[go: up one dir, main page]

WO2025068281A1 - CORTÉXOLONE-17α-PROPIONATE POUR LE TRAITEMENT D'ÉRUPTIONS ACNÉIFORMES - Google Patents

CORTÉXOLONE-17α-PROPIONATE POUR LE TRAITEMENT D'ÉRUPTIONS ACNÉIFORMES Download PDF

Info

Publication number
WO2025068281A1
WO2025068281A1 PCT/EP2024/076924 EP2024076924W WO2025068281A1 WO 2025068281 A1 WO2025068281 A1 WO 2025068281A1 EP 2024076924 W EP2024076924 W EP 2024076924W WO 2025068281 A1 WO2025068281 A1 WO 2025068281A1
Authority
WO
WIPO (PCT)
Prior art keywords
cortexolone
propionate
acid
aspects
inhibitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/076924
Other languages
English (en)
Inventor
Luigi Maria Longo
Mara Gerloni
Stefania Pagani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cassiopea SpA
Original Assignee
Cassiopea SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP23199673.7A external-priority patent/EP4529925A1/fr
Application filed by Cassiopea SpA filed Critical Cassiopea SpA
Publication of WO2025068281A1 publication Critical patent/WO2025068281A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • Acneiform eruptions are a subset of acne rash on the skin characterized by a papulopustular rash on the face, scalp, chest, or upper back that can be specifically induced by certain medications.
  • the most common drugs associated with acneiform eruptions are corticosteroids, neuropsychotherapeutic drugs, anti-tuberculosis drugs, and immunomodulating molecules.
  • targeted therapeutic drug for oncology such as epidermal growth factor receptor (EGFR) inhibitors and other kinase inhibitors, have been associated with increased frequency of acneiform eruptions.
  • Dermatologic reactions are the most common adverse reactions associated with EGFR inhibitors, affecting up to 90% of patients.
  • Acneiform eruptions can, for example, decrease patient compliance, lead to discontinuation of therapy, affect quality of life, increase risk of infection, and reduce treatment effectiveness.
  • Acneiform eruptions typically have an acute onset as a mild to moderate skin rash, often resembling acne vulgaris that can escalate to lesions, such as more severe papules, pustules, crusts, and cysts.
  • Therapeutic intervention of acneiform eruption involves appropriate skincare, sun protection, moisturizers, topical corticosteroids, and topical systemic antibiotics.
  • acneiform eruptions are particularly resistant to conventional acne therapies. See e.g., Brezinski et al., Practical Dermatology: Clinical Focus, 37-40 (March 2013), which is incorporated herein by reference in its entirety.
  • Brezinski et al. discloses the usefulness of topical anti- androgenic therapy, in particular with spironolactone, in the treatment of cutaneous acneiform eruption indiced by EGFR inhibitors.
  • Cortexolone-17a-propionate also known as 17a-propionyloxy-21-hydroxy-pregna-4-ene-3, 20- dione and clascoterone, is a topical antiandrogen that inhibits the effect of androgenic hormones (e.g., testosterone and its more active metabolite dihydrotestosterone) by preventing the binding of the same at the androgen receptor (AR).
  • Cortexolone- 17a-propionate is known to be suitable for treating acne, alopecia, and other diseases of skin and cutaneous appendages. See, e.g., U.S. Patent Nos.
  • Cortexolone-17a-propionate is also known to exist in several distinct crystalline polymorphs, each having unique properties. See, e.g., U.S. Patent No. 8,785,427 the entirety of which is incorporated herein by reference.
  • acneiform eruptions can be effectively treated with cortexolone-17a-propionate for to treat or prevent rashes and/or palliation.
  • an advantageous clinical result can be realized after daily topical administration for an appropriate amount of time, such as a few days, weeks, or months.
  • the present disclosure provides a method of treating a cutaneous acneiform eruption in a subject in need thereof comprising topically administering an effective amount of cortexolone-17a- propionate to an affected area of the subject.
  • the acneiform eruption comprises a papule, a pustule, a nodule, crust, a cyst, or any combination thereof, on the affected area of the subject.
  • the acneiform eruption is a targeted therapeutic drug-induced lesion.
  • the subject is receiving treatment for cancer.
  • the treatment comprises a targeted therapeutic drug selected from the group consisting of an Epidermal Growth Factor Receptor (EGFR) inhibitor, a Mitogen-Activated Protein Kinase (MEK) inhibitor, a Human Epidermal Growth Factor Receptor (HER-2) inhibitor, a Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitor, a RAS/RAF/MEK/ERK (MAPK) inhibitor, a multikinase inhibitor, a mammalian Target of Rapamycin (mTOR) inhibitor, a Programmed Death (PD-1)/Programmed Death Ligand (PDL-1 and PDL-2) inhibitor, a Cytotoxic T Lymphocyte-Associated Antigen (CTLA-4) inhibitor, an Anaplastic Lymphoma Kinase (ALK) inhibitor, a Raf kinase (RAF) inhibitor, a Phosphoinositide 3- kinase (PI3K) inhibitor, an ANK-A gammTOR,
  • the targeted therapeutic drug is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, avitinib, olmutinib, pelitinib, pyrotinib, brigatinib, vandetanib, icotinib, mobocertinib, almonertinib, lazertinib, alflutinib, rociletinib, toartinib, naquotinib, cetuximab, panitumumab, necitumumab, amivantamab, trametinib, cobimetinib, pimasertib, mirdametinib, refametinib, binimetinib, selumetinib, trastuzumab, pertuzumab, bevaci
  • the cortexolone-17a-propionate is administered in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier.
  • the pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a biogel, a gel, a foam, an ointment, a wash -off agent, a patch, a hydrogel patch, or a pledget.
  • the pharmaceutical formulation comprises at least one additive selected from the group consisting of a solvent, an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and any combination thereof.
  • the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, tocopherol, propyl gallate, 2,4,5 -trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, pharmaceutically acceptable salts thereof, esters thereof, and any combination thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • ascorbyl palmitate ascorbic acid
  • tocopherol propyl gallate
  • 2,4,5 -trihydroxybutyrophenone 4-hydroxymethyl-2,6-di-tert-butylphenol
  • erythorbic acid gum guaiac
  • the emulsifier is selected from the group consisting of 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, glyceryl monostearate, cetomacrogol 1000, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate a propylene glycol ester of a fatty acid, a polyglycerol ester of a fatty acid, polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, caprylocapryl polyoxyl-8 glycerides, caprylocaproyl polyoxylglycerides, lauroyl polyoxylglycerides,
  • the penetration enhancer is selected from the group consisting of a polyol, a fatty acid, a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and any combination thereof.
  • the moisturizer is cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, glyceryl monostearate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin (e.g., mineral oil), shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or any combination thereof.
  • liquid paraffin e.g., mineral oil
  • shea butter a silicone oil
  • castor oil a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or any combination thereof.
  • the buffer is a phosphate buffer, citrate buffer, lactate buffer, or any combination thereof.
  • the pharmaceutical formulation comprises cortexolone 17a-propionate, propylene glycol, cetyl alcohol, tocopherol, citric acid (e.g., citric acid monohydrate), edetate disodium, mono- and di -glycerides, liquid paraffin (e.g., mineral oil), polysorbate 80, and water.
  • citric acid e.g., citric acid monohydrate
  • edetate disodium e.g., mono- and di -glycerides
  • liquid paraffin e.g., mineral oil
  • polysorbate 80 e.g., water
  • the pharmaceutical formulation comprises about 1 wt% cortexolone 17a-propionate, about 25 wt% propylene glycol, about 2.5 wt% cetyl alcohol, about 15 wt% glyceryl monostearate, about 10 wt% liquid paraffin (e.g., mineral oil), about 1 wt% polysorbate 80, and up to about 0.05 wt% tocopherol.
  • the pharmaceutical formulation can also comprise a suitable agent for adjusting the pH, such as citric acid.
  • the cortexolone-17a-propionate is administered in an amount of about 0.1 to about 5 wt%.
  • the cortexolone 17a-propionate is administered in an amount of about 1 wt%.
  • topically applying the cortexolone 17a-propionate comprises administering a formulation comprising cortexolone 17a-propionate dissolved therein and cortexolone 17a-propionate present in at least one of polymorphic Forms I, II, III, and IV, or any combination thereof.
  • the term “or” is a logical disjunction (i.e., and/or) and does not indicate an exclusive disjunction unless expressly indicated as such with the terms “either,” “unless,” “alternatively,” and words of similar effect.
  • the term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. “About” can mean a range of up to 10% (e.g., up to 5%, up to 1%) of a given value.
  • acneiform eruption or “acneiform rash” refers to a skin disease that can be characterized as a papule, a pustule, a nodule, crust, or a cyst.
  • the phrase “affected area” refers to an area of the skin that presents with acneiform eruptions.
  • An affected area can include any skin region on the body, including, e.g., face, arm, armpit, leg, chest, abdomen, back, neck, or any combination of the foregoing.
  • anhydrous means substantially free of water, i.e., having less than about 5 wt% water, and, in certain aspects as specified herein, less than about 3 wt% water, or less than about 1 wt% water.
  • anti-acneiform agent refers to an agent which treats, prevents, and/or ameliorates acneiform eruptions including, but not limited to, an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, and urea.
  • the term “at least” prior to a number or series of numbers is understood to include the number associated with the term “at least,” and all subsequent numbers or integers that could logically be included, as clear from context.
  • “at least” can modify each of the numbers in the series or range.
  • “at least 3” means at least 3, at least 4, at least 5, etc.
  • “Once Daily” or “OD” means “once a day.”
  • Bis In Die or “BID” means “twice a day.”
  • the term “buffer” refers to a compound or group of compounds (e.g., a weak conjugate acid-base pair, such as a weak acid and its conjugate base or a weak base and its conjugate acid) that controls the pH of a solution within a desired range.
  • the conjugate base can be added as a Group I or Group II salt.
  • a buffer include, e.g., a phosphate buffer, citrate buffer, lactate buffer, or any combination thereof.
  • C1-C7 alcohol refers to an alcohol having 1, 2, 3, 4, 5, 6, or 7 carbons that is suitable for use in a topical pharmaceutical formulation.
  • examples of such C1-C7 alcohols can include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, benzyl alcohol, and the like.
  • C1-C7 alcohols, and particularly short chain C1-C7 alcohols, like C2-C3 alcohols e.g., ethanol, n-propanol, or isopropyl alcohol
  • chelating agent refers to a compound that can bind metal ions or metallic compounds.
  • a chelating agent can stabilize the formulation by preventing, e.g., oxidation or precipitation.
  • Suitable chelating agents include, e.g., citric acid (e.g., citric acid monohydrate, anhydrous citric acid), phytic acid, sodium phytate, clioquinol, ethylenediaminetetraacetic acid (EDTA) or a salt thereof (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, or any combination thereof.
  • citric acid e.g., citric acid monohydrate, anhydrous citric acid
  • phytic acid sodium phytate
  • clioquinol ethylenediaminetetraacetic acid (EDTA) or a salt thereof (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, or
  • co-administration means concurrent or sequential administration of two different active agents, i.e., cortexolone-17a-propionate and a secondary anti-acneiform agent.
  • the active agents are administered close enough in time to each other that the first and second therapeutic agents are simultaneously present in subjects receiving the co-administration.
  • cortexolone also known as “11 -deoxycortisol” or “Reichstein’s substance” refers to the compound having the structure:
  • cortexolone-17a-propionate refers to the compound 17a-propionyloxy- 2 l-hydroxy-pregna-4-ene-3, 20-dione, which is also known as clascoterone and is equivalent to the chemical structure:
  • degradation product refers to those compounds that result from the in vitro degradation of cortexolone-17a-propionate.
  • exemplary known cortexolone-17a-propionate degradation products can include, but are not limited to, cortexolone-21 -propionate and cortexolone.
  • the term “effective amount” as used herein refers to an amount of a given active agent that is sufficient, when administered by a method of the disclosure, to efficaciously treat the condition or disease of interest in a subject in need thereof.
  • ethanol refers to ethyl alcohol, i.e., CH3CH2OH, and includes pure (absolute) ethanol and 96% ethanol, the latter being ethanol containing water in an amount typically ranging from about 4% to about 5.1% by volume.
  • fatty refers to an aliphatic carbon chain that is either saturated or unsaturated.
  • the chain is any suitable length, such as C4-C28 (e.g., C4, C5, Ce, C7, Cs, C>, C10, Cn, C12, C13, C14, C15, Cie, C17, Cis, C19, C20, C21, C22, C23, and C24), including more specifically C10-C24, C10- C20, C12-C22, and C12-C18 chain lengths.
  • C4-C28 e.g., C4, C5, Ce, C7, Cs, C>, C10, Cn, C12, C13, C14, C15, Cie, C17, Cis, C19, C20, C21, C22, C23, and C24
  • C10-C24 C10- C20, C12-C22, and C12-C18 chain lengths.
  • metabolite refers to those compounds that result from the in vivo metabolism or degradation of an active agent, such as cortexolone -17a-propionate.
  • an active agent such as cortexolone -17a-propionate.
  • exemplary known metabolites of cortexolone- 17a-propionate can include, but are not limited to, cortexolone and tetrahydrocortexolone .
  • moisturizer refers to those compounds that impart moisture to skin, soften skin, or both.
  • exemplary moisturizers are emollients that include, e.g., a fatty alcohol, a fatty acid, a fatty acid ester, an oil, a polyethylene glycol, glycerol, an alpha hydroxy acid (e.g., lactic acid, glycolic acid, malic acid, citric acid, or tartaric acid), and any combination thereof.
  • moisturizer examples include, e.g., cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin (e.g., mineral oil), shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, and any combination thereof.
  • a moisturizer include, e.g., cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin (e.g., mineral oil), shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, mal
  • natural oil refers to those oils isolable from natural sources.
  • exemplary natural oils can include, but are not limited to, olive oil, jojoba oil, coconut oil, almond oil, cottonseed oil, safflower oil, sunflower oil, sesame oil, soybean oil, castor oil, calendula oil, and the like.
  • penetration enhancer refers to those pharmaceutically acceptable compounds that increase penetration of the active agent through the dermis.
  • Exemplary penetration enhancers include, e.g., hydroxypropyl [3-cyclodextrin, polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide, pyrrolidone, N-methyl -2 -pyrrolidone, diethylene glycol monoethyl ether (e.g., TRANSCUTOLTM, Gattefosse, France), dimethyl isosorbide, diethyl sebacate, azone, menthol, nerol, camphor, methyl salicylate, polysorbate 80 (polyoxyethylene (80) sorbitan monooleate) (e.g., TWEENTM 80, Sigma-Aldrich, St.
  • hydroxypropyl [3-cyclodextrin polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide, pyrrolidone, N-methyl -2 -pyrrolidone, diethylene glycol monoe
  • FDAB didecyldimethylammonium bromide
  • DTAB didecyltrimethylammonium bromide
  • fatty acids esters e.g., isopropyl myristate, isopropyl palmitate
  • fatty acids e.g., oleic acid, palmitic acid, linoleic acid, and salts thereof
  • fatty alcohols e.g., oleyl alcohol, myristyl alcohol, stearyl alcohol
  • medium -chain triglycerides e.g., oleyl alcohol, myristyl alcohol, stearyl alcohol
  • pH should be considered an “apparent pH” to acknowledge the fact that the behavior of a pH electrode in a complex multicomponent dermatological vehicle which is not totally aqueous in nature cannot be considered a “pH” in the strictest sense.
  • polyol refers to organic molecules containing two or more hydroxyl groups (e.g., a diol, a triol, or higher).
  • exemplary polyols can include, but are not limited to, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, glycerol, 1,3 -butylene glycol, 1,4- butylene glycol, l-(l-butoxy-2-propoxy)-2 -propanol, 2-methyl-2,4-pentanediol, 1,5 -pentanediol, 1,6- hexanediol, glycerol, hexanetriol, and the like.
  • polyol ether refers to a polyol ether suitable for use in a topical pharmaceutical formulation.
  • exemplary polyol ethers can include, but are not limited to, diethylene glycol monobutyl ether, dipropylene glycol monobutyl ether, polypropylene glycol, polyethylene glycol, polyethylene -polypropylene triblock copolymers, dipropylene glycol, diethylene glycol monoethyl ether, and the like.
  • preservative refers to a compound with antimicrobial activity, such as an antibacterial or antifungal. Suitable preservatives include, e.g., a paraben (e.g., methyl paraben, ethyl paraben, propyl paraben, butyl paraben), a benzoate (e.g., sodium benzoate), a sorbate (e.g., potassium sorbate), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an alcohol (e.g., chlorobutanol, benzyl alcohol, ethanol, phenol, m-cresol, chlorocresol), sodium metabisulfite, imidazolidinyl urea, glycerol, glyceryl monostearate, propylene glycol, and any combination thereof.
  • a paraben e.g., methyl paraben, ethyl paraben
  • salt or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 23rd ed., Elsevier Inc., Academic Press, Cambridge, MA, pages 307-314, 2020, which is incorporated herein by reference in its entirety.
  • the compound can be a salt of an alkali metal (e.g., sodium or potassium), a salt of an alkaline earth metal (e.g., calcium), or a salt of ammonium.
  • solvent means one or a mixture of more than one pharmaceutically acceptable solvents suitable for topical application, including without limitation, the face, the scalp, the trunk, a shoulder, the back, a forearm, an arm, a limb, and a leg, that is used to solubilize cortexolone- 17a-propionate in a formulation described herein.
  • composition contains little no specified ingredient/component, such as less than about 5 wt%, less than about 4 wt%, less than about 3 wt%, less than about 2 wt%, less than about 1 wt%, less than about 0.5 wt%, less than about 0.3 wt%, less than about 0.2 wt%, less than about 0. 1 wt%, or about 0 wt% of the specified ingredient.
  • tetrahydrocortexolone refers to the compound having the Chemical Abstract Service (CAS) Registry Number 68-60-0.
  • the terms “treat,” “treating,” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, disease, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of one or more symptoms or making the injury, disease, or condition more tolerable to the subject; slowing in the rate of degeneration or decline; or improving a subject’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subject parameters, including the results of a physical examination, neuropsychiatric examination, or psychiatric evaluation.
  • the term “preventing” refers to keeping from happening or existing, or alternatively delaying the onset or recurrence of a disease, disorder, or condition to which such term applies, or of one or more symptoms associated with a disease, disorder, or condition.
  • the term “preventing” also refers to reducing the incidence of a disease, disorder, or condition.
  • prevention refers to the act of preventing.
  • the term “sequentially” means that a first active agent is co-administered to a subject in a first period of time followed by an administration of a second active agent in a second period of time.
  • the term “sequentially” includes a first therapy in a first period of time followed by a second therapy in a second period of time.
  • the first and second time periods can be separated on the order of seconds, minutes, hours, or days, as needed. In some aspects, the first and second time periods are separated by seconds (e.g., about 60 seconds or less, about 30 seconds or less).
  • the term “subject” typically is directed to a mammal. In some aspects, the subject to be treated is a human.
  • wt% is intended to encompass and disclose aspects wherein the wt% is percentage of weight by total weight (w/w) for a given value, unless otherwise specified.
  • the terms “comprises,” “comprising,” “having,” “including,” “containing,” and the like are open-ended terms meaning “including, but not limited to.” To the extent a given aspect disclosed herein “comprises” certain elements, it should be understood that present disclosure also specifically contemplates and discloses aspects that “consist essentially of’ those elements and that “consist of’ those elements.
  • the present disclosure provides a method of treating a cutaneous acneiform eruption (also known as acneiform rash) in a subject in need thereof comprising topically administering an effective amount of cortexolone-17a-propionate to an affected area of the subject.
  • a cutaneous acneiform eruption also known as acneiform rash
  • the subject can be a mammal, such as a human.
  • cortexolone-17a-propionate can be applied to any suitable body surface in need of treatment, such as a skin region susceptible to acneiform eruptions.
  • suitable skin regions include e.g., face, arm, armpit, forearm, leg, shoulder, trunk, chest, abdomen, back, neck, or any combination of the foregoing.
  • the formulation is not delivered to the face. In other aspects, the formulation can be applied to the face.
  • Acneiform eruptions comprise papules, pustules, nodules, crusts, or cysts, or any combination thereof. Lesions can be painful and itchy but differ from acne vulgaris in that acneiform eruptions typically do not have comedones.
  • Table 1 depicts the National Cancer Institute - US Common Terminology Criteria for Adverse Events (NCI-CTCAE), which provides a grading of the severity of acneiform eruptions.
  • ADL activity of daily living
  • the acneiform eruption can be scored a Grade 1, 2, 3, 4, or 5. In some aspects, the acneiform eruption can be scored a Grade 1. In some aspects, the acneiform eruption can be scored a Grade 2. In some aspects, the acneiform eruption can be scored a Grade 3. In some aspects, the acneiform eruption can be scored a Grade 4. In some aspects, the acneiform eruption can be scored a Grade 5.
  • Acneiform eruption e.g., acneiform rash
  • infections e.g., bacterial infection, fungal infection
  • hormonal or metabolic abnormalities e.g., genetic disorders (e.g., tuberous sclerosis, eruptive vellus hair cysts)
  • the acneiform eruptions can be an occupational exposure-induced lesions.
  • occupational exposure can include exposure to a chemical, such as a halogenated chemical (e.g., chloraphthalene, chlorophenyl, chlorophenol).
  • a chemical such as a halogenated chemical (e.g., chloraphthalene, chlorophenyl, chlorophenol).
  • the acneiform eruptions can be chemical exposure-induced lesions.
  • chemical exposure can include exposure to an oil (e.g., a heavy oil, vegetable oil), wax, coal tar or a derivative there (e.g., pitch, creosote). Exposure can be from a cosmetic or other topical product containing such chemical.
  • oil e.g., a heavy oil, vegetable oil
  • wax e.g., wax, coal tar or a derivative there (e.g., pitch, creosote).
  • Exposure can be from a cosmetic or other topical product containing such chemical.
  • the acneiform eruptions can be mechanical exposure-induced lesions.
  • mechanical exposure can include friction, pressure, or both, particularly from repeated contact. Exposure can be from, e.g., restrictive clothing, prolonged immobilization, and repetitive mechanical trauma.
  • the acneiform eruption can be a targeted therapeutic drug-induced lesion.
  • the targeted therapeutic drug can be, for example, an antibiotic (e.g., a penicillin, a tetracycline, a macrolide, co-trimoxazole, doxycycline, ofloxacin, chloramphenicol), a corticosteroid, an anticonvulsant (e.g., phenytoin), an antidepressant (e.g., amineptine), an antipsychotic (e.g., olanzapine, lithium), an antituberculosis agent (e.g., isoniazid (INH), thiourea, thiouracil, disulfiram, corticotropin), an antifungal (e.g., nystatin, itraconazole), an anticancer agent, hydroxychloroquine, naproxen, or mercury.
  • an antibiotic e.g., a penicillin, a tetracycl
  • the subject can be receiving treatment for cancer, e.g., treatment with one or more anticancer agents.
  • the anticancer agent can comprise a targeted therapeutic drug selected from the group consisting of an Epidermal Growth Factor Receptor (EGFR) inhibitor, a Mitogen-Activated Protein Kinase (MEK) inhibitor, a Human Epidermal Growth Factor Receptor (HER-2) inhibitor, a Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitor, a RAS/RAF/MEK/ERK (MAPK) inhibitor, a multikinase inhibitor, a mammalian Target of Rapamycin (mTOR) inhibitor, a Programmed Death (PD-1)/Programmed Death Ligand (PDL-1 and PDL-2) inhibitor, a Cytotoxic T Lymphocyte-Associated Antigen (CTLA-4) inhibitor, an Anaplastic Lymphoma Kinase (ALK) inhibitor, a Raf kinase (RAF) inhibitor, a PWD-4) inhibitor, a Cyto
  • Suitable EGFR inhibitors can include, but are not limited to, afatinib, alflutinib, almonertinib, brigatinib, cetuximab, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, lazerinib, mobocertinib, necitumumab, neratinib, olmutinib, osimertinib, panitumumab, pyrotinib, simotinib, and vandetanib.
  • Suitable MEK inhibitors can include, but are not limited to, binimetinib, cobimetinib, mirdametinib, pimasertib, refametinib, selumetinib, and trametinib.
  • Suitable HER-2 inhibitors can include, but are not limited to, dacomitinib, lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab, and tucatinib.
  • Suitable VEGFR inhibitors can include, but are not limited to, axitinib, bevacizumab, cabozantinib, lenvatinib, pazopanib, ponatinib, ramucirumab, regorafenib, sorafenib, sunitinib, tivozanib, and vandetanib.
  • Suitable MAPK inhibitors can include, but are not limited to, binimetinib, cobimetinib, and trametinib.
  • Suitable multikinase inhibitors can include, but are not limited to, afatinib, alectinib, avapritinib, axitinib, binimetinib, brigatinib, cabozantinib, capmatinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, deucravacitinib, encorafenib, entrectinib, erdafitinib, fedratinib, futibatinib, gilteritinb, imatinib, infigratinib, larotrectinib, lenvatinib, lorlatinib, midostaurin, nintedanib, pacritinib, pazopanib, pemigatinib, pexidartinib, ponatinib, pralsetinib
  • Suitable PD-l/PDL-1 inhibitors can include, but are not limited to, atezolizumab, avelumab, cemiplimab, durvalumab, nivolumab, and pembrolizumab.
  • Suitable CTLA-4 inhibitors include, but are not limited to ipilimumab and tremelimumab.
  • Suitable ALK inhibitors can include, but are not limited to, alectinib, alkotinib, belizatinib, brigatinib, certinib, conteltinib, crizotinib, ensartinib, entrectinib, fortinib, lorlatinib, reprotrectinib, and zotizalkib,
  • Suitable RAF inhibitors can include, but are not limited to, agerafenib,3%ometinib, dabrafenib, encorafenib, lifirafenib, sorafenib, tovorafenib, and vemurafenib.
  • Suitable PI3K inhibitors can include, but are not limited to alpelisib, apitolisib, bimiralisib, buparlisib, copanlisib, dactolisib, duvelisib, eganelisib, fimepinostat, gedatolisib, idelalisib, linperlisib, leniolisib, omipalisib, parsaclisib, paxalisib, pictilisib, pilaralisib, rigosertib, samotolisib, serabelisib, sonolisib, taselisib, tenalisisb, umbralisib, voxtalisib, wortmanin, and zandelisisb.
  • Suitable AKT kinase inhibitors can include, but are not limited to, afuresertib, capivasertib, ipatasertib, miransertib, perifosine, and uprosertib.
  • the targeted therapeutic drug can be gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, avitinib, olmutinib, pelitinib, pyrotinib, brigatinib, vandetanib, icotinib, mobocertinib, almonertinib, lazertinib, alflutinib, rociletinib, toartinib, naquotinib, cetuximab, panitumumab, necitumumab, amivantamab, trametinib, cobimetinib, pimasertib, mirdametinib, refametinib, binimetinib, selumetinib, trastuzumab, pertuzuma
  • the targeted therapeutic drug can be afatinib, alflutinib, almonertinib, brigatinib, cetuximab, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, lazerinib, mobocertinib, necitumumab, neratinib, olmutinib, osimertinib, panitumumab, pyrotinib, simotinib, vandetanib, binimetinib, cobimetinib, mirdametinib, pimasertib, refametinib, selumetinib, trametinib, or any combination thereof.
  • suitable acid additives include, e.g., 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; benzene sulfonic acid; benzoic acid; (+)-camphoric acid; (+)-camphor-10-sulfonic acid; capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid (e.g., citric acid monohydrate, anhydrous citric acid); cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethane sulfonic
  • the pharmaceutical formulation can include an emulsifier, particularly to provide a solution, a suspension, an emulsion, or a microemulsion.
  • an emulsifier particularly to provide a solution, a suspension, an emulsion, or a microemulsion.
  • emulsifiers when present, assist or facilitate dissolution of any solid substances, such as an active agent, in the pharmaceutical formulation.
  • the emulsifier can be present to facilitate incorporation of two non -miscible liquids into each other (e.g., to form an emulsion or microemulsion).
  • an emulsifier can increase product spreadability.
  • the pharmaceutical formulation is a liquid solution
  • the presence of a suitable amount of an emulsifier is believed to decrease the surface tension between the pharmaceutical formulation and the lipid environment of the superficial layer of the skin. This makes it easier to spread the pharmaceutical formulation and is believed to assist penetration of the active agent(s) into skin.
  • the emulsifier can be selected from the group comprising or the group consisting of: polyethylene glycol (PEG)-fatty acid monoesters such as PEG- 15 hydroxystearate (also known as polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate and the like; polyoxyethylene sorbitan fatty acid esters (polysorbates) such as polysorbate 20 (polyoxyethylene (20) sorbitan monooleate), polysorbate 60 (polyoxyethylene (60) sorbitan monooleate), polysorbate 80 (polyoxyethylene (80) sorbitan monooleate), and the like; polyoxyethylene alkyl ethers such as PEG- 20 cetostearyl ether, polyoxyl 25 cetostearyl, glyceryl monostearate, cetomacrogol 1000 and the like; sorbitan fatty acid esters such as sorbitan monolaurate,
  • the emulsifier can be polyoxyl 40 hydrogenated castor oil, polyoxyl-15-hydroxystearate, polysorbate 60, polysorbate 80, or any combination thereof. In some aspects, the emulsifier can be polysorbate 80, glyceryl monostearate, or a combination of polysorbate 80 and glyceryl monostearate.
  • the emulsifier can be present in an amount ranging from 1 wt% to 20 wt% (e.g., from about 1 wt% to about 19 wt%, from about 1 wt% to about 18 wt%, from about 1 wt% to about 17 wt%, from about 1 wt% to about 16 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 14 wt%, from about 1 wt% to about 13 wt%, from about 1 wt% to about 12 wt%, from about 1 wt% to about 11 wt%, from about 1 wt% to about 10 wt%, from about 1 wt% to about 9 wt%, from about 1 wt% to about 8 wt%, from about 1 wt% to about 7 wt%, from about 1 wt% to about 6 wt%, from about 1 wt% to about
  • the penetration enhancer can be selected from the group consisting of hydroxypropyl [3- cyclodextrin, a polyol, a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or any combination thereof), a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and any combination thereof.
  • hydroxypropyl [3- cyclodextrin
  • a polyol e.g., a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or any combination thereof), a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and any combination thereof
  • the penetration enhancer can be dimethyl isosorbide. In other aspects, the penetration enhancer can be a mixture comprising dimethyl isosorbide and diethylene glycol monoethyl ether. In other aspects, the penetration enhancer can be dimethyl sulfoxide.
  • the penetration enhancer can be present in an amount ranging from about 1 wt% to about 30 wt% with respect to the total weight of the pharmaceutical formulation. In other aspects, the penetration enhancer can be present from about 2 wt% to about 20 wt% with respect to the total weight of the pharmaceutical formulation; or from about 3 wt% to about 15 wt% with respect to the total weight of the pharmaceutical formulation or from about 5 wt% to about 10 wt% with respect to the total weight of the pharmaceutical formulation.
  • the pharmaceutical formulation can include one or more moisturizers.
  • a moisturizer is believed to impart moisture and/or softness into the skin, particularly when a component known to dry the skin, such as an alcohol, are also present in the formulation.
  • the moisturizer can be a fatty alcohol, a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or any combination thereof), a fatty acid ester, an oil, a polyethylene glycol, glycerol, an alpha hydroxy acid, or any combination thereof.
  • the moisturizer can be cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin (e.g., mineral oil), shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerol, lactic acid, glycolic acid, malic acid, citric acid, tartaric acid, or any combination thereof.
  • the moisturizer can be cetyl alcohol, stearyl alcohol, or a combination of cetyl alcohol and stearyl alcohol.
  • the moisturizer can be cetyl alcohol, liquid paraffin (e.g., mineral oil), or a combination of cetyl alcohol and liquid paraffin.
  • the pharmaceutical formulation can include the moisturizer in an amount of up to about 15 wt% of the total formulation.
  • the moisturizer can be present in an amount ranging from 1 wt% to 15 wt% (e.g., from about 1 wt% to about 14 wt%, from about 1 wt% to about 13 wt%, from about 1 wt% to about 12 wt%, from about 1 wt% to about 11 wt%, from about 1 wt% to about 10 wt%, from about 1 wt% to about 9 wt%, from about 1 wt% to about 8 wt%, from about 1 wt% to about 7 wt%, from about 1 wt% to about 6 wt%, from about 1 wt% to about 5 wt%, from about 1 wt% to about 4 wt%, from about 1 wt% to about 3 wt%, from about 1 wt% to about
  • the pharmaceutical formulation can include one or more preservatives (e.g., an antibacterial, an antifungal).
  • Suitable preservatives include, e.g., a paraben (e.g., methyl paraben, ethyl paraben, propyl paraben, butyl paraben), a benzoate (e.g., sodium benzoate), a sorbate (e.g., potassium sorbate), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an alcohol (e.g., chlorobutanol, benzyl alcohol, ethanol, phenol, m-cresol, chloro cresol), sodium metabisulfite, imidazolidinyl urea, glycerol, propylene glycol, or any combination thereof.
  • a paraben e.g., methyl paraben, ethyl paraben, propyl parab
  • the pharmaceutical formulation can include the chelating agent in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, or about 5 wt%.
  • the pharmaceutical formulation can comprise cortexolone 17a-propionate, a solvent comprising water and a diol, at least one emulsifier, at least one moisturizer, optionally an antioxidant, and optionally a chelating agent.
  • the pharmaceutical formulation can be an emulsified cream.
  • the pharmaceutical formulation can comprise cortexolone 17a-propionate, propylene glycol, cetyl alcohol, tocopherol, citric acid, edetate disodium, mono- and di-glycerides, mineral oil, polysorbate 80, and water.
  • the pharmaceutical formulation can be a cream, such as an emulsified cream.
  • the pharmaceutical formulation (e.g., an emulsified cream) can comprise, consist essentially of, or consist of: about 0. 1 to about 2 wt% cortexolone 17a-propionate, about 20 to about 30 wt% propylene glycol, about 0.5 to about 5 wt% cetyl alcohol, about 10 to about 20 wt% glyceryl monostearate, about 5 to about 15 wt% liquid paraffin, about 0.05 to about 5 wt% polysorbate 80, about 0 to about 0. 1 wt% tocopherol, and water.
  • the pharmaceutical formulation (e.g., an emulsified cream) can comprise, consist essentially of, or consist of: about 1 wt% cortexolone 17a-propionate, about 25 wt% propylene glycol, about 2.5 wt% cetyl alcohol, about 15 wt% glyceryl monostearate, about 10 wt% liquid paraffin, about 1 wt% polysorbate 80, up to about 0.05 wt% tocopherol, and the remainder water.
  • cortexolone 17a-propionate can be administered as WINLEVITM (Cosmo Pharmaceuticals NV, Ireland).
  • WINLEVITM Cosmetically-administrabled NV, Ireland.
  • the prescribing information for WINLEVITM is incorporated herein by reference in its entirety.
  • the pharmaceutical formulations described herein can be administered according to varying schedules.
  • the mode of administration of the pharmaceutical formulation can be continuous.
  • the pharmaceutical formulations can be applied topically once a day, twice daily, three times a day, four times a day, or more, as specified by a physician.
  • a formulation described herein can be applied topically once a day or twice daily.
  • the pharmaceutical formulation described herein can be applied topically once a day.
  • the pharmaceutical formulation described herein can be applied topically twice daily.
  • a dosing regimen can be tapered. That is, the pharmaceutical formulation can be applied once a day for a first period of time, twice daily thereafter for a second period of time, three times a day thereafter for a third period of time, and so on. In a particular aspect, the pharmaceutical formulation can be applied once a day on the first day, and twice daily thereafter, with the appropriate duration of treatment determined by, for example, a subject’s physician.
  • tapered administration can comprise administering the pharmaceutical formulation in a reducing schedule starting from multiple administrations per day for an appropriate period of time and reducing the number of administrations over an appropriate period of time until a maintenance scheduled can be achieved. It is within the skill of a physician of ordinary skill in the art armed with the present disclosure to determine the appropriate starting point, reducing taper, and maintenance schedule.
  • the pharmaceutical formulation can be applied over the course of a period of days, weeks, or months.
  • the pharmaceutical formulation can be applied one, two, three, four, or five times a day for up to: 1, 2, 3, 4, 5, 6, or 7 days (i.e., about 1 week); about 2 weeks, about 3 weeks, or about 4 weeks; about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months (i.e., about a year), about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months (i.e., about 2 years).
  • the pharmaceutical formulation can be applied once on the first day and twice daily thereafter for about 4 weeks.
  • the pharmaceutical formulation can be topically applied once a day for 1 month, once a day for 2 months, once a day for 3 months, once a day for 4 months, once a day 5 months, once a day for 6 months, once a day for 8 months, once a day for 12 months, once a day for 14 months, once a day for 16 months, once a day for 18 months, once a day for 20 months, once a day for 22 months, or once a day for 24 months.
  • the pharmaceutical formulation can be topically applied to the skin once daily for 6 months.
  • the pharmaceutical formulation can be topically applied to the skin once daily for 12 months.
  • the pharmaceutical formulation can be topically applied twice daily for: about 1 month; for about 2 months; for about 3 months; for about 4 months; for about 5 months; for about 6 months, for about 8 months, for about 12 months, for about 14 months, for about 16 months, for about 18 months, for about 20 months, for about 22 months, or for about 24 months.
  • the pharmaceutical formulation can be topically applied to the skin twice daily for 6 months.
  • the pharmaceutical formulation can be topically applied to the skin twice daily for 12 months.
  • the pharmaceutical formulation can be applied more than twice daily (i.e., 3 times a day (TID), 4 times a day (QID), etc.) for: about 1 month; for about 2 months; for about 3 months; for about 4 months; for about 5 months; for about 6 months, for about 8 months, for about 12 months, for about 14 months, for about 16 months, for about 18 months, for about 20 months, for about 22 months, or for about 24 months.
  • the pharmaceutical formulation can be topically applied to the skin more than twice daily (i.e., TID, QID, etc.) for 6 months.
  • the pharmaceutical formulation can be topically applied to the skin more than twice daily (i.e., TID, QID, etc.) for 12 months.
  • the mode of administration of the pharmaceutical formulations can be cyclic.
  • the pharmaceutical formulation can first be applied in a continuous way as described above for a desired period of time, the application can then be discontinued for a period of time, such as a few days, and then the application of the pharmaceutical formulations can be started again, as described above.
  • the treatment period can include one or more cycles which can be the same or different.
  • the treatment period can be as follows: a) the pharmaceutical formulation can be topically applied for a period of time, such as 4 months, by continuous administration, b) the application can be discontinued for a few days (e.g., 2 to 5 days), and 3) the topical application can be continued for an additional period of time, such as 6 months.
  • the “effective amount” is an amount that provides a desired outcome (e.g., to treat, ameliorate, and/or prevent acneiform eruptions).
  • the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of from about 0.1 wt% to about 5 wt%.
  • the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 0.
  • the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 1 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 1.5 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 2 wt%.
  • the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 2.5 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 3 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 3.5 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a- propionate at a concentration of about 4 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 4.5 wt%. In some aspects, the pharmaceutical formulation can comprise cortexolone-17a-propionate at a concentration of about 5 wt%.
  • the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 150 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 145 mg. In other aspects, the amount of cortexolone- 17a-propionate in a single application can range from about 2 mg to about 140 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 135 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 130 mg.
  • the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 125 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 120 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 115 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 110 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 105 mg.
  • the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 100 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 95 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 90 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 85 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 80 mg.
  • the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 75 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 70 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 65 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 60 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 55 mg.
  • the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 50 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 45 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 40 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 35 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 30 mg.
  • the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 25 mg. In some aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 20 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 17 mg. In other aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 15 mg. In some aspects, the amount of cortexolone-17a-propionate in a single application can range from about 2 mg to about 10 mg.
  • the amount of cortexolone-17a-propionate in a single application can be about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about
  • the amount of cortexolone-17a-propionate in a single application can be about 10 mg. In another aspect, the amount of cortexolone-17a-propionate in a single application can be about 20 mg. In yet another aspect, the amount of cortexolone-17a-propionate in a single application can be about 30 mg. In yet another aspect, the amount of cortexolone-17a-propionate in a single application can be about 40 mg. In yet another aspect, the amount of cortexolone-17a-propionate in a single application can be about 50 mg.
  • the pharmaceutical formulation can be self-administered by the subject once a day or twice daily.
  • the pharmaceutical formulation when the pharmaceutical formulation is a cream or in liquid form having a cortexolone-17a-propionate concentration of about 1 wt%, the pharmaceutical formulation can be self-administered once a day or twice daily at a dose ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in further aspects at about 1 mL or about 1.5 mL.
  • the pharmaceutical formulation described herein can be applied to any body surface in need of treatment, such as a skin region susceptible to acneiform eruptions. Suitable skin regions include e.g., face, arm, armpit, forearm, leg, chest, trunk, shoulder, abdomen, back, neck, or any combination of the foregoing. In some aspects, the formulation is not delivered to the face. In other aspects, the formulation can be applied to the face.
  • the method of treating acneiform eruptions can comprise administering a pharmaceutical formulation, as described herein, comprising a combination of an effective amount of cortexolone-17a-propionate and one or more secondary anti-acneiform agents.
  • a pharmaceutical formulation as described herein, comprising a combination of an effective amount of cortexolone-17a-propionate and one or more secondary anti-acneiform agents.
  • one, two, three, or four anti-acneiform agents can be administered in combination with cortexolone-17a- propionate as a formulation or administered sequentially.
  • the secondary anti-acneiform agent can be selected from the group consisting of an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, urea, and combinations thereof.
  • Storage stability is an important metric for pharmaceutical products. In general, greater stability means that a given formulation is both easier to transport and store, increasing the likelihood that it will be stocked by pharmacies and that subjects will not have to be concerned with special storage instructions.
  • the pharmaceutical formulation described herein can have a desirable stability profile allowing for storage of the final formulation for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about two years - each at room (about 20 °C) or refrigerated temperatures (e.g., about 4 °C).
  • cortexolone-17a-propionate is transesterification to cortexolone-21 -propionate (17a-hydroxy-21-propionyloxy-pregna-4-ene-3, 20- dione):
  • maintaining the pharmaceutical formulations disclosed herein at an acidic pH including a pH of less than about 7.0 (e.g., less than about 6.5, less than about 6, less than about 5.5, less than about 5, less than about 4.5, between about 4 and about 7, between about 4 and about 6.5, between about 4 and about 6, between about 4 and 5.5, between about 4 and 5, between about 4 and about 4.5, or at about 6.5, about 6, about 5.5, about 5, about 4.5, or about 4), can slow this degradation process.
  • the pH can be about 4.
  • the appropriate pH can be obtained via addition of a suitable amount of a pH modifier, such as the acids described herein.
  • the pharmaceutical formulations described herein can, at room (about 20 °C) or refrigerated (e.g., about 4 °C) temperatures, have less than about 5 wt% cortexolone-21 -propionate or other degradation products after storage for a period of about 24 months.
  • Cortexolone-17a-propionate for use in the treatment of a cutaneous acneiform eruption in a subject in need thereof, characterized in that it is administered topically to an affected area of the subject.
  • Cortexolone-17a-propionate for use according to (1), wherein the subject is receiving treatment for cancer.
  • the treatment comprises a targeted biologic agent selected from the group consisting of an Epidermal Growth Factor Receptor (EGFR) inhibitor, a Mitogen-Activated Protein Kinase (MEK) inhibitor, a Human Epidermal Growth Factor Receptor (HER-2) inhibitor, a Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitor, a RAS/RAF/MEK/ERK (MAPK) inhibitor, a multikinase inhibitor, a mammalian Target of Rapamycin (mTOR) inhibitor, a Programmed Death (PD-1)/Programmed Death Ligand (PDL-1 and PDL-2) inhibitor, a Cytotoxic T Lymphocyte-Associated Antigen (CTLA-4) inhibitor, an Anaplastic Lymphoma Kinase (ALK) inhibitor,
  • EGFR Epidermal Growth Factor Receptor
  • MEK Mitogen-Activated Protein Kinase
  • Cortexolone-17a-propionate for use according to any one of ( l)-(5), wherein the cortexolone- 17a-propionate is administered in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier, preferably said pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a biogel, a paste, a gel, a foam, an ointment, a wash-off agent, a patch, a hydrogel patch, or a pledget.
  • a pharmaceutical formulation is a solution, a suspension, an emulsion, a microemulsion, a cream, a biogel, a paste, a gel, a foam, an ointment, a wash-off agent, a patch, a hydrogel patch, or a pledget.
  • Cortexolone-17a-propionate for use according to (6), wherein the pharmaceutical formulation further comprises at least one additive selected from the group consisting of an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and any combination thereof.
  • Cortexolone-17a-propionate for use according to (7), wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, tocopherol, propyl gallate, 2,4,5 -trihydroxybutyrophenone, 4-hydroxymethyl- 2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, pharmaceutically acceptable salts thereof, esters thereof, and any combination thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • ascorbyl palmitate ascorbic acid
  • tocopherol propyl gallate
  • 2,4,5 -trihydroxybutyrophenone 4-hydroxymethyl- 2,6-di-tert-
  • Cortexolone-17a-propionate for use according to any one of (7)-( 10), wherein the penetration enhancer is selected from the group consisting of a diol, a polyol, a fatty acid, a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and any combination thereof.
  • Cortexolone-17a-propionate for use according to any one of (6) or (7), wherein the pharmaceutical formulation comprises propylene glycol, cetyl alcohol, tocopherol, citric acid, edetate disodium, mono- and di-glycerides, mineral oil, polysorbate 80, and water.
  • Cortexolone-17a-propionate for use according to (14), wherein the pharmaceutical formulation comprises: about 1 wt% cortexolone 17a-propionate, about 25 wt% propylene glycol, about 2.5 wt% cetyl alcohol, about 15 wt% glyceryl monostearate, about 10 wt% liquid paraffin, about 1 wt% polysorbate 80, and up to about 0.05 wt% tocopherol.
  • Cortexolone- 17a-propionate for use according to any one of (1)-(15), wherein the cortexolone- 17a-propionate is administered in an amount of about 0.1 to about 5 wt%, preferably the cortexolone 17a-propionate is administered in an amount of about 1 wt%.
  • Cortexolone- 17a-propionate for use according to any one of (1)-(16), wherein topically applying the cortexolone 17a-propionate comprises administering a formulation comprising cortexolone 17a-propionate dissolved therein and cortexolone 17a-propionate present in at least one of polymorphic Forms I, II, III, and IV, or any combination thereof.
  • One hundred g of cortexolone 17a-propionate of crystalline Form III was dissolved in 2500 g of propylene glycol under stirring at room temperature.
  • An emulsion with 250 g of cetyl alcohol, 1500 g of glyceryl monostearate, 1000 g of liquid paraffin (e.g., mineral oil), 5 g of mixed tocopherols (e.g., vitamin E), 100 g of polysorbate 80, and 4650 g of purified water was separately prepared by using a turboemulsifier, raising the temperature up to about 70 °C.
  • the cortexolone 17a-propionate solution was added, under stirring and under negative pressure, in propylene glycol.
  • the emulsioned cream was maintained under stifling heat until homogeneity was obtained, making sure the temperature remained low by means of circulation of a coolant.
  • a patient being treated with a targeted therapeutic drug presents to a physician with acneiform eruptions including pustules and crusts with pruritus and tenderness, which is scored as Grade 3 acneiform eruptions.
  • a physician of skill in the art instructs the patient to selfadminister the pharmaceutical formulation of Example 1 topically to the affected area twice a day for 4 weeks. After about two weeks of treatment with the pharmaceutical formulation, it is expected that the patient will present with improved acneiform eruptions scored as Grade 2. After about four weeks of treatment with the pharmaceutical formulation, it is expected that the patient will present with further improved acneiform eruptions scored as Grade 1. In the following weeks, it is expected that the patient’s acneiform eruptions will be cleared.
  • cortexolone 17a-propionate applied to acneiform eruptions induced by EGFR inhibitors can treat affected areas of the subject where the pharmaceutical formulation is topically administered.
  • a patient is diagnosed with cancer and prescribed an EGFR inhibitor, such as panitumumab or cetuximab.
  • an EGFR inhibitor such as panitumumab or cetuximab.
  • the patient is instructed to self-administer the pharmaceutical composition of Example 1 topically to any suitable skin area (e.g., face, chest) twice a day for 4 weeks.
  • any suitable skin area e.g., face, chest
  • the patient presents with no rash or cutaneous eruptions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente divulgation concerne une méthode de traitement d'une éruption acnéiforme cutanée chez un sujet en ayant besoin. La méthode comprend l'administration topique au sujet d'une quantité efficace de cortéxolone-17α-propionate. L'éruption acnéiforme peut comprendre une papule, un pustule, un nodule, une croûte, un kyste, ou toute combinaison de ceux-ci sur une zone affectée du sujet. La quantité efficace de cortéxolone-17α-propionate peut être administrée dans une formulation pharmaceutique topique comprenant du cortéxolone-17α-propionate et un ou plusieurs supports pharmaceutiquement acceptables.
PCT/EP2024/076924 2023-09-26 2024-09-25 CORTÉXOLONE-17α-PROPIONATE POUR LE TRAITEMENT D'ÉRUPTIONS ACNÉIFORMES Pending WO2025068281A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363585262P 2023-09-26 2023-09-26
EP23199673.7 2023-09-26
EP23199673.7A EP4529925A1 (fr) 2023-09-26 2023-09-26 Cortexolone-17-alpha-propionate pour le traitement des éruptions acneiformes
US63/585,262 2023-09-26

Publications (1)

Publication Number Publication Date
WO2025068281A1 true WO2025068281A1 (fr) 2025-04-03

Family

ID=92894658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/076924 Pending WO2025068281A1 (fr) 2023-09-26 2024-09-25 CORTÉXOLONE-17α-PROPIONATE POUR LE TRAITEMENT D'ÉRUPTIONS ACNÉIFORMES

Country Status (2)

Country Link
TW (1) TW202519237A (fr)
WO (1) WO2025068281A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009019138A2 (fr) 2007-08-03 2009-02-12 Cosmo Spa Procédé enzymatique pour obtenir des 17 alpha-monoesters de cortexolone et/ou ses dérivés 9,11-déshydro
US8143240B2 (en) 2001-08-10 2012-03-27 Cosmo S.P.A. 17α, 21-dihydroxypregnene esters as antiandrogenic agents
WO2015091733A1 (fr) 2013-12-20 2015-06-25 Cassiopea S.P.A. Propionate de cortexolone-17α destiné à être utilisé dans le traitement de lésions cutanées et/ou de troubles de la peau atrophique
WO2016207778A1 (fr) 2015-06-22 2016-12-29 Cassiopea S.P.A Formulation à haute concentration

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8143240B2 (en) 2001-08-10 2012-03-27 Cosmo S.P.A. 17α, 21-dihydroxypregnene esters as antiandrogenic agents
US8865690B2 (en) 2001-08-10 2014-10-21 Cosmo Dermatos Srl 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
WO2009019138A2 (fr) 2007-08-03 2009-02-12 Cosmo Spa Procédé enzymatique pour obtenir des 17 alpha-monoesters de cortexolone et/ou ses dérivés 9,11-déshydro
US8785427B2 (en) 2007-08-03 2014-07-22 Cosmo Dermatos Srl Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
WO2015091733A1 (fr) 2013-12-20 2015-06-25 Cassiopea S.P.A. Propionate de cortexolone-17α destiné à être utilisé dans le traitement de lésions cutanées et/ou de troubles de la peau atrophique
WO2016207778A1 (fr) 2015-06-22 2016-12-29 Cassiopea S.P.A Formulation à haute concentration

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 2020, ELSEVIER INC, pages: 307 - 314
BREZINSKI ET AL., PRACTICAL DERMATOLOGY: CLINICAL FOCUS, August 2013 (2013-08-01), pages 37 - 40
BREZINSKI ET AL., PRATICAL DERMATOLOGY, 2013, pages 37 - 40
ELIZABETH A. BREZINSKI ET AL: "EGFR Inhibitor-induced Acneiform Rash: A Review of Current Management Strategies", PRACTICAL DERMATOLOGY, 1 August 2013 (2013-08-01), pages 37 - 40, XP093130470, Retrieved from the Internet <URL:https://assets.bmctoday.net/practicaldermatology/pdfs/pd0813_ClinFocus.pdf> [retrieved on 20240213] *
KALABALIK-HOGANSON JULIE ET AL: "Clascoterone: A Novel Topical Androgen Receptor Inhibitor for the Treatment of Acne", ANNALS OF PHARMACOTHERAPY, vol. 55, no. 10, 1 October 2021 (2021-10-01), US, pages 1290 - 1296, XP093130409, ISSN: 1060-0280, DOI: 10.1177/1060028021992053 *
LE RADEMACHER J ET AL., AMERICAN JOURNAL OF HOSPICE &PALLIATIVE CARE., vol. 36, no. 6, 2019, pages 519 - 525
LE-RADEMACHER JENNIFER G. ET AL: "Androgen Mediation-and Antiandrogens Mitigation-of the Epidermal Growth Factor Receptor (EGFR) Inhibitor-Induced Rash: Results From a Pilot Randomized Trial and Small Translational Case Series", vol. 36, no. 6, 2 January 2019 (2019-01-02), US, pages 519 - 525, XP093130471, ISSN: 1049-9091, Retrieved from the Internet <URL:http://journals.sagepub.com/doi/full-xml/10.1177/1049909118819820> DOI: 10.1177/1049909118819820 *
no. 68-60-0
PISZCZATOSKI CHRISTOPHER R ET AL: "Topical Clascoterone: The First Novel Agent for Acne Vulgaris in 40 Years", CLINICAL THERAPEUTICS, ELSEVIER, AMSTERDAM, NL, vol. 43, no. 10, 1 October 2021 (2021-10-01), pages 1638 - 1644, XP086869562, ISSN: 0149-2918, [retrieved on 20211002], DOI: 10.1016/J.CLINTHERA.2021.08.007 *

Also Published As

Publication number Publication date
TW202519237A (zh) 2025-05-16

Similar Documents

Publication Publication Date Title
JP7458464B2 (ja) 高濃度配合物
CA3107702A1 (fr) Compositions oleagineuses topiques
TWI729371B (zh) 治療搔癢症的組合物與方法
JP2020505322A (ja) 局所用デトミジン製剤
WO2025068281A1 (fr) CORTÉXOLONE-17α-PROPIONATE POUR LE TRAITEMENT D&#39;ÉRUPTIONS ACNÉIFORMES
EP4529925A1 (fr) Cortexolone-17-alpha-propionate pour le traitement des éruptions acneiformes
JP7124234B2 (ja) フェノルドパムの安定な局所用組成物
WO2025172818A1 (fr) Polythérapie à base de pyrilutamide
IL322781A (en) Combination treatment with calcitriol and minoxidil

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24776292

Country of ref document: EP

Kind code of ref document: A1