embodiments, the humectant can be cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, silicone oil, castor oil, polyethylene glycol, glycerin, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or combinations thereof. In some embodiments, the humectant can be cetyl alcohol, stearyl alcohol, or a combination of cetyl alcohol and stearyl alcohol.

[0152] In some embodiments, the pharmaceutical formulation can include one or more preservatives (e.g., antibacterial agents, antifungal agents). Suitable preservatives include, for example, parabens (e.g., methylparaben, ethylparaben, propylparaben, butylparaben), benzoic acid salts (e.g., sodium benzoate), sorbates (e.g., potassium sorbate), quaternary ammonium compounds (e.g., benzalkonium chloride, benzethonium chloride), alcohols (e.g., chlorobutanol, benzyl alcohol, ethanol, phenol, m-cresol, chlorocresol), sodium metabisulfite, imidazolidinyl urea, glycerin, propylene glycol, or combinations thereof.

[0153] In some embodiments, the pharmaceutical formulation can include one or more chelating agents. Suitable chelating agents include, for example, citric acid, phytic acid, sodium phytate, chloroiodohydroxyquin, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronate, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, or combinations thereof.

[0154] Modes of administration

[0155] The pharmaceutical formulations described herein can be co-administered according to different regimens. In one embodiment, the mode of administration of the pharmaceutical formulation can be continuous. For example, the pharmaceutical formulation can be applied topically once daily, twice daily, three times daily, four times daily, or more, as specified by a physician. In some embodiments, the formulations described herein can be applied topically once daily or twice daily. According to one specific embodiment, the pharmaceutical formulations described herein can be applied topically once daily. According to another embodiment, the pharmaceutical formulations described herein can be applied topically twice daily.

[0156] In some embodiments, the dosing regimen can be tapered. That is, the pharmaceutical formulation can be applied once daily for a first period of time, then twice daily for a second period of time, then three times daily for a third period of time, and so on. In one specific embodiment, the pharmaceutical formulation can be applied once daily on the first day, and then twice daily, with the appropriate duration of treatment determined by the physician of the subject. In an alternative embodiment, the tapered administration can include administration of the pharmaceutical formulation at a gradually decreasing regimen over an appropriate period of time starting from a multiple daily administration and decreasing the number of administrations over an appropriate period of time until a maintenance regimen can be achieved. Determining the appropriate starting point, taper, and maintenance regimen are within the skill of a physician of ordinary skill in the art having the benefit of the present disclosure.

[0157] In some embodiments, the pharmaceutical formulation can be applied over a period of days, weeks, or months. For example, the pharmaceutical formulation can be applied once, twice, three times, four times, 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 1 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 one specific embodiment, the pharmaceutical formulation can be applied once on the first day, and then twice daily for about 4 weeks.

[0158] In another embodiment, the pharmaceutical preparation can be topically applied to the scalp once daily for 1 month, once daily for 2 months, once daily for 3 months, once daily for 4 months, once daily for 5 months, once daily for 6 months, once daily for 8 months, once daily for 12 months, once daily for 14 months, once daily for 16 months, once daily for 18 months, once daily for 20 months, once daily for 22 months, or once daily for 24 months. In some embodiments, the pharmaceutical preparation can be topically applied to the scalp once daily for 6 months. In some embodiments, the pharmaceutical preparation can be topically applied to the scalp once daily for 12 months.

[0159] In other embodiments, the pharmaceutical preparation can be topically applied to the scalp twice daily for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, about 22 months, or about 24 months. In some embodiments, the pharmaceutical preparation can be topically applied to the scalp twice daily for 6 months. In some embodiments, the pharmaceutical preparation can be topically applied to the scalp twice daily for 12 months.

[0160] In other embodiments, the pharmaceutical preparation can be applied more than twice daily (i.e., three times daily (TID), four times daily (QID), etc.) for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, about 22 months, or about 24 months. In some embodiments, the pharmaceutical preparation can be topically applied to the scalp more than twice daily (i.e., TID, QID, etc.) for 6 months. In some embodiments, the pharmaceutical preparation can be topically applied to the scalp more than twice daily (i.e., TID, QID, etc.) for 12 months.

[0161] In another embodiment, the mode of administration of the pharmaceutical preparation can be cyclic. For example, the pharmaceutical preparation can be applied in a continuous manner as described above for a desired period of time, then application can be discontinued for a period of time, e.g., a few days, and then application of the pharmaceutical preparation can be resumed as described above. A treatment period can include one or more cycles that are the same or different. In some embodiments, a treatment period can be as follows: a) the pharmaceutical preparation can be topically applied to the scalp by continuous administration for a period of time, e.g., 4 months, b) application can be discontinued for a few days (e.g., 2 to 5 days), and 3) topical application can be continued for another period of time, e.g., 6 months.

[0162] In some embodiments, the mode of administration can be periodic, in which the epitiostanol- 17a-propionate and minoxidil can be co-administered sequentially. For example, a pharmaceutical formulation comprising epitiostanol- 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 epitiostanol- 17a-propionate can be administered second. The period of time between the administration of the first pharmaceutical composition and the administration of the second pharmaceutical composition can be any suitable period of time. For example, the time between each administration can be on the order of seconds, minutes, hours, or days, as desired. In some embodiments, the 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, the 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, the 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, the administration of the first and second pharmaceutical compositions can be separated by weeks (e.g., about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks).

[0163] In some embodiments, a first pharmaceutical formulation comprising epitiostanol- 17a-propionate or minoxidil can be administered for a first period of time, where the first period of time can be on the order of days or weeks. During the first period of time, the first pharmaceutical formulation can be administered to the skin or scalp multiple times as described herein, and then a second pharmaceutical formulation comprising the other active agent can be administered for a second period of time. Similar to the first period of time, the second period of time can be on the order of days or weeks. For example, a first pharmaceutical formulation comprising epitiostanol- 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 administration of the first and second pharmaceutical formulations (e.g., cycle administration of the first and second pharmaceutical formulations) for a given period of time to achieve treatment.

[0164] An "effective amount" of each active agent is an amount that provides the desired outcome (e.g., induction of hair growth and / or regrowth). In some embodiments, a pharmaceutical preparation can include between about 0.1% and about 20% by weight of the concentration of the cortexolone-17a-propionate, minoxidil, or both active agents. For example, a pharmaceutical preparation can include the cortexolone-17a-propionate, minoxidil, or both active agents at a concentration of about 0.1% or more (e.g., about 0.2% or more, about 0.3% or more, about 0.4% or more, about 0.5% or more, about 0.6% or more, about 0.7% or more, about 0.8% or more, about 0.9% or more, about 1% or more, about 1.2% or more, about 1.4% or more, about 1.6% or more, about 1.8% or more, about 2% or more, about 2.2% or more, about 2.4% or more, about 2.6% or more, about 2.8% or more, about 3% or more, about 3.2% or more, about 3.4% or more, about 3.6% or more, about 3.8% or more, about 4% or more, about 4.2% or more, about 4.4% or more, about 4.6% or more, about 4.8% or more, about 5% or more, about 5.2% or more, about 5.4% or more, about 5.6% or more, about 5.8% or more, about 6% or more, about 6.2% or more, about 6.4% or more, about 6.6% or more, about 6.8% or more, about 7% or more, about 7.2% or more, about 7.4% or more, about 7.6% or more, about 7.8% or more, about 8% or more, about 8.2% or more, about 8.4% or more, about 8.6% or more, about 8.8% or more, about 9% or more, about 9.2% or more, about 9.4% or more, about 9.6% or more, about 9.8% or more, about 10% or more, about 10.5% or more, about 11% or more, about 11.5% or more, about 12% or more, about 12.5% or more, about 13% or more, about 13.5% or more, about 14% or more, about 14.5% or more, about 15% or more, about 15.5% or more, about 16% or more, about 16.5% or more, about 17% or more, about 17.5% or more, about 18% or more, about 18.5% or more, about 19% or more, about 19.5% or more, or about 20% or less (e.g., about 19.5% or less, about 19% or less, about 18.5% or less, about 18% or less, about 17.5% or less, about 17% or less, about 16.5% or less, about 16% or less, about 15.5% or less, about 15% or less, about 14.5% or less, about 14% or less, about 13.5% or less, about 13% or less, about 12.5% or less, about 12% or less, about 11.5% or less, about 11% or less, about 10.5% or less, about 10% or less, about 9.5% or less, about 9% or less, about 8.5% or less, about 8% or less, about 7.5% or less, about 7% or less, about 6.5% or less, about 6% or less, about 5.8% or less, about 5.6% or less, about 5.4% or less, about 5.2% or less, about 5% or less, about 4.8% or less, about 4.6% or less, about 4.4% or less, about 4.2% or less, about 4% or less, about 3.8% or less, about 3.6% or less, about 3.4% or less, about 3.2% or less, about 3% or less, about 2.8% or less, about 2.6% or less, about 2.4% or less, about 2.2% or less, about 2% or less, about 1.8% or less, about 1.6% or less, about 1.4% or less, about 1.2% or less, about 1% or less, about 0.9% or less, about 0.8% or less, about 0.7% or less, about 0.6% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, or about 0.2% or less. In some preferred embodiments, the pharmaceutical formulation can comprise a concentration of epitiostanol-17a-propionate, minoxidil, or both active agents of about 0.5% to about 18%, or about 1% to about 15%, or about 1.5% to about 15%, or about 2% to about 12%, or about 2.5% to about 10%, or about 2.5% to about 8%, or about 3% to about 7% by weight.

[0165] In some embodiments, the pharmaceutical formulation can comprise a concentration of epitiostanol-17a-propionate of about 1% to about 20% by weight. In some embodiments, the pharmaceutical formulation can comprise a concentration of minoxidil of about 0.1% to about 20% by weight. In some embodiments, the pharmaceutical formulation can be a solution that can comprise a concentration of epitiostanol-17a-propionate of about 1% to about 20% by weight and a concentration of minoxidil of about 0.1% to about 20% by weight. In some preferred embodiments, the pharmaceutical formulation can be a solution that can comprise about 5% epitiostanol-17a-propionate and about 5% minoxidil by weight.

[0166] In some embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 400 mg. In other embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 350 mg. In other embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 300 mg. In other embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 250 mg.

[0167] In some embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 200 mg. In other embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 170 mg. In other embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 150 mg. In some embodiments, the amount of corticosterone- 17a-propionate in a single application can be about 20 mg to about 100 mg. In some embodiments, the amount of corticosterone- 17a-propionate 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 corticosterone- 17a-propionate in a single application can be about 25 mg. In another embodiment, the amount of corticosterone- 17a-propionate in a single application can be about 30 mg. In another embodiment, the amount of corticosterone- 17a-propionate in a single application can be about 50 mg. In another embodiment, the amount of corticosterone- 17a-propionate in a single application can be about 75 mg. In another embodiment, the amount of corticosterone- 17a-propionate in a single application can be about 80 mg. In another embodiment, the amount of corticosterone- 17a-propionate in a single application can be about 100 mg. In other embodiments, the amount of corticosterone- 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 another embodiment, the amount of corticosterone- 17a-propionate in a single application can be about 150 mg.

[0168] In some embodiments, the amount of minoxidil applied in a single application can be about 2 mg to about 20 mg. In other embodiments, the amount of minoxidil applied in a single application can be about 2 mg to about 15 mg. In other embodiments, the amount of minoxidil applied in a single application can be about 2 mg to about 10 mg. In other embodiments, the amount of minoxidil applied in a single application can be about 2 mg to about 5 mg.

[0169] In some embodiments, the pharmaceutical preparation can be self-administered by the subject once daily or twice daily. In some embodiments, when the pharmaceutical preparation can be in a liquid form having a concentration of about 5% by weight of the cortexolone-17a-propionate and a concentration of about 5% by weight of minoxidil, the pharmaceutical preparation can be self-administered in a dosage of about 0.2 ml to about 2.0 ml, about 0.5 ml to about 1.5 ml, and in some further embodiments about 1 mL or about 1.5 mL once daily or twice daily.

[0170] In some embodiments, when the pharmaceutical preparation can be in a liquid form having a concentration of about 2.5% by weight of the cortexolone-17a-propionate and a concentration of about 2% by weight of minoxidil, the pharmaceutical preparation can be self-administered in a dosage of about 0.2 to about 2.0 ml, about 0.5 to about 1.5 ml, and in some further embodiments about 1 mL or about 1.5 mL once daily or twice daily.

[0171] In some embodiments, when the pharmaceutical preparation can be in a liquid form having a concentration of about 3% by weight of the cortexolone-17a-propionate and a concentration of about 3% by weight of minoxidil, the pharmaceutical preparation can be self-administered in a dosage of about 0.2 to about 2.0 ml, about 0.5 to about 1.5 ml, and in some further embodiments about 1 mL or about 1.5 mL once daily or twice daily.

[0172] In some embodiments, when the pharmaceutical preparation can be in a liquid form having a concentration of about 7.5% by weight of the cortexolone-17a-propionate and a concentration of about 1.5% by weight of minoxidil, the pharmaceutical preparation can be self-administered in a dosage of about 0.2 to about 2.0 ml, about 0.5 to about 1.5 ml, and in some further embodiments about 1 mL or about 1.5 mL once daily or twice daily.

[0173] The pharmaceutical preparations described herein can be applied to any body surface in need of treatment, such as an area of skin susceptible to inducing hair growth. Suitable areas of skin include, for example, the scalp, the face (e.g., the eyebrows, the eyelashes, the upper lip, the lower lip, the chin, the cheeks, the mustache area, or the beard area), the arms, the armpits, the legs, the chest, the abdomen, or any combination of the foregoing. In some embodiments, treatment is not delivered to the face. In other embodiments, the pharmaceutical preparation can be applied to the scalp.

[0174] Kit

[0175] The present disclosure also provides kits comprising one or more of the various forms of topical pharmaceutical formulations as described herein. The kit can contain one or more liquid or semi-solid formulations suitable for administration. The kit can also comprise an administration device for use by one of skill in the art, such as a dropper, pipette, or injection device (e.g., manually or electronically driven). The kit can also comprise instructions for preparing and administering one or more of the pharmaceutical formulations. The instructions can be in a variety of forms, such as a printout, diskette, tape, optical disk, flash memory, or other medium suitable for communicating the appropriate information.

[0176] In some embodiments, the kit can comprise a pharmaceutical formulation comprising corticosterone-17a-propionate as a first component and a pharmaceutical formulation comprising minoxidil as a second component. The kit can also comprise instructions for use of the first and second components. In some embodiments, the first and second components can be combined just prior to use (e.g., within 1 hour prior to use, within 45 minutes prior to use, within 30 minutes prior to use, within 20 minutes prior to use, within 15 minutes prior to use, within 10 minutes prior to use, or within 5 minutes prior to 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.

[0177] In some embodiments, the kit can comprise corticosterone-17a-propionate in solid form as a first component and a pharmaceutical formulation comprising minoxidil as a second component. The kit can also comprise instructions for use of the first and second components. In some embodiments, the corticosterone-17a-propionate in solid form can be a powder, a fast-dissolving tablet, a granule, a granulate, or the like. Preferably, the corticosterone-17a-propionate is in powder form. In some embodiments, the corticosterone-17a-propionate in solid form can be stored separately from the container comprising the pharmaceutical formulation comprising minoxidil. In some such embodiments, the corticosterone-17a-propionate in solid form can be stored in a capped vial or a closed bottle.

[0178] In some embodiments, the solid form of corticosterone-17a-propionate can be stored within the same container as the pharmaceutical formulation containing minoxidil. According to some such embodiments, the solid form of corticosterone-17a-propionate can be stored in a component of the container containing the pharmaceutical formulation containing minoxidil that is designed to prevent contact between the two active agents. In some embodiments, the component of the container designed to prevent contact between the solid form of corticosterone-17a-propionate and the pharmaceutical formulation containing minoxidil can be a cap containing a storage chamber for solid material (e.g., a reservoir cap), or a chamber separate from the main chamber containing the pharmaceutical formulation containing minoxidil. In some embodiments, the container containing the pharmaceutical formulation containing minoxidil can be capped with a reservoir cap containing the solid form of corticosterone-17a-propionate equipped with a cutting device activated by the subject pushing, twisting, or pulling the cap itself. According to some such embodiments, activating the cutting device in the reservoir cap allows the solid form of corticosterone-17a-propionate to come into contact with the pharmaceutical formulation containing minoxidil.

[0179] In some embodiments, the first component and the second component can be combined just prior to use (e.g., within 1 hour prior to use, within 45 minutes prior to use, within 30 minutes prior to use, within 20 minutes prior to use, within 15 minutes prior to use, within 10 minutes prior to use, or within 5 minutes prior to use) and applied to the skin or scalp as a single combined preparation. 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 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.

[0180] In some embodiments, the kit can comprise a solid form of minoxidil as the first component and a pharmaceutical formulation containing corticosterone-17a-propionate as the second component. The kit can further comprise instructions for using the first component and the second component. In some embodiments, the solid form of minoxidil can be a powder, a fast-dissolving tablet, a granule, a granular material, or the like. In some embodiments, the solid form of minoxidil can be stored separately from the container containing the pharmaceutical formulation containing corticosterone-17a-propionate. In some such embodiments, the solid form of minoxidil can be stored in a capped vial or a closed bottle.

[0181] In some embodiments, the solid form of minoxidil can be stored within the same container as the pharmaceutical formulation comprising corticosterone-17a-propionate. According to some such embodiments, the solid form of minoxidil can be stored as a component of the container comprising the pharmaceutical formulation comprising corticosterone-17a-propionate, which component is designed to prevent contact between the two. In some embodiments, the component of the container designed to prevent contact between the solid form of minoxidil and the pharmaceutical formulation comprising corticosterone-17a-propionate can be a cap comprising a storage chamber for the solid substance (e.g., a reservoir cap), or a chamber separate from the main chamber comprising the pharmaceutical formulation comprising corticosterone-17a-propionate. In some embodiments, the container comprising the pharmaceutical formulation comprising corticosterone-17a-propionate can be capped with a reservoir cap containing the solid form of minoxidil, which reservoir cap is equipped with a cutting device activated by the subject pushing, twisting, or pulling the cap itself. According to some such embodiments, activation of the cutting device in the reservoir cap allows the solid form of minoxidil to come into contact with the pharmaceutical formulation comprising corticosterone-17a-propionate. In some embodiments, the first component and the second component can be combined just prior to use (e.g., within 1 hour prior to use, within 45 minutes prior to use, within 30 minutes prior to use, within 20 minutes prior to use, within 15 minutes prior to use, within 10 minutes prior to use, or within 5 minutes prior to use) and applied to the skin or scalp as a single combined preparation. In some embodiments, the first component can be a solid form and the second component can be a solution. In some embodiments, the first component can be a solid form and the second component can be a gel. In some embodiments, the first component can be a solid form and the second component can be a cream. In some embodiments, the first component can be a solid form and the second component can be a foam.

[0182] Storage stability

[0183] Storage stability is an important measure of a pharmaceutical product. Generally speaking, higher stability means that a given formulation is easier to both ship and store, increasing the likelihood that a pharmacy will stock the formulation, and that a subject does not have to worry about special storage instructions. In some embodiments, the pharmaceutical formulations described herein can have a desirable stability profile, allowing the final formulation to be stored at room temperature (about 20°C) or refrigerated temperature (e.g., about 4°C) 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.

[0184] For example, one of the major degradation pathways of corticosterone-17a-propionate is transesterification to corticosterone-21-propionate (17a-hydroxy-21-propionyloxy-pregna-4- ene-3,20-dione):

[0185] .

[0186] 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, from about 4 to about 7, from about 4 to about 6.5, from about 4 to about 6, from about 4 to about 5.5, from about 4 to about 5, from about 4 to about 4.5, or about 6.5, about 6, about 5.5, about 5, about 4.5, or about 4), can slow the degradation process. In some embodiments, the pH can be about 4. An appropriate pH can be obtained by adding a suitable amount of a pH adjusting agent, such as an acid described herein.

[0187] In some embodiments, the pharmaceutical formulations described herein can have less than about 5% by weight of the compound of Formula (I) or other degradation products after storage at room temperature (about 20°C) or refrigerated (e.g., about 4°C) temperature for a period of about 24 months. BRIEF DESCRIPTION OF DRAWINGS

[0189] Figure 1 Concentration of IL-6 in human Hair Follicle Dermal Papilla cell (HFDPC) cell cultures after 24 hours of drug treatment.

[0190] Figure 2 Side-by-side comparison of IL-6 concentration in HFDPC for Clascoterone + DHT group versus Clascoterone + DHT + Minoxidil group.

[0191] EMBODIMENT

[0192] The pharmaceutical formulations described herein are now described in further detail with reference to the following examples. These examples are provided for illustrative purposes only, and the embodiments described herein should not be construed as being limited to these examples. Rather, these embodiments should be construed to encompass any and all variations that become apparent as a result of the teachings provided herein.

[0193] Example 1: Anhydrous 5% w / w Clascoterone-17a-propionate solution

[0194] A 5% by weight (w / w) clascoterone-17a-propionate solution having the components shown in Table 1 below was prepared by dissolving the active agent in a solvent mixture followed by the addition of an emulsifier (polysorbate 80).

[0195] Table 1

[0196]

[0197] The stability profile (40°C and 75% relative humidity (RH)) provided by this formulation is shown in Table 2.

[0198] Table 2

[0199] The content of corticosterone-21 -propionate was calculated as follows: (% (w / w) of corticosterone-21 -propionate) / (% (w / w) of corticosterone-17a-propionate x 100).

[0200] Example 2: 5% w / w minoxidil foam

[0201] A 5% w / w minoxidil foam having the components shown in Table 3 can be prepared.

[0202] Table 3

[0203]

[0204] q.s.: quantity sufficient.

[0205] Example 3: 5% w / w minoxidil solution

[0206] A 5% w / w minoxidil solution having the components shown in Table 4 can be prepared.

[0207] Table 4

[0208]

[0209] The ethanol and propylene glycol are mixed and heated to 60°C to 70°C; once the temperature is within the above range (60°C to 70°C), the minoxidil is added and the mixture is kept under stirring until the minoxidil is completely dissolved. Thereafter, the water is slowly added to the mixture under stirring and the temperature is maintained at 60°C to 70°C until the final weight is reached. Thereafter, the mixture is slowly cooled to room temperature under stirring.

[0210] Example 4: Solution of minoxidil (2.5% w / w) and corticosterone-17a-propionate (2.5% w / w)

[0211] A solution of minoxidil (2.5% w / w) and corticosterone-17a-propionate (2.5% w / w) having the components shown in Table 5 can be prepared.

[0212] Table 5

[0213]

[0214] Ethanol and propylene glycol are mixed and heated to 60°C to 70°C; once the temperature is within the above range (60°C to 70°C), minoxidil is added and the mixture is kept under stirring until minoxidil is completely dissolved. Then, the hydrocortisone-17a-propionate is added and the mixture is kept under stirring until minoxidil is completely dissolved. After that, water is slowly added to the mixture under stirring and the temperature is kept at 60°C to 70°C until the final weight is reached. After that, the mixture is slowly cooled to room temperature under stirring.

[0215] Example 5: Kit comprising a solution of minoxidil (5.0% w / w) and hydrocortisone-17a-propionate in solid form

[0216] A 5% by weight (w / w) minoxidil solution with the components shown in Table 6 can be prepared.

[0217] Table 6

[0218]

[0219] Ethanol and propylene glycol are mixed and heated to 60°C to 70°C; once the temperature is within the above range (60°C to 70°C), minoxidil is added and the mixture is kept under stirring until minoxidil is completely dissolved. After that, water is slowly added to the mixture under stirring and the temperature is kept at 60°C to 70°C until the final weight is reached. After that, the mixture is slowly cooled to room temperature under stirring. The solution containing minoxidil is then filled in 60 mL glass bottles. The hydrocortisone-17a-propionate in powder form is filled in storage containers with reservoir caps (about 3 g per cap). The 60 mL bottles containing the solution of minoxidil are then capped with the reservoir caps filled with the hydrocortisone-17a-propionate powder.

[0220] Example 6: Kit containing a solution of hydrocortisone-17a-propionate (5.0% w / w) and minoxidil in solid form

[0221] A 5% by weight (w / w) hydrocortisone-17a-propionate solution with the components shown in Table 7 can be prepared.

[0222] Table 7

[0223]

[0224] A 5% by weight (w / w) solution of cortexolone-17a-propionate was prepared by dissolving the active agent in a solvent mixture followed by the addition of an emulsifier (polysorbate 80) with the components shown in Table 7. The solution containing cortexolone-17a-propionate was then filled in a 60 mL glass bottle. The minoxidil in powder form was filled into a storage container with a reservoir cap (about 3 g per cap). The 60 mL bottle containing the cortexolone-17a-propionate solution was then capped with the reservoir cap filled with the minoxidil powder.

[0225] Example 7. Combination treatment of clascoterone and minoxidil synergistically inhibits IL-6 secretion in human hair follicle dermal papilla cells (HFDPCs)

[0226] Clascoterone is a potent antiandrogen that blocks the action of androgen receptors in human hair follicles. It exhibits clinically meaningful efficacy when topically applied in AGA. Part of its mechanism of action is to suppress androgen-induced IL-6 secretion by HFDPCs, and this reduces IL-6-induced hair follicle damage. Thus, IL-6 secretion by these cells is a relevant efficacy biomarker related to hair growth.

[0227] Minoxidil is a K ATP channel modulator that exhibits topical efficacy in AGA. There are no reports on its effect on IL-6 secretion in HFDPCs.

[0228] In this study, the combination of clascoterone with minoxidil was superior to expected in inhibiting IL-6 secretion by HFDPCs. That is, the efficacy of the combination was greater than the sum of the efficacy of each agent alone.

[0229] The results indicate that the synergistic combination of topical clascoterone and topical minoxidil should provide significantly improved efficacy when used in AGA patients.

[0230] BACKGROUND

[0231] The majority of the hair follicle is composed of keratinocytes, which are epithelial cells that include the hair shaft itself as well as the surrounding inner and outer root sheaths. However, a specialized mesenchymal population, the dermal papilla (DP), plays a key role in directing the activities of these keratinocytes to form the hair follicle and generate the hair shaft (Greco et al. 2009). Active communication between the DP or its precursors and the epithelial compartments regulates many aspects of hair follicle biology. The DP influences the size and shape of the hair shaft by producing signals that act on the keratinocytes.

[0232] In androgenetic alopecia, the reduction in size of hair follicles associated with progressive hair thinning and loss includes the inability to maintain DP cell function (Elliott et al. 1999). Several observations suggest that this is caused by a primary defect in the DP. In male pattern baldness, one of the key paracrine factors produced by the bald DP cells is the cytokine IL-6.

[0233] IL-6 is upregulated in bald DP cells in response to dihydrotestosterone (DHT) compared to non-bald DP cells (Kwack et al. 2012); IL-6 receptor is expressed in hair follicle keratinocytes, including matrix cells. Recombinant human IL-6 (rhIL-6) inhibits the elongation of the hair shaft and the proliferation of matrix cells in cultured human hair follicles. Furthermore, injection of rhIL-6 into the lower skin of mice during the anagen phase (hair growth phase) leads to the premature appearance of catagen phase (growth inhibition). Thus, DHT-induced IL-6 acts as a paracrine mediator of DP to inhibit hair growth (Kwack et al. 2012).

[0234] There are three classes of drugs that are effective in preventing the progression of hair loss: antiandrogens (e.g. cyproterone), 5-alpha reductase type 2 inhibitors (e.g. finasteride) and K ATP channel openers (e.g. minoxidil). These compounds act on DP cells in cell culture or isolated hair follicles (Kaufman et al. 1998; Randall 2008; Shorter et al. 2008).

[0235] It has been shown that cyproterone can inhibit DHT-induced IL-6 expression in dermal papilla cells (Rosette et al. 2019). However, it is not known whether minoxidil can modulate IL-6 expression in DP cells, or whether a combination of cyproterone and minoxidil can show better efficacy than either agent alone.

[0236] Experimental Section

[0237] Cell lines

[0238] Human follicular dermal papilla cells (HFDPCs) from the vertex region of the human scalp were obtained from Cell Applications (San Diego, CA). Cells were proliferated in complete follicular dermal papilla cell basal medium (Cell Applications, San Diego, CA) and 10% fetal bovine serum (Gibco, Gaithersburg, MD). All flasks and plates used were coated with collagen. Collagen was obtained from Cell Applications (San Diego, CA) and used according to the manufacturer's instructions. For analysis of IL-6 secretion, cells were trypsinized and seeded (2 × 10⁶ cells / year). 5 Cells (1 cell / well) were added to collagen-coated 24-well plates containing basal medium for dermal papilla cells of hair follicle and 5% carbon-dextran filtered serum (DCC-FBS) (Omega Scientific, Tarzana, CA) and incubated overnight. Experiments were performed in triplicate in the wells. The next day, the medium was removed, and fresh basal medium containing the compound and DHT + 5% DCC-FBS was added, followed by incubation for 24 hours. All cell cultures were performed at 37°C and 5% CO2. The concentrations of the compound used in these experiments were determined to have no significant effect on cell proliferation (data not shown).

[0239] Compounds

[0240] Clastatin (CB0301) was custom-synthesized by Cosmo Pharmaceutical (Lainate, Italy). Dihydrotestosterone (DHT) was obtained from Millipore-Sigma (Saint Louis, MO), and minoxidil from VWR (San Diego, CA). All compounds were dissolved in 100% DMSO and subsequently diluted in HFDP basal medium + 5% DCC-FBS for cell culture experiments. The final concentration of DMSO in each well was 0.1%.

[0241] IL-6 protein expression was quantified by ELISA

[0242] Dermal papilla cells were treated with various concentrations of DHT, clascoterone, and minoxidil. Compounds were added to the wells at the same time (no pre-incubation). After 24 hours of culture, the medium in each well was collected and immediately used to determine secreted IL-6. Human IL-6 ELISA detection kit was from Invitrogen (San Diego, CA) and used according to the manufacturer’s instructions. Absorbance was quantified on a ClarioStar microplate reader (Ortenberg, Germany) and data analyzed in Prism software version 10.1.1 (GraphPad, La Jolla, CA).

[0243] Results

[0244] Figure 1 Incubation of HFDPC with 100 nM DHT for 24 hours resulted in a significant increase in IL-6 secretion compared to 0.1% DMSO used as a control (47.5 pg / mL vs. 39.2 pg / mL; p<0.004). Minoxidil at a concentration of 1 uM only slightly decreased IL-6 secretion by 7% in the presence of DHT (47.5 pg / mL to 44.3 pg / mL).

[0245] Clascoterone dose-dependently inhibited IL-6 secretion at 24 hours in the presence of 100 nM DHT. Importantly, the combination of 1 uM minoxidil with clascoterone at a dose of 15 nM or 30 nM exhibited an unexpected synergistic effect resulting in a significantly stronger inhibition of IL-6 secretion compared to clascoterone treatment alone. The 60 nM clascoterone group also exhibited a synergistic effect, but not statistically significant.

[0246] All clascoterone treatment groups showed a statistically significant inhibition of IL-6 secretion relative to 100 nM DHT. Table 8 lists the concentration of IL-6 and the relative inhibition of the compounds under each treatment condition.

[0247] Table 8. Mean and standard deviation of IL-6 concentration and relative inhibition of the compounds in each experimental treatment group.

[0248]

[0249] As Figure 2 shown when comparing the effect of clascoterone + DHT to clascoterone + DHT + minoxidil, the clascoterone treatment group containing 1 uM minoxidil showed more than additive effects. That is, all clascoterone concentrations had a synergistic inhibition of IL-6 in HFDPC when combined with 1 uM minoxidil.

[0250] The predicted additive effect of spironolactone in combination with minoxidil and the actual observed combined effect are listed in Table 9. This also includes the p value from the ANOVA statistical analysis comparing the mean of the spironolactone + DHT group to the spironolactone + DHT + minoxidil group.

[0251] Table 9. Predicted additive effect of (spironolactone + DHT) + (minoxidil + DHT) vs. observed combined effect, and statistical p value analysis of spironolactone vs. mean of spironolactone + minoxidil treatment groups.

[0252]

[0253] The 15 nM spironolactone + DHT group showed 16% inhibition relative to DHT alone, and the 1 μM minoxidil + DHT group showed 7% inhibition relative to DHT alone. Therefore, the additive effect should provide 23% (16% + 7%) inhibition. However, the observed inhibition of the combination of spironolactone + DHT + minoxidil was 34%, greater than 23%, indicating a synergistic inhibition between spironolactone and minoxidil when used in combination. The combination treatment was significantly different (p < 0.009) compared to spironolactone + DHT.

[0254] The 30 nM spironolactone group showed 19% inhibition relative to DHT alone, and the 1 μM minoxidil group showed 7% inhibition relative to DHT alone. Therefore, the additive effect should provide 26% (19% + 9%) inhibition, however, a greater combined inhibition was observed, 36%, indicating a synergistic inhibition between spironolactone and minoxidil when used in combination. The combination treatment (spironolactone + DHT + minoxidil) was significantly different (p < 0.003) compared to spironolactone + DHT.

[0255] The 60 nM spironolactone group showed 34% inhibition relative to DHT alone, and the 1 μM minoxidil group showed 7% inhibition relative to DHT alone. Therefore, the additive effect should provide 41% (34% + 7%) inhibition. A greater combined inhibition was observed, 43%, which can indicate a synergistic inhibition. However, this difference was not significant (p < 0.7).

[0256] CONCLUSIONS

[0257] Human dermal papilla cells respond to DHT to activate the androgen receptor. IL-6 is a key negative regulator of hair growth and has been shown to be elevated in balding scalp hair follicles relative to non-balding scalp hair follicles. Cyproterone is a potent anti-androgen and has shown clinical efficacy in androgenetic alopecia patients for improving hair growth. Cyproterone has previously been shown to inhibit DHT-induced IL-6 secretion in human dermal papilla cells. Thus, IL-6 is a HFDPC biomarker associated with hair growth.

[0258] Minoxidil is also approved for the treatment of androgenetic alopecia, but there is no information in the literature about its effect on IL-6 secretion by dermal papilla cells. In the experimental data shown, minoxidil showed a slight, non-significant inhibition of IL-6 secretion by HFDPC. Cyproterone showed statistically significant inhibition of IL-6 at all concentrations tested compared to DHT-treated HFDPC. The comparison of cyproterone + DHT to cyproterone + DHT + minoxidil showed that the combination was more than additive. In fact, the combination of cyproterone with minoxidil showed a synergistic efficacy in inhibiting IL-6 secretion by HFDPC.

[0259] Thus, it is clear that androgenetic alopecia patients should significantly benefit from the combination treatment of cyproterone plus minoxidil.

[0260] The phraseology or terminology used herein is for the purpose of description and not of limitation. Thus, the terminology and / or phraseology employed herein, as would be understood by those skilled in the art, is intended to be interpreted broadly.

[0261] The breadth and scope of the present application should not be limited by any of the above-described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents.

[0262] All patents, patent applications, and other references mentioned in or cited by this application are incorporated by reference in their entireties.

[0263] REFERENCES

[0264]

Claims

1. A method for treating hair loss in a subject with this need, comprising applying to the surface of the subject an effective amount of corticosterone-17α-propionate and an effective amount of minoxidil.

2. The method of claim 1, wherein corticosterone-17α-propionate is co-administered in an amount of at least 1% by weight to about 20% by weight.

3. The method of claim 1, wherein minoxidil is co-administered in an amount of about 0.1% by weight to about 20% by weight.

4. The method of any one of claims 1 to 3, wherein the corticosterone-17α-propionate and minoxidil are sequentially co-administered.

5. The method of claim 4, wherein the corticosterone-17α-propionate and minoxidil are in separate pharmaceutical formulations.

6. The method of any one of claims 1 to 3, wherein the corticosterone-17α-propionate and minoxidil are administered simultaneously.

7. The method of claim 6, wherein corticosterone-17α-propionate and minoxidil are in the same pharmaceutical formulation.

8. The method of claim 7, wherein the pharmaceutical preparation is a liquid or semi-solid preparation.

9. The method of claim 7 or 8, wherein the pharmaceutical preparation is a solution, suspension, emulsion, microemulsion, cream, paste, gel, ointment, or foam.

10. The method of any one of claims 7 to 9, wherein the pharmaceutical preparation is a solution.

11. The method of claim 10, wherein the solution comprises water, brine, buffered salt solution, polyol, polyol ether, C1-C7 alcohol, or a combination thereof.

12. The method of any one of claims 7 to 11, wherein the pharmaceutical formulation further comprises at least one additive selected from the group consisting of acids, buffers, antioxidants, emulsifiers, penetration enhancers, humectants, preservatives, chelating agents, and combinations thereof.

13. The method of any one of claims 1 to 12, wherein the corticosterone-17α-propionate is administered in a pharmaceutical formulation comprising less than about 5% by weight of water.

14. The method of any one of claims 1 to 13, wherein the pharmaceutical preparation is applied topically once or twice daily.

15. The method of any one of claims 1 to 14, wherein the hair loss is hair loss.

16. The method of claim 15, wherein the hair loss is androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination thereof.

17. The method of claim 16, wherein the alopecia areata is selected from diffuse alopecia areata, unifocal alopecia areata, multifocal alopecia areata, serpentine alopecia areata, total alopecia and universal alopecia.

18. The method of claim 16, wherein the hair loss is androgenetic alopecia.

19. A surface pharmaceutical preparation comprising corticosterone-17α-propionate, minoxidil, and one or more pharmaceutically acceptable carriers.

20. The surface pharmaceutical formulation of claim 19, wherein the corticosterone-17α-propionate is completely dissolved in the pharmaceutical formulation.

21. The surface pharmaceutical formulation of claim 19 or 20, wherein the pharmaceutical formulation comprises corticosterone-17α-propionate at a concentration of about 1% to about 20% by weight.

22. The surface pharmaceutical formulation of any one of claims 19 to 21, wherein the pharmaceutical formulation comprises minoxidil at a concentration of about 0.1% to about 20% by weight.

23. The surface pharmaceutical preparation of any one of claims 19 to 22, wherein the pharmaceutical preparation is a liquid or semi-solid preparation.

24. The surface pharmaceutical formulation of claim 23, wherein the liquid or semi-solid formulation is a solution, suspension, emulsion, microemulsion, cream, paste, gel, ointment, or foam.

25. The surface pharmaceutical formulation of claim 24, wherein the pharmaceutical formulation is a solution.

26. The surface pharmaceutical formulation of claim 24 or 25, wherein the solution comprises water, saline, buffered salt solution, or a combination thereof.

27. The surface pharmaceutical preparation of any one of claims 19 to 26, wherein the pharmaceutical preparation comprises less than about 5% water by weight.

28. The surface pharmaceutical formulation of any one of claims 19 to 27, wherein the one or more pharmaceutically acceptable carriers are selected from polyols, polyol ethers, and C1-C7 alcohols.

29. The surface pharmaceutical formulation of claim 28, wherein the C1-C7 alcohol is ethanol, isopropanol, methanol, or a combination thereof.

30. The surface pharmaceutical formulation of claim 29, wherein the C1-C7 alcohol is ethanol.

31. The surface pharmaceutical formulation of any one of claims 28 to 30, wherein the polyol is selected from ethylene glycol, propylene glycol, glycerol, hexanetriol, and combinations thereof.

32. The surface pharmaceutical formulation of claim 31, wherein the polyol is propylene glycol.

33. The surface pharmaceutical formulation of any one of claims 28 to 32, wherein the polyol ether is selected from polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether, and combinations thereof.

34. The surface pharmaceutical formulation of claim 33, wherein the polyol ether is diethylene glycol monoethyl ether.

35. The surface pharmaceutical formulation of any one of claims 28 to 34, wherein the polyol is propylene glycol, the polyol ether is diethylene glycol monoethyl ether, and the C1-C7 alcohol is ethanol.

36. The surface pharmaceutical formulation of any one of claims 19 to 35, wherein the pharmaceutical formulation further comprises at least one additive selected from the group consisting of acids, buffers, antioxidants, emulsifiers, penetration enhancers, humectants, preservatives, chelating agents, and combinations thereof.

37. The surface pharmaceutical formulation of claim 36, wherein the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, α-tocopherol, propyl gallate, 2,4,5-trihydroxyphenylbutanone, 4-hydroxymethyl-2,6-di-tert-butylphenol, isoascorbic acid, guaiacol, thiodipropionic acid, dilauryl thiodipropionic acid, tert-butylhydroquinone, pharmaceutically acceptable salts or esters thereof, and combinations thereof.

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

39. The surface pharmaceutical formulation of any one of claims 36 to 38, wherein the emulsifier is selected from PEG-15 hydroxystearate (polyethylene glycol-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbate 20, polysorbate 60, polysorbate 80, PEG-20 cetearyl alcohol ether, polyethylene glycol 25 cetearyl alcohol, polystearate Alcohol 1000, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, propylene glycol esters of fatty acids, polyglycerol esters of fatty acids, polyethylene glycol 5 castor oil, polyethylene glycol 15 castor oil, polyethylene glycol 35 castor oil, polyethylene glycol 40 hydrogenated castor oil, capryloyl capryloyl polyethylene glycol-8 glycerol ester, capryloyl hexanoyl polyoxyglycerol ester, lauroyl polyoxyglycerol ester, oleoyl polyoxyglycerol ester, and combinations thereof.

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

41. The surface pharmaceutical formulation of any one of claims 36 to 40, wherein the penetration enhancer is selected from glycols, polyols, fatty acids, fatty alcohols, fatty acid esters, surfactants, pyrrolidones, and combinations thereof.

42. The surface pharmaceutical formulation of any one of claims 36 to 41, wherein the humectant is selected from fatty alcohols, fatty acids, fatty acid esters, oils, polyethylene glycol, glycerin, α-hydroxy acids, and combinations thereof.

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

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

45. A method for treating hair loss, the method comprising applying a surface pharmaceutical preparation of any one of claims 19 to 44 to a surface of a subject in need of hair loss, wherein surface application of the pharmaceutical preparation for at least six months achieves a weighted average hair growth assessment (HGA) score of about 0.30 compared to a carrier.

46. ​​A method for treating hair loss, the method comprising applying a surface pharmaceutical preparation of any one of claims 19 to 44 to the surface of a subject in need, wherein surface application of the pharmaceutical preparation for at least six months achieves a weighted average Investigator Global Assessment (IGA) score of about 0.43 compared to a carrier.

47. A method for treating hair loss, the method comprising applying to the surface of an object in need of hair loss any of claims 19 to 44, wherein the surface application of the pharmaceutical preparation is continued for at least six months without systemic anti-androgenic side effects.

48. A method for treating hair loss, the method comprising applying to a surface pharmaceutical preparation of any one of claims 19 to 44, wherein surface application of the pharmaceutical preparation provides: a) Six months after daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 9 hairs / cm². 2 ;or b) Six months after daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 10 hairs / cm². 2 ;or c) Six months after daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 11 hairs / cm². 2 ;or d) After 6 months of daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 12 hairs / cm. 2 ;or e) After 6 months of daily or BID application, the weighted average HGA score is equal to or greater than 0.20; or f) After 6 months of daily or BID application, the weighted average HGA score is equal to or greater than 0.30; or g) After 6 months of daily or BID application, the weighted average HGA score is equal to or greater than 0.40; or h) After 6 months of daily or BID application, the weighted average IGA score is equal to or greater than 0.10; or i) After 6 months of daily or BID application, the weighted average IGA score is equal to or greater than 0.20; or j) After 6 months of daily or BID application, the weighted average IGA score is equal to or greater than 0.30; or k) After 6 months of daily or BID application, at least approximately 10% of subjects have a good (positive) HGA score; or l) After 6 months of daily or BID application, at least approximately 20% of subjects had a good (positive) HGA score; or m) After 6 months of daily or BID application, at least approximately 30% of subjects had a good (positive) HGA score; or n) After 6 months of daily or BID application, at least approximately 10% of subjects have a good (positive) IGA score; or o) After 6 months of daily or BID application, at least approximately 20% of subjects had a good (positive) IGA score; or p) After 6 months of daily or BID application, at least approximately 30% of subjects had a good (positive) IGA score; or q) After 6 months of daily or BID application, at least approximately 40% of the subjects had a good (positive) IGA score.

49. A combination of corticosterone-17α-propionate and minoxidil for treating hair loss in subjects with this need, characterized in that... They are applied to the object by the surface.

50. The application of corticosterone-17α-propionate and minoxidil according to claim 49, wherein corticosterone-17α-propionate is co-administered in an amount of at least 1% by weight to about 20% by weight.

51. The application of corticosterone-17α-propionate and minoxidil according to claim 49, wherein minoxidil is co-administered in an amount of about 0.1% by weight to about 20% by weight.

52. The application of corticosterone-17α-propionate and minoxidil according to any one of claims 49 to 51, wherein the corticosterone-17α-propionate and minoxidil are administered sequentially, preferably in separate pharmaceutical formulations.

53. The application of corticosterone-17α-propionate and minoxidil according to any one of claims 49 to 51, wherein the corticosterone-17α-propionate and minoxidil are administered simultaneously, preferably the corticosterone-17α-propionate and minoxidil are in the same pharmaceutical formulation.

54. The application of corticosterone-17α-propionate and minoxidil according to claim 53, wherein the pharmaceutical formulation is a liquid or semi-solid formulation, preferably a solution, suspension, emulsion, microemulsion, cream, paste, gel, ointment or foam, and more preferably a solution.

55. The corticosterone-17α-propionate and minoxidil of claim 54, wherein the solution comprises water, saline, buffered saline solution, polyol, polyol ether, C1-C7 alcohol, or a combination thereof.

56. The corticosterone-17α-propionate and minoxidil of any one of claims 54 to 55, wherein the pharmaceutical formulation further comprises at least one additive selected from the group consisting of acids, buffers, antioxidants, emulsifiers, penetration enhancers, humectants, preservatives, chelating agents, and combinations thereof.

57. The corticosterone-17α-propionate and minoxidil according to any one of claims 49 to 56, wherein the corticosterone-17α-propionate is administered in a pharmaceutical formulation comprising less than about 5% by weight of water.

58. The application of corticosterone-17α-propionate and minoxidil according to any one of claims 49 to 57, wherein the pharmaceutical formulation is applied topically once or twice daily.

59. The application of corticosterone-17α-propionate and minoxidil according to any one of claims 49 to 58, wherein the hair loss is alopecia, preferably androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia or any combination thereof, more preferably androgenetic alopecia.

60. The corticosterone-17α-propionate and minoxidil used according to claim 59, wherein the alopecia areata is selected from diffuse alopecia areata, unifocal alopecia areata, multifocal alopecia areata, serpentine alopecia areata, total alopecia and universal alopecia.

61. The surface pharmaceutical preparation according to any one of claims 19 to 44, wherein the preparation is used to treat hair loss in a subject in which such a need exists.

62. The surface pharmaceutical formulation of claim 61, wherein the hair loss is alopecia.

63. The surface pharmaceutical formulation according to claim 62, wherein the hair loss is androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination thereof.

64. The topical pharmaceutical formulation of claim 63, wherein the alopecia areata is selected from diffuse alopecia areata, unifocal alopecia areata, multifocal alopecia areata, serpentine alopecia areata, total alopecia and universal alopecia.

65. The surface pharmaceutical formulation of claim 62, wherein the hair loss is androgenetic alopecia.

66. A surface pharmaceutical formulation for the application of any one of claims 61 to 65, wherein surface application of the pharmaceutical formulation for at least six months achieves a weighted average hair growth assessment (HGA) score of about 0.30 compared to a carrier.

67. A surface pharmaceutical formulation for any of the applications of claims 61 to 65, wherein surface application of the pharmaceutical formulation for at least six months achieves a weighted average Investigator Global Assessment (IGA) score of approximately 0.43 compared to a carrier.

68. A surface pharmaceutical preparation according to any one of claims 61 to 67, wherein surface application of the pharmaceutical preparation for at least six months is free from systemic anti-androgen side effects.

69. A surface pharmaceutical formulation for any of the applications described in any one of claims 61 to 67, wherein surface application of the pharmaceutical formulation provides: a) Six months after daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 9 hairs / cm². 2 ;or b) Six months after daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 10 hairs / cm². 2 ;or c) Six months after daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 11 hairs / cm². 2 ;or d) After 6 months of daily or BID application, the mean change in hair count in the target area relative to baseline is equal to or greater than 12 hairs / cm. 2 ;or e) After 6 months of daily or BID application, the weighted average HGA score is equal to or greater than 0.20; or f) After 6 months of daily or BID application, the weighted average HGA score is equal to or greater than 0.30; or g) After 6 months of daily or BID application, the weighted average HGA score is equal to or greater than 0.40; or h) After 6 months of daily or BID application, the weighted average IGA score is equal to or greater than 0.10; or i) After 6 months of daily or BID application, the weighted average IGA score is equal to or greater than 0.20; or j) After 6 months of daily or BID application, the weighted average IGA score is equal to or greater than 0.30; or k) After 6 months of daily or BID application, at least approximately 10% of subjects have a good (positive) HGA score; or l) After 6 months of daily or BID application, at least approximately 20% of subjects had a good (positive) HGA score; or m) After 6 months of daily or BID application, at least approximately 30% of subjects had a good (positive) HGA score; or n) After 6 months of daily or BID application, at least approximately 10% of subjects have a good (positive) IGA score; or o) After 6 months of daily or BID application, at least approximately 20% of subjects had a good (positive) IGA score; or p) After 6 months of daily or BID application, at least approximately 30% of subjects had a good (positive) IGA score; or q) After 6 months of daily or BID application, at least approximately 40% of the subjects had a good (positive) IGA score.

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