Clascoterone formulations and methods of use thereof

Abstract

The present disclosure is related to a topical formulation comprising clascoterone in a mixture of aqueous and oily gel phases. The present disclosure further relates to a method of treating or preventing skin conditions such acne vulgaris, acne conglobata, acne fulminans, androgenetic alopecia, hidradenitis suppurativa (also known as acne inversa), hirsutism, cancer-therapy-induced rash, eczema, rosacea, atopic dermatitis, psoriasis, inverse psoriasis, seborrheic dermatitis, acanthosis nigricans, wound, and female pattern hair loss, comprising topically administering to a subject in need thereof an effective amount of the formulation.

Description

CLASCOTERONE FORMULATIONS AND METHODS OF USE THEREOF BACKGROUND

[0001] Clascoterone, also known as cortexolone- 17a-propi onate and 17a-propionyloxy- 2 l-hydroxy-pregna-4-ene-3, 20-dione, 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). Clascoterone is also known to exist in several distinct crystalline polymorphs, each having unique properties. Various topical compositions comprising clascoterone are known to be suitable for treating acne, alopecia, and other diseases of skin and cutaneous appendages.

[0002] WO 2003 / 014141 describes 17a,21-dihydroxypregnane esters, the processes to prepare these esters, and their use as anti androgenic drugs, particularly for the treatment of acne and alopecia.

[0003] WO 2009 / 019138 describes enzymatic processes to obtain 17a monoesters of cortexolone or 9,11 -dehydro cortexolone, several crystalline forms of clascoterone, as well as formulations comprising the same.

[0004] WO 2016 / 207778 describes high concentration formulations of clascoterone suitable for topical administration and for treatment of skin disease such as androgenetic alopecia. The formulations disclosed in this application include the entire amount of clascoterone solubilized in the vehicle, show good stability profiles, and are substantially anhydrous, as they contain less than 5% of water by weight.

[0005] Despite the various formulations of clascoterone known in the art, there remains a need for topical formulations of clascoterone capable of delivering a larger effective dose of clascoterone to a subject in need thereof.BRIEF SUMMARY

[0006] The present disclosure provides aqueous clascoterone pharmaceutical formulations capable of solubilizing increased amounts of clascoterone relative formulations known in the art. In addition to comprising water and providing enhanced clascoterone solubility, the formulations described herein surprisingly provide not only enhanced clascoteronedelivery across the stratum corneum, but also provide enhanced clascoterone stability at varying temperatures-even in the presence of water.

[0007] Accordingly, and in some embodiments, the present disclosure provides a bigel pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises a mixture of a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone.

[0008] In some embodiments, the formulation further comprises a clascoterone stabilizer in the aqueous gel phase.

[0009] In some embodiments, the pharmaceutical formulation comprises about 0.05 wt% to about 5 wt% of the first amount of clascoterone based on the total weight of the formulation and about 0.05 wt% to about 5 wt% of the second amount of clascoterone based on the total weight of the formulation.

[0010] In some embodiments of the pharmaceutical formulation, the clascoterone stabilizer is a cyclodextrin selected from the group consisting of a-cyclodextrin, P -cyclodextrin, y - cyclodextrin, methylated-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, hydroxypropyl- P-cyclodextrin, and hydroxypropyl-y-cyclodextrin.

[0011] In some embodiments, at least 50% of the first amount of clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex.

[0012] In some embodiments, at least 75% of the first amount of clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex.

[0013] In some embodiments, all or substantially all of the first amount of clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex.

[0014] In some embodiments the cyclodextrin is present in an amount of from about 1 wt% to about 40 wt% based on the total weight of the formulation.

[0015] In some embodiments, the aqueous gel phase further comprises at least one aqueous phase gelling agent selected from the group consisting of xanthan gum, acrylic acid polymers, acrylic acid crosspolymers, alginic acid and salts and derivatives thereof (such as sodium alginate or potassium alginate), gum arabic, povidone and combinations thereof.

[0016] In some embodiments, the formulation comprises at least one aqueous phase gelling agent in an amount of from about 0.1 wt% to about 5 wt% based on the total weight of the formulation.

[0017] In some embodiments, the aqueous gel phase further comprises at least one excipient selected from the group consisting of a polyol, a polyol ether, a glycol ester, a Ci- C7 alcohol, and combinations thereof.

[0018] In some embodiments, the aqueous phase excipient is glycerol in an amount of from about 1 wt% to about 30 wt% based on the total weight of the formulation.

[0019] In some embodiments, the formulation comprises from about 35 wt% to about 80 wt% water based on the total weight of the formulation.

[0020] In some embodiments of the pharmaceutical formulation provided herein, the oily gel phase further comprises at least one oily phase excipient.

[0021] In some embodiments, the at least one oily phase excipient is selected from the group consisting of a polyol, a polyol ether, a glycol ester, a C1-C7 alcohol, and combinations thereof.

[0022] In some embodiments, the at least one oily phase excipient is a glycol ester selected from the group consisting of propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, propylene glycol monocaprylate, and combinations thereof.

[0023] In some embodiments, the formulation comprises the at least one oily phase excipient in an amount from about 1 wt% to about 50 wt% based on the total weight of the formulation.

[0024] In some embodiments, the oily gel phase further comprises an oily phase gelling agent selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide, and combinations thereof.

[0025] In some embodiments, the oily phase gelling agent is present in an amount from about 1 wt% to about 30 wt% based on the total weight of the formulation.

[0026] In some embodiments, the oily gel phase further comprises an antioxidant selected from the group consisting of a-tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, vitamin A and combinations thereof. In some embodiments, the formulation comprises the antioxidant in an amount of from about 0.01 wt% to about 1 wt% based on the total weight of the formulation.

[0027] In some embodiments, the formulation has a pH ranging from about 3 to about 7, from about 3 to about 6, or from about 3 to about 5.

[0028] In some embodiments, the formulation comprises at least one permeation enhancer.

[0029] In further embodiments, the present disclosure provides a method of treating a skin condition related to androgenic disorders comprising topically administering to a subject in need thereof an effective amount of the pharmaceutical formulation comprising a mixture of a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone.

[0030] In some embodiments of the method, the skin condition is selected from the group consisting of acne vulgaris, acne conglobata, acne fulminans, androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, hidradenitis suppurativa (also known as acne inversa), hirsutism, cancer-therapy-induced rash, eczema, rosacea, atopic dermatitis, psoriasis, inverse psoriasis, seborrhoea, seborrheic dermatitis, and female pattern hair loss.

[0031] In some embodiments, the skin condition is inflamed acne or non-inflamed acne.

[0032] In other embodiments, the skin condition is inflamed hidradenitis suppurativa.

[0033] In some embodiments, the acne or the hidradenitis suppurativa are located on the face, back, and / or chest.

[0034] In some embodiments, the acne is acne vulgaris, which is mild, moderate or severe.

[0035] In some embodiments of the method, the subject achieves a net clinical benefit upon application of the pharmaceutical formulation expressed by one or more of the following: an improved IGA score, an IGA score of “clear” or “almost clear,” a reduced acne lesion count, a reduced inflammatory lesion count, a reduced non-inflammatory lesion count, or a significant improvement in Dermatology Life Quality Index.

[0036] In further embodiments, the present disclosure provides a method of increasing skin permeation of clascoterone comprising topically administering to a subject in need thereof, an effective amount of a pharmaceutical formulation comprising a mixture of a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone.

[0037] In some embodiments, the present disclosure provides a method of increasing skin permeation of clascoterone, the method comprising administering to a subject in need thereof, an effective amount of a pharmaceutical formulation comprising a mixture of a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone, wherein the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation.

[0038] In some embodiments, the pharmaceutical formulation has a total clascoterone concentration of about 0.2 wt% to about 10 wt%.

[0039] In other embodiments, the pharmaceutical formulation has a total clascoterone concentration of about 0.5 wt% to about 7.5 wt%.

[0040] In some embodiments, the pharmaceutical formulation has a total clascoterone concentration of about 1 wt% to about 5 wt%.

[0041] In some embodiments, the formulation has a total clascoterone concentration of about 1.5 wt%.

[0042] In some embodiments, the formulation has a total clascoterone concentration of about 2 wt%.

[0043] In some embodiments, the formulation has a total clascoterone concentration of about 2.5 wt%.

[0044] In some embodiments, the formulation has a total clascoterone concentration of about 3 wt%.

[0045] In some embodiments, the formulation has a total clascoterone concentration of about 3.5 wt%.

[0046] In some embodiments, the formulation has a total clascoterone concentration of about 4 wt%.

[0047] In some embodiments, the formulation has a total clascoterone concentration of about 4.5 wt%.

[0048] In some embodiments, the formulation has a total clascoterone concentration of about 5 wt%.

[0049] In some embodiments, the formulation exhibits less than 2% total impurities after 1 month at room temperature.

[0050] In some embodiments, the formulation exhibits less than 0.35% total impurities after 2 months at refrigerated condition.

[0051] In some embodiments, the formulation comprises a detectable amount of cortexol one-21 -propionate that is less than about 1.3 wt% after 1 month at room temperature.

[0052] In some embodiments, the formulation comprises a detectable amount of cortexol one-21 -propionate that is less than about 0.25 wt% after 2 months at refrigerated conditions.

[0053] In some embodiments, the formulation provides a cumulative diffusion in pig ear skin of about 20 pg / cm2to about 1000 pg / cm2after 24 hours.

[0054] In some embodiments, the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 8 wt% after 6 months at 25 °C and 60% relative humidity.

[0055] In some embodiments, the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 0.9 wt% after 6 months at 5 °C.

[0056] In some embodiments, 0.5% of the clascoterone in the formulation is complexed with cyclodextrins, wherein formulation comprises about 2.5 wt% of clascoterone based on the total weight of the formulation.

[0057] In some embodiments, 1% of the clascoterone in the formulation is complexed with cyclodextrins, wherein formulation comprises about 2.5 wt% of clascoterone based on the total weight of the formulation. In a further embodiment the pharmaceutical formulation of the present invention is for use in the treatment of a skin condition related to androgenic disorders, characterized in that it is administered topically to a subject in need thereof.

[0058] In a further embodiment the pharmaceutical formulation of the present invention is for use in increasing skin permeation of clascoterone, characterized in that it is administered topically to a subject in need thereof.

[0059] A further embodiment is the use of the pharmaceutical formulation of the present invention for increasing skin permeation of clascoterone, wherein said formulation is administered topically to a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0060] The drawings described herein are provided for the purpose of illustration only and the aspects described herein should in no way be construed as being limited by the drawings or by the examples that reference the drawings. Rather, the drawings described herein should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0061] FIG 1 is a graph comparing the in vitro pig ear skin permeation profiles between a commercial clascoterone cream formulation (WINLEVI) and clascoterone bigel pharmaceutical formulations.

[0062] FIG 2 is a graph comparing the in vitro pig ear skin permeation profiles of bigel pharmaceutical formulations with 2.5% clascoterone complexed with cyclodextrins.

[0063] FIG 3 is a graph comparing the in vitro pig ear skin permeation profiles of bigel pharmaceutical formulations with varying clascoterone concentrations complexed with cyclodextrins.

[0064] FIG 4 is a graph comparing the in vitro pig ear skin permeation profiles of bigel pharmaceutical formulations with 1% clascoterone with and without cyclodextrins.

[0065] FIG 5 is a graph showing stability of bigel pharmaceutical formulations with 1% and 2.5% clascoterone with and without cyclodextrins, at 25 °C and 60% relative humidity, over 6 months.

[0066] FIG 6 is a graph showing stability of bigel pharmaceutical formulations with 1% and 2.5% clascoterone with and without cyclodextrins, at 5 °C, over 6 months.DETAILED DESCRIPTION

[0067] The headings provided herein are not limitations of the various embodiments of the disclosure, which can be defined by reference to the specification as a whole. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.Definitions

[0068] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed technology, because the scope of the technology is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification will control.

[0069] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0070] As used herein, the term “or” is a logical disjunction (z.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.

[0071] As used herein, the term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. “About” can mean a range of up to 10% (e.g., up to 5%, up to 1%) of a given value.

[0072] As used herein, the phrases “acne” and “acne vulgaris” refer to a skin disease characterized by papules, pustules, nodules, open comedones, closed comedones, crusts, cysts, or any combination thereof.

[0073] As used herein, the phrases “acne conglobata” refers to a rare and very severe form of nodulocystic acne that can cause significant disfigurement. It usually presents with tender, disfiguring, double or triple interconnecting comedones, cysts, inflammatory nodules, and deep burrowing abscesses on the face, shoulders, back, chest, upper arms, buttocks, and thighs. The comedones often occur in groups of three, and the cysts often contain purulent, foul-smelling material that is discharged on the skin surface. It is a chronic inflammatory disease that inevitably leads to scar formation and disfigurement. Acne conglobata may occur following the sudden worsening of pustular acne, or the disorder may occur gradually following the recrudescence of acne that has been quiet for many years.

[0074] As used here in the phrase “acne fulminans” refers to a rare skin disorder presenting as an acute, painful, ulcerating, and hemorrhagic clinical form of acne. It may or may not be associated with systemic symptoms such as fever and polyarthritis. Acne fulminans also may cause bone lesions and laboratory abnormalities. The condition usually is resistant to the antibiotics typically used to treat acne.

[0075] As used herein, the phrase “alopecia” refers to collectively, or individually as specified, androgenetic alopecia (AGA), alopecia areata (including diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, ophiasis, alopecia totalis, and alopecia universalis), telogen effluvium, anagen effluvium, and traction alopecia.

[0076] As used herein, the phrase “hidradenitis suppurativa” and “acne inversa” refer to a chronic inflammatory skin condition characterized by painful lesions such as deep-seatednodules, abscesses, skin tunnels, and fibrotic scars that manifest in the groin, perianal, perineal, and inframammary regions (i.e., intertriginous areas).

[0077] As used herein, the phrase “hirsutism,” refers to a condition in women that results in excessive growth of dark or coarse hair in a male-like pattern on the face, chest and back.

[0078] As used herein, the phrase “cancer-therapy-induced rash” refers to any cutaneous or dermatologic reactions, i.e., skin changes, on the epidermis, including the scalp, such as rashes, that are a common side effects of many cancer treatments.

[0079] As used herein, the phrase “eczema” refers to a group of inflammatory skin conditions that cause itchiness, dry skin, rashes, scaly patches, blisters and skin infections. The different types of eczema include: atopic dermatitis, contact dermatitis, dyshidrotic eczema, nummular eczema, seborrheic dermatitis and stasis dermatitis.

[0080] As used herein, the phrase “rosacea” refers to a skin condition that causes flushing or long-term redness on the face. Rosacea can also cause enlarged blood vessels and small, pus-filled bumps.

[0081] As used herein, the phrase “psoriasis” refers to a skin disease that causes a rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp. As used herein, the phrase “inverse psoriasis” refers to psoriasis on the skin folds such as the armpits, groin, under the breasts, and in other skin folds on the body.

[0082] As used herein, the phrases “seborrhea” and “seborrheic dermatitis” refer to skin conditions that mainly affect the scalp by causing scaly patches, inflamed skin and stubborn dandruff.

[0083] As used herein, the phrase “Acanthosis nigricans” refers to a condition that causes areas of dark, thick velvety skin in body folds and creases. It typically affects the armpits, groin and neck.

[0084] As used herein, the phrase “wound” refers to injuries to the body, that typically involve laceration or breaking of a membrane (as the skin) and usually damage to the underlying tissues. As used herein, the phrase “chronic wounds” refers to particular skin lesions, which are chronic open wounds that fail to proceed through an orderly and timely series of events to provide wound repair (or wound healing). A particular type of chronic wounds are the “trophic ulcers of the skin”: as used herein, such phrase refers to disabling skin disorders, which include a group of lesions caused by a faulty nutrition to the skin. These trophic ulcers of the skin include, for example, decubitus ulcers (also known aspressure or bed sores), lower extremity ulcers (also known as leg ulcers), diabetic ulcers, neuropathic ulcers, venous stasis ulcers, arterial ulcers, diabetic foot ulcers, and similar.

[0085] As used herein, the phrase “wound healing” refers to the process of repair of the skin from a wound.

[0086] As used herein, the phrase “affected area” refers to an area of the skin that presents with acne. 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.

[0087] As used herein, the term “at least” prior to a number or series of numbers is understood to include the number associated with the term “at least,” and all subsequent numbers or integers that could logically be included, as clear from context. When at least is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range. For example, “at least 3” means at least 3, at least 4, at least 5, etc. When at least is present before a component in a method step, then that component is included in the step, whereas additional components are optional.

[0088] As used herein, the terms “comprises,” “comprising,” “having,” “including,” “containing,” and the like are open-ended terms meaning “including, but not limited to.” To the extent a given embodiment disclosed herein “comprises” certain elements, it should be understood that present disclosure also specifically contemplates and discloses embodiments that “consist essentially of’ those elements and that “consist of’ those elements.

[0089] As used herein the term “cortexolone” (also known as “11-deoxy corti sol” or “Reichstein’s substance”) refers to the compound having the Chemical Abstract Service (CAS) Registry Number 152-58-9 and the structure below:

[0090] As used herein, the term “clascoterone” refers to the compound 17a-propionyloxy- 2 l-hydroxy-pregna-4-ene-3, 20-dione, which is also known as clascoterone, has the Chemical Abstract Service (CAS) Registry Number 19608-29-8 and is equivalent to the chemical structure:HO

[0091] As used herein “tetrahydrocortexolone” refers to the compound having the Chemical Abstract Service (CAS) Registry Number 68-60-0.

[0092] As used herein, “cortexol one-21 -propionate” refers to the compound having Chemical Abstract Service (CAS) Registry Number 95624-09-2.

[0093] As used herein, the term “degradation product” refers to those compounds that result from the in vitro degradation of clascoterone. Exemplary clascoterone degradation products include but are not limited to cortexol one-21 -propionate and cortexol one.

[0094] 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 or prevent the condition or disease of interest in a subject in need thereof.

[0095] As used herein, the term “clascoterone-cyclodextrin complex” refers to a non- covalent bonding interaction between clascoterone and a cyclodextrin, such as y-cyclodextrin.

[0096] As used herein, the “Investigator’s Global Assessment (IGA) score” is a static evaluation of the overall severity or average degree of severity of a subject’s disease by a blinded evaluator, taking into account all of the subject’s facial acne lesions as the subject appears on the day of the evaluation. The IGA is described in the Food and Drug Administration guideline “Acne Vulgaris: Establishing Effectiveness of Drugs Intended for Treatment” (2018). Overall severity of acne can be assessed using a five-point scale from 0-Clear to 5- Very Severe. Subjects must have an identical IGA score of moderate severity (IGA Grade 3) on both the right and left side of the face at baseline. In some embodiments, the subject is assessed for acne severity before, during, or after treatment using the IGA score depicted in Table 1.Table 1. Investigator Global Assessment (IGA) scale.Score Description0 = Clear Skin Clear Skin; no inflammatory or non-inflammatorylesions1 = Almost Clear Almost clear; rare non-inflammatory lesions with no more than one small inflammatory lesion2 = Mild Severity Mild severity; greater than Grade 1; some noninflammatory lesions with no more than a few inflammatory lesions (papules / pustules only, no nodular lesions)3 = Moderate Severity Moderate severity; greater than Grade 2; some to many non-inflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion4 = Severe Severe; greater than Grade 3; some to many noninflammatory and inflammatory lesions, but no more than a few nodular lesions5 = Very Severe Very Severe; greater than Grade 4; many noninflammatory and / or inflammatory lesions with some or many nodular lesions

[0097] As used herein, the term “pH” is considered an “apparent pH” to acknowledge the fact that the behavior of a pH electrode in a dermatological vehicle which is not entirely aqueous in nature cannot be considered a “pH” in the strictest sense. To measure the pH of formulations described herein, 1g sample of the formulation is diluted 1:10 with deionized water. After mixing under magnetic stirring for 10 minutes, pH is measured using a standard pH electrode.

[0098] As used herein, the term “stable” refers to the ability of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout a known period of time, e.g., during storage.

[0099] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent to, a subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with acne vulgaris.

[0100] As used herein, the term “preventing” refers to keeping from happening or existing, or alternatively delaying the onset or recurrence of a disease, disorder, or condition to which such term applies, or of one or more symptoms associated with a disease, disorder, or condition. The term “preventing” also refers to reducing the incidence of a disease, disorder, or condition. The term “prevention” refers to the act of preventing.

[0101] As used herein, the phrase “mild acne” refers to acne comprising mostly open and closed comedones, with a few papules and pustules and no nodules.

[0102] As used herein, the phrase “moderate acne” refers to acne comprising more widespread open and closed comedones, with several to many papules and pustules and few to several nodules.

[0103] As used herein, the phrase “severe acne” refers to acne comprising many large, painful papules, pustules, nodules or cysts, and optionally scarring.

[0104] As used herein “cancer-therapy -induced rash” refers to skin rash that can be a side effect of certain types of cancer treatments. Cancer treatments that can cause skin rash can include chemotherapy, radiation therapy, immunotherapy, targeted therapy, and stem cell transplant.

[0105] As used herein, the phrase “net clinical benefit” refers to a favorable effect on a meaningful embodiment of how a subject feels (e.g., symptom relief), functions (e.g., improved skin condition) or survives as a result of treatment.Pharmaceutical formulations

[0106] In some embodiments, the disclosure provides a pharmaceutical formulation comprising a mixture of a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone. The aqueous gel phase can further optionally comprise at least one of a clascoterone stabilizer, an aqueous phase gelling agent, and an aqueous phase excipient, and the oily gel phase can further optionally comprise at least one oily phase excipient, an oily phase gelling agent, and an antioxidant.

[0107] In typical embodiments, the pharmaceutical formulations described herein can have a total clascoterone concentration, i.e. a total amount of clascoterone equal to the sum of the amounts of clascoterone in the aqueous gel phase and the oily gel phase, ranging from about 0.2 wt% to about 10 wt% based on the total weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulations described herein can have a total clascoterone concentration ranging from about 0.5 wt% to about 7.5 wt% based on the total weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulations described herein can have a total clascoterone concentration ranging from about 1 wt% to about 5 wt% based on the total weight of the pharmaceutical formulation. For example, in some embodiments, the first amount of clascoterone in the aqueous gelphase can be from about 0.2 wt % to about 5 wt%, from about 0.2 wt % to about 4.5 wt%, from about 0.2 wt% to about 4 wt%, from about 0.2 to about 3.5 wt%, from about 0.2 wt% to about 3 wt %, from about 0.2 wt % to about 2.5 wt%, from about 0.2 wt% to about 2 wt%, from about 0.2 wt% to about 1.5 wt%, from about 0.25 wt% to about 5 wt%, from about 0.3 wt% to about 5 wt%, from about 0.35 wt% to about 5 wt%, from about 0.40 wt% to about 5 wt%, from about 0.45 wt% to about 5 wt%, from about 0.5 wt% to about 5 wt%, from about 0.55 wt% to about 5 wt%, from about 0.60 wt% to about 5 wt%, from about 0.65 wt% to about 5 wt%, from about 0.7 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 0.8 wt% to about 5 wt%, from about 0.85 wt% to about 5 wt%, from about 0.9 wt% to about 5 wt%, from about 0.95 wt% to about 5 wt%, from about 1 wt% to about 5 wt%, from about 1.05 wt% to about 5 wt%, from about 1.10 wt% to about 5 wt%, from about 1.15 wt% to about 5 wt%, from about 1.2 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt%. In some embodiments, the second amount of clascoterone in the oily gel phase can be from about 0.2 wt % to about 5 wt%, from about 0.2 wt % to about 4.5 wt%, from about 0.2 wt% to about 4 wt%, from about 0.2 to about 3.5 wt%, from about 0.2 wt% to about 3 wt %, from about 0.2 wt % to about 2.5 wt%, from about 0.2 wt% to about 2 wt%, from about 0.2 wt% to about 1.5 wt%, from about 0.3 wt% to about 5 wt%, from about 0.35 wt% to about 5 wt%, from about 0.4 wt% to about 5 wt%, from about 0.45 wt% to about 5 wt%, from about 0.5 wt% to about 5 wt%, from about 0.55 wt% to about 5 wt%, from about 0.6 wt% to about 5 wt%, from about 0.65 wt% to about 5 wt%, from about 0.7 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 0.8 wt% to about 5 wt%, from about 0.85 wt% to about 5 wt%, from about 0.9 wt% to about 5 wt%, from about 0.95 wt% to about 5 wt%, from about 1 wt% to about 5 wt%, from about 1.05 wt% to about 5 wt%, from about 1.1 wt% to about 5 wt%, from about 1.15 wt% to about 5 wt%, from about 1.2 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt%. In some embodiments, the first amount of clascoterone in the aqueous gel phase can be about 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, or 2.5 wt%, based on the total weight of the pharmaceutical formulation, andthe second amount of clascoterone in the oily gel phase can be about 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, or 2.5 wt% based on the total weight of the pharmaceutical formulation. In some embodiments, the first amount of clascoterone in the aqueous gel phase can be about 1 wt%, and the second amount of clascoterone in the oily gel phase can be about 2.5 wt%, based on the total weight of the pharmaceutical formulation.Aqueous Gel Phase

[0108] In some embodiments of the pharmaceutical formulation, the first amount of clascoterone can be present in the aqueous gel phase in an amount from about 0.05 wt% to about 5 wt% based on the total weight of the formulation. In some embodiments, the first amount of clascoterone can be present in the aqueous gel phase in an amount ranging from about 0.05 wt % to about 4.5 wt%, from about 0.05 wt% to about 4 wt%, from about 0.05 to about 3.5 wt%, from about 0.05 wt% to about 3 wt %, from about 0.05 wt % to about 2.5 wt%, from about 0.05 wt% to about 2 wt% from about 0.05 wt% to about 1.5 wt%, from about 0.05 wt% to about 1 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.05 wt% to about 0.25 wt%, from about 0.1 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt%. In some embodiments of the pharmaceutical formulation, the first amount of clascoterone can be present in the aqueous gel phase at about 0.05 wt%, 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%.

[0109] In some embodiments, the pharmaceutical formulation can further comprise a clascoterone stabilizer in the aqueous gel phase. In some embodiments, the clascoterone stabilizer can be a cyclodextrin. In some embodiments, the cyclodextrin can be an a-cyclodextrin, a P-cyclodextrin, a y-cyclodextrin, a methylated-P-cyclodextrin, P- cyclodextrin sulfobutyl ether, a hydroxypropyl-P-cyclodextrin, or a hydroxypropyl-y- cyclodextrin. In one embodiment, the cyclodextrin can be P-cyclodextrin. In another embodiment, the cyclodextrin can be y-cyclodextrin. In a preferred embodiment, the cyclodextrin can be y-cyclodextrin.

[0110] In some embodiments, the first amount of clascoterone present in the aqueous gel phase can be present in the form of a clascoterone-cyclodextrin complex. In some embodiments, at least 50% of the first amount of clascoterone in the aqueous gel phase can be present in the form of a clascoterone-cyclodextrin complex. In some embodiments, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% of the first amount of clascoterone in the aqueous gel phase can be present in the form of a clascoterone-cyclodextrin complex. In some embodiments, all of the clascoterone can be present in the form of a clascoterone-cyclodextrin complex. In some embodiments, substantially all of the clascoterone can be present in the form of a clascoterone- cyclodextrin complex.[OHl] In some embodiments, the pharmaceutical formulation can contain an amount of cyclodextrin in the aqueous gel phase ranging from about 0.5 wt% to about 40 wt%, based on the total weight of formulation. For example, the amount of cyclodextrin in the aqueous gel phase can range from about 0.5 wt % to about 40 wt%, from about 1 wt% to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt %, from about 1 wt % to about 10 wt%, from about 1 wt% to about 5 wt%, from about 3 wt% to about 40 wt% from about 7 wt% to about 40 wt%, from about 12 wt% to about 40 wt%, from about 18 wt% to about 40 wt%, from about 22 wt% to about 40 wt%, from about 28 wt% to about 40 wt%, from about 32 wt% to about 40 wt%, from about 38 wt% to about 40 wt%, based on the total weight of the formulation. In some embodiments, the pharmaceutical formulation can contain about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 38.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%,about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, about 19.5 wt%, about 20 wt%, about 20.5 wt%, about 21 wt%, about 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 30.5 wt%, about 31 wt%, about 31.5 wt%, about 32 wt%, about 32.5 wt%, about 33 wt%, about 33.5 wt%, about 34 wt%, about 34.5 wt%, about 35 wt%, about 35.5 wt%, about 36 wt%, about 36.5 wt%, about 37 wt%, about 37.5 wt%, about 38 wt%, about 38.5 wt%, about 39 wt%, about 39.5 wt%, or about 40 wt% cyclodextrin based on the total weight of the formulation.

[0112] In some embodiments, the pharmaceutical formulation disclosed herein can contain an aqueous gel phase comprising water, a first amount of clascoterone in an amount ranging from about 0.05 wt% to about 5 wt% based on the total weight of the formulation, and a clascoterone stabilizer that is a cyclodextrin, e.g., an a-cyclodextrin, a P-cyclodextrin, a y-cyclodextrin, a methylated-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, a hydroxypropyl-P-cyclodextrin, or a hydroxypropyl-y-cyclodextrin, wherein at least 50% of the first amount of clascoterone is present in the formulation in the form of the clascoterone- cyclodextrin complex, and wherein the formulation comprises the cyclodextrin in an amount of from about 1 wt% to about 40 wt% based on the total weight of the formulation. In some embodiments, the pharmaceutical formulation disclosed herein can contain an aqueous gel phase comprising water, a first amount of clascoterone in an amount ranging from about 0.05 wt% to about 5 wt% based on the total weight of the formulation, and a clascoterone stabilizer that is hydroxypropyl-y-cyclodextrin, wherein at least 50% of the first amount of clascoterone is present in the formulation in the form of the clascoterone- cyclodextrin complex, and wherein the formulation comprises the cyclodextrin in an amount of from about 0.5 wt% to about 40 wt% based on the total weight of the formulation. In some embodiments, the pharmaceutical formulation can contain about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18wt%, about 18.5 wt%, about 19 wt%, about 19.5 wt%, about 20 wt%, about 20.5 wt%, about 21 wt%, about 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 30.5 wt%, about 31 wt%, about 31.5 wt%, about 32 wt%, about 32.5 wt%, about 33 wt%, about 33.5 wt%, about 34 wt%, about 34.5 wt%, about 35 wt%, about 35.5 wt%, about 36 wt%, about 36.5 wt%, about 37 wt%, about 37.5 wt%, about 38 wt%, about 38.5 wt%, about 39 wt%, about 39.5 wt%, or about 40 wt% cyclodextrin based on the total weight of the formulation.

[0113] In some embodiments, the clascoterone stabilizer is an a-cyclodextrin. In some embodiments, the pharmaceutical formulation disclosed herein can contain an aqueous gel phase comprising water, a first amount of clascoterone in an amount ranging from 0.05 wt % to about 4.5 wt%, from about 0.05 wt% to about 4 wt%, from about 0.05 to about 3.5 wt%, from about 0.05 wt% to about 3 wt %, from about 0.05 wt % to about 2.5 wt%, from about 0.05 wt% to about 2 wt% from about 0.05 wt% to about 1.5 wt%, from about 0.05 wt% to about 1 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.05 wt% to about 0.25 wt%, from about 0.1 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt%, based on the total weight of the formulation, and a clascoterone stabilizer that is an a-cyclodextrin, and wherein the formulation comprises the a-cyclodextrin in an amount of from about 0.5 wt% to about 40 wt% based on the total weight of the formulation. In some embodiments, the pharmaceutical formulation can contain about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, about 19.5 wt%, about 20 wt%, about 20.5 wt%, about 21 wt%, about 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%,about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 30.5 wt%, about 31 wt%, about 31.5 wt%, about 32 wt%, about 32.5 wt%, about 33 wt%, about 33.5 wt%, about 34 wt%, about 34.5 wt%, about 35 wt%, about 35.5 wt%, about 36 wt%, about 36.5 wt%, about 37 wt%, about 37.5 wt%, about 38 wt%, about 38.5 wt%, about 39 wt%, about 39.5 wt%, or about 40 wt% cyclodextrin based on the total weight of the formulation, optionally wherein at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% of the first amount of clascoterone is present in the clascoterone-cyclodextrin complex.

[0114] In some embodiments, the clascoterone stabilizer is a P-cyclodextrin, e.g., a methylated-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, or a hydroxypropyl-P- cyclodextrin. In some embodiments, the pharmaceutical formulation disclosed herein can contain an aqueous gel phase comprising water, a first amount of clascoterone in an amount ranging from 0.05 wt % to about 4.5 wt%, from about 0.05 wt% to about 4 wt%, from about 0.05 to about 3.5 wt%, from about 0.05 wt% to about 3 wt %, from about 0.05 wt % to about 2.5 wt%, from about 0.05 wt% to about 2 wt%, from about 0.05 wt% to about 1.5 wt%, from about 0.05 wt% to about 1 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.05 wt% to about 0.25 wt%, from about 0.1 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt% based on the total weight of the formulation, and a clascoterone stabilizer that is a P-cyclodextrin, e.g., a methylated-P- cyclodextrin, P-cyclodextrin sulfobutyl ether, or a hydroxypropyl-P-cyclodextrin, and wherein the formulation comprises the P-cyclodextrin, e.g., a methylated-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, or a hydroxypropyl-P-cyclodextrin in an amount of from 0.5 wt% to about 40 wt% based on the total weight of the formulation. In some embodiments, the pharmaceutical formulation can contain about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%,about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, about 19.5 wt%, about 20 wt%, about 20.5 wt%, about 21 wt%, about 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 30.5 wt%, about 31 wt%, about 31.5 wt%, about 32 wt%, about 32.5 wt%, about 33 wt%, about 33.5 wt%, about 34 wt%, about 34.5 wt%, about 35 wt%, about 35.5 wt%, about 36 wt%, about 36.5 wt%, about 37 wt%, about 37.5 wt%, about 38 wt%, about 38.5 wt%, about 39 wt%, about 39.5 wt%, or about 40 wt% cyclodextrin based on the total weight of the formulation, optionally wherein at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% of the first amount of clascoterone is present in the clascoterone-cyclodextrin complex. In some embodiments, the clascoterone stabilizer is a y-cyclodextrin, e.g., hydroxypropyl-y-cyclodextrin. In some embodiments, the pharmaceutical formulation disclosed herein can contain an aqueous gel phase comprising water, a first amount of clascoterone in an amount ranging from 0.05 wt % to about 4.5 wt%, from about 0.05 wt% to about 4 wt%, from about 0.05 to about 3.5 wt%, from about 0.05 wt% to about 3 wt %, from about 0.05 wt % to about 2.5 wt%, from about 0.05 wt% to about 2 wt%, from about 0.05 wt% to about 1.5 wt%, from about 0.05 wt% to about 1 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.05 wt% to about 0.25 wt%, from about 0.1 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt% based on the total weight of the formulation, and a clascoterone stabilizer that is a y-cyclodextrin, and wherein the formulation comprises the y-cyclodextrin an amount of from about 0.5 wt% to about 40 wt% based on the total weight of the formulation. In some embodiments, the pharmaceutical formulation can contain about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%,about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, about 19.5 wt%, about 20 wt%, about 20.5 wt%, about 21 wt%, about 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 30.5 wt%, about 31 wt%, about 31.5 wt%, about 32 wt%, about 32.5 wt%, about 33 wt%, about 33.5 wt%, about 34 wt%, about 34.5 wt%, about 35 wt%, about 35.5 wt%, about 36 wt%, about 36.5 wt%, about 37 wt%, about 37.5 wt%, about 38 wt%, about 38.5 wt%, about 39 wt%, about 39.5 wt%, or about 40 wt% cyclodextrin based on the total weight of the formulation, optionally wherein at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% of the first amount of clascoterone is present in the clascoterone-cyclodextrin complex.

[0115] In some embodiments, the clascoterone stabilizer is hydroxypropyl-y-cyclodextrin.In some embodiments, the pharmaceutical formulation disclosed herein can contain an aqueous gel phase comprising water, a first amount of clascoterone in an amount ranging from 0.05 wt % to about 4.5 wt%, from about 0.05 wt% to about 4 wt%, from about 0.05 to about 3.5 wt%, from about 0.05 wt% to about 3 wt %, from about 0.05 wt % to about 2.5 wt%, from about 0.05 wt% to about 2 wt%, from about 0.05 wt% to about 1.5 wt%, from about 0.05 wt% to about 1 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.05 wt% to about 0.25 wt%, from about 0.1 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt% based on the total weight of the formulation, and the clascoterone stabilizer is hydroxypropyl-y-cyclodextrin, wherein the formulation comprises the hydroxypropyl-y-cyclodextrin in an amount of from about 0.5 wt% to about 40 wt% based on the total weight of the formulation. In some embodiments, the pharmaceutical formulation can contain about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, about 19.5 wt%, about 20 wt%, about 20.5 wt%, about 21 wt%, about 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 30.5 wt%, about 31 wt%, about 31.5 wt%, about 32 wt%, about 32.5 wt%, about 33 wt%, about 33.5 wt%, about 34 wt%, about 34.5 wt%, about 35 wt%, about 35.5 wt%, about 36 wt%, about 36.5 wt%, about 37 wt%, about 37.5 wt%, about 38 wt%, about 38.5 wt%, about 39 wt%, about 39.5 wt%, or about 40 wt% cyclodextrin based on the total weight of the formulation, optionally wherein at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% of the first amount of clascoterone is present in the clascoterone-cyclodextrin complex.

[0116] In some embodiments, the pharmaceutical formulation disclosed herein can contain an aqueous gel phase comprising water, about 1 wt% clascoterone based on the total weight of the formulation, and about 7 wt% hydroxypropyl-y-cyclodextrin based on the total weight of the formulation, optionally wherein substantially all of the clascoterone present in the aqueous gel phase is present in the formulation in the form of the clascoterone- cyclodextrin complex.

[0117] In some embodiments, the aqueous gel phase can further comprise at least one aqueous phase gelling agent. Suitable gelling agents for use in the aqueous phase include, but are not limited to, alginates, bentonite, gelatins, chitosan, cellulose and cellulose derivatives, gums (e.g. xanthan gum), carrageenan, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), starches, modified starches, pullulan, poloxamer, alginic acid and salts and derivatives thereof (such as sodium alginate or potassium alginate), gum arabic, povidone and sodium hyaluronate. In some embodiments, the aqueous phase gelling agent can be a carbomer such as acrylates / Cio-Cso alkyl acrylate crosspolymer,carbopol homopolymers such as acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, carbopol copolymers such as acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol, or carbopol interpolymers such as carbomer homopolymer or copolymer that contains a block copolymer of polyethylene glycol and a long chain alkyl acid ester (Lubrizol Corp., Wickliffe, OH).

[0118] In some embodiments, the at least one aqueous phase gelling agent can be present in the aqueous gel phase in amounts ranging from about 0.1 wt% to about 5 wt% based on the total weight of the formulation. For example, the aqueous phase gelling agent can be present in the aqueous gel phase in an amount from about 0.1 wt % to about 4.5 wt%, from about 0.1 wt% to about 4 wt%, from about 0.1 to about 3.5 wt%, from about 0.1 wt% to about 3 wt %, from about 0.1 wt % to about 2.5 wt%, from about 0.1 wt% to about 2 wt%, from about 0.1 wt% to about 1.5 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 0.5 wt%, from about 0.1 wt% to about 0.25 wt%, from about 0.25 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt% based on the total weight of the formulation. In some embodiments, the at least one aqueous phase gelling agent can be present at 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% based on the total weight of the formulation.

[0119] In a preferred embodiment, the aqueous phase gelling agent is a carbomer that is present at 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% based on the total weight of the formulation.

[0120] In a preferred embodiment, the aqueous phase gelling agent is a carbopol that is present at 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% based on the total weight of the formulation.

[0121] In some embodiments of the pharmaceutical formulation disclosed herein, the at least one aqueous phase gelling agent in the aqueous gel phase can be xanthan gum, acrylic acid polymers, acrylic acid crosspolymers, or combinations thereof. In some embodiments, the xanthan gum, acrylic acid polymers, acrylic acid cross-polymers, or combinations thereof can be present in the aqueous gel phase in amounts ranging from about 0.1 wt% to about 5 wt%, e.g., 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation. In a preferred embodiment the at least one aqueous phase gelling agent in the aqueous gel phase is a gum, that is present in the aqueous gelphase in amounts ranging from about 0.1 wt% to about 5 wt%, e.g., 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation.

[0122] In some embodiments, the xanthan gum can be present in the aqueous gel phase in amounts of about 0.1 wt% to about 5 wt%, e.g., 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation. In some embodiments, the acrylic acid polymers can be present in the aqueous gel phase in amounts of about 0.1 wt% to about 5 wt%, e.g., 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%., based on the total weight of the formulation. In some embodiments, the acrylic acid crosspolymers can be present in the aqueous gel phase in amounts of about 0.1 wt% to about 5wt%, e.g., 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation.

[0123] In some embodiments, a combination of any one of xanthan gum, acrylic acid polymers, and / or acrylic acid cross-polymers can be present in the aqueous gel phase in amounts of about 0.1 wt% to about 5 wt%, e.g., 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation.

[0124] In some embodiments of the pharmaceutical formulation disclosed herein, the at least one aqueous phase gelling agent in the aqueous gel phase can be acrylic acid crosspolymers, e.g., acrylates / C10-C30 alkyl acrylate crosspolymer (CARBOPOL™ polymers or PEMULEN TRI™ polymers, Lubrizol Corp., Wickliffe, OH), and can be present in the aqueous gel phase in amounts ranging from about 0.1 wt% to about 2 wt%, e.g., 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%, or about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2 wt%, based on the total weight of the formulation. In some embodiments, the at least one aqueous phase gelling agent in the aqueous gel phase can be acrylates / C10-C30 alkyl acrylate cross-polymer (CARBOPOL™ polymers or PEMULENTR1™ polymers, Lubrizol Corp., Wickliffe, OH), and can be present in the aqueous gel phase in about 0.1 wt% to about 2 wt%, e.g., 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%, or about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2 wt%, based on the total weight of the formulation. In a preferred embodiment, the acrylates / ClO- C30 alkyl acrylate cross-polymer is present in the aqueous gel phase at about 0.4 wt%, based on the total weight of the formulation.

[0125] In some embodiments the aqueous gel phase can comprise at least one aqueous phase excipient. Suitable aqueous phase excipients include, but are not limited to, polyols, polyolethers, glycol esters, C1-C7 alcohols, glycerol, and combinations thereof. In some embodiments, the at least one aqueous phase excipient can be present in the aqueous gel phase in an amount ranging from about 1 wt% to about 30 wt%, based on the total weight of the formulation. For example, the at least one aqueous phase excipient can be present in the aqueous gel phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%. In some embodiments, the at least one aqueous phase excipient can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation. In a preferred embodiment the at least one aqueous phase excipient is a polyol. In some embodiments, the polyol can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0126] In some embodiments, the aqueous phase excipient can be a polyol selected from the group consisting of propylene glycol, ethylene glycol, glycerol, hexanetriol, sorbitol and combinations thereof. In some embodiments, these polyols can be present in the aqueous phase, either individually, or collectively, in an amount ranging from about 1 wt% to about 30 wt%, based on the total weight of the formulation. For example, the polyol(s) can be present in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt% based on the total weight of the formulation. In some embodiments, the polyol(s) can be present in the aqueous phase in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0127] In some embodiments, the aqueous phase excipient can be a polyol ether selected from the group consisting of polyethylene glycol, polypropylene glycol, polyethylenepolypropylene triblock copolymers, dipropylene glycol, diethylene glycol monoethyl ether (TRANSCUTOL®), and combinations thereof. In some embodiments, the polyol ether, or combination thereof, can be present in an amount ranging from about 1 wt% to about 30 wt%, based on the total weight of the formulation. For example, the polyol ether, or combination thereof, can be present in the aqueous phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the polyol ether, or combination thereof, can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0128] In some embodiments the aqueous phase excipient can be a glycol ester selected from the group consisting of propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, propylene glycol monocaprylate, and combinations thereof. In embodiments wherein the aqueous phase comprises a glycol ester such as any of those described in this paragraph, the aqueous phase will also include a sufficient amount of a C1-C7 alcohol, such as any of the C1-C7 alcohols described in the following paragraph, (e.g. ethanol) in an amount sufficient to solubilize the glycol ester. In some embodiments, the glycol ester or combinations thereof can be present in the aqueous phase in an amount ranging from about 1 wt% to about 30 wt%, based on the total weight of the formulation. For example, the amount of the glycol ester, or combinations thereof, can be present in the aqueous phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt% based on the total weight of the formulation. In some embodiments, the glycol ester, or combinations thereof, can be present in the aqueous phase in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0129] In some embodiments, the aqueous phase excipient can be a C1-C7 alcohol selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, n-propanol, benzyl alcohol, or a combination thereof. In some embodiments, the C1-C7 alcohol can be present in the aqueous phase in an amount ranging from about 1 wt% to about 30 wt%, based on the total weight of the formulation. For example, the amount of the C1-C7 alcohol, or combinations thereof, can be present in the aqueous phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the C1-C7 alcohol, or combinations thereof, can be present in the aqueous phase in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0130] In some embodiments, the at least one aqueous phase excipient can be glycerol. In some embodiments, the glycerol can be present in the aqueous phase in an amount ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation. For example, the amount of glycerol in the aqueous gel phase can range from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt% based on the total weight of the formulation. In some embodiments, the aqueous gel phase can comprise glycerol at about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation. In some embodiments, the formulation comprises glycerol in an amount of from about 1 wt% to about 30 wt% based on the total weight of the formulation. In some embodiments, the formulation comprises glycerol in an amount of from about 15.5 wt%, about 16.5 wt%, about 17.5 wt%, about 18.5 wt%, about 19.5 wt%, or about 20 wt%, based on the total weight of the formulation. In some embodiments, the formulation comprises glycerol in an amount of about 17.5 wt%, based on the total weight of the formulation.

[0131] In some embodiments, the aqueous gel phase can comprise water in an amount ranging from about 35 wt% to about 80 wt% based on the total formulation. For example, the amount of water in the aqueous gel phase can range from about 35 wt % to about 75 wt%, from about 35 wt% to about 70 wt%, from about 35 wt% to about 65 wt%, from about 35 wt% to about 60 wt %, from about 35 wt % to about 55 wt%, from about 35 wt% to about 40 wt% from about 38 wt% to about 80 wt%, from about 42 wt% to about 80 wt%, from about 48 wt% to about 80 wt%, from about 52 wt% to about 80 wt%, from about 58 wt% to about 80 wt%, from about 62 wt% to about 80 wt%, from about 68 wt% to about 80 wt%, from about 72 wt% to about 80 wt%, or from about 78 wt% to about 80 wt% based on the total weight of the formulation. In some embodiments, the aqueous gel phase can comprise about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, about 60 wt%, about 61 wt%, about 62 wt%, about 63 wt%, about 64 wt%, about 65 wt%, about 66 wt%, about 67 wt%, about 68 wt%, about 69 wt%, about 70 wt%, about 71 wt%, about 72 wt%, about 73 wt%, about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, or about 80 wt% water, based on the total weight of the formulation.

[0132] In some embodiments of the formulation provided herein, the aqueous gel phase can comprise: clascoterone in an amount ranging from 0.05 wt% to about 5 wt%, based on the total weight of the formulation, y -cyclodextrin in an amount ranging from about 1 wt% to about 40 wt% based on the total weight of the formulation, optionally wherein substantially all of the clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex, acrylic acid crosspolymers in an amount ranging from about 0.1 wt% to about 5 wt% based on the total weight of the formulation, glycerol in an amount ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation, water in an amount ranging from about 35 wt% to about 80 wt%, and a chelating agent, e.g., disodium EDTA, in an amount ranging from about 0.005 wt% to about 5 wt% based on the total weight of the formulation. In some embodiments, a chelating agent, e.g., disodium EDTA, is present in the formulation in an amount ranging from about 0.005 wt% to about 0.1 wt% based on the total weight of the formulation.

[0133] In some embodiments of the formulation provided herein, the aqueous gel phase can comprise: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, y -cyclodextrin in an amount of about 7 wt% based on the total weight of the formulation, optionally wherein substantially all of the clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex, acrylic acid crosspolymers in an amount of about 0.4 wt% based on the total weight of the formulation, glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, water in an amount of about 51 wt% to 52 wt%, and a chelating agent, e.g., disodium EDTA, in an amount of about 0.10 wt% based on the total weight of the formulation.Oily Gel Phase

[0134] As described above, this disclosure provides a pharmaceutical formulation comprising a mixture of a) an aqueous gel phase, discussed above, and b) an oily gel phase comprising a second amount of clascoterone.

[0135] In some embodiments of the pharmaceutical formulation, the second amount of clascoterone can be present in the oily gel phase in an amount ranging from about 0.05 wt% to about 5 wt% based on the total weight of the formulation. In some embodiments, the second amount of clascoterone can be present in the oily gel phase in an amount ranging from about 0.05 wt % to about 4.5 wt%, from about 0.05 wt% to about 4 wt%, from about 0.05 to about 3.5 wt%, from about 0.05 wt% to about 3 wt %, from about 0.05 wt % to about 2.5 wt%, from about 0.05 wt% to about 2 wt%, from about 0.05 wt% to about 1.5 wt%, from about 0.05 wt% to about 1 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.05 wt% to about 0.25 wt%, from about 0.1 wt% to about 5 wt%, from about 0.75 wt% to about 5 wt%, from about 1.25 wt% to about 5 wt%, from about 1.75 wt% to about 5 wt%, from about 2.25 wt% to about 5 wt%, from about 2.75 wt% to about 5 wt%, from about 3.25 wt% to about 5 wt%, from about 3.75 wt% to about 5 wt%, from about 4.25 wt% to about 5 wt%, or from about 4.75 wt% to about 5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the second amount of clascoterone can be present in the oily gel phase at about 0.05 wt%, 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 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%,about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation.

[0136] In some embodiments of the pharmaceutical formulation, the oily gel phase can comprise at least one oily phase excipient. In some embodiments, the formulation can comprise the at least one oily phase excipient in an amount ranging from about 1 wt% to about 50 wt% based on the total weight of the formulation. For example, the at least one oily phase excipient can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, or from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the at least one oily phase excipient can be present in an amount of aboutl wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0137] In some embodiments, the at least one oily phase excipient can be selected from the group consisting of a polyol, a polyol ether, a natural oil, a glycol and esters thereof, a Ci- C7 alcohol, glycerol, diethylene glycol monoethyl ether, a glycerides such as capryl ocaproyl polyoxyl 8 glycerides, medium chain triglycerides, dibutyl sebacate, and combinations thereof.

[0138] In a preferred embodiment, the least one oily phase excipient is a glycol and esters thereof and the glycol and esters thereof can be present in an amount of aboutl wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%,about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0139] In some embodiments, the at least one oily phase excipient can be a polyol selected from the group consisting of propylene glycol, ethylene glycol, glycerol, hexanetriol, and combinations thereof. In some embodiments, the formulation can comprise the polyol, and combinations thereof, in an amount ranging from about 1 wt% to about 50 wt% based on the total weight of the formulation. For example, the polyol present in the oily phase can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the polyol present in the oily phase can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0140] In some embodiments, the polyol ether of the oily gel phase can be selected from the group consisting of polyethylene glycol, polypropylene glycol, polyethylenepolypropylene triblock copolymers, dipropylene glycol, diethylene glycol monoethyl ether(TRANSCUTOL®), and combinations thereof. In some embodiments, the formulation can comprise the polyol ether in an amount ranging from about 1 wt% to about 50 wt% based on the total weight of the formulation. For example, the polyol ether can be present in an amount of from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the polyol ether present in the oily phase can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0141] In some embodiments, the formulation can comprise the glycol ester in an amount ranging from about 1 wt% to about 50 wt% based on the total weight of the formulation. For example, the glycol ester can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the glycol ester can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%,about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0142] In some embodiments, the at least one oily phase excipient can be a C1-C7 alcohol.In some embodiments, the alcohol can be selected from the group consisting of ethanol, isopropanol, n-butanol, n-propanol, and benzyl alcohol. In some embodiments, the formulation can comprise the C1-C7 alcohol in an amount ranging from about 1 wt% to about 50 wt% based on the total weight of the formulation. In some embodiments, the formulation can comprise the C1-C7 alcohol in an amount ranging from about 10 wt% to about 50 wt% based on the total weight of the formulation. For example, the C1-C7 alcohol can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the C1-C7 alcohol can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0143] In some embodiments, the at least one oily phase excipient can be a glycol ester selected from the group consisting of propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, propylene glycol monocaprylate, propylene glycol dicaprolate / dicaprate, and combinations thereof.

[0144] In some embodiments, the propylene glycol monolaurate can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the propylene glycol monolaurate can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0145] In some embodiments, the propylene glycol monostearate can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the propylene glycol monostearate can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0146] In some embodiments, the propylene glycol isostearate can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the propylene glycol isostearate can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0147] In some embodiments, the propylene glycol monocaprylate can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the propylene glycol monocaprylate can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0148] In some embodiments, the propylene glycol dicaprolate / dicaprate can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the propylene glycol dicaprolate / dicaprate can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0149] In some embodiments, propylene glycol monocaprylate can be present in an amount ranging from about 1 wt % to about 20 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the propylene glycol monocaprylate can be present in an amount of about 10 wt%, based on the total weight of the formulation.

[0150] In some embodiments, the combination of any of propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, propylene glycol monocaprylate, and or propylene glycol dicaprolate / dicaprate, can be present in an amount ranging from about 1 wt % to about 50 wt%, from about 1 wt % to about 45 wt%, from about 5 wt% to about 45 wt%, from about 10 wt % to about 50 wt%, from about 10 wt% to about 45 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 35 wt %, from about 10 wt % to about 30 wt%, from about 10 wt% to about 25 wt%, from about 10 wt % to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% toabout 12.5 wt%, based on the total weight of the formulation. In some embodiments of the pharmaceutical formulation, the combination of any of propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, propylene glycol monocaprylate, and / or propylene glycol dicaprylate / dicaprate can be present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%, based on the total weight of the formulation.

[0151] In some embodiments, the oily gel phase can comprise at least one oily phase gelling agent. In some embodiments, the at least one oily phase gelling agent of the oily phase can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the amount of the at least one oily phase gelling agent in the oily phase can be present in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation.. In some embodiments, the at least one oily phase gelling agent of the oily phase can be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0152] In some embodiments, the oily phase gelling agent can be selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, silicon dioxide, carboxymethyl cellulose, methylcellulose,silicones, waxes, aluminum monostearate, bentonite and combinations thereof. In preferred embodiments, the at least one oily phase gelling agent comprises commercially available mixtures of propylene glycol monolaurate, ethyl cellulose, and propylene glycol isosterarate cellulose and propylene glycol isostearate (e.g., Emulfree Duo™, Gattefosse, Saint-Priest, France).

[0153] In a preferred embodiment, the oily phase gelling agent is cellulose and mixture of cellulose with glycols that is present in an amount of 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation. Preferably the cellulose and mixture of cellulose with glycols that is present in an amount of 10%, based on the total weight of the formulation.

[0154] In some embodiments, the oily phase gelling agent can be ethyl cellulose which can be present in the oily phase in amounts ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation. For example, the ethyl cellulose can be present in the oily phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the ethyl cellulose can be present in the oily phase in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0155] In some embodiments, the hydroxypropyl cellulose can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the hydroxypropyl cellulose can be present in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%,from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the hydroxypropyl cellulose be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0156] In some embodiments, the oily phase gelling agent can be hydroxyethyl cellulose which can be present in the oily phase in amounts ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation. For example, the hydroxyethyl cellulose can be present in the oily phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the hydroxyethyl cellulose can be present in the oily phase in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0157] In some embodiments, the oily phase gelling agent can be hydroxypropyl methyl cellulose which can be present in the oily phase in amounts ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation. For example, the hydroxypropyl methyl cellulose can be present in the oily phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%,from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the hydroxypropyl methyl cellulose can be present in the oily phase in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0158] In some embodiments, the oily phase gelling agent can be silicon dioxide which can be present in the oily phase in amounts ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation. For example, the silicon dioxide can be present in the oily phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the silicon dioxide can be present in the oily phase in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0159] In some embodiments, the carboxymethyl cellulose can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the amount of carboxymethyl cellulose can be present in amounts ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the carboxymethyl cellulose can be present in amounts of about 1 wt%, 2wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0160] In some embodiments, the methylcellulose can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the methylcellulose can be present in amounts ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, methylcellulose can be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0161] In some embodiments, the silicones can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the silicones can be present in amounts ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, silicones can be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%,about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0162] In some embodiments, the waxes can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the waxes can be present in amounts ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, waxes can be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0163] In some embodiments, the aluminum monostearate can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the aluminum monostearate can be present in amounts ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, aluminum monostearate can be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0164] In some embodiments, the bentonite can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the bentonite can be present in amounts ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, bentonite can be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0165] In some embodiments, the combination of any one of ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide, carboxymethyl cellulose, methylcellulose, silicones, waxes, aluminum monostearate, and bentonite e can be present in amounts ranging from about 1 wt% to about 30 wt% based on the total formulation. For example, the amount of the combination of any one of ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and / or methylcellulose can be present in amounts ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the combination of any one of ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and / or methylcellulose can be present in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0166] In some embodiments, the oily phase gelling agent can be a combination of propylene glycol monolaurate, ethyl cellulose, and propylene glycol isosterarate, and this combination can be present in the oily phase in amounts ranging from about 1 wt% to about30 wt% based on the total weight of the formulation. For example, the combination of propylene glycol monolaurate, ethyl cellulose, and propylene glycol isosterarate can be present in the oily phase in an amount ranging from about 1 wt % to about 25 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 10 wt %, from about 1 wt % to about 5 wt%, from about 3 wt% to about 30 wt% from about 7 wt% to about 30 wt%, from about 12 wt% to about 30 wt%, from about 18 wt% to about 30 wt%, from about 22 wt% to about 30 wt%, or from about 28 wt% to about 30 wt%, based on the total weight of the formulation. In some embodiments, the combination of propylene glycol monolaurate, ethyl cellulose, and propylene glycol isosterarate can be present the oily phase in amounts of about 1 wt%, 2 wt%, 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, based on the total weight of the formulation.

[0167] In some embodiments, the formulation can further include an antioxidant. In some embodiments, the antioxidant can be selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol (a-tocopherol), propyl gallate, vitamin A, and combinations thereof. In a preferred embodiment, the antioxidant is alpha tocopherol.

[0168] In some embodiments, the antioxidant can be present in the formulation in an amount ranging from about 0.01 wt% to about 1 wt%, based on the total weight of the formulation. For example, the antioxidant can be present in an amount from about 0.01 wt % to about 0.5 wt%, from about 0.01 wt% to about 0.4 wt%, from about 0.01 wt% to about 0.03 wt%, or from about 0.01 wt% to about 0.2 wt %, based on the total weight of the formulation. In some embodiments, the antioxidant can be present in the formulation in an amount of about 0.01 wt%, 0.02 wt%, 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, 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%, or about 1 wt%, based on the total weight of the formulation.

[0169] In some embodiments, the antioxidant can be a-tocopherol which can be present in the formulation in an amount of about 0.01 wt%, 0.02 wt%, 0.03 wt%, about 0.04 wt%,about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, 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%, or about 1 wt% based on the total weight of the formulation. In a preferred embodiment the a-tocopherol can be present in the formulation in an amount of about 0.08 wt%, based on the total weight of the formulation. In some embodiments, the antioxidant can be BHA, which can be present in the formulation in an amount of about 0.01 wt%, 0.02 wt%, 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, 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%, or about 1 wt% based on the total weight of the formulation. In some embodiments, the antioxidant can be ascorbyl palmitate which can be present in the formulation in an amount of about 0.01 wt%, 0.02 wt%, 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, 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%, or about 1 wt% based on the total weight of the formulation. In some embodiments, the antioxidant can be vitamin A which can be present in the formulation in an amount of about 0.01 wt%, 0.02 wt%, 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.10 wt%, about 0.20 wt%, about 0.30 wt%, about 0.40 wt%, about 0.50 wt%, about 0.60 wt%, about 0.70 wt%, about 0.80 wt%, about 0.90 wt%, or about 1 wt% based on the total weight of the formulation.

[0170] In some embodiments, the pH of the pharmaceutical formulation described herein can be from about 3 to about 5. For example the pH can be from about 3 to about 4.5, from about 3 to about 4, from about 3 to about 3.5, from about 3.1 to about 5, from about 3.3 to about 5, from about 3.7 to about 5, from about 3.9 to about 5, from about 4.1 to about 5, from about 4.3 to about 5, from about 4.7 to about 5, from about 4.9 to about 5, about 3.2, about 3.4, about 3.6, about 3.8, about 4, about 4.1, about 4.2, about 4.4, about 4.6, or about 4.8. In some embodiments, the pH of the pharmaceutical formulation described herein can be about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5. In some embodiments, the pH of the pharmaceutical formulation described herein can be from about 3 to about 7, from about 3to about 6. In some embodiments, the pH of the pharmaceutical formulation described herein can be from about 3 to about 5.

[0171] In some embodiments, the formulation provided herein can further comprise one or more permeation enhancers. The one or more permeation enhancers can be selected from the group consisting of a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof), a fatty alcohol, a fatty acid ester, solvent and co solvent, a carbonate, a surfactant, a pyrrolidone, and combinations thereof. Examples of further permeation enhancers for use in the formulations described herein include, but are not limited to, polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide (DMSO), dimethyl acetamide, propylene carbonate, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether (e.g., TRANSCUTOL™, (Gattefosse, France), dimethyl isosorbide, diethyl sebacate, azone, menthol, nerol, camphor, methyl salicylate, polysorbate 80 (e.g., TWEEN™ 80, Croda, England), SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (e.g., CREMOPHOR™ RH40, KOLLIPHOR™ RH40, BASF, Germany), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB), fatty acids esters (e.g., isopropyl myristate, isopropyl palmitate), fatty acids (e.g., oleic acid, palmitic acid, linoleic acid, and salts thereof), fatty alcohols (e.g., oleyl alcohol, myristyl alcohol, and stearyl alcohol), medium-chain triglycerides, and combinations thereof. In a preferred embodiment, the permeation enhancer is transcutol. In a preferred embodiment, the permeation enhancer is oleic acid

[0172] In some embodiments, the formulation disclosed herein can include one or more chelating agents. Suitable chelating agents include, e.g., citric acid, phytic acid, sodium phytate, clioquinol, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, or a combination thereof. In a preferred embodiment, the chelating agent is EDTA.

[0173] In some embodiments of the formulation provided herein, the oily gel phase can comprise: about 0.05 wt% to about 5 wt% clascoterone based on the total weight of the formulation, about 8 wt% to about 50 wt% propylene glycol monocaprylate based on the total weight of the formulation, about 1 wt% to about 30 wt% of a combination of propylene glycol monolaurate, ethyl cellulose, and propylene glycol isosterarate based on the totalweight of the formulation, and about 0.01 wt% to about 1 wt% a-tocopherol based on the total weight of the formulation.

[0174] In some embodiments of the formulation provided herein, the oily gel phase can comprise: about 2.5 wt% clascoterone based on the total weight of the formulation, about 10 wt% propylene glycol monocaprylate based on the total weight of the formulation, about 10 wt% of a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate based on the total weight of the formulation, and about 0.08 wt% a- tocopherol based on the total weight of the formulation.

[0175] In a preferred embodiment of the formulation provided herein, the aqueous gel phase can comprise: about 1 wt% clascoterone based on the total weight of the formulation, about 7 wt% y -cyclodextrin based on the total weight of the formulation optionally wherein substantially all of the clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex, about 0.4 wt% acrylic acid crosspolymers based on the total weight of the formulation, about 17.5 wt% glycerol based on the total weight of the formulation, about 51 wt% to about 52 wt% water based on the total weight of the formulation, and about 0.1 wt% of a chelating agent, e.g., disodium EDTA, based on the total weight of the formulation, and the oily gel phase can comprise: about 2.50 wt% clascoterone based on the total weight of the formulation, about 10 wt% propylene glycol monocaprylate based on the total weight of the formulation, about 10 wt% of a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate based on the total weight of the formulation, and about 0.08 wt% a-tocopherol based on the total weight of the formulation.

[0176] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, propylene glycol monocaprylate in an amount of about 8 wt% based on the total weight of the formulation, and a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 6 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 7.5 wt% based on the total weight of the formulation, xanthan gum in an amountof about 1 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0177] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 8 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 8 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 10 wt% based on the total weight of the formulation, and xanthan gum in an amount of about 2 wt% based on the total weight of the formulation.

[0178] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 8 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.05 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 8 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 20 wt% based on the total weight of the formulation, xanthan gum in an amount of about 2 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0179] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol inan amount of about 17.5 wt% based on the total weight of the formulation, xanthan gum in an amount of about 2 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0180] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, carbomer interpolymer Type B in an amount of about 0.5 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0181] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, Acrylates / Cio- C30 Alkyl acrylate crosspolymer in an amount of about 0.5 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0182] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of theformulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and Propylene Glycol Monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, Carbomer in an amount of about 0.5 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.Storage Stability

[0183] 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 patients will not have to be concerned with special storage instructions. The formulations described herein have a desirable stability profile allowing for storage of the final formulation for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months or at least about two years.

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

[0185] It has now been surprisingly discovered that the formulations disclosed herein can slow and / or inhibit degradation of clascoterone into its known degradation products.

[0186] In some embodiments, and advantageously, the pharmaceutical formulation described herein can exhibit, after one month at room temperature, a detectable amount of total impurities less than about 2% (as measured by HPLC). For example, the formulation can exhibit a detectable amount of total impurities less than about 1.5% total impurities, less than about 1% total impurities, less than about 0.5% total impurities, less than about 0.25% total impurities, less than about 0.1% total impurities, or less than about 0.05% total impurities after 1 month at room temperature.

[0187] In some embodiments, and advantageously, the pharmaceutical formulation described herein can exhibit, after two months at about 5 °C, a detectable amount of impurities less than about 0.35% total impurities (as measured by HPLC). For example, the formulation can exhibit a detectable amount of total impurities of less that about 0.30%, less than about 0.25% total impurities, less than about 0.2% total impurities, less than about 0.15% total impurities, less than about 0.1% total impurities, less than about 0.05% total impurities, or less than about 0.02% total impurities.

[0188] In some embodiments, and advantageously, the pharmaceutical formulation described herein can exhibit, after one month at room temperature, a detectable amount of total impurities less than about 1.3% (as measured by HPLC). For example, the formulation can exhibit a detectable amount of total impurities less than about 1.2% total impurities, less than about 1.1% total impurities, less than about 1 % total impurities, less than about 0.75% total impurities, less than about 0.5% total impurities, less than about 0.25% total impurities, or less than about 0.01% total impurities after 1 month at room temperature.

[0189] In some embodiments, and advantageously, the pharmaceutical formulation described herein can exhibit, after two months at about 5 °C, a detectable amount of impurities less than about 0.25% total impurities (as measured by HPLC). For example, the formulation can exhibit a detectable amount of total impurities of less that about 0.20%, less than about 0.15% total impurities, less than about 0.1% total impurities, less than about 0.5% total impurities, less than about 0.4% total impurities, less than about 0.3% total impurities, less than about 0.2% total impurities, or less than about 0.1% total impurities.

[0190] In some embodiments, and advantageously, the pharmaceutical formulation described herein can exhibit, after six months at about 25 °C, a detectable amount of cortexol one 21 -propionate not exceeding about 8%, that is, less than about 8% (as measured by HPLC). For example, the formulation can exhibit a detectable amount of cortexolone 21 -propionate of less that about 7.5%, less than about 7%, less than about 6.5%, less thanabout 6%, less than about 5.5%, less than about 5%, less than about 4.5%, or less than about 4% of the formulation, after six months at about 25 °C.

[0191] In a particular embodiment, the pharmaceutical formulation comprises an aqueous phase comprising about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, or about 20 wt% y- cyclodextrin complexed with about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about2.7wt%, about2.8 wt%, about2.9wt%, about3 wt%, about3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% clascoterone, and an oily gel phase wherein clascoterone is present in the oily gel phase in an amount of about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation, wherein the pharmaceutical formulation exhibits, after six months at about 25 °C / 60% relative humidity, a detectable amount of cortexolone 21 -propionate not exceeding about 6%, that is, less than about 6% of the formulation (as measured by HPLC). In a particular embodiment, the aqueous phase comprises about 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%, about 5 wt%, about 5.5wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt% y-cyclodextrin complexed with 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%, or about 1 wt% clascoterone, the oily gel phase comprises about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, or about 2.5 wt% clascoterone, based on the total weight of the formulation, and the pharmaceutical formulation exhibits, after six months at about 25 °C / 60% relative humidity, a detectable amount of cortexolone 21 -propionate not exceeding about 6% , that is, less than about 6% of the formulation (as measured by HPLC). In a particular embodiment, a pharmaceutical formulation described herein comprises about 0.5% clascoterone complexed with about 3.5% y-cyclodextrin in the aqueous phase, about 2 wt% clascoterone present in the oily gel phase (based on the total weight of the formulation), and exhibits, after six months at about 25 °C / 60% relative humidity, a detectable amount of cortexolone 21 -propionate not exceeding about 6% , that is, less than about 6% of the formulation (as measured by HPLC).

[0192] In a particular embodiment, the pharmaceutical formulation comprises an aqueous phase comprising about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, or about 20 wt% y- cyclodextrin complexed with about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about2.7wt%, about2.8 wt%, about2.9wt%, about3 wt%, about3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about4.9 wt%, or about 5 wt% clascoterone, and and an oily gel phase wherein clascoterone is present in the oily gel phase in an amount of about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation, wherein the pharmaceutical formulation exhibits, after six months at about 25 °C / 60% relative humidity, a detectable amount of cortexolone 21 -propionate not exceeding about 6% , that is, less than about 6% of the formulation (as measured by HPLC). In a particular embodiment, the aqueous phase comprises about 4 wt%, about 4.5 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, or about 15 wt% y-cyclodextrin complexed with about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, or about 1.5 wt%, clascoterone, the oily gel phase comprises about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2 wt% clascoterone, based on the total weight of the formulation, and the pharmaceutical formulation exhibits, after six months at about 25 °C / 60% relative humidity, a detectable amount of cortexolone 21 -propionate not exceeding about 6% , that is, less than about 6% of the formulation (as measured by HPLC). In a particular embodiment, a pharmaceutical formulation described herein comprises about 1% clascoterone complexed with about 7% y-cyclodextrin in the aqueous phase, about 1.5 wt% clascoterone present in the oily gel phase (based on the total weight of the formulation), and exhibits, after six months at about 25 °C / 60% relative humidity, a detectable amount of cortexolone 21 -propionate not exceeding about 7.0%, that is, less than about 7% (as measured by HPLC), after six months at about 25 °C.

[0193] In some embodiments, and advantageously, the pharmaceutical formulation described herein can exhibit, after six months at about 5 °C, a detectable amount of cortexolone 21 -propionate of less than about 1% (as measured by HPLC). For example, the formulation can exhibit a detectable amount of cortexolone 21 -propionate of less that about 1.0% less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, or less than about 0.5%.

[0194] In a particular embodiment, the pharmaceutical formulation comprises an aqueous phase comprising about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, or about 20 wt% or y- cyclodextrin complexed with about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about2.7wt%, about2.8 wt%, about2.9wt%, about3 wt%, about3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, and an oily gel phase wherein clascoterone is present in the oily gel phase in an amount of about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about2.7wt%, about2.8 wt%, about2.9wt%, about3 wt%, about3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation, wherein the pharmaceutical formulation exhibits, after six months at about 5 °C, a detectable amountof cortexolone 21-propionate of less than about 0.7% cortexolone 21 -propionate, after six months at about 5 °C, that is, less than about 0.7% of the formulation (as measured by HPLC). In a particular embodiment, the aqueous phase comprises about 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt% y-cyclodextrin complexed with 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%, to about 1 wt% clascoterone, the oily gel phase comprises about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, to about 2.5 wt% clascoterone, based on the total weight of the formulation, and the pharmaceutical formulation exhibits, after six months at about 5 °C, a detectable amount of cortexolone 21-propionate of less than about 0.7%, that is, less than about 0.7% of the formulation (as measured by HPLC). In a particular embodiment, a pharmaceutical formulation described herein, comprises 0.5% clascoterone complexed with 3.5% y- cyclodextrin in the aqueous phase, about 2 wt% clascoterone present in the oily gel phase (based on the total weight of the formulation), and exhibits, after six months at about 5 °C, a detectable amount of cortexolone 21-propionate of less than about 0.7% cortexolone 21- propionate, after six months at about 5 °C.

[0195] In a particular embodiment, the pharmaceutical formulation comprises an aqueous phase comprising about .5 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%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, or about 20 wt% y- cyclodextrin complexed with about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about2.6 wt%, about2.7wt%, about2.8 wt%, about2.9wt%, about3 wt%, about3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%clascoterone, and an oily gel phase wherein clascoterone is present in the oily gel phase in an amount of about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%, based on the total weight of the formulation, wherein the pharmaceutical formulation exhibits, after six months at about 5 °C, a detectable amount of cortexol one 21 -propionate not exceeding 0.9%, that is, less than about 0.9% cortexolone 21 -propionate, after six months at about 5 °C. In a particular embodiment, the aqueous phase comprises 4 wt%, about 4.5 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt %, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 12.5 wt%, about 13 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, or about 15 wt% y-cyclodextrin complexed with about 0.5 wt%, to about 1.5 wt% clascoterone, the oily gel phase comprises about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt %, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, to about 2 wt%, clascoterone, based on the total weight of the formulation, and the pharmaceutical formulation exhibits, after six months at about 5 °C, a detectable amount of cortexolone 21-propionate of less than about 0.9% cortexolone 21 -propionate, after six months at about 5 °C, that is, less than about 0.9% cortexolone 21-propionate, after six months at about 5 °C. In a particular embodiment, a pharmaceutical formulation described herein comprises about 1% clascoterone complexed with about 7% y-cyclodextrin in the aqueous phase, about 1.5 wt% clascoterone present in the oily gel phase (based on the total weight of the formulation), and exhibits, after six months at about 5 °C,a detectable amount of cortexolone 21 -propionate of less than about 0.9% cortexolone 21- propionate, after six months at about 5 °C, that is, less than about 0.9% cortexolone 21- propionate, after six months at about 5 °C.Methods of Treating Skin Conditions

[0196] In some embodiments, the present disclosure provides a method of treating a skin condition related to androgenic disorders, the method comprising topically administering to a subject in need thereof an effective amount of the pharmaceutical formulation described herein, i.e. a pharmaceutical formulation comprising a mixture of: (a) an aqueous gel phase comprising water and a first amount of clascoterone; and (b) an oily gel phase comprising a second amount of clascoterone. In some embodiments, topically administering an effective amount of the pharmaceutical formulation described herein increases skin permeation of clascoterone. In some embodiments, the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation such as WINLEVI, a 1% clascoterone topical cream formulation. In some embodiments, the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a gel formulation.

[0197] In some embodiments, the skin condition can be selected from the group consisting of acne vulgaris, acne conglobata, acne fulminans, androgenetic alopecia, hidradenitis suppurativa (also known as acne inversa), hirsutism, acneiform rash including cancertherapy-induced rash, eczema, rosacea, atopic dermatitis, psoriasis, inverse psoriasis, seborrheic dermatitis, acanthosis nigricans, wound healing female pattern hair loss.

[0198] In some embodiments, the skin condition is acne vulgaris. In some embodiments, the skin condition is inflamed acne or non-inflamed acne. In some embodiments, the skin condition is acne conglobata. In some embodiments, the skin condition is acne fulminans.

[0199] In some embodiments, the skin condition is androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, or traction alopecia.

[0200] In some embodiments, the skin condition is inflamed hidradenitis suppurativa (also known as acne inversa).

[0201] In some embodiments, the skin condition is hirsutism.

[0202] In some embodiments, the skin condition is cutaneous acneiform eruption.

[0203] In some embodiments, the skin condition is seborrheic dermatitis.

[0204] In some embodiments, the acneiform eruption comprises a papule, a pustule, a nodule, crust, a cyst, or any combination thereof, on the affected area of the subject. In some embodiments, the acneiform eruption is 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 anti cancer agent, hydroxychloroquine, naproxen, or mercury.

[0205] Acneiform eruption (e.g., acneiform rash) can be caused by several conditions, including drug reactions, infections (e.g., bacterial infection, fungal infection), hormonal or metabolic abnormalities, genetic disorders (e.g., tuberous sclerosis, eruptive vellus hair cysts), contact with chemicals, or mechanical actions. In some aspects, the acneiform can be induced by occupational exposure, chemical exposure, mechanical exposure, or targeted therapeutic drug-exposure.

[0206] In some embodiments, the acneiform eruptions can be an occupational exposure- induced lesions. For example, occupational exposure can include exposure to a chemical, such as a halogenated chemical (e.g., chloraphthalene, chlorophenyl, chlorophenol).

[0207] In some embodiments, the acneiform eruptions can be chemical exposure-induced lesions. For example, 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.

[0208] In some embodiments, the acneiform eruptions can be mechanical exposure- induced lesions. For example, 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.

[0209] In some embodiments, the acneiform eruption occurs in a subject is receiving treatment for cancer. In some embodiments, 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 AKT kinase inhibitor, or any combination thereof. In some aspects, the targeted therapeutic drug is gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, lapatinib, neratinib, avitinib, olmutinib, pelitinib, pyrotinib, brigatinib, vandetanib, icotinib, mobocertinib, almonertinib, lazertinib, alflutinib, rociletinib, nazartinib, naquotinib, cetuximab, panitumumab, necitumumab, amivantamab, trametinib, cobimetinib, pimasertib, mirdametinib, refametinib, binimetinib, selumetinib, trastuzumab, pertuzumab, bevacizumab, aflibercept, vemurafenib, dabrafenib, encorafenib, pictilisib, copanlisib, buparlisib, taselisib, ipatasertib, uprosertib, sorafenib, sunitinib, everolimus, sirolimus, nivolumab, pembrolizumab, ipilimumab, tremelimumab, or any combination thereof.

[0210] In some embodiments, the skin condition is a cancer-therapy-induced rash.

[0211] In some embodiments, the skin condition is eczema.

[0212] In some embodiments, the skin condition is rosacea.

[0213] In some embodiments, the skin condition is atopic dermatitis.

[0214] In some embodiments, the skin condition is psoriasis.

[0215] In some embodiments, the skin condition is inverse psoriasis.

[0216] In some embodiments, the skin condition is seborrheic dermatitis.

[0217] In some embodiments, the skin condition is female pattern hair loss.

[0218] In some embodiments, the skin condition is acanthosis Nigricans,

[0219] In some embodiments, the skin condition is a wound, preferably a chronic wound of the skin. In some embodiments, the chronic wound of the skin is a trophic ulcer of the skin, selected from the group consisting of decubitus ulcers (also known as pressure or bed sores), lower extremity ulcers (also known as leg ulcers), diabetic ulcers, neuropathic ulcers, venous stasis ulcers, arterial ulcers, diabetic foot ulcers, and similar. In some embodiments, the pharmaceutical formulation described herein can be applied on the skin to promote or help or support the wound healing process.

[0220] In some embodiments, the pharmaceutical formulation described herein can be applied to any suitable body surface on a subject in need of treatment, such as a skin region susceptible to acne lesions. Suitable skin regions include, but are not limited to, e.g., the subject’s face, arm, armpit, forearm, leg, shoulder, trunk, chest, abdomen, back, neck, or any combination of the foregoing.

[0221] Inflammatory and non-inflammatory acne lesions comprise papules, pustules, nodules, crusts, comedones, cysts, or any combination thereof. Lesions can be painful and itchy.

[0222] In some embodiments, the subject being treated can have mild to moderate acne before starting treatment. In some embodiments, the subject can have moderate to severe acne before starting treatment. In some embodiments, the acne is facial acne. In some embodiments, the subject’s face comprises one or more of the following before starting treatment: mild to moderate acne; moderate to severe acne; Fitzpatrick skin types I- VI; 10- 100 total non-inflammatory lesions; 10-50 total inflammatory lesions; or up to 2 nodules. In some embodiments, the subject’s face does not comprise cysts before starting treatment.

[0223] In some embodiments, the subject can be assessed for facial appearance in terms of oily appearance, pore size, and / or facial shine. In some embodiments, such an assessment is performed again following application of a topical pharmaceutical composition comprising clascoterone for a period of time, e.g., 3 months. Typically, the assessment is more favorable after application of the topical pharmaceutical composition for an appropriate period of time, including any period of time as described elsewhere herein.

[0224] In some embodiments, the subject achieves a net clinical benefit after administering the pharmaceutical formulation described herein. In some embodiments, the net clinical benefit can be expressed by one or more of the following: a reduction in causal sebum from baseline; a reduction or change in facial microbiome (such as C. acnes or Staphylococcus sp.) from baseline; an improvement in the IGA score from baseline; an IGA score of “clear” (score = 0) or “almost clear” (score = 1) with at least a two-grade reduction from baseline; a reduction in inflammatory acne lesion counts from baseline; a reduction in noninflammatory acne lesion counts from baseline; a score of “none” (score = 0) or “minimal” (score = 1) with at least a two-grade reduction from baseline; a score of “none” (score = 0) or “minimal” (score = 1) with at least a two-grade reduction from baseline in one or more conditions selected from the group consisting of peeling, dryness, redness, and swelling; a score of “none” (score = 0) or “minimal” (score = 1) with at least a two-grade reduction from baseline in one or more conditions selected from the group consisting of stinging, itching and burning or a score of “none” (score = 0) or “minimal” (score = 1) with at least a two-grade reduction from baseline in one or more conditions selected from the group consisting of oily appearance, pore size, and facial shine.

[0225] In some embodiments, the subject can achieve a net clinical benefit upon application of the pharmaceutical formulation described herein expressed by one or more of the following: an improved IGA score, an IGA score of “clear” or “almost clear,” a reduced acne lesion count, a reduced inflammatory lesion count, a reduced noninflammatory lesion count, or a significant improvement in Dermatology Life Quality Index. In some embodiments, the subject is assessed for acne severity before, during, or after treatment using the IGA score depicted in Table 1.Table 1. Investigator Global Assessment (IGA) scale.Score Description0 = Clear Skin Clear Skin; no inflammatory or non-inflammatory lesions1 = Almost Clear Almost clear; rare non-inflammatory lesions with no more than one small inflammatory lesion2 = Mild Severity Mild severity; greater than Grade 1; some noninflammatory lesions with no more than a few inflammatory lesions (papules / pustules only, no nodular lesions)3 = Moderate Severity Moderate severity; greater than Grade 2; some to many non-inflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion4 = Severe Severe; greater than Grade 3; some to many noninflammatory and inflammatory lesions, but no more than a few nodular lesions5 = Very Severe Very Severe; greater than Grade 4; many noninflammatory and / or inflammatory lesions with some or many nodular lesions

[0226] In some embodiments, the tolerability criteria of peeling, dryness, redness, and swelling can be assessed on a 5 -point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe). In some embodiments, the tolerability criteria of peeling, dryness, redness, and swelling can be assessed using sebumeter.

[0227] In some embodiments, the tolerability criteria of stinging, itching, and burning can be assessed on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe).

[0228] In some embodiments, the oily appearance, pore size, facial shine can be assessed on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe). In some embodiments, the oily appearance, pore size, facial shine can be assessed using the shotgun sequencing method.

[0229] In some embodiments, the inflammatory and / or non-inflammatory acne lesion counts are defined and can be assessed as per the methods described in USFDA May 2018 guidance for Industry “Acne Vulgaris: Establishing Effectiveness of Drugs Intended for Treatment”.

[0230] In some embodiments, the subject can achieve a net clinical benefit within about 2 weeks to about 56 weeks, about 3 weeks to about 56 weeks, or 4 weeks to about 56 weeks. For example, the net clinical benefit can be achieved after about 2 weeks, 3 weeks, 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, about 50 weeks, about 52 weeks, about 54 weeks, or about 56 weeks.

[0231] Sebum secretion can be measured by methods known in the art. In some embodiments, sebum secretion can be measured with a sebumeter. In some embodiments, the measurement is taken from the subject’s forehead.

[0232] In some embodiments, the subject can be a male or a female. In some embodiments, the subject can be at least 9 years of age or older. In some embodiments, the subject is at least 12 years of age or older. In some embodiments, the subject can be at least 16 years of age or older. In some embodiments, the subject can be 9 years of age or older. In some embodiments, the subject can be 12 years of age or older. In some embodiments, the subject can be 16 years of age or older.

[0233] The pharmaceutical formulation can be administered according to varying schedules. In some embodiments, the mode of administration of the pharmaceutical formulation described herein can be administered daily, or more frequently. For example, the pharmaceutical compositions can be administered once daily, twice daily, three times a day, four times a day, or more, as specified by a physician. In some embodiments, the pharmaceutical formulation can be administered once daily or twice daily. In oneembodiment, the pharmaceutical formulation can be administered once daily. In another embodiment, the pharmaceutical formulation can be administered twice daily.

[0234] In some embodiments, the pharmaceutical formulation can be administered to the subject once or twice daily. In some embodiments, the pharmaceutical formulation can be administered to the subject once daily. In some embodiments, the pharmaceutical formulation can be administered to the subject twice daily. In some embodiments, the pharmaceutical formulation can be administered to the subject in the morning and evening.

[0235] The pharmaceutical formulation can be administered at any time of day that provides an effective therapeutic benefit. In some embodiments, the pharmaceutical formulation can be administered in the morning, midday, or evening. In some embodiments, the pharmaceutical formulation can be administered in the morning and in the evening. In some embodiments, the pharmaceutical formulation can be administered once in the morning and once in the evening.

[0236] The pharmaceutical formulation can be administered for any total length of time which provides an effective therapeutic benefit. In some embodiments, the pharmaceutical formulation can be administered over the course of a period of days, weeks, or months. For example, the pharmaceutical composition can be administered once or twice daily for at least 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 1 month, 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, or about 12 months (i.e., about a year). In some embodiments, the pharmaceutical formulation is administered to the subject for at least one week. In some embodiments, the pharmaceutical formulation is administered to the subject for at least one month. In some embodiments, the pharmaceutical formulation is administered to the subject for at least two months. In some embodiments, the pharmaceutical formulation is administered to the subject for at least 52 weeks.

[0237] In some embodiments, the pharmaceutical formulation disclosed herein can be applied to any suitable body surface in need of treatment, such as a skin region susceptible to acne lesions. Suitable skin regions include, but are not limited to, e.g., the subject’s face, arm, armpit, forearm, leg, shoulder, trunk, chest, abdomen, back, neck, or any combination of the foregoing.

[0238] Inflammatory and non-inflammatory acne lesions comprise papules, pustules, nodules, crusts, comedones, cysts, or any combination thereof. Lesions can be painful and itchy.

[0239] In some embodiments, the method comprises treating inflamed acne or noninflamed acne by topically administering the pharmaceutical formulation. In some embodiments, the acne can be acne vulgaris. In some embodiments, acne vulgaris can be of mild, moderate, or severe. In some embodiments, the acne can be located on the face, back, and / or chest of the subject.

[0240] In some embodiments, the present disclosure provides a method of treating a skin condition related to androgenic disorders, the method comprising topically administering an effective amount of the pharmaceutical formulation described herein, comprising a mixture of: (a) an aqueous gel phase comprising water and a first amount of clascoterone; and (b) an oily gel phase comprising a second amount of clascoterone. In some embodiments, the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation such as WINLEVI, a 1% clascoterone topical cream formulation. In some embodiments, the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a gel formulation.

[0241] The amount of clascoterone that can be applied to a patient in need thereof using the formulation described herein can vary. In some embodiments, about 400 mg of clascoterone can be applied, about 375 mg of clascoterone can be applied, about 350 mg of clascoterone can be applied, about 325 mg of clascoterone can be applied, about 300 mg of clascoterone can be applied, about 275 mg of clascoterone can be applied, about 250 mg of clascoterone can be applied, or about 225 mg of clascoterone can be applied. In some embodiments, about 200 mg of clascoterone can be applied, about 175 mg of clascoterone can be applied, about 150 mg of clascoterone can be applied, about 125 mg of clascoterone can be applied, about 100 mg of clascoterone can be applied, about 75 mg of clascoterone can be applied, about 50 mg of clascoterone can be applied, about 25 mg of clascoterone can be applied, about 12.5 mg of clascoterone can be applied, or about 6.25 mg of clascoterone can be applied. Determination of the appropriate amount of the formulation that should be administered to a given patient in a single application is within the skill of the ordinarily skilled physician.

[0242] In some embodiments, the amount of clascoterone in a single application can range from about 10 mg to about 400 mg. In other embodiments, the amount of clascoterone in a single application can range from about 10 mg to about 350 mg. In other embodiments, the amount of clascoterone in a single application can range from about 10 mg to about 300 mg. In other embodiments, the amount of clascoterone in a single application can range from about 10 mg to about 250 mg.

[0243] In some embodiments, the amount of clascoterone applied in a single application of the formulation provided herein can range from about 10 mg to about 200 mg. In other embodiments, the amount of clascoterone applied in a single application can range from about 10 mg to about 170 mg. In other embodiments, the amount of clascoterone applied in a single application can range from about 10 mg to about 150 mg. In some embodiments, the amount of clascoterone applied in a single application can range from about 10 mg to about 100 mg. In some embodiments, the amount of clascoterone applied in a single application can be about 10 mg, about 15 mg, 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 clascoterone applied in a single application can be about 25 mg. In another embodiment, the amount of clascoterone in a single application can be about 30 mg. In yet another embodiment, the amount of clascoterone applied in a single application can be about 50 mg. In yet another embodiment, the amount of clascoterone in a single application can be about 75 mg. In yet another embodiment, the amount of clascoterone applied in a single application can be about 80 mg. In yet another embodiment, the amount of clascoterone in a single application can be about 100 mg. In other embodiments, the amount of clascoterone applied in a single application can be about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, or about 200 mg. In yet another embodiment, the amount of clascoterone applied in a single application can be about 150 mg.

[0244] By way of example only, about 50 mg of clascoterone could be administered in 1 g of an embodiment of a formulation disclosed herein, wherein the formulation comprises about 5 total wt% clascoterone.

[0245] In some embodiments, the formulation can be self-administered by the patient once a day or twice daily. In some embodiments, when the formulation is in the form described herein, having an active agent concentration of about 5 weight percent, the formulation canbe self-administered once a day or twice daily at a dose ranging from about 0.2 to about 10 g, from about 0.5 to about 9 g, from about 0.6 to about 8 g, from about 0.7 to about 7 g, from about 0.8 to about 6 g, from about 0.9 to about 5 g, from about 1 to about 4 g, from about 0.5 to about 3 g, from about 0.5 to about 2 g, from about 0.5 to about 1.5 g, and in further embodiments at about 1 g.

[0246] In other embodiments, when the formulation is in the form described herein, having an active agent concentration of about 4 weight percent, the formulation can be selfadministered once a day or twice daily at a dose ranging from about 0.2 to about 2 g, from about 0.5 to about 1.5 g, and in further embodiments at about 1 g.

[0247] In other embodiments, when the formulation is formulation is in the form described herein, having an active agent concentration of about 3 weight percent, the formulation can be self-administered once a day or twice daily at a dose ranging from about 0.2 to about 2 g, from about 0.5 to about 1.5 g, and in further embodiments at about 1 g.

[0248] In other embodiments, when the formulation is in the form described herein, having total clascoterone concentration of about 2 weight percent, the formulation can be selfadministered once a day or twice daily at a dose ranging from about 0.2 to about 2 g, from about 0.5 to about 1.5 g, and in further embodiments at about 1 g.

[0249] In other embodiments, when the formulation is in the form described herein, having total clascoterone concentration of about 1 weight percent, the formulation can be selfadministered once a day or twice daily at a dose ranging from about 0.2 to about 2 g, from about 0.5 to about 1.5 g, and in further embodiments at about 1 g.

[0250] The pharmaceutical formulation described herein can be applied to any body surface in need of treatment, such as the face (e.g., the eyebrow, eyelashes, upper lip, lower lip, chin, cheeks, beard area, or mustache area), arms, legs, chest, abdomen, or any combination of the foregoing. In certain embodiments, treatment is delivered to the face.Drug Release from Clascoterone Pharmaceutical Formulation

[0251] It was surprisingly and advantageously found that including a clascoterone stabilizer, e.g., a cyclodextrin, works very well as clascoterone permeation enhancer in the pharmaceutical formulations described herein.

[0252] In some embodiments, the pharmaceutical formulation described herein can provide a cumulative diffusion of clascoterone in pig ear skin from about 20 pg / cm2to about 1000 pg / cm2after 24 hours. For example, the formulation can provide a cumulative diffusionfrom about 20 gg / cm2to about 900 gg / cm2, from about 20 gg / cm2to about 800 gg / cm2, from about 20 gg / cm2to about 700 gg / cm2, from about 20 gg / cm2to about 600 gg / cm2, from about 20 gg / cm2to about 500 gg / cm2, from about 20 gg / cm2to about 400 gg / cm2, from about 20 gg / cm2to about 300 gg / cm2, from about 20 gg / cm2to about 200 gg / cm2, from about 20 gg / cm2to about 100 gg / cm2, from about 20 gg / cm2to about 50 gg / cm2, from about 25 gg / cm2to about 1000 gg / cm2, from about 75 gg / cm2to about 1000 gg / cm2, from about 150 gg / cm2to about 1000 gg / cm2, from about 250gg / cm2to about 1000 gg / cm2, from about 350 gg / cm2to about 1000 gg / cm2, from about 450 gg / cm2to about 1000 gg / cm2, from about 550 gg / cm2to about 1000 gg / cm2, from about 650 gg / cm2to about 1000 gg / cm2, from about 750 gg / cm2to about 1000 gg / cm2, from about 850 gg / cm2to about 1000 gg / cm2, or about 1000 gg / cm2.

[0253] In some embodiments, the pharmaceutical formulation described herein can provide an absorbed amount of clascoterone in the pig ear skin from about 100 gg / g to about 1800 gg / g after 24 hours. For example, the formulation can provide a cumulative diffusion from about 100 gg / cm2to about 1600 gg / cm2, from about 100 gg / cm2to about 1400 gg / cm2, from about 100 gg / cm2to about 1200 gg / cm2, from about 100 gg / cm2to about 1000 gg / cm2, from about 100 gg / cm2to about 800 gg / cm2, from about 100 gg / cm2to about 600 gg / cm2, from about 100 gg / cm2to about 400 gg / cm2, from about 100 gg / cm2to about 200 gg / cm2, from about 150 gg / cm2to about 1800 gg / cm2, from about 300 gg / cm2to about 1800 gg / cm2, from about 500 gg / cm2to about 1800 gg / cm2, from about 700 gg / cm2to about 1800 gg / cm2, from about 900 gg / cm2to about 1800 gg / cm2, from about 1100 gg / cm2to about 1800 gg / cm2, from about 1300 gg / cm2to about 1800 gg / cm2, from about 1500 gg / cm2to about 1800 gg / cm2, or from about 1700 gg / cm2to about 1800 gg / cm2.Methods of Making Pharmaceutical Formulations

[0254] In some embodiments, the disclosure provides methods of making pharmaceutical formulations. As described herein, the method comprises preparing a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone, and mixing the same to provide the pharmaceutical formulation described herein. In some embodiments, the method can comprise preparing the aqueous phase by mixing an aqueous phase gelling agent, a chelating agent, and aclascoterone stabilizer until all the components are completely dissolved. Thereafter the clascoterone can be added.

[0255] In some embodiments, the oily gel phase can be prepared by mixing at least one oily phase excipient, clascoterone, an oily phase gelling agent, and an antioxidant, and then mixing the first and second mixtures for a length of time, optionally at room temperature or an elevated temperature, sufficient to result in a desired texture.

[0256] In some embodiments, the pharmaceutical formulations described herein can be prepared using any one of clascoterone polymorphic forms I, II, III, IV, and / or amorphous material.EXAMPLES

[0257] The pharmaceutical formulations described herein are now further detailed with reference to the following examples. These examples are provided for the purpose of illustration only and the embodiments described herein should in no way be construed as being limited to these examples. Rather, the embodiments should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.Example 1: Bigel Formulations of Clascoterone

[0258] Clascoterone formulations were prepared as mixtures of an aqueous gel phase and an oily gel phase (“bigels”) with differing concentrations of clascoterone and excipients as shown in Tables 2-5.Glycerol 20Xanthan gum 2Di sodium edetate 0.1Water 60.85Table 5Formulation DOily Phase Components %Clascoterone 2.5Mixture of propylene glycol monolaurate,Ethyl cellulose and propylene glycol isostearate 10a tocopherol 0.08Propylene Glycol Monocaprylate 10Aqueous Phase Components %Glycerol 17.5Xanthan gum 2Di sodium edetate 0.1Water 57.83

[0259] The stability of clascoterone formulations A-D after storage for fifteen days at room temperature (about 23 °C) and at 5 °C was determined by assessing each formulation for the presence of cortexol one-21 -propionate (C-21-P) via HPLC. The observed data is presented below in Table 6.Table 6: Stability of Clascoterone Bigel Formulations A-DCortexol one-21 -propionate (HPLC)FormulationTo T = 15 DaysRoom temperature 5 °CA 0.07 0.25 0.05 B 0.20 1.11 0.35 C 0.05 0.41 0.12 D 0.09 0.27 0.06Example 2: Additional Bigel Formulations of Clascoterone

[0260] Further bigel formulations of clascoterone, incorporating additional excipients and gelling agents as shown in tables 7, 8, and 9 below were prepared. In each case (formulations E, F, and G), 2.5% of clascoterone was incorporated into the oily gel phase.

[0261] Each formulation includes triethanolamine as a pH adjusting agent (not shown) to reach a pH in the range 4-5.Table 7Formulation EOily Gel Phase Components %Clascoterone 2.5Mixture of propylene glycol monolaurate,Ethyl cellulose and propylene glycol isostearate 10a tocopherol 0.08Propylene Glycol Monocaprylate 10Aqueous Gel Phase Components %Glycerol 17.5Carbomer Interpolymer Type B 0.5Di sodium edetate 0.1Water 59.33Table 8Formulation FOily Gel Phase Components %Clascoterone 2.5Mixture of propylene glycol monolaurate,Ethyl cellulose and propylene glycol isostearate 10a tocopherol 0.08Propylene Glycol Monocaprylate 10Aqueous Gel Phase Components %Glycerol 17.50.5Acrylates / Cio-Cso Alkyl acrylate crosspolymerDi sodium edetate 0.1Water 59.33Table 9Formulation GOily Phase Components %Clascoterone 2.5Mixture of propylene glycol monolaurate,Ethyl cellulose and propylene glycol isostearate 10a tocopherol 0.08Propylene Glycol Monocaprylate 10Aqueous Phase Components %Glycerol 17.5Carbomer 0.5Di sodium edetate 0.1Water 59.33

[0262] Stability of clascoterone bigel formulations E-G was compared to WINLEVI® (clascoterone cream 1%), a commercial formulation of clascoterone. The results are shown below in Tables 10 and 11.Table 10: Stability of Clascoterone Bigel FormulationsCortexol one-21 -propionate (HPLC) FormulationTo T = 15 DaysRoom temperature 5 °CE 0.04 0.20 0.05F 0.04 0.19 0.05G 0.03 0.15 0.04Table 11: WINLEVI® Stability DataWINLEVI CREAM 1%Cortexol one-21 -propionate (HPLC)To 0.0425 °C 1 MONTH 0.230 °C 1 MONTH 0.73

[0263] The data provided in Tables 10 and 11 demonstrates that clascoterone bigel formulations as mixtures of aqueous and oily gel phases provide stability comparable to commercial formulations. As shown, very little degradation is observed under refrigeration. At room temperature for 15 days, the amount of cortexol one-21 -propionate is essentially the same for each formulation as that observed with WINLEVI® at the 1 month timepoint.Example 3: Evaluation of Cyclodextrins

[0264] The bigel formulations can incorporate up to 5% of API in the oily phase (maintaining a water content of around 60%). The possibility of including clascoterone in the water phase using cyclodextrins (CD) was then investigated. It was hypothesized that a cyclodextrin complex in the water phase should prevent the API from contacting water and therefore reduce degradation. Two kinds of cyclodextrins were evaluated. CAVASOL® W8 HP PHARMA is a pharmaceutical grade hydropropyl y-cyclodextrin. CAVITRON™ W7HP is a pharmaceutical grade hydroxypropyl P-cyclodextrin.

[0265] To investigate the ability of the CAVASOL® to incorporate 1% clascoterone, increasing amounts of the cyclodextrins in citrate buffer (pH 4.4) were tested. Samples containing increasing amount of CD in citrate buffer were prepared by mixing until complete dissolution of the excipients, then 1% of clascoterone was added and mix until complete solubilization (visual inspection). Starting from 7% cyclodextrins, the total amount of API was dissolved in citrate buffer in 20-30 minutes and the recovered amount of cortexolone 17-a-propionate and the observed impurities were evaluated by HPLC as shown in table 12 below.Table 12: Solubility and Stability of Clascoterone Complexed With hydroxy propyl y- cyclodextrinC ortexol one-21- CD (W8 HP) Total impurities Recovered APPEARANCE propi onateConcentration (HPLC Clascoterone (%)(HPLC)7% Clear 0.17 0.30 101 10% Clear 0.16 0.28 9420% Clear 0.17 0.26 9430% Clear 0.15 0.23 9540% Clear 0.06 0.29 111

[0266] The same approach was applied to CAVITRON™ cyclodextrins. Starting from 20% of cyclodextrins and incorporating 1% of clascoterone, all of the API dissolved in 20- 30 minutes. The recovered amount of clascoterone and observed impurities were evaluated as shown in table 13 below.Table 13: Solubility and Stability of Clascoterone Complexed With hydroxy propyl fi- cyclodextrinC ortexol one-21- RecoveredCD (W7HP) Total impuritiesAPPEARANCE propi onate Clascoterone Concentration (HPLC)(HPLC (%)20% Clear 0.11 0.22 9730% Clear 0.11 0.21 10040% Clear 0.10 0.15 98

[0267] These results suggest that complexation of clascoterone with y-cyclodextrin could be accomplished at lower cyclodextrin concentrations relative to B-cyclodextrin, with lower concentrations of y-cyclodextrin providing a similar impurity profile and clascoterone recovery relative to B-cyclodextrin based formulations.

[0268] Additional formulations of bigels comprising y-cyclodextrin were then prepared to evaluate the effects of different media on clascoterone stability and recoverability.Example 4: Solubility and Stability of Clascoterone Cyclodextrin Complexes

[0269] A formulation containing 2.5% of clascoterone completely solubilized in the oily phase and 1% complexed in cyclodextrin in the water phase (total amount of API 3.5%) was prepared and analyzed after 19 days of storage at refrigerated conditions and room temperature. The formulation is shown in Table 14 and the stability data is shown in Table 15.Table 14Formulation UOily Gel Components %Clascoterone 2.5Mixture of propylene glycol monolaurate,Ethyl cellulose and propylene glycol isostearate 10a tocopherol 0.08Propylene Glycol Monocaprylate NF 10Aqueous Gel Phase Components %Glycerol 17.5Acrylates / Cio-Cso Alkyl acrylate cross-polymer 0.4Di sodium edetate 0.1Clascoterone 1Hydropropyl y-cyclodextrins 7Water 51.42Table 15C ortexol one-21- Total impuritiespropi onate(HPLC)(HPLC)T=0 0.05 0.1919 days 5°C 0.08 0.1619 days RT 0.63 0.72

[0270] These results demonstrate that higher total API concentrations in the formulation (prepared with the excipients reported in table 14) can be achieved with cyclodextrin complexation in the aqueous gel phase. Further, the formulation resulted in little degradation or impurity.Example 5: In-vitro Permeation Tests

[0271] Additional formulations were tested in in-vitro permeation tests in Franz diffusion cells using pig ear skin. The results are shown in FIGS. 1-4 and discussed below.

[0272] The most favorable clascoterone to cyclodextrin ratio for effective diffusion out of pharmaceutical formulations for the topical treatments of skin conditions described herein was investigated. The pharmaceutical formulations shown in Table 16 were prepared in batches (i.e., batches L, M, N, O, P, Q, R, S, T and U) and topically applied to pig ear skin (Franz diffusion cells). After 24 hours the cumulative drug release (pg / cm2) was calculated. A commercial formulation of clascoterone cream (WINLEVI®, 1%) was tested as a comparison. The diffusion results are shown in Table 17.Table 16: Formulations of clascoterone tested in-vitroWITH CD1%Total 2% Total No 2.5% Total Clasco 1.5% Total Clascoteron Cyclodextrins Clascoterone terone Clascoterone e PharmaceuticalFormulation L M N O P Q R S U T ComponentsOily Gel Phase Components1 2.5 1.5 2 2.25 2.4 0.5 1 0.5 1.5 ClascoteronePropylene glycolmonolaurate, Ethylcellulose, 10 10 10 10 10 10 10 10 10 10 propylene glycolisosteraratea-tocopherol 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Propyleneglycol 10 10 10 10 10 10 10 10 10 10 monocaprylateAqueous Gel Phase ComponentsGlycerol 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5 Acrylates / Cio-CsoAlkyl acrylate 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 crosspolymerDi sodium edetate 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Clascoterone N / A N / A 1 0.5 0.25 0.1 0.5 0.5 1 0.5 Hydroxypropyl y- cyclodextrins (HP N / A N / A 7 3.5 1.75 0.7 3.5 3.5 7 3.5 y-CD)Triethanolamine 0.2 0.25 0.25 0.25 0.2 0.2 0.25 0.25 0.2 0.25 Purified water 60.73 59.17 52.17 55.68 57.48 58.53 57.18 56.68 53.22 56.18Table 17: Cumulative diffusion of clascoterone 24 hours after topical application Clascoterone Cumulative clascoterone release Pharmaceutical (pg / cm2) at 24 hoursformulationsWINLEVI 11L 23.2M 22.7N 858.8O 452.8P 37.51Q 47.02T 393.4S 268.8R 261.4U 405.7

[0273] Based on the cumulative drug release results shown above, 0.5% of clascoterone in cyclodextrin was selected as best ratio of API / CD for further testing.

[0274] The data provided in table 17 is graphically presented in FIGs 1-4. Overall, the data demonstrates that skin permeation is higher over time for pharmaceutical formulations comprising clascoterone complexed with hydroxypropyl gamma cyclodextrins than without. As shown in FIG. 1, WINLEVI and formulations L and M (without CD) each demonstrated low cumulative drug release of 11 pg / cm2and 23.2 pg / cm2at 24 hours, respectively. Formulations N (1% clascoterone complexed with hydroxypropyl gamma cyclodextrins) and O (0.5% clascoterone complexed with hydroxypropyl gamma cyclodextrins, demonstrated a 20 to 40 fold increase in diffusion of clascoterone, as compared to formulations L and M.

[0275] As shown in FIG. 2, formulations P (0.25% clascoterone complexed with hydroxypropyl gamma cyclodextrins) and Q (0.10% clascoterone complexed with hydroxypropyl gamma cyclodextrins, comprise less clascoterone in the aqueous gel phase with cyclodextrin than formulations N and O. As shown in FIG. 2, formulations P and Q resulted in an at least 10 fold lower drug release than formulations N and O.

[0276] Formulations R, S, and T each comprise 0.5% clascoterone in the aqueous gel phase with cyclodextrin, and have varying amounts of total clascoterone: Formulation R comprises 1% total clascoterone, formulation S comprises 1.5% total clascoterone, and formulation T comprises 2% total clascoterone. As shown in FIG. 3, when compared to formulation O, which comprises 2.5% total clascoterone with 0.5% in the aqueous gel phase with cyclodextrin, skin permeability results demonstrated that formulas O and T deliver similar levels of drug, with each providing about 2 fold more drug than formulations S and R.

[0277] As shown in FIG. 4, formulation R (1% total clascoterone, 0.5% in aqueous gel phase with cyclodextrin), provides at least 10 fold more cumulative drug release than WINLEVI (1%) and formulation L (1% clascoterone in bigel formulation without cyclodextrin).Example 6: Preparation of bigel formulation with 2.5% clascoterone

[0278] A 2.5 wt % solution of clascoterone having the components shown in Table 16, above, was prepared by solubilizing the appropriate amount of clascoterone in a mixture of oily phase solvents followed by the addition of the antioxidant (tocopherol) and the mixture of propylene glycol monolaurate, ethyl cellulose, propylene glycol isosterarate to produce a gel. Separately, the water phase was prepared by dissolving EDTA, acrylate gelling agent, cyclodextrin and the remaining clascoterone in water. Once clascoterone was completely complexed, the solution was neutralized using triethanolamine. Glycerol was then added to produce a gel. The oily gel was slowly poured in the aqueous gel and mixed at 2000 rpm with a conventional propeller at room temperature for about 15 minutes. The final pH was about 4.5.Example 7: Stability of bigel formulations with 1% and 2.5% clascoterone

[0279] Sample bigel formulations were prepared in laboratory scale batches for stability experiments. Each batch contained 1% or 2.5% clascoterone by weight and the batches were prepared with clascoterone complexed in varying concentrations of HP y-CD, as set forth in Table 18. The batches without cyclodextrins were prepared as controls.

[0280] To evaluate stability, samples from each batch were stored for 6 months at either (1) 25 °C and 60% relative humidity; or (2) 5 °C. Cortexolone 21-propionate concentrationwas measured at 1, 3, and 6 months by HPLC. The HPLC analytical conditions for this example are provided below:Instrumentation:Liquid Chromatograph with an autosampler, a pump, an UV detector and PC workstation for data acquisition and analysis;Column: C18, 75x4.6 mm, 2.6 pm equipped with a C18 pre-column;Flow rate: 1 mL / min;Injection volume: 5 pl;Detector wavelength: 240 nm;Column temperature: 35 °C;Mobile phase: Water / acetonitrile according to the following gradient composition:Time Water Acetonitrile(min) (%) (%)0 70 304 70 3020 50 5030 50 5033 20 8035 70 3040 70 30

[0281] Results are shown in FIGs. 5 and 6. FIG. 5 shows the percentage of cortexolone 21- propionate over six months when stored at 25 °C / 60% relative humidity. FIG. 6 shows the percentage of cortexolone 21-propionate over six months when stored at 5°C.Table 18: Bigel 6-month stability dataFORMULATIONS BATCH DOSAGE STRENGTH COMPLEXED IN CDs L 1% (L) —M 2.50% (M) —R, Rl* 1% 0.5%N 2.50% 1%O, 01* 2.50% 0.5%*Formulations R and R1 and formulations O and 01 differ solely in the source of y-CDEMBODIMENTS

[0282] El. A pharmaceutical formulation comprising a mixture of: (a) an aqueous gel phase comprising water and a first amount of clascoterone; and (b) an oily gel phase comprising a second amount of clascoterone.

[0283] E2. The pharmaceutical formulation of El, wherein formulation further comprises a clascoterone stabilizer in the aqueous gel phase.

[0284] E3. The pharmaceutical formulation of El or E2, wherein formulation comprises about 0.05 wt% to about 5 wt% of the first amount of clascoterone based on the total weight of the formulation and about 0.05 wt% to about 5 wt% of the second amount of clascoterone based on the total weight of the formulation.

[0285] E4. The pharmaceutical formulation of El orE2, wherein the clascoterone stabilizer is a cyclodextrin.

[0286] E5. The pharmaceutical formulation of E4, wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, P -cyclodextrin, y -cyclodextrin, methylated- P-cyclodextrin, P-cyclodextrin sulfobutyl ether, hydroxypropyl-P-cyclodextrin, and hydroxypropyl-y-cyclodextrin.

[0287] E6. The pharmaceutical formulation of any of El to E5, wherein at least 50 % of the first amount of clascoterone is present in the formulation in the form of a clascoterone- cyclodextrin complex.

[0288] E7. The pharmaceutical formulation of any of El to E6, wherein at least 75 % of the first amount of clascoterone is present in the formulation in the form of a clascoterone- cyclodextrin complex.

[0289] E8. The pharmaceutical formulation of any of El to E7, wherein all or substantially all of the first amount of clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex.

[0290] E9. The pharmaceutical formulation of any one of E3- E8, wherein the formulation comprises the cyclodextrin in an amount of from about 1 wt% to about 40 wt% based on the total weight of the formulation.

[0291] E10. The pharmaceutical formulation any one of El- E9, wherein the aqueous gel phase further comprises at least one aqueous phase gelling agent.

[0292] Ell. The pharmaceutical formulation E10, wherein the at least one aqueous phase gelling agent is selected from the group consisting of xanthan gum, acrylic acid polymers, acrylic acid crosspolymers, and combinations thereof.

[0293] E12. The pharmaceutical formulation of E10 or Ell, wherein the formulation comprises the at least one aqueous phase gelling agent in an amount of from about 0.1 wt% to about 5 wt% based on the total weight of the formulation.

[0294] El 3. The pharmaceutical formulation of any one of El 1- E12, wherein the aqueous gel phase further comprises at least one aqueous phase excipient selected from the group consisting of a polyol, a polyol ether, a glycol ester, a C1-C7 alcohol, and combinations thereof.

[0295] E14. The pharmaceutical formulation of E13, wherein the at least one aqueous phase excipient is glycerol.

[0296] E15. The pharmaceutical formulation of E14, wherein the formulation comprises glycerol in an amount of from about 1 wt% to about 30 wt% based on the total weight of the formulation.

[0297] E16. The pharmaceutical formulation of any one of E1-E15, wherein the formulation comprises from about 35 wt% to about 80 wt% water based on the total weight of the formulation.

[0298] E17. The pharmaceutical formulation any one of E1-E15, wherein the oily gel phase further comprises at least one oily phase excipient.

[0299] E18. The pharmaceutical formulation of E17, wherein the at least one oily phase excipient is selected from the group consisting of a polyol, a polyol ether, a glycol ester, a C1-C7 alcohol, and combinations thereof.

[0300] E19. The pharmaceutical formulation of E18, wherein the at least one oily phase excipient is a glycol ester selected from the group consisting of propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, propylene glycol monocaprylate, and combinations thereof.

[0301] E20. The pharmaceutical formulation of any of E1-E19, wherein the formulation comprises the at least one oily phase excipient in an amount from about 1 wt% to about 50 wt% based on the total weight of the formulation.

[0302] E21. The pharmaceutical formulation of any one of El - E20, wherein the oily gel phase further comprises an oily phase gelling agent.

[0303] E22. The pharmaceutical formulation of E 21, wherein the oily phase gelling agent is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methylcellulose, and combinations thereof.

[0304] E23. The pharmaceutical formulation of E21 or E22, wherein formulation comprises the oily phase gelling agent in an amount from about 1 wt% to about 30 wt% based on the total weight of the formulation.

[0305] E24. The pharmaceutical formulation of any one of El - E23, wherein the oily gel phase further comprises an antioxidant selected from the group consisting of a-tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, vitamin A and combinations thereof.

[0306] E25. The pharmaceutical formulation of E24, wherein formulation comprises the antioxidant in an amount of from about 0.01 wt% to about 1 wt% based on the total weight of the formulation.

[0307] E26. The pharmaceutical formulation of any one of El- E25, wherein the formulation has a pH ranging from about 3 to about 5.

[0308] E27. The pharmaceutical formulation of E1-E26, wherein the formulation comprises at least one permeation enhancer.

[0309] E28. A method of treating a skin condition related to androgenic disorders, the method comprising topically administering to a subject in need thereof an effective amount of the pharmaceutical formulation of any one of El- E27.

[0310] E29. The method of E28, wherein the skin condition is selected from the group consisting of acne, androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia hidradenitis suppurativa, hirsutism, cancer-therapy-induced rash, eczema, rosacea, seborrheic dermatitis, acanthosis nigricans and wound healing.

[0311] E30. The method of E29, wherein the skin condition is inflamed acne or noninflamed acne.

[0312] E31. The method of E30 or E31 wherein the acne is located on the face, back, and / or chest.

[0313] E32. The method of any one of E29- E31, wherein the acne is acne vulgaris.

[0314] E33. The method of E32, wherein the acne vulgaris is mild, moderate, or severe.

[0315] E34. The method of any one of E29- E33, wherein the subject achieves a net clinical benefit upon application of the pharmaceutical formulation expressed by one or more ofthe following: an improved IGA score, an IGA score of “clear” or “almost clear,” a reduced acne lesion count, a reduced inflammatory lesion count, a reduced non-inflammatory lesion count, or a significant improvement in Dermatology Life Quality Index.

[0316] E35. A method of increasing skin permeation of clascoterone, the method comprising topically administering to a subject in need thereof, an effective amount of the formulation of any one of E - E27.

[0317] E36. A method of increasing skin permeation of clascoterone, the method comprising topically administering to a subject in need thereof, an effective amount of the formulation of any one of El- E27, wherein the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation.

[0318] E37. The pharmaceutical formulation according to any one of E1-E27, wherein the formulation has a total clascoterone concentration of about 1 wt% to about 5 wt%.

[0319] E38. The pharmaceutical formulation according to any one of E1-E27, wherein the formulation has a total clascoterone concentration of about 2.5 wt%.

[0320] E39. The pharmaceutical formulation of any one of E1-E27, wherein the formulation exhibits less than 2% total impurities after 1 month at room temperature.

[0321] E40. The pharmaceutical formulation of any one of E1-E27, wherein the formulation exhibits less than 0.35% total impurities after 2 months at refrigerated condition.

[0322] E41. The pharmaceutical formulation of any one of E1-E27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 1.3 wt% after 1 month at room temperature.

[0323] E42. The pharmaceutical formulation of any one of E1-E27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 0.25 wt% after 2 months at refrigerated conditions.

[0324] E43. The pharmaceutical formulation of any one of E1-E27, wherein the formulation provides a cumulative diffusion in pig ear skin of about 20 pg / cm2to about 1000 pg / cm2after 24 hours.

[0325] E44. The pharmaceutical formulation of any one of E1-E27, wherein the formulation provides an absorbed amount in the pig ear skin of about 100 pg / g to about 1800 pg / g after 24 hours.

[0326] E45. A pharmaceutical formulation comprising a mixture of: a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone, wherein the aqueous gel phase comprises: clascoterone in an amount ranging from 0.05 wt% to about 5 wt%, based on the total weight of the formulation, y -cyclodextrin in an amount ranging from about 1 wt% to about 40 wt% based on the total weight of the formulation, wherein substantially all of the clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex, acrylic acid crosspolymers in an amount ranging from about 0.1 wt% to about 5 wt% based on the total weight of the formulation, glycerol in an amount ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation, water in an amount ranging from about 35 wt% to about 80 wt% and a chelating agent in an amount ranging from about 0.01 wt% to about 5 wt% based on the total weight of the formulation.

[0327] E46. A pharmaceutical formulation comprising a mixture of: a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone, wherein the aqueous gel phase comprises: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, y - cyclodextrin in an amount of about 7 wt% based on the total weight of the formulation, wherein substantially all of the clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex, acrylic acid crosspolymers in an amount of about 0.4 wt% based on the total weight of the formulation, glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, water in an amount of about 51 wt% to 52 wt%, and disodium EDTA, in an amount of about 1 wt% based on the total weight of the formulation.

[0328] E47. A pharmaceutical formulation comprising a mixture of: a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone, wherein the oily gel phase comprises: clascoterone in an amount ranging from about 0.05 wt% to about 5 wt% based on the total weight of the formulation, propylene glycol monocaprylate in an amount ranging from about 1 wt% to about 50 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount ranging from about 1 wt% to about 30 wt% based on the total weight of the formulation, and a-tocopherol in an amount ranging from 0.01 wt% to about 1 wt% based on the total weight of the formulation.

[0329] E48. A pharmaceutical formulation comprising a mixture of: a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.50 wt% based on the total weight of the formulation, propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, and a-tocopherol in an amount of from about 0.08 wt% based on the total weight of the formulation.

[0330] E49. A pharmaceutical formulation comprising a mixture of: a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone, wherein the aqueous gel phase comprises: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, y - cyclodextrin in an amount of about 7 wt% based on the total weight of the formulation, wherein substantially all of the clascoterone is present in the formulation in the form of a clascoterone-cyclodextrin complex, acrylic acid crosspolymers in an amount of about 0.4 wt% based on the total weight of the formulation, glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, water in an amount of about 51 wt% to 52 wt%, and a chelating agent, e.g., disodium EDTA, in an amount of about 0.1 wt% based on the total weight of the formulation, and wherein the oily gel phase comprises: clascoterone in an amount of about 2.50 wt% based on the total weight of the formulation, propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, and a-tocopherol in an amount of from about 0.08 wt% based on the total weight of the formulation.

[0331] E50. A method of treating a skin condition related to androgenic disorders, the method comprising topically administering to a subject in need thereof an effective amount of the pharmaceutical formulation of any one of E45- E49.

[0332] E51. The method of E50, wherein the skin condition is selected from the group consisting of acne vulgaris, acne conglobata, acne fulminans, androgenetic alopecia, hidradenitis suppurativa, hirsutism, cancer-therapy-induced rash, eczema, rosacea, atopicdermatitis, psoriasis, inverse psoriasis, seborrheic dermatitis, acanthosis nigricans, wound healing , and female pattern hair loss

[0333] E52. A method of increasing skin permeation of clascoterone, the method comprising topically administering to a subject in need thereof, an effective amount of the formulation of any one of E45- E49.

[0334] E53. A method of increasing skin permeation of clascoterone, the method comprising topically administering to a subject in need thereof, an effective amount of the formulation of any one of E45- E49, wherein the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation.

[0335] E54. A pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, propylene glycol monocaprylate in an amount of about 8 wt% based on the total weight of the formulation, and a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 6 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 7.5 wt% based on the total weight of the formulation, xanthan gum in an amount of about 1 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0336] E55. A pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 1 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 8 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 8 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 10 wt% based on the total weight of the formulation, and xanthan gum in an amount of about 2 wt% based on the total weight of the formulation.

[0337] E56. A pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 1 wt% based onthe total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 8 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.05 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 8 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 20 wt% based on the total weight of the formulation, xanthan gum in an amount of about 2 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0338] E57. A pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, xanthan gum in an amount of about 2 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0339] E58. A pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, carbomer interpolymer Type B in an amount of about 0.5 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0340] E59. A pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and propylene glycol monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, Acrylates / Cio-Cso Alkyl acrylate crosspolymer in an amount of about 0.5 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0341] E60. A pharmaceutical formulation comprising a mixture of: a) an oily gel phase comprising clascoterone; and b) an aqueous phase that does not comprise clascoterone, wherein the oily gel phase comprises: clascoterone in an amount of about 2.5 wt% based on the total weight of the formulation, a combination of propylene glycol monolaurate, ethyl cellulose and propylene glycol isosterarate in an amount of about 10 wt% based on the total weight of the formulation, a-tocopherol in an amount of about 0.08 wt% based on the total weight of the formulation, and Propylene Glycol Monocaprylate in an amount of about 10 wt% based on the total weight of the formulation, wherein the aqueous gel phase comprises: glycerol in an amount of about 17.5 wt% based on the total weight of the formulation, Carbomer in an amount of about 0.5 wt% based on the total weight of the formulation, and disodium EDTA in an amount of about 0.1 wt% based on the total weight of the formulation.

[0342] E61. The pharmaceutical formulation of any one of E1-E27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 8 wt% after 6 months at 25 °C and 60% RH.

[0343] E62. The pharmaceutical formulation of any one of E1-E27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 0.9 wt% after 6 months at 5 °C.

[0344] E63. The pharmaceutical formulation of any one of E1-E27, wherein .5% of the clascoterone in the formulation is complexed with cyclodextrins, wherein formulation comprises about 2.5 wt% of clascoterone based on the total weight of the formulation.

[0345] E64. The pharmaceutical formulation of any one of E1-E27, wherein 1% of the clascoterone in the formulation is complexed with cyclodextrins, wherein formulation comprises about 2.5 wt% of clascoterone based on the total weight of the formulation.

[0346] E65. A pharmaceutical formulation according to any one of E1-E27 for use in the treatment of a skin condition related to androgenic disorders, characterized in that it is administered topically to a subject in need thereof.

[0347] E66. A pharmaceutical formulation for use according to E65, wherein the skin condition is selected from the group consisting of acne vulgaris, acne conglobata, acne fulminans, androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, hidradenitis suppurativa, hirsutism, cancer-therapy-induced rash, eczema, rosacea, atopic dermatitis, psoriasis, inverse psoriasis, seborrheic dermatitis, acanthosis nigricans, wounds, and female pattern hair loss.

[0348] E67. A pharmaceutical formulation for use according to E66, wherein the skin condition is inflamed acne or non-inflamed acne.

[0349] E68. A pharmaceutical formulation for use according to claim E66 or E67 wherein the acne is located on the face, back, and / or chest.

[0350] E69. A pharmaceutical formulation for use according to E67, wherein the acne is acne vulgaris.

[0351] E70. A pharmaceutical formulation for use according to E67, wherein the acne vulgaris is mild, moderate, or severe.

[0352] E71. A pharmaceutical formulation for use according to any one of E54 to E64, wherein the subject achieves a net clinical benefit upon application of the pharmaceutical formulation expressed by one or more of the following: an improved IGA score, an IGA score of “clear” or “almost clear,” a reduced acne lesion count, a reduced inflammatory lesion count, a reduced non-inflammatory lesion count, or a significant improvement in Dermatology Life Quality Index.

[0353] E72. A pharmaceutical formulation according to any one E1-E27 for use in increasing skin permeation of clascoterone, characterized in that it is administered topically to a subject in need thereof.

[0354] E73. A pharmaceutical formulation for use according to claim E72 wherein the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation.

[0355] It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections can set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.

[0356] The foregoing description of the preferred embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and / or adapt for various applications such preferred embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0357] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0358] The phraseology or terminology herein is for the purpose of description and not of limitation. As such, the terminology and / or phraseology of the present specification should be interpreted by the skilled artisan in light of the teachings and guidance herein.

[0359] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0360] All patents, patent applications, and other references noted or referenced in this application are hereby incorporated by reference in their entirety.

Claims

1. CLAIMS:

1. A pharmaceutical formulation comprising a mixture of:3.a) an aqueous gel phase comprising water and a first amount of clascoterone; and b) an oily gel phase comprising a second amount of clascoterone.

2. The pharmaceutical formulation of claim 1, wherein formulation further comprises a clascoterone stabilizer in the aqueous gel phase.

3. The pharmaceutical formulation of claim 1 or 2, wherein formulation comprises about 0.05 wt% to about 5 wt% of the first amount of clascoterone based on the total weight of the formulation and about 0.05 wt% to about 5 wt% of the second amount of clascoterone based on the total weight of the formulation.

4. The pharmaceutical formulation of claim 2 or 3, wherein the clascoterone stabilizer is a cyclodextrin.

5. The pharmaceutical formulation of claim 4, wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, P -cyclodextrin, y -cyclodextrin, methylated-P- cyclodextrin, P-cyclodextrin sulfobutyl ether, hydroxypropyl-P-cyclodextrin, and hydroxypropyl-y-cyclodextrin.

6. The pharmaceutical formulation of any of claims 1 to 5, wherein at least 50 % of the first amount of clascoterone is present in the formulation in the form of a clascoterone- cyclodextrin complex.

7. The pharmaceutical formulation of any of claims 1 to 6, wherein at least 75 % of the first amount of clascoterone is present in the formulation in the form of a clascoterone- cyclodextrin complex.

8. The pharmaceutical formulation of any of claims 1 to 7, wherein all or substantially all of the first amount of clascoterone is present in the formulation in the form of a clascoterone- cyclodextrin complex.

9. The pharmaceutical formulation of any one of claims 4-8, wherein the formulation comprises the cyclodextrin in an amount of from about 1 wt% to about 40 wt% based on the total weight of the formulation.

10. The pharmaceutical formulation any one of claims 1-9, wherein the aqueous gel phase further comprises at least one aqueous phase gelling agent.

11. The pharmaceutical formulation claim 10, wherein the at least one aqueous phase gelling agent is selected from the group consisting of xanthan gum, acrylic acid polymers, acrylic acid crosspolymers, alginic acid and salts and derivatives thereof (such as sodium alginate or potassium alginate), gum arabic, povidone, and combinations thereof.

12. The pharmaceutical formulation of claim 10 or 11, wherein the formulation comprises the at least one aqueous phase gelling agent in an amount of from about 0.1 wt% to about 5 wt% based on the total weight of the formulation.

13. The pharmaceutical formulation of any one of claims 1-12, wherein the aqueous gel phase further comprises at least one aqueous phase excipient selected from the group consisting of a polyol, a polyol ether, a glycol ester, a C1-C7 alcohol, and combinations thereof.

14. The pharmaceutical formulation of claim 13, wherein the at least one aqueous phase excipient is glycerol.

15. The pharmaceutical formulation of claim 14, wherein the formulation comprises glycerol in an amount of from about 1 wt% to about 30 wt% based on the total weight of the formulation.

16. The pharmaceutical formulation of any one of claims 1-15, wherein the formulation comprises from about 35 wt% to about 80 wt% water based on the total weight of the formulation.

17. The pharmaceutical formulation any one of claims 1-16, wherein the oily gel phase further comprises at least one oily phase excipient.

18. The pharmaceutical formulation of claim 17, wherein the at least one oily phase excipient is selected from the group consisting of a polyol, a polyol ether, a natural oil, a glycol andesters thereof, a C1-C7 alcohol, glycerol, diethylene glycol monoethyl ether, glycerides, capryl ocaproyl polyoxyl 8 glycerides, medium chain triglycerides, dibutyl sebacate, and combinations thereof.

19. The pharmaceutical formulation of claim 18, wherein the at least one oily phase excipient is a glycol ester selected from the group consisting of propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, propylene glycol monocaprylate, and combinations thereof.

20. The pharmaceutical formulation of any of claims 1-19, wherein the formulation comprises the at least one oily phase excipient in an amount from about 1 wt% to about 50 wt% based on the total weight of the formulation.

21. The pharmaceutical formulation of any one of claims 1-20, wherein the oily gel phase further comprises an oily phase gelling agent.

22. The pharmaceutical formulation of claim 21, wherein the oily phase gelling agent is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide, and combinations thereof.

23. The pharmaceutical formulation of claim 21 or 22, wherein formulation comprises the oily phase gelling agent in an amount from about 1 wt% to about 30 wt% based on the total weight of the formulation.

24. The pharmaceutical formulation of any one of claims 1-23, wherein the oily gel phase further comprises an antioxidant selected from the group consisting of a-tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, vitamin A and combinations thereof.

25. The pharmaceutical formulation of claim 24, wherein formulation comprises the antioxidant in an amount of from about 0.01 wt% to about 1 wt% based on the total weight of the formulation.

26. The pharmaceutical formulation of any one of claims 1-25, wherein the formulation has a pH ranging from about 3 to about 5.

27. The pharmaceutical formulation of claims 1 -26, wherein the formulation comprises at least one permeation enhancer.

28. A method of treating a skin condition related to androgenic disorders, the method comprising topically administering to a subject in need thereof an effective amount of the pharmaceutical formulation of any one of claims 1-27.

29. The method of claim 28, wherein the skin condition is selected from the group consisting of acne vulgaris, acne conglobata, acne fulminans, androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, hidradenitis suppurativa, hirsutism, cancer-therapy-induced rash, eczema, rosacea, atopic dermatitis, psoriasis, inverse psoriasis, seborrheic dermatitis, acanthosis nigricans, wounds , and female pattern hairloss.

30. The method of claim 29, wherein the skin condition is inflamed acne or non-inflamed acne.

31. The method of claim 29 or 30 wherein the acne is located on the face, back, and / or chest.

32. The method of any one of claims 29-31, wherein the acne is acne vulgaris.

33. The method of claim 32, wherein the acne vulgaris is mild, moderate, or severe.

34. The method of any one of claims 29-33, wherein the subject achieves a net clinical benefit upon application of the pharmaceutical formulation expressed by one or more of the following: an improved IGA score, an IGA score of “clear” or “almost clear,” a reduced acne lesion count, a reduced inflammatory lesion count, a reduced non-inflammatory lesion count, or a significant improvement in Dermatology Life Quality Index.

35. A method of increasing skin permeation of clascoterone, the method comprising topically administering to a subject in need thereof, an effective amount of the formulation of any one of claims 1-27.

36. A method of increasing skin permeation of clascoterone, the method comprising topically administering to a subject in need thereof, an effective amount of the formulation of any one of claims 1-27, wherein the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation.

37. The pharmaceutical formulation according to any one of claims 1-27, wherein the formulation has a total clascoterone concentration of about 1 wt% to about 5 wt%.

38. The pharmaceutical formulation according to any one of claims 1-27, wherein the formulation has a total clascoterone concentration of about 2.5 wt%.

39. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation exhibits less than 2% total impurities after 1 month at room temperature.

40. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation exhibits less than 0.35% total impurities after 2 months at refrigerated condition.

41. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 1.3 wt% after 1 month at room temperature.

42. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 0.25 wt% after 2 months at refrigerated conditions.

43. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation provides a cumulative diffusion in pig ear skin of about 20 pg / cm2to about 1000 pg / cm2after 24 hours.

44. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation provides an absorbed amount in the pig ear skin of about 100 pg / g to about 1800 pg / g after 24 hours.

45. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 8 wt% after 6 months at 25 °C and 60% relative humidity.

46. The pharmaceutical formulation of any one of claims 1-27, wherein the formulation comprises a detectable amount of cortexolone 21 propionate that is less than about 0.9 wt% after 6 months at 5 °C.

47. The pharmaceutical formulation of any one of claims 1-27, wherein 0.5% of the clascoterone in the formulation is complexed with cyclodextrins, wherein formulation comprises about 2.5 wt% of clascoterone based on the total weight of the formulation.

48. The pharmaceutical formulation of any one of claims 1-27, wherein 1% of the clascoterone in the formulation is complexed with cyclodextrins, wherein formulation comprises about 2.5 wt% of clascoterone based on the total weight of the formulation.

49. A pharmaceutical formulation according to any one of claims 1-27 for use in the treatment of a skin condition related to androgenic disorders, characterized in that it is administered topically to a subject in need thereof.

50. A pharmaceutical formulation for use according to claim 49, wherein the skin condition is selected from the group consisting of acne vulgaris, acne conglobata, acne fulminans, androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, hidradenitis suppurativa, hirsutism, cancer-therapy-induced rash, eczema, rosacea, atopic dermatitis, psoriasis, inverse psoriasis, seborrheic dermatitis, acanthosis nigricans, wounds, and female pattern hair loss.

51. A pharmaceutical formulation for use according to claim 50, wherein the skin condition is inflamed acne or non-inflamed acne.

52. A pharmaceutical formulation for use according to claim 50 or 51 wherein the acne is located on the face, back, and / or chest.

53. A pharmaceutical formulation for use according to any one of claims 50-52, wherein the acne is acne vulgaris.

54. A pharmaceutical formulation for use according to claim 53, wherein the acne vulgaris is mild, moderate, or severe.

55. A pharmaceutical formulation for use according to any one of claims 49-54, wherein the subject achieves a net clinical benefit upon application of the pharmaceutical formulation expressed by one or more of the following: an improved IGA score, an IGA score of “clear” or “almost clear,” a reduced acne lesion count, a reduced inflammatory lesion count, a reduced non-inflammatory lesion count, or a significant improvement in Dermatology Life Quality Index.

56. A pharmaceutical formulation according to any one of claims 1-27 for use in increasing skin permeation of clascoterone, characterized in that it is administered topically to a subject in need thereof.

57. A pharmaceutical formulation for use according to claim 56 wherein the skin permeation of clascoterone is increased relative to the skin permeation of an equivalent amount of topically applied clascoterone in a cream formulation.

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