Combination therapy of clacotelon and minoxidil for use in the treatment of hair loss.

Abstract

This disclosure provides a method for treating hair loss in a subject requiring treatment for hair loss, comprising topically administering an effective amount of cortexolone-17α-propionate and an effective amount of minoxidil to the subject. This disclosure further provides a topical pharmaceutical formulation comprising cortexolone-17α-propionate, minoxidil, and one or more pharmaceutically acceptable carriers.

Description

[Technical Field]

[0001] Alopecia is a group of disorders resulting from multiple different etiologies that cause hair loss from the body. The most common form of alopecia is androgenetic alopecia ("AGA"). AGA is also commonly known as androgenetic alopecia (alopecia androgenetica), male pattern baldness, or male-pattern or female-pattern hair loss. It is reported that nearly 50% of men over the age of 40 suffer from AGA. Ultimately, it is estimated that up to 80% of Caucasian men and about half of all women suffer from this form of alopecia by the age of 70. Hair loss is often a major concern for those affected for cosmetic and psychological reasons, but it can also be an important sign of a systemic disease. [Background technology]

[0002] Medical management of AGA (androgenetic alopecia) includes surgical treatment options, including hair transplantation. This procedure has been performed successfully for decades. Hair transplantation involves harvesting intact hair follicles from a safe donor area (SDA) on the patient's scalp, either through follicular unit strip surgery (FUSS) or follicular unit extraction (FUE). While the cosmetic results after surgery are often satisfactory, the procedure can only be performed if a sufficient quantity of donor plugs (or hair follicles) are available to cover (one or more) areas of baldness. Furthermore, hair transplantation is generally limited to patients who have experienced significant hair loss and whose AGA has not yet progressed. For example, hair transplantation is generally not recommended for younger patients because androgens, particularly dihydrotestosterone (DHT), can act on newly transplanted hair follicles, potentially causing the same thinning and eventual hair loss that would have affected the original hair follicles.

[0003] Given the shortcomings and limitations associated with surgical treatment options, pharmacological therapies for treating hair loss (including alopecia, particularly AGA) remain a need in this field. [Overview of the project]

[0004] Minoxidil, also known as 2,4-diamino-6-piperidinopyrimidine 3-oxide, is typically formulated as a topical medication for treating AGA (androgenetic alopecia) in two standard levels—2% (topical solution) and 5% (as a topical solution or topical foam). See, for example, U.S. Patent Nos. 4,596,812 and 6,946,120. These U.S. patents are incorporated herein by reference in their entirety. To exert its effects, minoxidil needs to be converted to its active metabolite, minoxidil sulfate, by the enzyme sulfotransferase. This enzyme is present in the outer root sheath of the growing hair follicle. Unfortunately, clinical trials have shown that topical application of a 2% minoxidil solution to patients experiencing hair loss stimulates dense hair regrowth in less than 5% of patients, and moderate hair regrowth in only about 30% of patients. For example, see E.A. Olsen, et al., "Topical Minoxidil in Early Male Pattern Baldness," Journal of the American Academy of Dermatology (J.Amer.Acad.Derm.) 13, 185-192 (1985) and J. Roberts, "Androgenetic Alopecia: Treatment with Topical Minoxidil," Journal of the American Academy of Dermatology (J.Amer.Acad.Derm.) 16(3) 705-710 (1987).

[0005] Cortexolone-17α-propionate, also known as 17α-propionyloxy-21-hydroxypregna-4-ene-3,20-dione and clascoterone, is a topical anti-androgenic agent that shuts out androgen hormones from binding to their receptors. Cortexolone-17α-propionate is known to be suitable for the treatment of acne, alopecia, and other diseases of the skin and skin appendages. See, for example, U.S. Patents 8,143,240 and 8,865,690, International Publications 2009 / 019138 and 2016 / 207778. This compound is also known to exist in several different crystalline polymorphs, each with unique properties. See, for example, U.S. Patent 8,785,427. Each of these patents is incorporated herein by reference in whole.

[0006] Surprisingly, we discovered that hair loss, including alopecia, can be effectively treated with a combination of cortexolone-17α-propionate and minoxidil. Surprisingly, in some embodiments, this combination yields synergistic effects that allow for a reduction in the effective amount of each active substance used for effective treatment, or a greater combined synergistic effect to be obtained using the same amount of each active substance. As a result of this combination therapy, beneficial clinical outcomes can be achieved after daily topical administration over an appropriate period, such as several days, weeks, or months.

[0007] Accordingly, this disclosure provides a method for treating hair loss in a subject requiring treatment for hair loss, comprising topically administering an effective amount of cortexolone-17α-propionate and an effective amount of minoxidil to the subject.

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

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

[0010] In some embodiments, the pharmaceutical formulation may be a liquid or semi-solid formulation. In further embodiments, the pharmaceutical formulation may be a solution, suspension, emulsion, microemulsion, cream, paste, gel, ointment, or foam. In further embodiments, the pharmaceutical formulation may be a solution. In some embodiments of the solution, the solution may comprise water, saline, buffered saline solution, polyol, polyol ether, C1-C7 alcohol, or a combination thereof.

[0011] In some embodiments of the above method, the pharmaceutical formulation may further contain at least one (e.g., one, two, three, four, five, six, seven, or eight) additives selected from the group consisting of acids, buffers, antioxidants, emulsifiers, penetration enhancers, humectants, preservatives, chelating agents, and combinations thereof. In some embodiments, the cortexolone-17α-propionate is co-administered as a pharmaceutical formulation containing less than about 5% by weight of water. In some embodiments, the cortexolone-17α-propionate and minoxidil are combined in the same pharmaceutical formulation containing less than about 5% by weight of water. In some embodiments, the pharmaceutical formulation is co-administered by topical application once or twice daily.

[0012] In some embodiments of the above method, the hair loss is alopecia. In some embodiments, the alopecia is male pattern baldness, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination thereof. In some embodiments, the alopecia areata is selected from the group consisting of diffuse alopecia areata, solitary alopecia areata, multiple alopecia areata, serpentine alopecia, alopecia totalis, and alopecia universalis. In some specific embodiments, the alopecia is male pattern baldness.

[0013] This disclosure further provides topical pharmaceutical formulations comprising cortexolone-17α-propionate, minoxidil, and one or more pharmaceutically acceptable carriers. In some embodiments, the cortexolone-17α-propionate is completely solubilized in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation contains cortexolone-17α-propionate in concentrations of about 1% to about 20% by weight (including about 2% to about 15% by weight, about 3% to about 10% by weight, or about 4% to about 7.5% by weight). In some embodiments, the pharmaceutical formulation contains cortexolone-17α-propionate in concentrations 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 contains minoxidil in concentrations ranging from about 0.1% to about 20% by weight (including about 2% to about 15% by weight, about 3% to about 10% by weight, and about 4% to about 7.5% by weight). In some embodiments, the pharmaceutical formulation contains minoxidil in concentrations ranging from about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 7.5% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight. In some embodiments, the pharmaceutical formulation contains a combination of cortexolone-17α-propionate and minoxidil in concentrations ranging from about 0.1% to about 20% by weight (including about 2% to about 15% by weight, about 3% to about 10% by weight, 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, suspension, emulsion, microemulsion, cream, paste, gel, ointment, or foam. In some embodiments, the pharmaceutical formulation is a solution. In some of these embodiments, the solution includes water, saline, buffered saline solution, or a combination thereof. In some embodiments, the pharmaceutical formulation contains less than about 5 percent by weight of water.

[0015] In some embodiments, the one or more pharmaceutically acceptable carriers are selected from the group consisting of polyols, polyol ethers, and C1-C7 alcohols. In some embodiments, the C1-C7 alcohol is ethanol, isopropanol, 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 triblock 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 additive (e.g., one, two, three, four, five, six, seven, or eight) selected from acids, buffers, antioxidants, emulsifiers, penetration enhancers, humectants, preservatives, chelating agents, and combinations thereof. In some embodiments, the buffer is a phosphate buffer, a citrate buffer, a lactic acid buffer, or a combination 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, guaiac resin, thiodipropionic acid, dilauryl thiodipropionate, tert-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 emulsifier is PEG-15 hydroxystearate (polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbate (e.g., polysorbate 20, polysorbate 60, polysorbate 80), PEG-20 cetostearyl ether, polyoxyl-25 cetostearyl, cetomacrogol 1000, sorbitan monolaurate, sorbitan monopalmitate The following are selected from the group consisting of castor oil, sorbitan monooleate, propylene glycol fatty acid ester, polyglycerin fatty acid ester, polyoxyl-5 castor oil, polyoxyl-15 castor oil, polyoxyl-35 castor oil, polyoxyl-40 hydrogenated castor oil, caprylocapryl polyoxyyl-8 glyceride, caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, oleoyl polyoxylglyceride, and combinations thereof.In some embodiments, the emulsifier is a polysorbate, such as 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 diols, 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 glycol, glycerin, alpha hydroxy acids, and combinations thereof. In some embodiments, 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.

[0017] In certain embodiments, the Disclosure provides a method for treating alopecia, comprising topically administering a topical pharmaceutical formulation described herein to a subject requiring treatment for alopecia, wherein topical administration of the pharmaceutical formulation for at least six months achieves a weighted mean hair growth assessment (HGA) score of approximately 0.30 compared to a control (vehicle).

[0018] In certain embodiments, the Disclosure provides a method for treating alopecia, comprising topically administering a topical pharmaceutical formulation described herein to a subject requiring treatment for alopecia, wherein topical administration of the pharmaceutical formulation for at least six months achieves a weighted mean IGA (Investigator's Global Assessment) score of approximately 0.43 compared to a control.

[0019] In certain embodiments, the present disclosure includes topically administering to a subject in need of treatment for alopecia the topical pharmaceutical formulation described herein, wherein topical administration of the pharmaceutical formulation for at least 6 months is not accompanied by systemic anti-androgenic side effects, and provides a method for treating alopecia.

[0020] In certain embodiments, the present disclosure includes topically administering to a subject in need of treatment for alopecia the topical pharmaceutical formulation described herein, wherein topical administration of the pharmaceutical formulation

[0021] a) after 6 months of daily or BID application, an average change from baseline in Target Area Hair Count of 9 hairs / cm , ,

[0028] , , , 2 ,

[0026] , 2 , , ,

[0021] , ,

[0023] , ,

[0022] , ,

[0027] , , 2 , , , 2 ,

[0025] , , , ,

[0024] , or more; or

[0022] b) after 6 months of daily or BID application, an average change from baseline in Target Area Hair Count of 10 hairs / cm 2 or more; or

[0023] c) after 6 months of daily or BID application, an average change from baseline in Target Area Hair Count of 11 hairs / cm 2 or more; or

[0024] <​​​​​​​​​​​​​​​​​​h) A weighted average IGA score of 0.10 or higher after 6 months of daily application or BID application; or

[0029] i) A weighted average IGA score of 0.20 or higher after 6 months of daily application or BID application; or

[0030] j) A weighted average IGA score of 0.30 or higher after 6 months of daily application or BID application; or

[0031] k) A favorable (positive) HGA score in at least approximately 10% of the subjects after 6 months of daily application or BID application; or

[0032] l) A favorable (positive) HGA score in at least approximately 20% of the subjects after 6 months of daily application or BID application; or

[0033] m) A favorable (positive) HGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or

[0034] n) A favorable (positive) IGA score in at least approximately 10% of the subjects after 6 months of daily application or BID application; or

[0035] o) A favorable (positive) IGA score in at least approximately 20% of the subjects after 6 months of daily application or BID application; or

[0036] p) A favorable (positive) IGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or

[0037] q) After 6 months of daily application or BID application, a favorable (positive) IGA score was observed in at least approximately 40% of the subjects. It provides a treatment method for alopecia.

[0038] In a further embodiment, the topical pharmaceutical formulation of the present invention is intended for use in the treatment of hair loss in subjects requiring treatment for hair loss. [Modes for carrying out the invention]

[0039] The articles "a," "an," and "the" are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one or more elements.

[0040] As used herein, the term “approximately” means that a particular value is within an acceptable margin of error as determined by those skilled in the art, which in part depends on how the value is measured or determined, i.e., the limits of the measurement system. For example, “approximately” may mean within or above three standard deviations, according to convention in the art. Alternatively, “approximately” may mean a range of up to 10% (e.g., up to 5%, up to 1%) of a given value.

[0041] As used herein, the term “activator” refers to either cortexolone-17α-propionate or minoxidil.

[0042] As used herein, the term “alopecia” refers collectively or individually to male pattern baldness (AGA), alopecia areata (including diffuse alopecia areata, single-spot alopecia areata, multiple-spot alopecia areata, serpentine alopecia, alopecia totalis, and alopecia universalis), telogen effluvium, anagenogenetic alopecia, and traction alopecia.

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

[0044] Where used herein, the term “at least” preceding a number or set of numbers is understood, as is clear from the context, to include the number accompanied by the term “at least” and all subsequent numbers or integers that may logically be included. Where “at least” precedes a set of digits or range, it is understood that “at least” may modify each of the numbers within or within that set of digits. For example, “at least three” means at least three, at least four, at least five, and so on. Where “at least” precedes a component in a method step, the step includes that component, but additional components may also be present, if desired.

[0045] As used herein, the terms "Bis In Die" or "BID" mean "twice a day".

[0046] As used herein, the term “buffer” refers to a compound or group of compounds (e.g., weak conjugate acid-base pairs, e.g., 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 may be added as a Group I salt or a Group II salt. Examples of buffers include phosphate buffers, citrate buffers, lactate buffers, or combinations thereof.

[0047] As used herein, the term "C1-C7 alcohol" refers to an alcohol having one, two, three, four, five, six, or seven carbon atoms that is suitable for use in topical pharmaceutical formulations. Examples of such C1-C7 alcohols include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, and benzyl alcohol. While we do not wish to be bound by any particular theory, C1-C7 alcohols, particularly short-chain C1-C7 alcohols such as C2-C3 alcohols (e.g., ethanol, n-propanol, or isopropyl alcohol), are considered to contribute to the spreadability of the pharmaceutical formulations described herein.

[0048] As used herein, the term "chelating agent" refers to a compound that can bind to a metal ion or metal compound. In some embodiments, chelating agents can stabilize the formulation, for example, by preventing oxidation or precipitation. Suitable chelating agents include, for example, citric acid, phytic acid, sodium phytate, cryoquinol, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropylethylenediamine, sodium metasilicate, or combinations thereof.

[0049] As used herein, the term “co-administration” means the simultaneous or sequential administration of two different activators, namely cortexolone-17α-propionate and minoxidil. In some embodiments, the activators are administered within a sufficiently short time interval from each other so that the first and second therapeutic agents are present simultaneously within the subject receiving the co-administration.

[0050] As used herein, the term "cortexolone" (also known as "11-deoxycortisol" or "Reichstein substance") refers to its structure: [ka] This refers to compounds that possess [a certain characteristic].

[0051] As used herein, the term "cortexolone-17α-propionate" refers to the compound 17α-propionyloxy-21-hydroxypregna-4-ene-3,20-dione, also known as clascoterone, with the chemical structure: [ka] It holds.

[0052] As used herein, the term "degradation product" refers to a compound resulting from the in vitro degradation of cortisone acetate. Exemplary known cortisone acetate degradation products include, but are not limited to, cortisone-21-propionate and cortisone.

[0053] As used herein, the term "ester" refers to an esterified organic solvent, such as, but not limited to, ethyl acetate and ethyl lactate.

[0054] As used herein, the term "ethanol" refers to ethyl alcohol, i.e., CH3CH2OH, which includes pure (anhydrous) ethanol and 96° ethanol, the latter being ethanol containing an amount of water typically within the range of about 4% to about 5.1% by volume. In some embodiments, ethanol is denatured alcohol, such as specially denatured (SD) alcohol, which contains a denaturing agent to prevent ingestion.

[0055] As used herein, the term "fatty" refers to an aliphatic carbon chain that is either saturated or unsaturated. The chain can be of any suitable length, such as chains of, for example, C4-C 28 , more specifically C 10 -C 20 , C 12 -C 22 , and C 12 -C 18 and the like.

[0056] As used herein, the term "gelling agent" refers to a pharmaceutically acceptable compound that can convert an aqueous or an oil phase into a gel. A gelling agent acts as a thickening agent and typically does not impart rigidity. The gelling agent can be an inorganic gelling agent, an organic gelling agent, a hydrogel, an organogel, or a combination thereof.

[0057] As used herein, the term "minoxidil" refers to the compound 2,4-diamino-6-piperidinopyrimidine 3-oxide, with the chemical structure: [ka] It is equivalent to this. In some embodiments, the minoxidil exists in the form of a salt. The salt may be, for example, an acetate, citrate, succinate, benzoate, hydrochloride, sulfate, phosphate, or lactate. In some embodiments, an acetate or lactate of minoxidil is used.

[0058] As used herein, the term “metabolite” refers to compounds resulting from the in vivo metabolism or in vivo degradation of an active agent such as cortexolone-17α-propionate or minoxidil. Exemplary known metabolites of cortexolone-17α-propionate include, but are not limited to, cortexolone and tetrahydrocortexolone. Exemplary known metabolites of minoxidil include, but are not limited to, minoxidil sulfate.

[0059] As used herein, the term “moisturizer” refers to a compound that provides moisture to the skin, softens the skin, or both. Exemplary moisturizers are softeners, which include, for example, fatty alcohols, fatty acids, fatty acid esters, oils, polyethylene glycol, glycerin, alpha hydroxy acids (e.g., lactic acid, glycolic acid, malic acid, citric acid, or tartaric acid), and combinations thereof. Specific examples of moisturizers include, for example, 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, preferably the moisturizer is selected from cetyl alcohol and stearyl alcohol.

[0060] As used herein, the term “natural oil” refers to oils that can be isolated from natural sources. Examples of 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, and calendula oil.

[0061] As used herein, the term “penetration enhancer” refers to a pharmaceutically acceptable compound that increases the penetration of an active ingredient through the dermis. Exemplary penetration enhancers include, for example, hydroxypropyl β-cyclodextrin, polyoxyethylene alkyl ethers, polyoxylglycerides, dimethyl sulfoxides, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether (e.g., TRANSCUTOL®, Gattefosse, France), dimethyl isosorbide, diethyl sebacate, azon, menthol, nerol, camphor, methyl salicylate, polysorbate 80 (e.g., TWEEN® 80, Sigma-Aldrich, St. Louis, Missouri), Examples include SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (e.g., Cremophor (trademark) RH40, Kolliphor (trademark) 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 their salts), fatty alcohols (e.g., oleyl alcohol, myristyl alcohol, stearyl alcohol), medium-chain triglycerides, and any combination thereof.

[0062] Where used herein, the term "pH" should be considered "apparent pH" to acknowledge the fact that the behavior of a pH electrode in complex, multi-component dermatological controls that are not entirely aqueous in nature cannot be considered "pH" in the most strict sense, unless it is evident from the context in which it is used.

[0063] As used herein, the term "polyol" refers to an organic molecule containing two or more hydroxyl groups. Examples of polyols include, but are not limited to, ethylene glycol, propylene glycol, glycerol, and hexanetriol, with propylene glycol being preferred.

[0064] As used herein, the term "polyol ether" refers to a polyol ether suitable for use in topical pharmaceutical formulations. Examples of polyol ethers include, but are not limited to, polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, and diethylene glycol monoethyl ether.

[0065] As used herein, the term “preservative” refers to a compound having antimicrobial activity, such as an antibacterial or antifungal agent. Suitable preservatives include, for example, parabens (e.g., methylparaben, ethylparaben, propylparaben, butylparaben), benzoates (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.

[0066] As used herein, the term “solvent” means a pharmaceutically acceptable solvent, or a mixture of two or more pharmaceutically acceptable solvents, suitable for topical application (including but not limited to the scalp), used to solubilize cortexolone-17α-propionate and / or minoxidil in the formulations described herein.

[0067] As used herein, "tetrahydrocortexolone" refers to the compound having Chemical Abstract Service (CAS) registry number 68-60-0.

[0068] As used herein, the terms “to treat,” “to treat,” and “treatment” mean any sign of success in treating or improving an injury, disease, or condition, including any objective or subjective parameters such as reduction; remission; a decrease in one or more symptoms, or making the injury, disease, or condition more tolerable to the subject; a slowing of the rate of degeneration or decline; or an improvement in the physical or mental well-being of the subject. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, or psychiatric assessment.

[0069] As used herein, the term “prevent” means to avoid the occurrence or presence of, or one or more symptoms associated with, a disease, disorder, or condition, or a disease, disorder, or condition, to which such term applies, or to delay the onset or recurrence of such conditions. The term “prevent” also means to reduce the incidence of a disease, disorder, or condition. The term “prevent” means the act of preventing.

[0070] As used herein, the term “sequentially” means that the subject receives co-administration of the first activator during the first period, followed by administration of the second activator during the second period. In other words, the term “sequentially” includes the first treatment during the first period and the second treatment during the subsequent second period. The interval between the first and second periods may be in seconds, minutes, hours, or days, as necessary. In some embodiments, the interval between the first and second periods is in seconds (e.g., about 60 seconds or less, about 30 seconds or less).

[0071] As used herein, the term “subject” is typically directed toward mammals. In some embodiments, the subject being treated is human.

[0072] As used herein, the term “weight %” is intended to encompass and disclose embodiments in which weight % is a percentage of weight divided by volume (w / v) and a percentage of weight divided by total weight (w / w) with respect to a given value. For example, an embodiment containing 10 wt% of element “X” discloses both an embodiment containing 10 wt% of “X” (w / v) and an embodiment containing 10 wt% of “X” (w / w). Similarly, again as an example, an embodiment containing 10 wt% of “X”, 20 wt% of “Y”, and 60 wt% of “Z” discloses a) an embodiment containing 10 wt% of “X” (w / v), 20 wt% of “Y” (w / v), and 60 wt% of “Z” (w / v), and b) an embodiment containing 10 wt% of “X” (w / w), 20 wt% of “Y” (w / w), and 60 wt% of “Z” (w / w). Notwithstanding the foregoing, in some embodiments, values ​​are specifically marked with "(w / w)" or "(w / v)". In these examples, the values ​​should be interpreted as disclosing only the explicitly stated values, i.e., only (w / w) or only (w / v), and not both.

[0073] As used herein, terms such as “comprises,” “comprising,” “having,” “including,” and “containing” are open-ended terms meaning “including, but not limited to.” To the extent that a given embodiment disclosed herein “comprises” certain elements, it should be understood that this disclosure also specifically envisions and discloses embodiments that “essentially consist of” those elements and embodiments that “consist of” those elements.

[0074] Where used herein, terms such as "consists essentially of" and "consisting essentially of" should be interpreted as semi-closed terms, meaning that no other components that substantially affect the basic and novel features of the embodiments are included.

[0075] As used herein, terms such as "consists of" and "consisting of" are closed terms; therefore, any embodiment "consisting of" a particular set of elements, processes, or components excludes any elements, processes, or components not explicitly specified in that embodiment.

[0076] As used herein, the terms “Target Area Hair Count” or “TAHC” refer to the change from baseline in the number of non-vellus hairs in a target area of ​​the scalp. The target area is, for example, 1 cm². 2 Or a circle with a diameter of 1 inch (5.1 cm) 2 ) This could be the case.

[0077] As used herein, the terms “Hair Growth Assessment” or “HGA” refer to a score given by a subject by comparing a baseline standardized whole-body photograph of the subject’s scalp with a “real-time” standardized whole-body photograph.

[0078] As used herein, the terms “Physician’s Global Assessment” or “IGA” refer to a score given by the assessor by comparing a baseline standardized whole-body photograph of the subject’s scalp with a “real-time” standardized whole-body photograph.

[0079] method This disclosure provides a method for treating hair loss in subjects requiring treatment for alopecia, such as alopecia, comprising topically administering an effective amount of cortexolone-17α-propionate and an effective amount of minoxidil to the subject. Topical administration includes the application of cortexolone-17α-propionate and minoxidil to the skin and / or scalp of the subject, as described herein.

[0080] In a preferred embodiment, the subject is a mammal, such as a human.

[0081] In some embodiments, the hair loss may be related to alopecia. Alopecia may include, for example, male pattern baldness (AGA), alopecia areata (including diffuse alopecia areata, solitary alopecia areata, multiple alopecia areata, serpentine alopecia, alopecia totalis and alopecia universalis), telogen effluvium, anagenous alopecia, and traction alopecia. In some embodiments, the alopecia being treated may be AGA.

[0082] In some embodiments, the cortexolone-17α-propionate and the minoxidil are co-administered sequentially, with the first activator being administered to the subject during a first period, followed by the second activator being administered during a second period. The specific order of administration is not limited. In some embodiments, the cortexolone-17α-propionate may be administered first, and the minoxidil second. In another embodiment, the minoxidil may be administered first, and the cortexolone-17α-propionate second. The interval between the two administration steps may be in seconds, minutes, hours, or days, as necessary. In some embodiments, the interval between the first and second administration steps may be in seconds (e.g., about 60 seconds or less, about 30 seconds or less).

[0083] In certain embodiments, the Disclosure provides a method for treating alopecia, comprising topically administering a topical pharmaceutical formulation described herein to a subject requiring treatment for alopecia, wherein topical administration of the pharmaceutical formulation for at least six months achieves a weighted mean hair growth assessment (HGA) score of approximately 0.30 compared to a control.

[0084] In certain embodiments, the Disclosure provides a method for treating alopecia, comprising topically administering a topical pharmaceutical formulation described herein to a subject requiring treatment for alopecia, wherein topical administration of the pharmaceutical formulation for at least six months achieves a weighted mean IGA (Physician's Global Assessment) score of approximately 0.43 compared to a control.

[0085] In certain embodiments, the present disclosure provides a method for treating alopecia, comprising topically administering a topical pharmaceutical formulation described herein to a subject requiring treatment for alopecia, wherein topical administration of the pharmaceutical formulation for at least six months does not result in systemic antiandrogenic side effects in the subject.

[0086] In certain embodiments, the present disclosure includes topical administration of the topical pharmaceutical formulation described herein to a subject requiring treatment for alopecia, wherein the topical administration of the pharmaceutical formulation

[0087] a) Apply daily for 6 months or, after BID application, 9 bottles / cm 2 The above is the mean change from baseline in the number of hairs in the target area; or

[0088] b) Apply daily for 6 months or, after BID application, 10 bottles / cm 2 The above is the mean change from baseline in the number of hairs in the target area; or

[0089] c) 11 bottles / cm² after 6 months of continuous application or BID application. 2 The above is the mean change from baseline in the number of hairs in the target area; or

[0090] d) 12 bottles / cm² after 6 months of continuous application or BID application. 2 The above is the mean change from baseline in the number of hairs in the target area; or

[0091] e) A weighted average HGA score of 0.20 or higher after 6 months of daily application or BID application; or

[0092] f) A weighted average HGA score of 0.30 or higher after 6 months of daily application or BID application; or

[0093] g) A weighted average HGA score of 0.40 or higher after 6 months of daily application or BID application; or

[0094] h) A weighted average IGA score of 0.10 or higher after 6 months of daily application or BID application; or

[0095] i) A weighted average IGA score of 0.20 or higher after 6 months of daily application or BID application; or

[0096] j) A weighted average IGA score of 0.30 or higher after 6 months of daily application or BID application; or

[0097] k) A favorable (positive) HGA score in at least approximately 10% of the subjects after 6 months of daily application or BID application; or

[0098] l) A favorable (positive) HGA score in at least approximately 20% of the subjects after 6 months of daily application or BID application; or

[0099] m) A favorable (positive) HGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or

[0100] n) A favorable (positive) IGA score in at least approximately 10% of the subjects after 6 months of daily application or BID application; or

[0101] o) A favorable (positive) IGA score in at least approximately 20% of the subjects after 6 months of daily application or BID application; or

[0102] p) A favorable (positive) IGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or

[0103] q) After 6 months of daily application or BID application, a favorable (positive) IGA score was observed in at least approximately 40% of the subjects. It provides a treatment method for alopecia.

[0104] Pharmaceutical preparations In some embodiments, the cortexolone-17α-propionate and the minoxidil may be administered sequentially. In such embodiments, the cortexolone-17α-propionate and the minoxidil may be provided as separate pharmaceutical formulations. Each pharmaceutical formulation may be as described herein.

[0105] In another embodiment, the cortexolone-17α-propionate and the minoxidil may be co-administered simultaneously (i.e., concurrently). In some embodiments, the cortexolone-17α-propionate and the minoxidil may be provided as the same pharmaceutical formulation (e.g., a combination formulation).

[0106] The pharmaceutical formulation may take any form suitable for topical administration. In some embodiments, the pharmaceutical formulation may be a liquid or semi-solid formulation, depending on the carriers and excipients present, as described herein. Examples of the liquid or semi-solid formulation include, for example, solutions, suspensions, emulsions, microemulsions, creams, pastes, gels, ointments, or foams. In a preferred embodiment, the pharmaceutical formulation may be a solution.

[0107] In some embodiments, the formulation may be a cream. In some embodiments, the cream may contain equal amounts of oil and water in the form of an emulsion.

[0108] In some embodiments, the formulation may be a paste. In some embodiments, the paste may contain fatty acids (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof), oils, or a combination thereof.

[0109] In some embodiments, the formulation may be a gel comprising at least one gelling agent. The gelling agent may be, for example, an inorganic gelling agent (e.g., aluminum hydroxide gel, bentonite magma), an organic gelling agent (e.g., carbomer polymer, tragacanth), a hydrogel (e.g., organic hydrogel, natural or synthetic rubber, or inorganic hydrogel), an organogel (e.g., hydrocarbon type, vegetable fat, soap-based grease, or hydrophilic organogel), or a combination thereof. The organic hydrogel may include, for example, pectin paste and tragacanth jelly. The natural or synthetic rubber may include, for example, methylcellulose, sodium carboxymethylcellulose, and poloxamer. The inorganic hydrogel may include, for example, bentonite gel, smectite (e.g., VEEGUM®, Vanderbilt Minerals, LLC, Norwalk, Connecticut), or silica. The hydrocarbon type organogel may include, for example, petrolatum and mineral oil / polyethylene gel. The aforementioned vegetable fat-type organogel may include, for example, cocoa butter. The aforementioned soap-based grease-type organogel may include, for example, a gel of aluminum stearate and heavy mineral oil. The aforementioned hydrophilic organogel may include, for example, a carbowax base such as polyethylene glycol (PEG) ointment.

[0110] In some embodiments, the gelling agent may be a carbomer polymer. The term "carbomer" is a general term for high molecular weight polymers of acrylic acid that are lightly crosslinked with allyl ethers of polyalcohols (e.g., allyl curethrose, allyl pentaerythritol). The term may also be used to describe Carbopol (trademark) polymers (Lubrizol Corp., Wycliffe, Ohio).

[0111] In some embodiments, the formulation may be an ointment. In some embodiments, the ointment may contain hydrocarbons (e.g., paraffin, petrolatum), lanolin, beeswax, macrogol, polyethylene glycol, emulsifying wax, alkyltrimethylammonium bromide (e.g., cetrimide), vegetable oils (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 may contain about 20% by weight or less of water.

[0112] In some embodiments, the formulation may be a foam. The foam formulation may be used in combination with one or more acceptable propellants, such as propane, butane, isobutene, nitrogen, propellant P75, etc.

[0113] solvent In some embodiments where the pharmaceutical formulation is a solution, the pharmaceutical formulation may include water, a saline solution (e.g., a sodium chloride salt solution), a buffered saline solution (e.g., a phosphate buffered salt solution), or a combination thereof.

[0114] In some embodiments, the pharmaceutical formulation can be considered anhydrous and may contain less than about 5 wt% (e.g., less than about 4 wt%, less than about 3 wt%, less than about 2 wt%, or less than about 1 wt%) of water.

[0115] In some embodiments, particularly in embodiments containing less than about 5% by weight of water, the cortexolone-17α-propionate can be completely solubilized in the pharmaceutical formulation. The topical pharmaceutical formulation may, in addition to or in place of water, comprise one or more pharmaceutically acceptable carriers (e.g., solvents), such as polyols, polyol ethers, C1-C7 alcohols, and combinations thereof.

[0116] In some embodiments, the pharmaceutical formulation may contain water, C1-C7 alcohols, polyol ethers, polyols, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), natural oils, esters, tricaprylin (2,3-di(octanoyloxy)propyl octanoate), medium-chain triglycerides, caprylocaproyl polyoxyl-8 glycerides, and solvents selected from the group comprising any combination thereof or the group comprising them. In preferred embodiments, the one or more pharmaceutically acceptable carriers are selected from the group comprising polyols, polyol ethers, C1-C7 alcohols, and combinations thereof.

[0117] In some embodiments, the pharmaceutical formulation may contain at least about 50% by weight of a solvent (e.g., water, saline, buffered saline solution, polyol, polyol ether, C1-C7 alcohol, or a combination thereof). In another embodiment, the pharmaceutical formulation may contain at least about 60% by weight of a solvent. In another embodiment, the pharmaceutical formulation may contain at least about 70% by weight of a solvent. In another embodiment, the pharmaceutical formulation may contain at least about 80% by weight of a solvent. In another embodiment, the pharmaceutical formulation may contain 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.

[0118] In some embodiments, the solvent may comprise a mixture of C1-C7 alcohols, polyol ethers, and polyols. In such embodiments, the pharmaceutical formulation may comprise about 10% to about 50% by weight of the polyol ether, about 5% to about 55% by weight of the polyol, and about 5% to about 50% by weight of the C1-C7 alcohol. In some embodiments, the mixture of the C1-C7 alcohol, the polyol ether, and the polyol may be present in a ratio of about 1:1:1 on a w / w / w basis. In some embodiments, each of the C1-C7 alcohol, the polyol ether, and the polyol may be present in about 30% by weight.

[0119] In some embodiments, the pharmaceutical formulation may contain about 15% to about 45% by weight of the polyol ether, about 20% to about 40% by weight of the polyol ether, about 25% to about 35% by weight of the polyol ether, or about 30% to about 35% by weight of the polyol ether. In some embodiments, the pharmaceutical formulation may contain about 30% by weight of the polyol ether. In another embodiment, the pharmaceutical formulation may contain about 32% by weight of the polyol ether.

[0120] In some embodiments, the polyol ether may be selected from the group including or consisting of polyethylene glycol, polypropylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether (TRANSCUTOL (trademark), Gattefosse, France), and combinations thereof.

[0121] When the polyol ether is polyethylene glycol (PEG), the number average molecular weight (M) of the PEG can range from approximately 200 g / mol to approximately 6,000 g / mol. n) may have. In some embodiments, the PEG may be selected from the group including or consisting of PEG200, PEG300, PEG400, PEG540, and PEG600. In some embodiments, the polyol ether may be PEG200. In another embodiment, the polyol ether may be PEG400. In yet another embodiment, the polyol ether may be diethylene glycol monoethyl ether.

[0122] In some embodiments, the polyol may be selected from the group including or consisting of propylene glycol, ethylene glycol, glycerol, hexanetriol, and combinations thereof. In some embodiments, the polyol may be glycerol. In preferred embodiments, the polyol may be propylene glycol.

[0123] In some embodiments, the polyol may be present in amounts ranging from about 5% to about 55% by weight of the entire formulation, about 10% to about 50% by weight of the entire formulation, about 20% to about 45% by weight of the entire formulation, and in some embodiments, about 25% to about 40% by weight. In certain embodiments, the polyol may constitute about 30% by weight of the entire formulation. In further embodiments, the polyol constituting about 30% by weight of the entire formulation may be propylene glycol.

[0124] In some embodiments, the pharmaceutical formulation may contain about 5% to about 50% by weight of the C1-C7 alcohol. In some embodiments, the pharmaceutical formulation may contain about 15% to about 45% by weight of the C1-C7 alcohol, about 20% to about 40% by weight of the C1-C7 alcohol, or about 25% to about 35% by weight of the C1-C7 alcohol. In some embodiments, the pharmaceutical formulation may contain about 30% by weight of the C1-C7 alcohol. In another further embodiment, the pharmaceutical formulation may contain an amount of the C1-C7 alcohol in the range of about 10% to about 40% by weight, or about 15% to about 35% by weight.

[0125] In some embodiments, the C1-C7 alcohol may be selected from the group comprising or consisting of methanol, ethanol, isopropanol, n-butanol, n-propanol, and benzyl alcohol. In a preferred embodiment, the C1-C7 alcohol may be ethanol. In some embodiments, the ethanol constitutes about 30% by weight of the entire formulation. In another embodiment, the C1-C7 alcohol may be isopropanol.

[0126] In some embodiments, the C1-C7 alcohol may contain a small fraction of water, generally in the range of about 4 percent to about 5.1 percent by volume. In embodiments in which the pharmaceutical formulation may be anhydrous, the C1-C7 alcohol having about 4% to about 5.1% water by volume may be present in the pharmaceutical formulation in such an amount that the water content of the final formulation itself may be less than about 5% by weight or less than about 3% by weight.

[0127] In some embodiments, the solvent may comprise a polyol, a polyol ether, and a C1-C7 alcohol. In some embodiments, the solvent may comprise ethanol as the C1-C7 alcohol, diethylene glycol monomethyl ether as the polyol ether, and propylene glycol as the polyol. These solvents may be present in any acceptable ratio, but typically each is present in an amount of about 25% to about 35% by weight of the pharmaceutical formulation.

[0128] Other components In some embodiments, the pharmaceutical formulation may further include at least one additive selected from acids, buffers, antioxidants, emulsifiers, penetration enhancers, humectants, preservatives, chelating agents, and combinations thereof.

[0129] In some embodiments, the pharmaceutical formulation may contain, based on the total weight of the composition (i.e., as 100% by weight), about 0.1% to about 50% by weight of each additive (e.g., acids, buffers, antioxidants, emulsifiers, penetration enhancers, humectants, preservatives, chelating agents). For example, each additive may be present in the pharmaceutical formulation in amounts of about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 2%, and about 0.5% to about 5% of the total weight of the composition. 0% by weight, about 0.5% to about 45% by weight, about 0.5% to about 40% by weight, about 0.5% to about 35% by weight, about 0.5% to about 30% by weight, about 0.5% to about 25% by weight, about 0.5% to about 20% by weight , about 0.5% to about 15% by weight, about 0.5% to about 10% by weight, about 0.5% to about 5% by weight, about 0.5% to about 2% by weight, about 1% to about 50% by weight, about 1% to about 45% by weight, about 1% to about 40% by weight Weight%, about 1% to about 35% by weight, about 1% to about 30% by weight, about 1% to about 25% by weight, about 1% to about 20% by weight, about 1% to about 15% by weight, about 1% to about 10% by weight, about 1% to about 5% by weight, About 1% by weight to about 2% by weight, about 50% by weight, about 48% by weight, about 46% by weight, about 44% by weight, about 42% by weight, about 40% by weight, about 38% by weight, about 36% by weight, about 34% by weight, about 2% by weight, about 30% by weight, about 28% by weight It may be present in amounts of approximately 26% by weight, approximately 24% by weight, approximately 22% by weight, approximately 20% by weight, approximately 18% by weight, approximately 16% by weight, approximately 14% by weight, approximately 12% by weight, approximately 10% by weight, approximately 8% by weight, approximately 6% by weight, approximately 5% by weight, approximately 4% by weight, approximately 3% by weight, approximately 2% by weight, approximately 1% by weight, approximately 0.9% by weight, approximately 0.8% by weight, approximately 0.7% by weight, approximately 0.6% by weight, approximately 0.5% by weight, approximately 0.4% by weight, approximately 0.3% by weight, approximately 0.2% by weight, or approximately 0.1% by weight.

[0130] In some embodiments, the pharmaceutical formulation may contain an acid to help solubilize one or both of the activators, to maintain a desired pH, or both. Any suitable acid, such as mineral acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid), organic acids (e.g., citric acid, acetic acid, succinic acid, or maleic acid), or mixtures thereof, may be used. 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, (+)-campanulic acid, (+)-campanulic acid-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, and gentidine. Examples include acids, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, 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 may be added to the pharmaceutical formulation.

[0131] In some embodiments, the acid can be added in sufficient quantity to bring the pH of the pharmaceutical formulation to about 7.0 or less (for example, 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).

[0132] In some embodiments, the pharmaceutical formulation may contain a buffer to help maintain the pH of the formulation within a desired range. In some embodiments, the buffer may be a phosphate buffer, a citrate buffer, a lactic acid buffer, or a combination thereof. In some embodiments, the formulation may contain phosphoric acid, citrate, lactic acid, or a combination thereof.

[0133] Since oxidation can lead to the decomposition of activators, in some embodiments the pharmaceutical formulation may contain antioxidants. In some embodiments, the antioxidant may 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, erythrobic acid, guaiac resin, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, pharmaceutically acceptable salts or esters thereof, and combinations thereof. In some embodiments, the antioxidant may be ascorbyl palmitate, BHA, BHT, or a combination thereof. In some embodiments, the antioxidant may be BHT, ascorbyl palmitate, or a combination of BHT and ascorbyl palmitate.

[0134] In some embodiments, the pharmaceutical formulation may contain up to about 1% by weight of an antioxidant. In some embodiments, the pharmaceutical formulation may contain up to about 0.5% by weight of an antioxidant, or about 0.5% by weight of an antioxidant.

[0135] In some embodiments, the pharmaceutical formulation may include an emulsifier, particularly to provide a solution, suspension, emulsion, or microemulsion. While we do not wish to be bound by any particular theory, it is believed that, where an emulsifier is present, it assists or facilitates the dissolution of any solid substance (e.g., an activator) in the pharmaceutical formulation. However, in other embodiments, the emulsifier may be present to facilitate the combination of two immiscible liquids into each other (e.g., to form an emulsion or microemulsion).

[0136] In another embodiment, and without wishing to be bound by any particular theory, emulsifiers can enhance the spreadability of a product. For example, without wishing to be bound by any particular theory, if the pharmaceutical formulation is a liquid solution, the presence of an appropriate amount of emulsifier is thought to reduce the surface tension between the pharmaceutical formulation and the superficial lipid environment of the skin and / or scalp. This facilitates the spreadability of the pharmaceutical formulation. It is also thought to help the (one or more) activators penetrate the skin (including the scalp), hair follicles, or both.

[0137] In some embodiments, the emulsifier is polyethylene glycol (PEG) fatty acid monoester, e.g., PEG-15 hydroxystearate (also known as polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, etc.; polyoxyethylene sorbitan fatty acid ester (polysorbate), e.g., polysorbate 20, polysorbate 60, polysorbate 80, etc.; polyoxyethylene alkyl ether, e.g., PEG-20 cetostearyl ether, polyoxyl-25 cetostearyl, cetomacrogol 1000, etc.; sorbitan fatty acid ester, e.g., sorbitan monolaurate, etc. Polysorbates such as sorbitan monopalmitate and sorbitan monooleate; propylene glycol fatty acid esters; polyglycerin fatty acid esters; polyoxyethylene castor oil derivatives, e.g., polyoxyl-5 castor oil, polyoxyl-15 castor oil, polyoxyl-35 castor oil, polyoxyl-40 hydrogenated castor oil; caprylocapryl polyoxyyl-8 glyceride; polyoxyl glycerides, e.g., caprylocaproyl polyoxyl glyceride, lauroyl polyoxyl glyceride, oleoyl polyoxyl glyceride; polyoxyethylene lauryl alcohol; and any combination thereof may be selected from the group comprising these or the group comprising them. In some embodiments, the emulsifier may be polyoxyl-40 hydrogenated castor oil, polyoxyl-15 hydroxystearate, polysorbate 60, polysorbate 80, or a combination thereof. In a preferred embodiment, the emulsifier may be a polysorbate, such as polysorbate 60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80.

[0138] In some embodiments, the pharmaceutical formulation may contain the 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 may be present in an amount ranging from 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 preferred embodiments, the pharmaceutical formulation may contain the 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 another further embodiment, the pharmaceutical formulation may contain the emulsifier in an amount of up to about 0.1% by weight, or about 0.1% by weight of the emulsifier. In yet another further embodiment, the emulsifier may be present in the pharmaceutical formulation in an amount of about 0.1% by weight.

[0139] In some embodiments, the pharmaceutical formulation may comprise one or more penetration enhancers. While we do not wish to be bound by any particular theory, penetration enhancers are considered to have a beneficial effect on the delivery of the activator to the skin (including the scalp) and / or hair follicles. Advantageously, and in some embodiments, the solvent or some or some components of the solvent act as a penetration enhancer. For example, in embodiments in which the pharmaceutical formulation comprises ethanol and / or diethylene glycol monoethyl ether, these solvents may also act to promote the penetration of the activator to the skin (including the scalp), hair follicles, or both. The pharmaceutical formulations described herein may further comprise additional penetration enhancers, regardless of the presence of ethanol and / or diethylene glycol monoethyl ether.

[0140] In some embodiments, the penetration enhancer may be selected from the group consisting of hydroxypropyl β-cyclodextrin, diols, 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. Examples of further penetration enhancers that may be incorporated into the formulations described herein include polyoxymethylene alkyl ethers, polyoxylglycerides, dimethyl sulfoxides, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether (e.g., TRANSCUTOL®, Gattefosse, France), dimethyl isosorbide, diethyl sebacate, azon, menthol, nerol, camphor, methyl salicylate, polysorbate 80 (e.g., TWEEN® 80, Sigma-Aldrich, St. Louis, Missouri), SDS, and benzalkonium chloride. Examples of such substances include, but are not limited to, ruconium, polyoxyl 40 hydrogenated castor oil (e.g., Cremophor (trademark) RH40, Kolliphor (trademark) 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 their salts), fatty alcohols (e.g., oleyl alcohol, myristyl alcohol, and stearyl alcohol), medium-chain triglycerides, and any combination thereof.

[0141] In some embodiments, the penetration enhancer may be dimethyl isosorbide. In another embodiment, the penetration enhancer may be a mixture comprising dimethyl isosorbide and diethylene glycol monoethyl ether. In yet another embodiment, the penetration enhancer may be dimethyl sulfoxide.

[0142] In some embodiments, the penetration enhancer may be present in an amount ranging from about 1% by weight to about 50% by weight relative to the total weight of the pharmaceutical formulation. In other embodiments, the penetration enhancer may be present in an amount ranging from about 2% by weight to about 40% by weight, or from about 5% by weight to about 35% by weight, relative to the total weight of the pharmaceutical formulation. According to some embodiments, the penetration enhancer may be present in the pharmaceutical formulation described herein in an amount ranging from about 1% by weight, about 2% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight, relative to the total weight of the pharmaceutical formulation.

[0143] In some embodiments, the pharmaceutical formulation may comprise one or more humectants. While not wishing to be bound by any particular theory, humectants are considered to impart moisture and / or flexibility to the skin (including the scalp), especially if the formulation contains components known to dry out the skin, such as alcohol. In some embodiments, the humectant may be fatty alcohols, fatty acids (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof), fatty acid esters, oils, polyethylene glycol, glycerin, alpha hydroxy acids, or a combination thereof. In some embodiments, the humectant may 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 a combination thereof. In some embodiments, the humectant may be cetyl alcohol, stearyl alcohol, or a combination of cetyl alcohol and stearyl alcohol.

[0144] In some embodiments, the pharmaceutical formulation may contain one or more preservatives (e.g., antibacterial agents, antifungal agents). Suitable preservatives include, for example, parabens (e.g., methylparaben, ethylparaben, propylparaben, butylparaben), benzoates (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.

[0145] In some embodiments, the pharmaceutical formulation may contain one or more chelating agents. Suitable chelating agents include, for example, citric acid, phytic acid, sodium phytate, cryoquinol, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropylethylenediamine, sodium metasilicate, or combinations thereof.

[0146] Mode of administration The pharmaceutical formulations described herein may be co-administered according to various schedules. In one embodiment, the mode of administration of the pharmaceutical formulation may be continuous. For example, the pharmaceutical formulation may be applied topically once, twice, three times, four times, or more times a day, as specified by a physician. In some embodiments, the formulations described herein may be applied topically once or twice a day. According to a particular embodiment, the pharmaceutical formulations described herein may be applied topically once a day. According to another embodiment, the pharmaceutical formulations described herein may be applied topically twice a day.

[0147] In some embodiments, the administration regimen may be tapered. That is, the pharmaceutical formulation may be administered once daily in the first period, then twice daily in the second period, then three times daily in the third period, and so on. In a particular embodiment, the pharmaceutical formulation may be administered once daily on day 1, and then twice daily thereafter. Here, the appropriate duration of treatment is determined by the physician in question. In an alternative embodiment, tapered administration may include administering the pharmaceutical formulation in a tapering schedule, starting with multiple doses per day over an appropriate period, and gradually reducing the number of doses over an appropriate period until the scheduled maintenance can be achieved. Determining an appropriate starting point, tapering gradient, and maintenance schedule is within the scope of the skills of a physician with the usual skills given this disclosure.

[0148] In some embodiments, the pharmaceutical formulation may be applied over a period of several days, several weeks, or several months. For example, the pharmaceutical formulation may be applied once, twice, three, four, or five times per day over a maximum of one, two, three, four, five, six, or seven days (i.e., about one week); about two weeks, about three weeks, or about four weeks; about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about one year (i.e., about twelve months), about thirteen months, about fourteen months, about fifteen months, about sixteen months, about seventeen months, about eighteen months, about nineteen months, about twenty months, about twenty-one months, about twenty-two months, about twenty-three months, or about twenty-four months. According to a particular embodiment, the pharmaceutical formulation may be applied once on day one, and then twice per day for about four weeks thereafter.

[0149] In another embodiment, the pharmaceutical formulation may be applied topically to the scalp once a day for one month, once a day for two months, once a day for three months, once a day for four months, once a day for five months, once a day for six months, once a day for eight months, once a day for twelve months, once a day for fourteen months, once a day for sixteen months, once a day for eighteen months, once a day for twenty months, once a day for twenty-two months, or once a day for twenty-four months. In some embodiments, the pharmaceutical formulation may be applied topically to the scalp once a day for six months. In some embodiments, the pharmaceutical formulation may be applied topically to the scalp once a day for twelve months.

[0150] In another embodiment, the pharmaceutical formulation may be applied topically to the scalp twice a day 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 formulation may be applied topically to the scalp twice a day for 6 months. In some embodiments, the pharmaceutical formulation may be applied topically to the scalp twice a day for 12 months.

[0151] In another embodiment, the pharmaceutical formulation may be applied more than twice a day (i.e., three times a day (TID), four times a day (QID), etc.) for a period of 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 formulation may be applied topically to the scalp more than twice a day (i.e., TID, QID, etc.) for a period of 6 months. In some embodiments, the pharmaceutical formulation may be applied topically to the scalp more than twice a day (i.e., TID, QID, etc.) for a period of 12 months.

[0152] In another embodiment, the mode of administration of the pharmaceutical preparation may be periodic. For example, the pharmaceutical preparation may first be applied continuously as described above over a desired period, then the application may be interrupted for a period, e.g., several days, and then the application of the pharmaceutical preparation may be resumed as described above. The treatment period may consist of one or more cycles, which may be the same or different. In some embodiments, the treatment period may be as follows: a) the pharmaceutical preparation may be applied topically to the scalp by continuous administration over a period, e.g., four months; b) the application may be interrupted for several days (e.g., two to five days); and 3) topical application may be continued for a further period, e.g., six months.

[0153] In some embodiments, the administration pattern is cyclical in that cortexolone-17α-propionate and minoxidil may be co-administered sequentially. For example, a pharmaceutical formulation containing cortexolone-17α-propionate may be administered first over a first period, and a pharmaceutical composition containing minoxidil may be administered second over a second period. In another embodiment, a pharmaceutical composition containing minoxidil may be administered first, and a pharmaceutical composition containing cortexolone-17α-propionate may be administered second. The period between the administration of the first pharmaceutical composition and the administration of the second pharmaceutical composition may be any appropriate period. For example, the time between each administration may be in seconds, minutes, hours, or days, as needed. In some embodiments, the interval between the administration of the first pharmaceutical composition and the administration of the second pharmaceutical composition may be in seconds (e.g., about 60 seconds or less, about 30 seconds or less). In some embodiments, the interval between the administration of the first pharmaceutical composition and the administration of the second pharmaceutical composition may be in 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 interval between the administration of the first pharmaceutical composition and the administration of the second pharmaceutical composition may be in 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 interval between the administration of the first pharmaceutical composition and the administration of the second pharmaceutical composition may be in weeks (e.g., about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks).

[0154] In some embodiments, a first pharmaceutical formulation containing either cortexolone-17α-propionate or minoxidil may be administered over a first period, which may be in days or weeks. During the first period, the first pharmaceutical formulation may be administered multiple times to the skin or scalp as described herein. Thereafter, during a second period, a second pharmaceutical formulation containing the other activator may be administered. Similar to the first period, the second period may be in days or weeks. For example, during the first period (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), the first pharmaceutical formulation containing cortexolone-17α-propionate may be administered. During the second period (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), the second pharmaceutical formulation containing minoxidil may be administered. In some embodiments, the subject may be administered the first pharmaceutical formulation and the second pharmaceutical formulation alternately (for example, circulating between the two).

[0155] The “effective amount” of each activator is the amount that gives the desired outcome (e.g., inducing hair growth and / or hair regeneration). In some embodiments, the pharmaceutical formulation may contain cortexolone-17α-propionate, minoxidil, or both activators in concentrations of about 0.1% to about 20% by weight. For example, the pharmaceutical preparation contains cortexolone-17α-propionate, minoxidil, or both active agents in an amount of about 0.1% by weight or more (e.g., about 0.2% by weight or more, about 0.3% by weight or more, about 0.4% by weight or more, about 0.5% by weight or more, about 0.6% by weight or more, about 0.7% by weight or more, about 0.8% by weight or more, about 0.9% by weight or more, about 1% by weight or more, about 1.2% by weight or more, about 1.4% by weight or more, about 1.6% by weight or more, about 1.8% by weight or more, about 2% by weight or more, about 2.2% by weight or more, about 2.4% by weight or more) % or more, about 2.6% by weight or more, about 2.8% by weight or more, about 3% by weight or more, about 3.2% by weight or more, about 3.4% by weight or more, about 3.6% by weight or more, about 3.8% by weight or more, about 4% by weight or more, about 4.2% by weight or more, about 4.4% by weight or more, about 4.6% by weight % or more, about 4.8% by weight or more, about 5% by weight or more, about 5.2% by weight or more, about 5.4% by weight or more, about 5.6% by weight or more, about 5.8% by weight or more, about 6% by weight or more, about 6.2% by weight or more, about 6.4% by weight or more, about 6.6% by weight or more, about 6.8% by weight % or more, about 7% by weight or more, about 7.2% by weight or more, about 7.4% by weight or more, about 7.6% by weight or more, about 7.8% by weight or more, about 8% by weight or more, about 8.2% by weight or more, about 8.4% by weight or more, about 8.6% by weight or more, about 8.8% by weight or more, about 9% by weight or more Above, about 9.2% by weight or more, about 9.4% by weight or more, about 9.6% by weight or more, about 9.8% by weight or more, about 10% by weight or more, about 10.5% by weight or more, about 11% by weight or more, about 11.5% by weight or more, about 12% by weight or more, about 12.5% ​​by weight or more, about 13% by weight % or more, approximately 13.5% or more by weight, approximately 14% or more by weight, approximately 14.5% or more by weight, approximately 15% or more by weight, approximately 15.5% or more by weight, approximately 16% or more by weight, approximately 16.5% or more by weight, approximately 17% or more by weight, approximately 17.5% or more by weight, approximately 18% or more by weight, approximately 18.5% or more by weight, approximately 19% or more by weight, or approximately 19.5% or more by weight) ~ approximately 20% or less by weight (for example, approximately 19.5% or less by weight, approximately 19% or less by weight, approximately 18.5% or less by weight, approximately 18% or less by weight, approximately 17.5% or less by weight, approximately 17% or less by weight, approximately 16.5% by weight or less, about 16% by weight or less, about 15.5% by weight or less, about 15% by weight or less, about 14.5% by weight or less, about 14% by weight or less, about 13.5% by weight or less, about 13% by weight or less, about 12.5% ​​by weight or less, about 12% by weight or less, about 11.5% by weight or less, about 11% by weight or less, about 10.5% by weight or less, about 10% by weight or less Lower, about 9.5% by weight or less, about 9% by weight or less, about 8.5% by weight or less, about 8% by weight or less, about 7.5% by weight or less, about 7% by weight or less, about 6.5% by weight or less, about 6% by weight or less, about 5.8% by weight or less, about 5.6% by weight or less, about 5.4% by weight or less, about 5.2% by weight or less, about 5% by weight or less, about 4.8% by weight or less, about 4. It may be contained in concentrations of 6% by weight or less, approximately 4.4% by weight or less, approximately 4.2% by weight or less, approximately 4% by weight or less, approximately 3.8% by weight or less, approximately 3.6% by weight or less, approximately 3.4% by weight or less, approximately 3.2% by weight or less, approximately 3% by weight or less, approximately 2.8% by weight or less, approximately 2.6% by weight or less, approximately 2.4% by weight or less, approximately 2.2% by weight or less, approximately 2% by weight or less, approximately 1.8% by weight or less, approximately 1.6% by weight or less, approximately 1.4% by weight or less, approximately 1.2% by weight or less, approximately 1% by weight or less, approximately 0.9% by weight or less, approximately 0.8% by weight or less, approximately 0.7% by weight or less, approximately 0.6% by weight or less, approximately 0.5% by weight or less, approximately 0.4% by weight or less, approximately 0.3% by weight or less, or approximately 0.2% by weight or less. In a preferred embodiment, the pharmaceutical formulation may contain cortexolone-17α-propionate, minoxidil, or both activators in concentrations of about 0.5% to about 18% by weight, about 1% to about 15% by weight, about 1.5% to about 15% by weight, about 2% to about 12% by weight, about 2.5% to about 10% by weight, about 2.5% to about 8% by weight, or about 3% to about 7% by weight.

[0156] In some embodiments, the pharmaceutical formulation may contain cortexolone-17α-propionate at a concentration of about 1% to about 20% by weight. In some embodiments, the pharmaceutical formulation may contain minoxidil at a concentration of about 0.1% to about 20% by weight. In some embodiments, the pharmaceutical formulation may be a solution containing cortexolone-17α-propionate at a concentration of about 1% to about 20% by weight and minoxidil at a concentration of about 0.1% to about 20% by weight. In a preferred embodiment, the pharmaceutical formulation may be a solution containing about 5% by weight of cortexolone-17α-propionate and about 5% by weight of minoxidil.

[0157] In some embodiments, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 400 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 350 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 300 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 250 mg.

[0158] In some embodiments, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 200 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 170 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 150 mg. In some embodiments, the amount of cortexolone-17α-propionate in a single application may be in the range of about 20 mg to about 100 mg. In some embodiments, the amount of cortexolone-17α-propionate in a single application may be about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or about 100 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 25 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 30 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 50 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 75 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 80 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 100 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, or about 200 mg. In yet another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 150 mg.

[0159] In some embodiments, the amount of minoxidil in a single application may be in the range of about 2 mg to about 20 mg. In another embodiment, the amount of minoxidil in a single application may be in the range of about 2 mg to about 15 mg. In another embodiment, the amount of minoxidil in a single application may be in the range of about 2 mg to about 10 mg. In another embodiment, the amount of minoxidil in a single application may be in the range of about 2 mg to about 5 mg.

[0160] In some embodiments, the pharmaceutical formulation may be self-administered once or twice daily, depending on the subject. In some embodiments, if the pharmaceutical formulation may be in liquid form having a concentration of about 5% by weight of cortexolone-17α-propionate and a concentration of about 5% by weight of minoxidil, the pharmaceutical formulation may be self-administered once or twice daily in doses ranging from about 0.2 ml to about 2.0 ml, or from about 0.5 ml to about 1.5 ml, and in further embodiments in doses of about 1 ml or about 1.5 ml.

[0161] In some embodiments, if the pharmaceutical formulation may be in liquid form having a cortexolone-17α-propionate concentration of about 2.5% by weight and a minoxidil concentration of about 2% by weight, the pharmaceutical formulation may be self-administered once or twice daily in doses ranging from about 0.2 ml to about 2.0 ml, or from about 0.5 ml to about 1.5 ml, and in further embodiments in doses of about 1 ml or about 1.5 ml.

[0162] In some embodiments, if the pharmaceutical formulation may be in liquid form having a cortexolone-17α-propionate concentration of about 3% by weight and a minoxidil concentration of about 3% by weight, the pharmaceutical formulation may be self-administered once or twice daily in doses ranging from about 0.2 ml to about 2.0 ml, or from about 0.5 ml to about 1.5 ml, and in further embodiments in doses of about 1 ml or about 1.5 ml.

[0163] In some embodiments, if the pharmaceutical formulation may be in liquid form having a cortexolone-17α-propionate concentration of about 7.5% by weight and a minoxidil concentration of about 1.5% by weight, the pharmaceutical formulation may be self-administered once or twice daily in doses ranging from about 0.2 ml to about 2.0 ml, or from about 0.5 ml to about 1.5 ml, and in further embodiments in doses of about 1 ml or about 1.5 ml.

[0164] The pharmaceutical formulations described herein may be applied to any body surface requiring treatment, such as skin areas susceptible to hair growth induction. Suitable skin areas include, for example, the scalp, face (e.g., brow ridge, eyelashes, upper lip, lower lip, chin, cheeks, beard area, or mustache area), arms, armpits, legs, chest, abdomen, or any combination thereof. In some embodiments, the treatment is not delivered to the face. In other embodiments, the pharmaceutical formulation may be applied to the scalp.

[0165] kit This disclosure further provides kits comprising one or more topical pharmaceutical formulations in various forms as described herein. The kit may comprise one or more liquid or semi-solid formulations suitable for administration. The kit may further comprise administration devices, such as droppers, pipettes, or injection devices (e.g., manual or electronically driven), for use by those skilled in the art. The kit may further comprise instructions for preparing and administering one or more pharmaceutical formulations. The instructions may be in various forms, such as printed matter, magnetic disks, magnetic tapes, compact disks, flash memory, or other media suitable for transmitting appropriate information.

[0166] In some embodiments, the kit may include a pharmaceutical formulation containing cortexolone-17α-propionate as a first component and a pharmaceutical formulation containing minoxidil as a second component. The kit may further include instructions for the use of the first and second components. In some embodiments, the first and second components may be combined immediately before use (e.g., within 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes before use) to be applied to the skin or scalp as a single compound formulation. In some embodiments, both the first and second components are solutions. In some embodiments, one or both of the first and second components may be gels. In some embodiments, one or both of the first and second components may be creams. In some embodiments, one or both of the first and second components may be foams.

[0167] In some embodiments, the kit may contain cortexolone-17α-propionate in solid form as a first component and a pharmaceutical formulation containing minoxidil as a second component. The kit may further include instructions for the use of the first and second components. In some embodiments, the cortexolone-17α-propionate in solid form may be a powder, fast-disintegrating tablet, granules, or granular form. Preferably, the cortexolone-17α-propionate is in powder form. In some embodiments, the cortexolone-17α-propionate in solid form may be stored separately from the container containing the pharmaceutical formulation containing minoxidil. In such embodiments, the cortexolone-17α-propionate in solid form may be stored in a capped vial or a sealed bottle.

[0168] In some embodiments, the cortexolone-17α-propionate in solid form may be housed in the same container as the pharmaceutical formulation containing minoxidil. According to such embodiments, the cortexolone-17α-propionate in solid form may be housed in a compartment of the container (designed to prevent contact between the two activators) that contains the pharmaceutical formulation containing minoxidil. In some embodiments, the constituent compartment of the container, designed to prevent contact between the cortexolone-17α-propionate in solid form and the pharmaceutical formulation containing minoxidil, may be a cap containing a storage chamber for the solid substance (for example, a reservoir cap) or a chamber isolated from the main chamber containing the pharmaceutical formulation containing minoxidil. In some embodiments, the container containing the pharmaceutical formulation containing minoxidil may be capped with a reservoir cap containing cortexolone-17α-propionate in solid form, the reservoir cap having a cutting device that is activated by pressing, twisting, or pulling the cap itself. According to such embodiments, activating the cutting device of the reservoir cap makes it possible to bring the cortexolone-17α-propionate in solid form into contact with the pharmaceutical formulation containing minoxidil.

[0169] In some embodiments, the first component and the second component may be combined immediately before use (e.g., within 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes before use) to form a single compound formulation that can be applied to the skin or scalp. In some embodiments, the first component may be in solid form and the second component may be a solution. In some embodiments, the first component may be in solid form and the second component may be a gel. In some embodiments, the first component may be in solid form and the second component may be a cream. In some embodiments, the first component may be in solid form and the second component may be a foam.

[0170] In some embodiments, the kit may contain minoxidil in solid form as a first component and a pharmaceutical formulation containing cortexolone-17α-propionate as a second component. The kit may further include instructions for the use of the first and second components. In some embodiments, the minoxidil in solid form may be a powder, fast-disintegrating tablet, granules, or granular form. In some embodiments, the minoxidil in solid form may be stored separately from the container containing the pharmaceutical formulation containing cortexolone-17α-propionate. In such embodiments, the minoxidil in solid form may be stored in a capped vial or a sealed bottle.

[0171] In some embodiments, the minoxidil in solid form may be housed in the same container as the pharmaceutical formulation containing cortexolone-17α-propionate. According to such embodiments, the minoxidil in solid form may be housed in a compartment of the container (designed to prevent contact between the two) that contains the pharmaceutical formulation containing cortexolone-17α-propionate. In some embodiments, the compartment of the container designed to prevent contact between the minoxidil in solid form and the pharmaceutical formulation containing cortexolone-17α-propionate may be a cap (e.g., a reservoir cap) containing a storage chamber for the solid, or a chamber isolated from the main chamber containing the pharmaceutical formulation containing cortexolone-17α-propionate. In some embodiments, the container holding the pharmaceutical formulation containing cortexolone-17α-propionate may be a reservoir cap containing minoxidil in solid form, the reservoir cap having a cutting device that is activated by pressing, twisting, or pulling the cap itself. According to such embodiments, activating the cutting device of the reservoir cap makes it possible to bring minoxidil in solid form into contact with the pharmaceutical formulation containing cortexolone-17α-propionate. In some embodiments, the first component and the second component may be combined immediately before use (e.g., within 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes before use) to be applied to the skin or scalp as a single compound formulation. In some embodiments, the first component may be in solid form and the second component may be a solution. In some embodiments, the first component may be in solid form and the second component may be a gel. In some embodiments, the first component may be in the form of a solid, and the second component may be a cream. In some embodiments, the first component may be in the form of a solid, and the second component may be a foam.

[0172] Storage stability Storage stability is an important evaluation metric for pharmaceuticals. Generally, high stability means that both the transport and storage of a given formulation are easy, increasing the likelihood that pharmacies will stock it and that consumers will not need to worry about special storage instructions. In some embodiments, the pharmaceutical formulations described herein may have a desirable stability profile that allows the final formulation to be stored 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 2 years, respectively, at room temperature (about 20°C) or refrigerated temperature (e.g., about 4°C).

[0173] For example, one of the main degradation pathways of cortexolone-17α-propionate is transesterification to cortexolone-21-propionate (17a-hydroxy-21-propionyloxy-pregna-4-ene-3,20-dione): [ka] That is the case.

[0174] In some embodiments, the degradation process of the pharmaceutical formulations disclosed herein can be slowed down by maintaining the pH at an acidic pH, for example, 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, about 4 to about 7, about 4 to about 6.5, about 4 to about 6, about 4 to about 5.5, about 4 to about 5, about 4 to about 4.5, or about 6.5, about 6, about 5.5, about 5, about 4.5, or about 4). In some embodiments, the pH is about 4. A suitable pH can be obtained by adding an appropriate amount of a pH adjuster (such as an acid as described herein).

[0175] In some embodiments, the amount of cortexolone-21-propionate or other degradation products contained in the pharmaceutical formulation described herein after a period of about 24 months at room temperature (about 20°C) or refrigerated temperature (about 4°C) may be less than about 5% by weight. [Brief explanation of the drawing]

[0176] [Figure 1] IL-6 concentration in human hair follicle dermal papilla cell (HFDPC) cell cultures after 24 hours of drug treatment.

[0177] [Figure 2] Parallel comparison of IL-6 concentrations in the clascoterone + DHT group and the clascoterone + DHT + minoxidil group in HFDPC. [Examples]

[0178] The pharmaceutical formulations described herein will be further described below 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, the embodiments should be construed as encompassing any variations that become apparent as a result of the teachings provided herein.

[0179] Example 1: 5% w / w anhydrous solution of cortexolone-17α-propionate

[0180] After solubilizing the activator in a solvent mixture, an emulsifier (polysorbate 80) was added to prepare a 5% by weight (w / w) solution of cortexolone-17α-propionate containing the components shown in Table 1 below. [Table 1]

[0181] This formulation exhibited the stability profile shown in Table 2 (at 40°C and 75% relative humidity (RH)). [Table 2]

[0182] Example 2: Minoxidil 5% w / w foam

[0183] A 5% wt (w / w) form of minoxidil containing the components shown in Table 3 can be prepared. [Table 3]

[0184] Example 3: 5% w / w solution of minoxidil

[0185] A 5% wt / w solution of minoxidil containing the components shown in Table 4 can be prepared. [Table 4]

[0186] Mix ethanol and propylene glycol and heat to 60°C-70°C. Once the temperature reaches the above range (60°C-70°C), add minoxidil and keep the mixture stirring until the minoxidil is completely solubilized. Then, slowly add water to the mixture while stirring and keeping the temperature within the range of 60°C-70°C until the final weight is reached. Finally, slowly cool the mixture to room temperature while stirring.

[0187] Example 4: Solution of minoxidil (2.5% w / w) and cortexolone-17α-propionate (2.5% w / w)

[0188] A solution can be prepared by combining minoxidil (2.5% w / w) containing the components shown in Table 5 with cortexolone-17α-propionate (2.5% w / w). [Table 5]

[0189] Mix ethanol and propylene glycol and heat to 60°C-70°C. Once the temperature reaches the above range (60°C-70°C), add minoxidil and keep the mixture stirring until the minoxidil is completely solubilized. Next, add cortexolone-17α-propionate and keep the mixture stirring until the minoxidil is completely solubilized. Then, slowly add water to the mixture while stirring and keeping the temperature within the range of 60°C-70°C until the final weight is reached. Finally, slowly cool the mixture to room temperature while stirring.

[0190] Example 5: A kit containing a minoxidil solution (5.0% w / w) and cortexolone-17α-propionate in solid form.

[0191] A 5% wt (w / w) solution of minoxidil containing the components shown in Table 6 can be prepared. [Table 6]

[0192] Mix ethanol and propylene glycol and heat to 60°C-70°C. Once the temperature reaches the above range (60°C-70°C), add minoxidil and keep the mixture stirring until all the minoxidil is completely solubilized. Then, slowly add water to the mixture while stirring and keeping the temperature within the range of 60°C-70°C until the final weight is reached. Then, slowly cool the mixture to room temperature while stirring. Next, fill a 60 mL glass bottle with the minoxidil solution. Fill a storage container with cortexolone-17α-propionate in powder form (approximately 3 g per cap). Next, cap the 60 mL bottle containing the minoxidil solution with the reservoir cap filled with cortexolone-17α-propionate powder.

[0193] Example 6: A kit containing a solution of cortexolone-17α-propionate (5.0% w / w) and minoxidil in solid form.

[0194] A 5% wt (w / w) solution of cortexolone-17α-propionate containing the components shown in Table 7 can be prepared. [Table 7]

[0195] After solubilizing the activator in a solvent mixture, an emulsifier (polysorbate 80) was added to prepare a 5% wt (w / w) solution of cortexolone-17α-propionate containing the components shown in Table 7. Next, the solution containing cortexolone-17α-propionate was filled into a 60 mL glass bottle. Minoxidil in powder form was filled into a storage container with a reservoir cap (approximately 3 g per cap). Next, the 60 mL bottle containing the cortexolone-17α-propionate solution was capped with a reservoir cap filled with minoxidil powder.

[0196] Example 7. Combination therapy with clascoterone and minoxidil synergistically inhibits IL-6 secretion in human dermal papilla cells (HFDPCs).

[0197] Clascoterone is a potent antiandrogenic agent that blocks the effects of androgen receptors in human hair follicles. Topical administration shows clinically meaningful efficacy in AGA. Part of its mechanism of action involves inhibiting androgen-induced IL-6 secretion from HFDPCs, which reduces IL-6-induced hair follicle damage. Therefore, IL-6 secretion from these cells is a relevant efficacy biomarker that correlates with hair growth.

[0198] Minoxidil shows efficacy when applied topically in AGA. ATP It is a channel modulator. There are no reports on its effect on IL-6 secretion in HFDPC.

[0199] This study showed that the combination of clascoterone and minoxidil was more effective than expected in inhibiting IL-6 secretion from HFDPCs. Specifically, the efficacy of this combination was greater than the sum of the efficacy of each drug individually.

[0200] These results suggest that the synergistic combination of topical crascoterone and topical minoxidil should provide significantly increased efficacy when used in patients with AGA.

[0201] background

[0202] The majority of a hair follicle consists of the hair shaft itself and keratinocytes, which are epithelial cells that make up the surrounding inner and outer root sheaths. However, the dermal papilla (DP), a specialized mesenchymal population, plays a crucial role in directing the activity 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 compartment regulates many aspects of hair follicle biology. The DP influences the size and shape of the hair shaft by generating signals that act on keratinocytes.

[0203] In male pattern baldness, the inability to maintain DP cell function is associated with progressive hair thinning and a reduction in hair follicle size (Elliott et al., 1999). Several observations suggest that this arises from a primary defect in DP. One of the important paracrine factors produced by alopecia DP cells in male pattern baldness is the cytokine IL-6.

[0204] IL-6 is upregulated in hair loss DP cells in response to dihydrotestosterone (DHT) compared to non-hair loss DP cells (Kwack et al., 2012), and the IL-6 receptor is expressed in hair follicle keratinocytes, including hair matrix cells. Recombinant human IL-6 (rhIL-6) inhibited hair shaft elongation and suppressed hair matrix cell proliferation in cultured human hair follicles. Furthermore, injection of rhIL-6 into the subcutaneous tissue of mice during the growth phase (hair growth phase) caused premature onset of the regression phase (growth inhibition). Thus, DHT-inducible IL-6 inhibits hair growth as a paracrine mediator derived from DP (Kwack et al., 2012).

[0205] Effective drugs to stop the progression of hair loss include antiandrogens (e.g., clascoterone), 5-α-reductase type 2 inhibitors (e.g., finasteride), and K ATP There are three types of channel openers (e.g., minoxidil). These compounds act on DP cells in cell culture or in isolated hair follicles (Kaufman et al., 1998; Randall, 2008; Shorter et al., 2008).

[0206] It has been demonstrated that clascoterone can inhibit DHT-induced IL-6 expression in dermal papilla cells (Rosette et al., 2019). However, it is unknown whether minoxidil can regulate IL-6 expression in DP cells, or whether the combination of clascoterone and minoxidil may be more effective than either drug alone.

[0207] Experiment Section

[0208] [Cell line]

[0209] Human dermal papilla cells (HFDPCs) from the vertex region of human scalp were obtained from Cell Applications (San Diego, California). Cells were grown in complete dermal papilla cell basal medium (Cell Applications, San Diego, California) and 10% fetal bovine serum (Gibco, Gaythersburg, Maryland). All flasks and plates used were collagen-coated. Collagen was obtained from Cell Applications (San Diego, California) and used according to the manufacturer's instructions. To analyze IL-6 secretion, cells were trypsin-treated and seeded (2 × 10⁶) in collagen-coated 24-well plates containing dermal papilla cell basal medium and 5% charcoal-dextran filtered serum (DCC-FBS) (Omega Scientific, Tarzana, California). 5 Cells were incubated overnight. Experiments were performed in sets of three wells. The following day, the medium was removed, and fresh basal medium + compound and 5% DCC-FBS containing DHT were added and incubated for 24 hours. All cell incubations were performed at 37°C and 5% CO2. It was determined that the concentrations of the compound used in these experiments did not have a significant effect on cell proliferation (data omitted).

[0210] [Compound]

[0211] Clascoterone (CB0301) was custom synthesized for Cosmo Pharmaceuticals (Linäte, Italy). Dihydrotestosterone (DHT) was obtained from Millipore-Sigma (St. Louis, Missouri), and minoxidil was obtained from VWR (San Diego, California). All compounds were dissolved in 100% DMSO and then diluted in HFDP base medium + 5% DCC-FBS for cell culture experiments. The final DMSO concentration in each well was 0.1%.

[0212] [Quantification of IL-6 protein expression by ELISA]

[0213] Hair papilla cells were treated with various concentrations of DHT, clacotelon, and minoxidil. The compounds were added to the wells simultaneously (no pre-incubation). After 24 hours of incubation, the culture medium in each well was collected and immediately used to determine the secreted IL-6. The human IL-6 ELISA detection kit was manufactured by Invitrogen (San Diego, California) and used according to the manufacturer's instructions. Absorbance was quantified using a ClarioStar microplate reader (Oltenberg, Germany), and the data were analyzed using Prism software version 10.1.1 (GraphPad, La Jolla, California).

[0214] result

[0215] Figure 1 shows that 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). In the presence of DHT, 1 μM minoxidil reduced IL-6 secretion by only 7% (from 47.5 pg / mL to 44.3 pg / mL).

[0216] In the presence of 100 nM DHT, clascoterone dose-dependently inhibited IL-6 secretion at 24 hours. Importantly, the combination of 1 μM minoxidil with either 15 nM or 30 nM clascoterone showed an unexpected synergistic effect, resulting in significantly stronger inhibition of IL-6 secretion compared to clascoterone treatment alone. The 60 nM clascoterone group also showed a synergistic effect, but it was not statistically significant.

[0217] All groups treated with clascoterone showed statistically significant inhibition of IL-6 secretion compared to 100 nM DHT. Table 8 lists the IL-6 concentration and relative inhibition by the compound under each treatment condition.

[0218] [Table 8]

[0219] As shown in Figure 2, when comparing the effects of classcoterone + DHT with those of classcoterone + DHT + minoxidil, the group treated with classcoterone containing 1 uM minoxidil showed a greater effect than the additive effect. In other words, when combined with 1 uM minoxidil, all classcoterone concentrations resulted in synergistic IL-6 inhibition in HFDPC.

[0220] Table 9 lists the expected additive efficacy and the actually observed combined efficacy of the combination of clascoterone and minoxidil. This includes p-values ​​from ANOVA statistical analysis comparing the mean values ​​of the clascoterone + DHT group and the clascoterone + DHT + minoxidil group.

[0221] [Table 9]

[0222] The 15nM classcoterone + DHT group showed 16% inhibition compared to DHT alone, and the 1μM minoxidil + DHT group showed 7% inhibition compared to DHT alone. Therefore, the additive effect should result in 23% (16% + 7%) inhibition. However, the 34% inhibition observed for the classcoterone + DHT + minoxidil combination was greater than 23%, indicating synergistic inhibition between classcoterone and minoxidil when used in combination. This combination therapy showed a significant difference compared to classcoterone + DHT (p<0.009).

[0223] The 30nM classcoterone group showed 19% inhibition compared to DHT alone, and the 1μM minoxidil group showed 7% inhibition compared to DHT alone. Therefore, the additive effect should result in 26% (19% + 9%) inhibition. However, the 36% inhibition observed for the aforementioned combination was larger, indicating synergistic inhibition between classcoterone and minoxidil when used in combination. This combination therapy (classcoterone + DHT + minoxidil) showed a significant difference compared to classcoterone + DHT (p<0.003).

[0224] The 60 nM class cotelone group showed 34% inhibition compared to DHT alone, and the 1 μM minoxidil group showed 7% inhibition compared to DHT alone. Therefore, the additive effect should result in 41% (34% + 7%) inhibition. The 43% inhibition observed for the aforementioned combination is larger, which may indicate synergistic inhibition. However, this difference was not statistically significant (p<0.7).

[0225] conclusion

[0226] Human dermal papilla cells activate androgen receptors in response to DHT. IL-6 is a key negative regulator of hair growth and has been shown to be elevated in hair follicles of bald scalps compared to those of non-bald scalps. Clascoterone is a potent anti-androgen agent that has clinically demonstrated efficacy in increasing hair growth in patients with male pattern baldness. It has been previously demonstrated that clascoterone inhibits DHT-induced IL-6 secretion from human dermal papilla cells. Therefore, IL-6 is an HFDPC biomarker that correlates with hair growth.

[0227] While minoxidil is approved for the treatment of male pattern baldness, there is no literature on its effect on IL-6 secretion from dermal papilla cells. The experimental data presented showed that minoxidil exhibited a mild, non-significant inhibition of IL-6 secretion from HFDPCs. Clascoterone showed a statistically significant inhibition of IL-6 in DHT-treated HFDPCs at all concentrations tested. A comparison of clascoterone + DHT versus clascoterone + DHT + minoxidil demonstrated that this combination is not merely additive. In fact, the combination of clascoterone and minoxidil showed a synergistic effect in inhibiting IL-6 secretion from HFDPCs.

[0228] Therefore, it is clear that male pattern baldness patients should dramatically benefit from combination therapy with clascoterone and minoxidil.

[0229] The terms and expressions used herein are for illustrative purposes only, and not for limitation. Therefore, the terms and / or expressions herein should be interpreted by those skilled in the art in light of the teachings and guidance provided herein.

[0230] The breadth and scope of the present invention should not be limited by any of the exemplary embodiments described above, but should be defined solely by the following claims and their equivalents.

[0231] Any patents, patent applications, and other references mentioned or referenced in this application are incorporated herein by reference in their entirety.

[0232] References

[0233] Greco V, Chen T, Rendl M, Schober M, Pasolli HA, Stokes N, Dela Cruz-Racelis J, Fuchs E, "A two-step mechanism for stem cell activation during hair regeneration," Cell Stem Cell 4:155-169. 2009.

[0234] Elliott K, Stephenson TJ, and Messenger AG, "Differences in hair follicle dermal papilla volume are due to extracellular matrix volume and cell number: Implications for the control of hair follicle size and androgen responses," Journal of Invest Dermatology 113:873-877. 1999.

[0235] Mi Hee Kwack, Ji Sup Ahn, Moon Kyu Kim, Jung Chul Kim, Young Kwan Sung, "Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice," Journal of Invest Dermatology (J Invest Dermatol.) 2012 Jan;132(1):43-9.

[0236] Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R, Bergfeld W, Price VH, Van Neste D, Roberts JL, Hordinsky M, et al., "Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group," Journal of the American Academy of Dermatology (J Am Acad Dermatol) 39:578-589. 1998.

[0237] Randall VA. 2008, "Androgens and hair growth," Dermatologic Therapy 21:314-328.

[0238] Shorter K, Farjo NP, Picksley SM, and Randall VA, "Human hair follicles contain two forms of ATP-sensitive potassium channels, only one of which is sensitive to minoxidil," FASEB J 22:1725-1736. 2008.

[0239] Caridad Rosette, Niccolette Rosette, Alessandro Mazzetti, Luigi Moro, and Mara Gerloni, "Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro," Journal of Drugs in Dermatology, 2019 Feb 1;18(2):197-201.

Claims

1. A method for treating hair loss in a subject requiring treatment for hair loss, comprising co-administering an effective amount of cortexolone-17α-propionate and an effective amount of minoxidil to the subject by topical application.

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

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

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

5. The method according to claim 4, wherein the cortexolone-17α-propionate and the minoxidil are present in separate pharmaceutical formulations.

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

7. The method according to claim 6, wherein the cortexolone-17α-propionate and the minoxidil are present in the same pharmaceutical formulation.

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

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

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

11. The aforementioned solution may be water, saline, buffered saline solution, polyol, polyol ether, or C １ -C ７ The method according to claim 10, comprising alcohol or a combination thereof.

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

13. The method according to any one of claims 1 to 12, wherein the cortexolone-17α-propionate is co-administered as a pharmaceutical preparation containing less than 5% by weight of water.

14. The method according to any one of claims 1 to 13, wherein the pharmaceutical preparation is co-administered by topical application once or twice a day.

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

16. The method according to claim 15, wherein the alopecia is male pattern baldness, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination thereof.

17. The method according to claim 16, wherein the alopecia areata is selected from the group consisting of diffuse alopecia areata, single-spot alopecia areata, multiple-spot alopecia areata, serpentine alopecia, alopecia totalis, and alopecia universalis.

18. The method according to claim 16, wherein the hair loss is male pattern baldness.

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

20. The topical pharmaceutical preparation according to claim 19, wherein the cortexolone-17α-propionate is completely solubilized in the pharmaceutical preparation.

21. The topical pharmaceutical preparation according to claim 19 or claim 20, wherein the pharmaceutical preparation contains cortexolone-17α-propionate at a concentration of about 1% to about 20% by weight.

22. The topical pharmaceutical preparation according to any one of claims 19 to 21, wherein the pharmaceutical preparation contains minoxidil at a concentration of about 0.1% to about 20% by weight.

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

24. The topical pharmaceutical preparation according to claim 23, wherein the liquid or semi-solid preparation is a solution, suspension, emulsion, microemulsion, cream, paste, gel, ointment, or foam.

25. The topical pharmaceutical preparation according to claim 24, wherein the pharmaceutical preparation is a solution.

26. The topical pharmaceutical preparation according to claim 24 or claim 25, wherein the solution comprises water, a saline solution, a buffered saline solution, or a combination thereof.

27. The topical pharmaceutical preparation according to any one of claims 19 to 26, wherein the pharmaceutical preparation contains less than 5% by weight of water.

28. The one or more pharmaceutically acceptable carriers are polyols, polyol ethers, and C １ -C ７ A topical pharmaceutical preparation according to any one of claims 19 to 27, selected from the group consisting of alcohols.

29. Said C １ -C ７ The topical pharmaceutical preparation according to claim 28, wherein the alcohol is ethanol, isopropanol, methanol, or a combination thereof.

30. Said C １ -C ７ The topical pharmaceutical preparation according to claim 29, wherein the alcohol is ethanol.

31. The topical pharmaceutical preparation according to any one of claims 28 to 30, wherein the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerol, hexanetriol, and combinations thereof.

32. The topical pharmaceutical preparation according to claim 31, wherein the polyol is propylene glycol.

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

34. The topical pharmaceutical preparation according to claim 33, wherein the polyol ether is diethylene glycol monoethyl ether.

35. The polyol is propylene glycol, the polyol ether is diethylene glycol monoethyl ether, and the C １ -C ７ -alcohol is ethanol. The topical pharmaceutical preparation according to any one of claims 28 to 34.

36. The topical pharmaceutical preparation according to any one of claims 19 to 35, wherein the pharmaceutical preparation further comprises at least one additive selected from an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a humectant, a preservative, a chelating agent, and a combination thereof.

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

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

39. The emulsifiers include PEG-15 hydroxystearate (polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbate 20, polysorbate 60, polysorbate 80, PEG-20 cetostearyl ether, polyoxyl-25 cetostearyl, cetomacrogol 1000, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, and propylene glycol fat. A topical pharmaceutical preparation according to any one of claims 36 to 38, selected from the group consisting of acid esters, polyglycerin fatty acid esters, polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, caprylocapryl polyoxyyl-8 glyceride, caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, oleoyl polyoxylglyceride, and combinations thereof.

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

41. The topical pharmaceutical preparation according to any one of claims 36 to 40, wherein the penetration enhancer is selected from the group consisting of diols, polyols, fatty acids, fatty alcohols, fatty acid esters, surfactants, pyrrolidones, and combinations thereof.

42. The topical pharmaceutical preparation according to any one of claims 36 to 41, wherein the humectant is selected from the group consisting of fatty alcohols, fatty acids, fatty acid esters, oils, polyethylene glycol, glycerin, alpha hydroxy acids, and combinations thereof.

43. The topical pharmaceutical preparation according to 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 topical pharmaceutical preparation according to any one of claims 36 to 43, wherein the buffering agent is a phosphate buffering agent, a citrate buffering agent, a lactic acid buffering agent, or a combination thereof.

45. A method for treating alopecia, comprising topically administering a topical pharmaceutical preparation described in any one of claims 19 to 44 to a subject requiring treatment for alopecia, wherein topical administration of the pharmaceutical preparation for at least six months achieves a weighted mean hair growth evaluation (HGA) score of approximately 0.30 compared to a control (vehicle).

46. A method for treating alopecia, comprising topically administering a topical pharmaceutical preparation according to any one of claims 19 to 44 to a subject requiring treatment for alopecia, wherein topical administration of the pharmaceutical preparation for at least six months achieves a weighted mean IGA (physician's overall assessment) score of approximately 0.43 compared to a control.

47. A method for treating alopecia, comprising topically administering a topical pharmaceutical preparation described in any one of claims 19 to 44 to a subject requiring treatment for alopecia, wherein the topical administration of the pharmaceutical preparation for at least six months is not accompanied by systemic antiandrogenic side effects.

48. The method includes administering a topical pharmaceutical preparation described in any one of claims 19 to 44 to a subject requiring treatment for alopecia, wherein the topical administration of the pharmaceutical preparation is a) Apply daily for 6 months or, after BID application, 9 bottles / cm ２ The above is the mean change from baseline in the number of hairs in the target area; or b) 10 bottles / cm after 6 months of continuous application or BID application. ２ The above is the mean change from baseline in the number of hairs in the target area; or c) 11 bottles / cm² after 6 months of continuous application or BID application. ２ The above is the mean change from baseline in the number of hairs in the target area; or d) 12 bottles / cm² after 6 months of continuous application or BID application. ２ The above is the mean change from baseline in the number of hairs in the target area; or e) A weighted average HGA score of 0.20 or higher after 6 months of daily application or BID application; or f) A weighted average HGA score of 0.30 or higher after 6 months of daily application or BID application; or g) A weighted average HGA score of 0.40 or higher after 6 months of daily application or BID application; or h) A weighted average IGA score of 0.10 or higher after 6 months of daily application or BID application; or i) A weighted average IGA score of 0.20 or higher after 6 months of daily application or BID application; or j) A weighted average IGA score of 0.30 or higher after 6 months of daily application or BID application; or k) A favorable (positive) HGA score in at least about 10% of the subjects after 6 months of daily application or BID application; or l) A favorable (positive) HGA score in at least approximately 20% of the subjects after 6 months of daily application or BID application; or m) A favorable (positive) HGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or n) A favorable (positive) IGA score in at least about 10% of the subjects after 6 months of daily application or BID application; or o) A favorable (positive) IGA score in at least about 20% of the subjects after 6 months of daily application or BID application; or p) A favorable (positive) IGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or q) After 6 months of daily application or BID application, a favorable (positive) IGA score was observed in at least approximately 40% of the subjects. A treatment method for alopecia that provides relief.

49. Cortexolone-17α-propionate and minoxidil for use in the treatment of hair loss in subjects requiring treatment for hair loss, characterized by being co-administered topically to the subject.

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

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

52. Cortexolone-17α-propionate and minoxidil for use according to any one of claims 49 to 51, wherein the cortexolone-17α-propionate and minoxidil are administered sequentially, preferably in separate pharmaceutical formulations.

53. Cortexolone-17α-propionate and minoxidil for use according to any one of claims 49 to 51, wherein the cortexolone-17α-propionate and minoxidil are co-administered simultaneously, preferably the cortexolone-17α-propionate and minoxidil are present in the same pharmaceutical preparation.

54. Cortexolone-17α-propionate and minoxidil for use according to claim 53, wherein the pharmaceutical preparation is a liquid or semi-solid preparation, preferably a solution, suspension, emulsion, microemulsion, cream, paste, gel, ointment, or foam, and more preferably a solution.

55. The aforementioned solution is water, saline solution, buffered saline solution, polyol, polyol ether, C １ -C ７ Cortexolone-17α-propionate and minoxidil for use according to claim 54, comprising alcohol or a combination thereof.

56. Cortexolone-17α-propionate and minoxidil for use according to any one of claims 54 to 55, wherein the pharmaceutical formulation further comprises at least one additive selected from an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a humectant, a preservative, a chelating agent, and a combination thereof.

57. Cortexolone-17α-propionate and minoxidil for use according to any one of claims 49 to 56, wherein the cortexolone-17α-propionate is co-administered as a pharmaceutical preparation containing less than 5% by weight of water.

58. Cortexolone-17α-propionate and minoxidil for use according to any one of claims 49 to 57, wherein the pharmaceutical preparation is co-administered by topical application once or twice a day.

59. Cortexolone-17α-propionate and minoxidil for use according to any one of claims 49 to 58, wherein the hair loss is alopecia, preferably the alopecia is male pattern baldness, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination thereof, and more preferably the alopecia is male pattern baldness.

60. Cortexolone-17α-propionate and minoxidil for use according to claim 59, wherein the alopecia areata is selected from the group consisting of diffuse alopecia areata, single-spot alopecia areata, multiple-spot alopecia areata, serpentine alopecia, alopecia totalis, and alopecia universalis.

61. A topical pharmaceutical preparation according to any one of claims 19 to 44, for use in the treatment of hair loss in subjects requiring treatment for hair loss.

62. The topical pharmaceutical preparation for use according to claim 61, wherein the hair loss is alopecia.

63. The topical pharmaceutical formulation for use according to claim 62, wherein the hair loss is male pattern baldness, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination thereof.

64. The topical pharmaceutical preparation for use according to claim 63, wherein the alopecia areata is selected from the group consisting of diffuse alopecia areata, single-spot alopecia areata, multiple-spot alopecia areata, serpentine alopecia, alopecia totalis, and alopecia universalis.

65. A topical pharmaceutical preparation for use according to claim 62, wherein the alopecia is male pattern baldness.

66. A topical pharmaceutical formulation for use according to any one of claims 61 to 65, wherein topical administration of the pharmaceutical formulation for at least six months achieves a weighted mean hair growth assessment (HGA) score of about 0.30 compared to a control.

67. A topical pharmaceutical formulation for use according to any one of claims 61 to 65, wherein topical administration of the pharmaceutical formulation for at least six months achieves a weighted mean IGA (Physician's Global Assessment) score of approximately 0.43 compared to a control.

68. A topical pharmaceutical preparation for use according to any one of claims 61 to 67, wherein topical administration of the pharmaceutical preparation for at least six months is not accompanied by systemic antiandrogenic side effects.

69. Topical administration of the aforementioned pharmaceutical preparation a) Apply daily for 6 months or, after BID application, 9 bottles / cm ２ The above is the mean change from baseline in the number of hairs in the target area; or b) 10 bottles / cm after 6 months of continuous application or BID application. ２ The above is the mean change from baseline in the number of hairs in the target area; or c) 11 bottles / cm² after 6 months of continuous application or BID application. ２ The above is the mean change from baseline in the number of hairs in the target area; or d) 12 bottles / cm² after 6 months of continuous application or BID application. ２ The above is the mean change from baseline in the number of hairs in the target area; or e) A weighted average HGA score of 0.20 or higher after 6 months of daily application or BID application; or f) A weighted average HGA score of 0.30 or higher after 6 months of daily application or BID application; or g) A weighted average HGA score of 0.40 or higher after 6 months of daily application or BID application; or h) A weighted average IGA score of 0.10 or higher after 6 months of daily application or BID application; or i) A weighted average IGA score of 0.20 or higher after 6 months of daily application or BID application; or j) A weighted average IGA score of 0.30 or higher after 6 months of daily application or BID application; or k) A favorable (positive) HGA score in at least about 10% of the subjects after 6 months of daily application or BID application; or l) A favorable (positive) HGA score in at least approximately 20% of the subjects after 6 months of daily application or BID application; or m) A favorable (positive) HGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or n) A favorable (positive) IGA score in at least about 10% of the subjects after 6 months of daily application or BID application; or o) A favorable (positive) IGA score in at least about 20% of the subjects after 6 months of daily application or BID application; or p) A favorable (positive) IGA score in at least approximately 30% of the subjects after 6 months of daily application or BID application; or q) After 6 months of daily application or BID application, a favorable (positive) IGA score was observed in at least approximately 40% of the subjects. A topical pharmaceutical preparation for use according to any one of claims 61 to 67, which provides the following:

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