Cortexolone-17αlpha-propionate combinations for treating acne

Abstract

The present disclosure relates to a method of treating or preventing acne, such as facial acne vulgaris, comprising administering to a subject in need thereof an effective amount of cortexolone- 17α-propionate in combination with an effective amount of one or more secondary anti-acne agents. The secondary anti-acne agents used in combination with cortexolone-17 α-propionate can be oral or topical agents. The secondary anti-acne agents can be administered in a combined formulation or independently in a sequential fashion. The present disclosure is further related to a topical formulation comprising cortexolone-17α-propionate, at least one topical anti-acne agent, and a pharmaceutically acceptable carrier.

Description

CORTEXOLONE-17a-PROPIONATE COMBINATIONS FOR TREATING ACNEBACKGROUND

[0001] Acne vulgaris is a common skin condition characterized by blockage or inflammation of the skin’s pilosebaceous units, leading to non-inflammatory lesions, inflammatory lesions, or both. Although it most commonly affects adolescents, 12% of adult women and 3% of adult men suffer from acne well into their 50’s. Acne can affect any skin on the body, but most commonly occurs on the face, neck, and back. Chronic acne can lead to scars and disfigurement in addition to emotional distress, lower confidence, depression, anxiety, and other detrimental mental health outcomes. The direct cost of acne is estimated to exceed $3 billion per year, but the indirect costs are likely significantly higher.

[0002] While Cutibacterium acnes (C. acnes) is generally identified as the primary cause of acne vulgaris, other factors, such as the environment, drug use, hormones, genetics, and diet can contribute to the severity of the condition. C. acnes is endemic to hair follicles, but bacterial overgrowth can lead to increased inflammation and progression of the condition. Treatment protocols for acne vulgaris are recommended according to both the inflammatory severity and the clinical features of the patient that affect severity, such as age, sex, metabolic condition, and reproductive health.

[0003] Despite the current treatment options available for acne vulgaris, there remains a need for treatment methods that are effective across diverse patient populations.BRIEF SUMMARY

[0004] It has been surprisingly discovered that acne can be effectively treated with a combination of cortexolone-17a-propionate and a secondary anti-acne agent. In some aspects, a synergistic effect can be provided by the combination such that, surprisingly, a lower effective amount of each active can be used for effective treatment. As a result of this combination therapy, an advantageous clinical result can be realized after administration of the combination for an appropriate amount of time, such as a few days, weeks, or months.

[0005] Accordingly, the present disclosure provides a method of treating or preventing acne comprising topically administering to a subject in need thereof an effective amount of cortexolone-17a-propionate (CTX) in combination with an effective amount of one or more secondary anti-acne agents.

[0006] In some aspects, the one or more secondary anti -acne agents is an oral agent.

[0007] In some aspects, the oral agent is an antibiotic, a hormonal agent, a retinoid, a dietary supplement, or a combination thereof.

[0008] In some aspects, the antibiotic is amoxicillin, azithromycin, cephalexin, doxycycline, erythromycin, minocycline, tetracycline, trimethoprim, sulfamethoxazole, or a combination thereof.

[0009] In some aspects, the hormonal agent is flutamide, spironolactone, cyproterone acetate, norethindrone, ethynodiol diacetate, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, ethinyl estradiol, or a combination thereof.

[0010] In some aspects, the retinoid is isotretinoin.

[0011] In some aspects, the dietary supplement is vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, biotin, niacin, zinc, selenium, iron, copper, an omega-3 fatty acid, or a combination thereof.

[0012] In some aspects, the one or more secondary anti-acne agents is one or more secondary topical anti-acne agents.

[0013] In some aspects, the one or more secondary topical anti-acne agents and cortexolone- 17a-propi onate are provided in a topical composition comprising the cortexolone-17a-propionate, the one or more secondary anti -acne agents, and at least one pharmaceutically acceptable carrier.

[0014] In some aspects, the topical composition is a gel, cream, lotion, solution, suspension, foam, ointment, wash-off agent, hydrogel patch, microemulsion, or pledget.

[0015] In some aspects, the topical composition is pre-prepared.

[0016] In some aspects, the one or more secondary topical anti-acne agents and cortexolone-17a-propi onate are provided in separate topical compositions, each comprising at least one active agent and at least one pharmaceutically acceptable carrier.

[0017] In some aspects, the separate topical compositions are combined just prior to use.

[0018] In some aspects, the separate topical compositions are administered sequentially.

[0019] In some aspects, each topical composition is independently selected from a gel, cream, lotion, solution, suspension, foam, ointment, wash-off agent, hydrogel patch, microemulsion, and pledget.

[0020] In some aspects, the at least one secondary topical anti-acne agent is an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, urea, or a combination thereof.

[0021] In some aspects, the antiseptic is benzoyl peroxide; the antibiotic is clindamycin, erythromycin, nadifloxacin, metronidazole, mafenide, minocycline, sodium sulfacetamide, diaminodiphenyl sulfone, or a combination thereof; the retinoid is tretinoin, adapalene, tazarotene, trifarotene, or a combination thereof; the antioxidant is sodium L-ascorbyl-2-phosphate; the organic acid is resorcinol, azelaic acid, salicylic acid, glycolic acid, or a combination thereof; the corticosteroid is hydrocortisone, triamcinolone acetonide, or a combination thereof; and the antiparasitic is ivermectin.

[0022] In some aspects, the acne is acne vulgaris of mild, moderate, or severe grade.

[0023] In some aspects, the acne vulgaris is facial acne vulgaris.

[0024] The present disclosure further provides a topical composition comprising cortexolone- 17a-propi onate, at least one topical anti-acne agent, and a pharmaceutically acceptable carrier.

[0025] In some aspects, the topical anti-acne agent is an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, urea, or a combination thereof.

[0026] In some aspects, the antiseptic is benzoyl peroxide.

[0027] In some aspects, the antibiotic is clindamycin, erythromycin, nadifloxacin, metronidazole, mafenide, minocycline, sodium sulfacetamide, diaminodiphenyl sulfone, or a combination thereof.

[0028] In some aspects, the retinoid is tretinoin, adapalene, tazarotene, trifarotene, or a combination thereof.

[0029] In some aspects, the antioxidant is sodium L-ascorbyl-2-phosphate or niacinamide.

[0030] In some aspects, the organic acid is resorcinol, azelaic acid, salicylic acid, glycolic acid, or a combination thereof.

[0031] In some aspects, the corticosteroid is hydrocortisone, triamcinolone acetonide, or a combination thereof.

[0032] In some aspects, the antiparasitic is ivermectin.

[0033] In some aspects, the composition is in the form of cream, lotion, gel, ointment, mousse, spray solution, suspension, emulsion, wash-off agent, patch, or pledget.

[0034] In a further embodiment the topical pharmaceutical formulation of the present invention is for use in the treatment or prevention of acne in a subject in need thereof.DETAILED DESCRIPTIONDefinitions

[0035] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0036] 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.

[0037] As used herein, the term “about” refers to ±10% of the noted value, unless otherwise specified, and unless the upper bound of the range would exceed 100%, in which case the upper limit of the range is limited to 99.99%. Thus, and by way of example only, a formulation including about 10 weight percent of a given ingredient could have from 9 to 11 weight percent of the ingredient. Similarly, a formulation including about 95 weight percent of a given ingredient could have from 85.5 to 99.99 weight percent of the ingredient in the formulation.

[0038] 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.

[0039] The term “effective amount” as used herein refers to an amount of a given active agent that is sufficient, when administered by a method of the disclosure, to efficaciously treat the condition or disease of interest in a subject in need thereof.

[0040] The term “co-admini strati on” and “co-administered” as used herein means that two or more active agents can be given simultaneously, i.e. at the same time, or sequentially, i.e. one after the other including embodiments where administration of a first active overlaps with administration of a second or subsequent active as well as embodiments wherein administration of the first active is separately by an appropriate period of time before the second active is administered. The appropriate period of time can be determined by a physician of ordinary skill in the art and can, for example, be about 30 seconds, about 1 minute, about 10 minutes, about 15 minutes, about 30 minutes, about an hour, about 2 hours, about 6 hours, about 12 hours, about 24, about 36 hours, or about 48 hours. Active agents that are co-administered can be administered as part of a combination formulation, or can be administered via individual formulations. Likewise, active agents that are co-administered, can be delivered via the same or different routes of administration. For example, two or more active agents can be co-administered topically (either as part of a combination formulation or as two separate formulations) or one active agent can be administered topically while the other is administered orally. Co-administration can be carried out at appropriate intervals, for example, the two or more actives can be co-administered once or multiple times per day (e.g. once a day, twice a day, three times a day, four times a day, etc.); once or multiple times every other day (e.g. once a day every other day, twice a day every other day, three times a day every other day, four times a day every other day, etc.); once or multiple times every three days (e.g. once a day every three days, twice a day every three days, three times a day every three days, four times a day every three days, etc.); at least one, two or three times a week; weekly; or less frequently until the condition being treated, i.e. acne, is reduced or alleviated. In certain aspects, the co-administration can be tailored to provide an initial loading dose of one or both active ingredients and can then be reduced to a maintenance level of one or both actives, if necessary or desirable. Likewise, and in some aspects, the co-administration, in any appropriate interval described above, can be carried out for about 1 to about 30 days, for example at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about28, at least about 29, or about 30 days. In other aspects, the co-administration can be carried out for at least about 30 days, at least about 45 days, at least about 60 days, at least about 75 days, at least about 90 days, at least about 120 days, at least about 150 days, at least about 180 days, at least about 210 days, at least about 240 days, at least about 270 days, at least about 300 days, at least about 1 year, or for a greater period of time until the condition being treated, i.e. acne, is sufficiently controlled.

[0041] 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.

[0042] Cortexolone-17a-propionate, also known as 17a-propionyloxy-21-hydroxy-pregna-4- ene-3, 20-dione and clascoterone, (“CTX”) is a topical antiandrogen that inhibits androgenic hormones, such as testosterone and dihydrotestosterone, from binding to androgen receptors in sebaceous glands. While its precise mechanism of action is not completely understood, cortexolone-17a-propionate is known to be suitable for treating acne, alopecia, and other diseases of skin and cutaneous appendages. See, e.g., U.S. Patent Nos. 8,143,240 and 8,865,690, and PCT publications WO 2009 / 019138, and WO 2016 / 207778. The compound is also known to exist in several distinct crystalline polymorphs, each having unique properties. See, e.g., U.S. Patent No. 8,785,427. Each of these publications is incorporated herein by reference in its entirety.

[0043] The present disclosure provides numerous compositions and methods for treating acne vulgaris comprising administering to a subject in need thereof an effective amount of CTX and a secondary active agent. In some aspects, CTX and the secondary active agent can be formulated as a composition suitable for topical application, i.e. a formulation comprising CTX, the secondary active agent, and one or more pharmaceutically acceptable excipients. In some aspects, CTX and the secondary active agent can be formulated in separate formulations and applied simultaneously. Alternatively, CTX and the secondary active agent can be formulated in separate formulations and the secondary active agent can be applied before or after applying a formulation comprising CTX. In still further aspects, the present disclosure provides a method of treating acnecomprising topically applying a CTX formulation and orally administering a secondary active agent.

[0044] Suitable secondary active agents include, but are not limited to, antibiotics, hormonal agents, retinoids, dietary supplements, antiseptics, antioxidants, organic acids, corticosteroids, antiparasitic agents, sulfur, urea, and combinations thereof.

[0045] Exemplary antibiotics include, but are not limited to amoxicillin, azithromycin, cephalexin, doxycycline, erythromycin, minocycline, tetracycline, trimethoprim, sulfamethoxazole, clindamycin, nadifloxacin, metronidazole, mafenide, sodium sulfacetamide, diaminodiphenyl sulfone, and combinations thereof.

[0046] Exemplary hormonal agents include, but are not limited to, flutamide, spironolactone, cyproterone acetate, norethindrone, ethynodiol diacetate, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, ethinyl estradiol, and combinations thereof.

[0047] Exemplary dietary supplements include, but are not limited to, vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, biotin, niacin, zinc, selenium, iron, copper, an omega-3 fatty acid, and combinations thereof.

[0048] Exemplary retinoids include, but are not limited to tretinoin, adapalene, tazarotene, trifarotene, and combinations thereof.

[0049] Exemplary antiseptics include, but are not limited to benzoyl peroxide.

[0050] Exemplary antioxidants include, but are not limited to sodium L-ascorbyl-2-phosphate and niacinamide.

[0051] Exemplary organic acids include, but are not limited to azelaic acid, salicylic acid, and resorcinol.

[0052] Exemplary corticosteroids include, but are not limited to hydrocortisone, triamcinolone acetonide, and combinations thereof.

[0053] Exemplary antiparasitic agents include, but are not limited to ivermectin.Formulations Comprising CTX and a Secondary Anti-Acne Agent

[0054] In some aspects, the present disclosure provides a combination formulation comprising CTX and one or more secondary anti-acne agents. In some aspects, the combination formulation can be a gel, cream, lotion, solution, suspension, foam, ointment, wash-off agent (e.g.a soap), hydrogel patch, microemulsion, or pledget. The secondary anti-acne agent can be selected from the group consisting of an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, urea, and combinations thereof.

[0055] In some aspects, the secondary anti-acne agent in the combination formulation can be an antiseptic. In some aspects, the antiseptic can be benzoyl peroxide. In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 25.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 10.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 7.5% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 6.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 5.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 4.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 3.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 2.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 1.0% (w / w) benzoyl peroxide, or from about 0.1% (w / w) to 0.5% (w / w) benzoyl peroxide.

[0056] Although benzoyl peroxide can be combined directly with CTX, because benzoyl peroxide is generally considered to be reactive, more typically the benzoyl peroxide can be encapsulated. For example, and in some aspects, the benzoyl peroxide can be encapsulated within a microparticle containing a solid core comprising either the solid particulate matter of benzoyl peroxide, CTX, or another secondary anti-acne agent, wherein the solid core can be coated by a metal oxide or inorganic polymer layer as described in U.S. Pat. No. 8,617,580 or U.S. Pat. No. 8,110,284, each of which is incorporated herein by reference in its entirety.

[0057] In some aspects, the secondary anti -acne agent in the combination formulation can be an antibiotic. In some aspects, the antibiotic can be selected from the group consisting of clindamycin, erythromycin, nadifloxacin, metronidazole, mafenide, minocycline, sodium sulfacetamide, diaminodiphenyl sulfone, and combinations thereof. In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 12.0% (w / w) antibiotic, from about 0.1% (w / w) to 10.0% (w / w) antibiotic, from about 0.1% (w / w) to 8.0% (w / w) antibiotic, from about 0.1% (w / w) to 6.0% (w / w) antibiotic, from about 0.1% (w / w) to 4.0% (w / w) antibiotic, or from about 0.1% (w / w) to 3.0% (w / w) antibiotic, from about 0.1% (w / w) to 2.0% (w / w) antibiotic, or from about 0.1% (w / w) to1.0% (w / w) antibiotic, from about 0.1% (w / w) to 0.5% (w / w) antibiotic, or from about 0.1% (w / w) to 0.1% (w / w) antibiotic.

[0058] In some aspects, the antibiotic can be clindamycin. In some aspects, the combination formulation can comprise clindamycin from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise clindamycin at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0059] In some aspects, the antibiotic can be erythromycin. In some aspects, the combination formulation can comprise erythromycin from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise erythromycin at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0060] In some aspects, the antibiotic can be nadifloxacin. In some aspects, the combination formulation can comprise nadifloxacin from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise nadifloxacin at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0061] In some aspects, the antibiotic can be metronidazole. In some aspects, the combination formulation can comprise metronidazole from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise metronidazole at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0062] In some aspects, the antibiotic can be mafenide. In some aspects, the combination formulation can comprise mafenide from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise mafenide at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0063] In some aspects, the antibiotic can be minocycline. In some aspects, the combination formulation can comprise minocycline from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise minocycline at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0064] In some aspects, the antibiotic can be sodium sulfacetamide. In some aspects, the combination formulation can comprise sodium sulfacetamide from about 0.5 % (w / w) to about 15.0 % (w / w). In some aspects, the formulation can comprise sodium sulfacetamide at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), about 6.0% (w / w), about 6.25% (w / w), about 6.5% (w / w), about 6.75% (w / w), about 7.0% (w / w), about 7.25% (w / w), about 7.5% (w / w), about 7.75% (w / w), about 8.0% (w / w), about 8.25% (w / w), about 8.5% (w / w), about 8.75% (w / w), about 9.0% (w / w), about 9.25% (w / w), about 9.5% (w / w), about 9.75% (w / w), about 10.0% (w / w), about 10.25% (w / w), about 10.5% (w / w), about 10.75% (w / w), about 11.0% (w / w), about 11.25% (w / w), about 11.5% (w / w), about 11.75% (w / w), about 12.0% (w / w), about 12.25% (w / w), about 12.5% (w / w), about 12.75% (w / w), about 13.0% (w / w), about 13.25% (w / w), about 13.5% (w / w), about 13.75% (w / w), about 14.0% (w / w), about 14.25% (w / w), about 14.5% (w / w), about 14.75% (w / w), or about 15.0% (w / w).

[0065] In some aspects, the antibiotic can be diaminodiphenyl sulfone. In some aspects, the combination formulation can comprise diaminodiphenyl sulfone at about 0.5% (w / w) to about 15% (wt / wt). In some aspects, the combination formulation can comprise diaminodiphenyl sulfone at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), about 6.0% (w / w), about 6.25% (w / w), about 6.5% (w / w), about 6.75% (w / w), about 7.0% (w / w), about 7.25% (w / w), about 7.5% (w / w), about 7.75% (w / w), about 8.0% (w / w), about 8.25% (w / w), about 8.5% (w / w), about 8.75% (w / w), about 9.0% (w / w), about 9.25% (w / w), about 9.5% (w / w), about 9.75% (w / w), about 10.0% (w / w), about 10.25% (w / w), about 10.5% (w / w), about 10.75% (w / w), about 11.0% (w / w), about 11.25% (w / w), about 11.5% (w / w), about 11.75% (w / w), about 12.0% (w / w), about 12.25% (w / w), about 12.5% (w / w), about 12.75% (w / w), about 13.0% (w / w), about 13.25% (w / w), about 13.5% (w / w), about 13.75% (w / w), about 14.0% (w / w), about 14.25% (w / w), about 14.5% (w / w), about 14.75% (w / w), or about 15.0% (w / w).

[0066] In some aspects, the secondary anti -acne agent in the combination formulation can be a retinoid. In some aspects, the retinoid can be selected from the group consisting of tretinoin, adapalene, tazarotene, trifarotene, and combinations thereof. In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 7.0% (w / w) retinoid, from about 0.01% (w / w) to 5.0% (w / w) retinoid, from about 0.01% (w / w) to 3.5% (w / w) retinoid, from about 0.01% (w / w) to 2.0% (w / w) retinoid, from about 0.01% (w / w) to 1.0% (w / w) retinoid, or from about 0.01% (w / w) to 0.75% (w / w) retinoid, from about 0.01% (w / w) to 0.5% (w / w) retinoid, or from about 0.01% (w / w) to 0.25% (w / w) retinoid, from about 0.01% (w / w) to 0.1% (w / w) retinoid, or from about 0.01% (w / w) to 0.05% (w / w) retinoid.

[0067] In some aspects, the retinoid can be tretinoin. In some aspects, the combination formulation can comprise about 0.001% (w / w) to about 0.20% (w / w) of tretinoin. In some aspects, the combination formulation can comprise about 0.001% (w / w), about 0.0025% (w / w), about 0.005% (w / w), about 0.075% (w / w), about 0.010% (w / w), about 0.015% (w / w), about 0.020%(w / w), about 0.025% (w / w), about 0.030% (w / w), about 0.035% (w / w), about 0.040% (w / w), about 0.045% (w / w), about 0.050% (w / w), about 0.055% (w / w), about 0.060% (w / w), about 0.065% (w / w), about 0.070% (w / w), about 0.075% (w / w), or about 0.080% (w / w), about 0.085% (w / w), about 0.090% (w / w), about 0.095% (w / w), or about 0.10% (w / w), about 0.12% (w / w), about 0.125% (w / w), about 0.130% (w / w), about 0.135% (w / w), about 0.140% (w / w), about 0.145% (w / w), about 0.150% (w / w), about 0.155% (w / w), about 0.160% (w / w), about 0.165% (w / w), about 0.170% (w / w), about 0.175% (w / w), or about 0.180% (w / w), about 0.185% (w / w), about 0.190% (w / w), about 0.195% (w / w), or about 0.20% (w / w) tretinoin.

[0068] In some aspects, the retinoid can be adapalene. In some aspects, the combination formulation can comprise about 0.010% (w / w) to about 0.50% (w / w) of adapalene. In some aspects, the combination formulation can comprise about 0.02% (w / w), about 0.025% (w / w), about 0.030% (w / w), about 0.035% (w / w), about 0.040% (w / w), about 0.045% (w / w), about 0.050% (w / w), about 0.055% (w / w), about 0.060% (w / w), about 0.065% (w / w), about 0.070% (w / w), about 0.075% (w / w), or about 0.080% (w / w), about 0.085% (w / w), about 0.090% (w / w), about 0.095% (w / w), or about 0.10% (w / w), about 0.12% (w / w), about 0.125% (w / w), about 0.130% (w / w), about 0.135% (w / w), about 0.140% (w / w), about 0.145% (w / w), about 0.150% (w / w), about 0.155% (w / w), about 0.160% (w / w), about 0.165% (w / w), about 0.170% (w / w), about 0.175% (w / w), or about 0.180% (w / w), about 0.185% (w / w), about 0.190% (w / w), about 0.195% (w / w), about 0.20% (w / w), about 0.30% (w / w), or about 0.40% (w / w) adapalene.

[0069] In some aspects, the retinoid can be tazarotene. In some aspects, the combination formulation can comprise about 0.010% (w / w) to about 0.20% (w / w) of tazarotene. In some aspects, the combination formulation can comprise about 0.02% (w / w), about 0.025% (w / w), about 0.030% (w / w), about 0.035% (w / w), about 0.040% (w / w), about 0.045% (w / w), about 0.050% (w / w), about 0.055% (w / w), about 0.060% (w / w), about 0.065% (w / w), about 0.070% (w / w), about 0.075% (w / w), or about 0.080% (w / w), about 0.085% (w / w), about 0.090% (w / w), about 0.095% (w / w), or about 0.10% (w / w), about 0.12% (w / w), about 0.125% (w / w), about 0.130% (w / w), about 0.135% (w / w), about 0.140% (w / w), about 0.145% (w / w), about 0.150% (w / w), about 0.155% (w / w), about 0.160% (w / w), about 0.165% (w / w), about 0.170% (w / w), about 0.175% (w / w), or about 0.180% (w / w), about 0.185% (w / w), about 0.190% (w / w), about 0.195% (w / w), or about 0.20% (w / w) tazarotene.

[0070] In some aspects, the retinoid can be trifarotene. In some aspects, the combination formulation can comprise about 0.001% (w / w) to about 0.015% (w / w) of trifarotene. In some aspects, the combination formulation can comprise about 0.001% (w / w) trifarotene, or about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), about 0.006% (w / w), about 0.007% (w / w), about 0.008% (w / w), about 0.009% (w / w), about 0.010% (w / w), about 0.011% (w / w), about 0.012% (w / w), or about 0.013% (w / w), about 0.014% (w / w), or about 0.015% (w / w) trifarotene.

[0071] In some aspects, the secondary anti -acne agent in the combination formulation can be an antioxidant. In some aspects, the antioxidant can be sodium L-ascorbyl-2-phosphate. In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 7.0% (w / w) sodium L-ascorbyl-2 -phosphate, or from about 0.01% (w / w) to 5.0% (w / w) t, from about 0.01% (w / w) to 3.5% (w / w), from about 0.01% (w / w) to 2.0% (w / w), from about 0.01% (w / w) to 1.0% (w / w), or from about 0.01% (w / w) to 0.75% (w / w), from about 0.01% (w / w) to 0.5% (w / w), from about 0.01% (w / w) to 0.25% (w / w), from about 0.01% (w / w) to 0.1% (w / w), or from about 0.01% (w / w) to 0.05% (w / w) sodium L- ascorbyl-2-phosphate.

[0072] In some aspects, the antioxidant in the combination formulation can be niacinamide. In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 7.0% (w / w) niacinamide, or from about 0.01% (w / w) to 5.0% (w / w), from about 0.01% (w / w) to 3.5% (w / w), from about 0.01% (w / w) to 2.0% (w / w), from about 0.01% (w / w) to 1.0% (w / w), or from about 0.01% (w / w) to 0.75% (w / w), from about 0.01% (w / w) to 0.5% (w / w), from about 0.01% (w / w) to 0.25% (w / w), from about 0.01% (w / w) to 0.1% (w / w), or from about 0.01% (w / w) to 0.05% (w / w) niacinamide.

[0073] In some aspects, the secondary anti -acne agent in the combination formulation can be an organic acid. In some aspects, the organic acid can be selected from the group consisting of resorcinol, azelaic acid, salicylic acid, glycolic acid, and combinations thereof. In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 20% (w / w) organic acid, or from about 0.1% (w / w) to 10.0% (w / w), from about 0.1% (w / w) to 7.5% (w / w), from about 0.1% (w / w) to 6.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 4.0% (w / w), from about 0.1% (w / w) to 3.0%(w / w), from about 0.1% (w / w) to 2.0% (w / w), from about 0.1% (w / w) to 1.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) organic acid.

[0074] In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 20% (w / w) resorcinol, or from about 0.1% (w / w) to 10.0% (w / w), from about 0.1% (w / w) to 7.5% (w / w), from about 0.1% (w / w) to 6.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 4.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), from about 0.1% (w / w) to 1.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) resorcinol.

[0075] In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 25% (w / w) azelaic acid, or from about 0.1% (w / w) to 15.0% (w / w), from about 0.1% (w / w) to 10% (w / w), from about 0.1% (w / w) to 6.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 4.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), from about 0.1% (w / w) to 1.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) azelaic acid.

[0076] In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 20% (w / w) salicylic acid, or from about 0.01% (w / w) to 10.0% (w / w), from about 0.01% (w / w) to 7.5% (w / w), from about 0.01% (w / w) to 6.0% (w / w), from about 0.01% (w / w) to 5.0% (w / w), from about 0.01% (w / w) to 4.0% (w / w), from about 0.01% (w / w) to 3.0% (w / w), from about 0.01% (w / w) to 2.0% (w / w), from about 0.01% (w / w) to 1.0% (w / w), or from about 0.01% (w / w) to 0.5% (w / w) salicylic acid.

[0077] In some aspects, the combination formulation can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 70% (w / w) glycolic acid, or from about 0.1% (w / w) to 50.0% (w / w), from about 0.1% (w / w) to 30.0% (w / w), from about 0.1% (w / w) to 20.0% (w / w), from about 0.1% (w / w) to 15.0% (w / w), from about 0.1% (w / w) to 10.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) glycolic acid.

[0078] In some aspects, the secondary anti -acne agent in the combination formulation can be a corticosteroid. In some aspects, the corticosteroid can be selected from the group consisting of hydrocortisone, triamcinolone acetonide, and combinations thereof.

[0079] In some aspects, the combination formulation can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 10.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 5.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 3.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 2.5% (w / w) hydrocortisone, from about 0.01% (w / w) to 2.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 1.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 0.5% (w / w) hydrocortisone, from about 0.01% (w / w) to 0.1% (w / w) hydrocortisone, or from about 0.01% (w / w) to 0.5% (w / w) hydrocortisone.

[0080] In some aspects, the combination formulation can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 1.0% (w / w) triamcinolone acetonide, or from about 0.01% (w / w) to 0.20% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.30% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.40% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.50% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.6% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.7% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.8% (w / w) triamcinolone acetonide, or from about 0.01% (w / w) to 0.9% (w / w) triamcinolone acetonide.

[0081] In some aspects, the secondary anti -acne agent in the combination formulation can be an antiparasitic. In some aspects, the antiparasitic can be ivermectin. In some aspects, the combination formulation can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 5.0% (w / w) ivermectin, from about 0.01% (w / w) to about 3.0% (w / w) ivermectin, from about 0.01% (w / w) to 2.0% (w / w) ivermectin, from about 0.01% (w / w) to about 1.0% (w / w) ivermectin, from about 0.01% (w / w) to about 0.5% (w / w) ivermectin, from about 0.01% (w / w) to about 0.3% (w / w) ivermectin, from about 0.01% (w / w) to about 0.1% (w / w) ivermectin, or from about 0.01% (w / w) to about 0.5% (w / w) ivermectin.

[0082] In some aspects, the secondary anti -acne agent in the combination formulation can be elemental sulfur. In some aspects, the combination formulation can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to 15.0% (w / w) sulfur, from about 0.01% (w / w) to 10.0% (w / w) sulfur, from about 0.01% (w / w) to 5.0% (w / w) sulfur, from about 0.01% (w / w) to 2.0% (w / w) sulfur, from about 0.01% (w / w) to 1.0% (w / w) sulfur, from about 0.01% (w / w) to 0.5% (w / w) sulfur, or from about 0.01% (w / w) to 0.1% (w / w) sulfur. In some aspects, the sulfur can be formulated in combination with an effective amound of sodium sulfacetamide.In some aspects, the sulfur can be formulated in combination with an effective amount of resorcinol.

[0083] In some aspects, the secondary anti -acne agent in the combination formulation can be urea. In some aspects, the combination formulation can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to 50.0% (w / w) urea, from about 0.1% (w / w) to 20.0% (w / w) urea, from about 0.01% (w / w) to 10.0% (w / w) urea, from about 0.01% (w / w) to 5.0% (w / w) urea, from about 0.01% (w / w) to 2.0% (w / w) urea, from about 0.01% (w / w) to 1.0% (w / w) urea, or from about 0.01% (w / w) to 0.5% (w / w) urea.

[0084] In some aspects, the combination formulation can further comprise at least one (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) additive(s) optionally selected from the group consisting of an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent, and combinations thereof.

[0085] In some aspects, the combination formulation can be a cream. In some aspects, the cream can comprise equal parts oil and water in the form of an emulsion.

[0086] In some aspects, the combination formulation can be a paste. In some aspects, the paste can comprise a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof), an oil, or a combination thereof.

[0087] In some aspects, the combination formulation can be a gel that includes at least one gelling agent. The gelling agent can be, e.g., an inorganic gelling agent (e.g., aluminum hydroxide gel, bentonite magma), an organic gelling agent (e.g., a carbomer polymer, tragacanth), a hydrogel (e.g., an organic hydrogel, a natural or synthetic polymer, or an inorganic hydrogel), an organogel (e.g., a hydrocarbon type, a vegetable fat, a soap based grease, or a hydrophilic organogel), or a combination thereof. The organic hydrogel can include, e.g., pectin paste and tragacanth jelly. Suitable natural or synthetic polymers include, e.g., methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and poloxamer. The inorganic hydrogel can include, e.g., bentonite gel, smectite (e.g., VEEGUM™, Vanderbilt Minerals, LLC, Norwalk, CT), or silica. The hydrocarbon type organogel can include, e.g., petrolatum and mineral oil / polyethylene gel. The vegetable fat type organogel can include, e.g., cocoa butter. The soap based grease type organogel can include, e.g., aluminum stearate withheavy mineral oil gel. The hydrophilic organogels can include, e.g., carbowax bases, such as polyethylene glycol (PEG) ointment.

[0088] In some aspects, the gelling agent can be a carbomer polymer. The term “carbomer” is a generic name for high molecular weight polymer of acrylic acid lightly crosslinked with allyl ethers of polyalcohols (e.g., allyl sucrose, allyl pentaerythritol). The term also can be used to describe CARBOPOL™ polymers (Lubrizol Corp., Wickliffe, OH).

[0089] In some aspects, the combination formulation can be an ointment. In some aspects, the ointment can comprise a hydrocarbon (e.g., paraffin, petrolatum), lanolin, beeswax, a macrogol, a polyethylene glycol, an emulsifying wax, an alklytrimethylammonium bromide (e.g., a cetrimide), a vegetable oil (e.g., olive oil, jojoba oil, coconut oil, almond oil, cottonseed oil, safflower oil, sunflower oil, sesame oil, soybean oil, castor oil, or calendula oil), or a combination thereof. In some aspects, the ointment can comprise about 20 % (w / w) or less of water.

[0090] In some aspects, the combination formulation can be a foam. Foam formulations can be used in combination with one or more acceptable propellants, such as propane, butane, isobutene, nitrogen, and the like.

[0091] In some aspects, the combination formulation can comprise from about 0.1 % (w / w) to about 50 % (w / w) of each additive (e.g., an acid, a buffer, an antioxidant, an emulsifier, a penetration enhancer, a moisturizer, a preservative, a chelating agent) relative to the total weight of the formulation (i.e., making up 100 % (w / w)). For example, each additive can be present in the combination formulation in an amount from about 0.1 % (w / w) to about 45 % (w / w), about 0.1 % (w / w) to about 40 % (w / w), about 0.1 % (w / w) to about 35 % (w / w), about 0.1 % (w / w) to about 30 % (w / w), about 0.1 % (w / w) to about 25 % (w / w), about 0.1 % (w / w) to about 20 % (w / w), about 0.1 % (w / w) to about 15 % (w / w), about 0.1 % (w / w) to about 10 % (w / w), about 0.1 % (w / w) to about 5 % (w / w), about 0.1 % (w / w) to about 2 % (w / w), about 0.5 % (w / w) to about 50 % (w / w), about 0.5 % (w / w) to about 45 % (w / w), about 0.5 % (w / w) to about 40 % (w / w), about 0.5 % (w / w) to about 35 % (w / w), about 0.5 % (w / w) to about 30 % (w / w), about 0.5 % (w / w) to about 25 % (w / w), about 0.5 % (w / w) to about 20 % (w / w), about 0.5 % (w / w) to about 15 % (w / w), about 0.5 % (w / w) to about 10 % (w / w), about 0.5 % (w / w) to about 5 % (w / w), about 0.5 % (w / w) to about 2 % (w / w), about 1 % (w / w) to about 50 % (w / w), about 1 % (w / w) to about 45 % (w / w), about 1 % (w / w) to about 40 % (w / w), about 1 % (w / w) to about 35% (w / w), about 1 % (w / w) to about 30 % (w / w), about 1 % (w / w) to about 25 % (w / w), about 1 % (w / w) to about 20 % (w / w), about 1 % (w / w) to about 15 % (w / w), about 1 % (w / w) to about 10 % (w / w), about 1 % (w / w) to about 5 % (w / w), about 1 % (w / w) to about 2 % (w / w), about 50 % (w / w), about 48 % (w / w), about 46 % (w / w), about 44 % (w / w), about 42 % (w / w), about 40% (w / w), about 38 wt %, about 36 % (w / w), about 34 % (w / w), about 2 % (w / w), about 30 %(w / w), about 28 % (w / w), about 26 % (w / w), about 24 % (w / w), about 22 % (w / w), about 20 %(w / w), about 18 % (w / w), about 16 % (w / w), about 14 % (w / w), about 12 % (w / w), about 10 %(w / w), about 8 % (w / w), about 6 % (w / w), about 5 % (w / w), about 4 % (w / w), about 3 % (w / w), about 2 % (w / w), about 1 % (w / w), about 0.9 % (w / w), about 0.8 % (w / w), about 0.7 % (w / w), about 0.6 % (w / w), about 0.5 % (w / w), about 0.4 % (w / w), about 0.3 % (w / w), about 0.2 % (w / w), or about 0.1 % (w / w) of the total weight of the formulation.

[0092] In some aspects, the combination formulation can include an acid to help solubilize one or more of the active agents, to maintain a desired pH, or both. Any suitable acid can be used, such as a mineral acid (e.g., hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid), an organic acid (e.g., citric acid, acetic acid, succinic acid, or maleic acid), or mixtures thereof. Examples of suitable acid additives include but are not limited to: l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; L-ascorbic acid; L-aspartic acid; benzenesulfonic acid; benzoic acid; (+)-camphoric acid; (+)-camphor-10-sulfonic acid; capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; D-glucoheptonic acid; D-gluconic acid; D-glucuronic acid; glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid; lactobionic acid; lauric acid; maleic acid; L-malic acid; malonic acid; mandelic acid; methanesulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; L-pyroglutamic acid; salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; L-tartaric acid; thiocyanic acid; p-toluenesulfonic acid; and undecylenic acid. In some aspects, acetic acid, citric acid, or lactic acid can be added to the combination formulation.

[0093] In some aspects, the acid can be added in a sufficient amount so that the pH of the topical composition can be about 7.0 or less (e.g., about 4 to about 7.0, about 4 to about 6.5, about4 to about 6, about 4 to about 5.5, about 4 to about 5, about 4.5 to about 7.0, about 4.5 to about 6.5, about 4.5 to about 6, about 4.5 to about 5.5, about 4.5 to about 5, about 5 to about 7.0, about5 to about 6.5, about 5 to about 6, about 5 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6, about 6 to about 7.0, or about 6 to about 6.5).

[0094] In some aspects, the combination formulation can include a buffer to help maintain the pH of the formulation within a desired range. In some aspects, the buffer can be a phosphate buffer, citrate buffer, lactate buffer, or a combination thereof. In some aspects, the combination formulation can comprise phosphoric acid, citric acid, lactic acid, or a combination thereof.

[0095] In some aspects, the combination formulation can include an emulsifier, particularly to provide a solution, a suspension, an emulsion, or a microemulsion. Without wishing to be bound to any particular theory, it is believed that emulsifiers, when present, assist or facilitate dissolution of any solid substances, such as an active agent, in the topical composition. In other aspects, however, the emulsifier can be present to facilitate incorporation of two non-miscible liquids into each other (e.g., to form an emulsion or microemulsion).

[0096] In some aspects, and without wishing to be bound by any particular theory, an emulsifier can increase product spreadability. For example, and without wishing to be bound to a particular theory, when the combination formulation is a liquid solution, the presence of a suitable amount of an emulsifier is believed to decrease the surface tension between the topical composition and the lipid environment of the superficial layer of the skin. This makes it easier to spread the topical composition and is believed to assist penetration of the active agent(s) into skin.

[0097] In some aspects, the emulsifier can be selected from the group comprising: polyethylene glycol (PEG)-fatty acid monoesters such as PEG- 15 hydroxystearate (also known as polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate and the like; polyoxyethylene sorbitan fatty acid esters (polysorbates) such as polysorbate 20, polysorbate 60, polysorbate 80, and the like; polyoxyethylene alkyl ethers such as PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000 and the like; sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, and the like; propylene glycol esters of fatty acids; polyglycerol esters of fatty acids; polyoxyethylene castor oil derivatives such aspolyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil and the like; caprylocapryl polyoxyil-8 glycerides; polyoxylglycerides such as capryl ocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoyl polyoxylglycerides, and the like; along with combinations of any of the foreoging. In some aspects, the emulsifier can be polyoxyl 40 hydrogenated castor oil, polyoxyl-15-hydroxystearate, polysorbate 60, polysorbate 80, or a combination thereof. In some aspects, the emulsifier can be a polysorbate, such as polysorbate 60, polysorbate 80, or a combination of polysorbate 60 and polysorbate 80.

[0098] In some aspects, the combination formulation can include the emulsifier in an amount of up to about 0.5 % (w / w) of the total formulation. In some aspects, the emulsifier can be present in an amount ranging from 0.05 to 0.2 % (w / w). In some aspects, the combination formulation can include the emulsifier in an amount up to about 0.1 % (w / w) or it can include about 0.1 % (w / w) emulsifier. In some aspects, the emulsifier can be present in the combination formulation at about 0.1 % (w / w).

[0099] In some aspects, the combination formulation can include one or more penetration enhancers. Without wishing to be bound by a particular theory, penetration enhancers are believed to beneficially affect delivery of the active agent(s) into the skin. Advantageously, and in some aspects, the solvent or some component(s) of the solvent act as a penetration enhancer. For example, in aspects wherein the combination formulation comprises ethanol and / or diethylene glycol monoethyl ether, these solvents can also act to enhance penetration of the active agent into the skin. The presence of ethanol and / or diethylene glycol monoethyl ether notwithstanding, the topical compositions described herein can further include additional penetration enhancers.

[0100] In some aspects, the penetration enhancer can be selected from the group consisting of hydroxypropyl P-cyclodextrin, a diol, a polyol, a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof), a fatty alcohol, a fatty acid ester, a surfactant, a pyrrolidone, and combinations thereof. Examples of further penetration enhancer that can be incorporated into formulations described herein include, but are not limited to, polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether (e.g., TRANSCUTOL™, Gattefosse, France), dimethyl isosorbide, diethyl sebacate, azone, menthol, nerol, camphor, methyl salicylate, polysorbate 80 (e.g., TWEEN™ 80, 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 of any of the foregoing.

[0101] In some aspects, the penetration enhancer can be dimethyl isosorbide. In some aspects, the penetration enhancer can be a mixture comprising dimethyl isosorbide and diethylene glycol monoethyl ether. In some aspects, the penetration enhancer can be dimethyl sulfoxide.

[0102] In some aspects, the penetration enhancer can be present in an amount ranging from about 1 % (w / w) to about 50 % (w / w) with respect to the total weight of the combination formulation. In some aspects, the penetration enhancer can be present from about 2 % (w / w) to about 40 % (w / w) with respect to the total weight of the combination formulation; or from about 5 % (w / w) to about 35 % (w / w) with respect to the total weight of the combination formulation. In some aspects, the penetration enhancer can be present in the combination formulation described herein in an amount of about 1% % (w / w), about 2 % (w / w), about 5 % (w / w), about 10 % (w / w), about 15 % (w / w), about 20 % (w / w), about 25 % (w / w), about 30 % (w / w), about 35 % (w / w), about 40 % (w / w), about 45 % (w / w), or about 50 % (w / w) with respect to the total weight of the combination formulation.

[0103] In some aspects, the combination formulation can include one or more moisturizers. Without wishing to be bound by a particular theory, a moisturizer is believed to impart moisture and / or softness into the skin, particularly when a component known to dry the skin, such as an alcohol, are also present in the combination formulation. In some aspects, the moisturizer can be a fatty alcohol, a fatty acid (e.g., myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof), a fatty acid ester, an oil, a polyethylene glycol, glycerin, an alpha hydroxy acid, or a combination thereof. In some aspects, the moisturizer can be cetyl alcohol, cetearyl alcohol, stearyl alcohol, stearic acid, isopropyl myristate, isopropyl palmitate, cocoa butter, lanolin, liquid paraffin, shea butter, a silicone oil, castor oil, a polyethylene glycol, glycerin, lactic acid, glycolic acid, malic acid, citric acid, tartaricacid, or a combination thereof. In some aspects, the moisturizer can be cetyl alcohol, stearyl alcohol, or a combination of cetyl alcohol and stearyl alcohol.

[0104] In some aspects, the combination formulation can include one or more preservatives (e.g., an antibacterial, an antifungal). Suitable preservatives include, e.g., a paraben (e.g., methyl paraben, ethyl paraben, propyl paraben, butyl paraben), a benzoate (e.g., sodium benzoate), a sorbate (e.g., potassium sorbate), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an alcohol (e.g., chlorobutanol, benzyl alcohol, ethanol, phenol, m-cresol, chloro cresol), sodium metabisulfite, imidazolidinyl urea, glycerin, propylene glycol, or combinations thereof.

[0105] In some aspects, the combination formulation can include one or more chelating agents. Suitable chelating agents include, e.g., citric acid, phytic acid, sodium phytate, clioquinol, ethylenediaminetetraacetic acid (EDTA) (e.g., disodium EDTA, tetrasodium EDTA), etidronic acid, galactaric acid, tetrahydroxypropyl ethylenediamine, sodium metasilicate, or a combination thereof.

[0106] In some aspects, the combination formulation can be prepared as a wash-off agent. A wash-off agent can be applied to the skin for an administered period of time and then can be rinsed thoroughly. In some aspects, the combination formulation can be prepared as a wash-off agent further comprising a soap or cleanser. The wash-off agent can be in the form of a solid bar, solution, suspension, cream, gel, paste, microemulsion, emulsion, or foam.

[0107] In some aspects, the combination formulation can be prepared as a lotion. In some aspects, the lotion can comprise the combination formulation and at least one component selected from the group consisting of humectant, occlusive, emollient, emulsifier, solvent, fragrance, pH adjuster, and preservative.

[0108] In some aspects, the combination formulation can be prepared as a solution. A solution can comprise the combination formulation in one or more appropriate solvents or combinations thereof. In some aspects, the solvent can be water. In some aspects, the solvent can be an alcohol.

[0109] In some aspects, the combination formulation can be prepared as a suspension. A suspension can comprise the combination formulation in one or more appropriate solvents or combinations thereof. In some aspects, the solvent can be water. In some aspects, the solvent can be an alcohol.

[0110] In some aspects, the combination formulation can be prepared as a hydrogel patch. A hydrogel patch can comprise the combination formulation, a film coating, a gel layer, and a backing layer.[OHl] In some aspects, the combination formulation can be prepared as a microemulsion. A microemulsion can comprise the combination formulation, an oil, water, and one or more surfactants.

[0112] In some aspects, the combination formulation can be prepared as a pledget.

[0113] In some aspects, the CTX and secondary anti-acne agent can be provided as separate formulations that can be mixed to generate the combination formulation prior to use. In some aspects, two or more separate formulations containing different actives can be combined into a single combination formulation prior to use. In some aspects, the combination formulation can be prepared by mixing two or more separate formulations together prior to application. In some aspects, the combination formulation can be pre-prepared.Methods of Treating Acne Comprising Administering a Combined Formulation Comprising CTX and the Secondary Anti-Acne Agent

[0114] The present disclosure also provides methods of treating acne comprising topically applying the combination formulations described herein. The combination formulation described herein can be applied to any body surface in need of treatment, such as a skin region susceptible to acne. Suitable skin regions include e.g., face, arms, armpits, legs, chest, abdomen, back, neck, or any combination of the foregoing. In some aspects, the combination formulation is not delivered to the face. In other aspects, the combination formulation can be applied to the face.

[0115] In some aspects, the method of treating acne comprises administering a combination formulation as described herein in an effective amount at appropriate intervals, for example, once or multiple times per day (e.g. once a day, twice a day, three times a day, four times a day, etc.); once or multiple times every other day (e.g. once a day every other day, twice a day every other day, three times a day every other day, four times a day every other day, etc.); once or multiple times every three days (e.g. once a day every three days, twice a day every three days, three times a day every three days, four times a day every three days, etc.); at least one, two or three times a week; weekly; or less frequently until the acne being treated is reduced or alleviated. In certainaspects, the combination formulation can be delivered to provide an initial loading dose and then be reduced to a maintenance level, if necessary or desirable. The amount of the combination formulation to be administered as well as the loading period can be determined by a physician of ordinary skill in the art as well as the condition of the patient and the disease or condition to be treated. Although the combination formulation described here can be given at any time during the day, in certain aspects, the formulation can be administered in the evening.

[0116] In some aspects the method of treating acne can comprise administering a combination formulation to a subject in need thereof as described herein for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. Alternatively, the combination formulation can be administered for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or for any other period of time as determined by a physician of ordinary skill in the art.

[0117] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and benozyl peroxide. In some aspects, the method can comprise administering a combination formulation comprising about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 25.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 10.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 7.5% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 6.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 5.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 4.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 3.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 2.0% (w / w) benzoyl peroxide, from about 0.1% (w / w) to 1.0% (w / w) benzoyl peroxide, or from about 0.1% (w / w) to 0.5% (w / w) benzoyl peroxide.

[0118] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and an antibiotic. In some aspects, the antibiotic can be selected from the group consisting of clindamycin, erythromycin, nadifloxacin, metronidazole, mafenide, minocycline, sodium sulfacetamide, diaminodiphenyl sulfone, and combinations thereof. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 12.0% (w / w) antibiotic, from about 0.1% (w / w) to 10.0% (w / w) antibiotic, from about 0.1% (w / w) to 8.0% (w / w) antibiotic, from about 0.1% (w / w) to 6.0% (w / w) antibiotic, from about 0.1% (w / w) to 4.0% (w / w) antibiotic, or from about 0.1% (w / w) to 3.0% (w / w)antibiotic, from about 0.1% (w / w) to 2.0% (w / w) antibiotic, or from about 0.1% (w / w) to 1.0% (w / w) antibiotic, from about 0.1% (w / w) to 0.5% (w / w) antibiotic, or from about 0.1% (w / w) to 0.1% (w / w) antibiotic.

[0119] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and clindamycin. In some aspects, the combination formulation suitable for use in the method can comprise clindamycin from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise clindamycin at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0120] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and erythromycin. In some aspects, the combination formulation suitable for use in the method can comprise erythromycin from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise erythromycin at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0121] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and nadifloxacin. In some aspects, the combination formulation suitable for use in the method can comprise nadifloxacin from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise nadifloxacin at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0122] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and metronidazole. In some aspects, the combination formulation suitable for use in the method can comprise metronidazole from about 0.5 % (w / w) to about 6.0 % (w / w). In some aspects, the formulation can comprise metronidazole at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0123] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and mafenide. In some aspects, the combination formulation suitable for use in the method can comprise mafenide at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0124] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and minocycline. In some aspects, the combination formulation suitable for use in the method can comprise minocycline at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), or about 6.0% (w / w).

[0125] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and sodium sulfacetamide. In some aspects, the combination formulation suitable for use in the method can comprise sodium sulfacetamide from about 0.5 % (w / w) to about 15.0 % (w / w). In some aspects, the formulation can comprise sodium sulfacetamide at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w),about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), about 6.0% (w / w), about 6.25% (w / w), about 6.5% (w / w), about 6.75% (w / w), about 7.0% (w / w), about 7.25% (w / w), about 7.5% (w / w), about 7.75% (w / w), about 8.0% (w / w), about 8.25% (w / w), about 8.5% (w / w), about 8.75% (w / w), about 9.0% (w / w), about 9.25% (w / w), about 9.5% (w / w), about 9.75% (w / w), about 10.0% (w / w), about 10.25% (w / w), about 10.5% (w / w), about 10.75% (w / w), about 11.0% (w / w), about 11.25% (w / w), about 11.5% (w / w), about 11.75% (w / w), about 12.0% (w / w), about 12.25% (w / w), about 12.5% (w / w), about 12.75% (w / w), about 13.0% (w / w), about 13.25% (w / w), about 13.5% (w / w), about 13.75% (w / w), about 14.0% (w / w), about 14.25% (w / w), about 14.5% (w / w), about 14.75% (w / w), or about 15.0% (w / w).

[0126] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and diaminodiphenyl sulfone. In some aspects, the combination formulation suitable for use in the method can comprise diaminodiphenyl sulfone at about 0.5% (w / w) to about 15% (wt / wt). In some aspects, the combination formulation can comprise diaminodiphenyl sulfone at about 0.5% (w / w), about 0.75% (w / w), about 1.0% (w / w), about 1.25% (w / w), about 1.5% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3.0% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 4.0% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5.0% (w / w), about 5.25% (w / w), about 5.5% (w / w), about 6.0% (w / w), about 6.25% (w / w), about 6.5% (w / w), about 6.75% (w / w), about 7.0% (w / w), about 7.25% (w / w), about 7.5% (w / w), about 7.75% (w / w), about 8.0% (w / w), about 8.25% (w / w), about 8.5% (w / w), about 8.75% (w / w), about 9.0% (w / w), about 9.25% (w / w), about 9.5% (w / w), about 9.75% (w / w), about 10.0% (w / w), about 10.25% (w / w), about 10.5% (w / w), about 10.75% (w / w), about 11.0% (w / w), about 11.25% (w / w), about 11.5% (w / w), about 11.75% (w / w), about 12.0% (w / w), about 12.25% (w / w), about 12.5% (w / w), about 12.75% (w / w), about 13.0% (w / w), about 13.25% (w / w), about 13.5% (w / w), about 13.75% (w / w), about 14.0% (w / w), about 14.25% (w / w), about 14.5% (w / w), about 14.75% (w / w), or about 15.0% (w / w).

[0127] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and a retinoid. In some aspects, the retinoid can be selected from the group consisting of tretinoin, adapalene, tazarotene, trifarotene, and combinations thereof. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 7.0% (w / w) retinoid, from about 0.01% (w / w) to 5.0% (w / w) retinoid, from about 0.01% (w / w) to 3.5% (w / w) retinoid, from about 0.01% (w / w) to 2.0% (w / w) retinoid, from about 0.01% (w / w) to 1.0% (w / w) retinoid, or from about 0.01% (w / w) to 0.75% (w / w) retinoid, from about 0.01% (w / w) to 0.5% (w / w) retinoid, or from about 0.01% (w / w) to 0.25% (w / w) retinoid, from about 0.01% (w / w) to 0.1% (w / w) retinoid, or from about 0.01% (w / w) to 0.05% (w / w) retinoid.

[0128] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and tretinoin. In some aspects, the combination formulation suitable for use in the method can comprise about 0.010% (w / w) to about 0.20% (w / w) of tretinoin. In some aspects, the combination formulation can comprise about 0.02% (w / w), about 0.025% (w / w), about 0.030% (w / w), about 0.035% (w / w), about 0.040% (w / w), about 0.045% (w / w), about 0.050% (w / w), about 0.055% (w / w), about 0.060% (w / w), about 0.065% (w / w), about 0.070% (w / w), about 0.075% (w / w), or about 0.080% (w / w), about 0.085% (w / w), about 0.090% (w / w), about 0.095% (w / w), or about 0.10% (w / w), about 0.12% (w / w), about 0.125% (w / w), about 0.130% (w / w), about 0.135% (w / w), about 0.140% (w / w), about 0.145% (w / w), about 0.150% (w / w), about 0.155% (w / w), about 0.160% (w / w), about 0.165% (w / w), about 0.170% (w / w), about 0.175% (w / w), or about 0.180% (w / w), about 0.185% (w / w), about 0.190% (w / w), about 0.195% (w / w), or about 0.20% (w / w) tretinoin.

[0129] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and adapalene. In some aspects, the combination formulation suitable for use in the method can comprise about 0.010% (w / w) to about 0.50% (w / w) of adapalene. In some aspects, the combination formulation can comprise about 0.02% (w / w), about 0.025% (w / w), about 0.030% (w / w), about 0.035% (w / w), about 0.040% (w / w), about 0.045% (w / w), about 0.050% (w / w), about 0.055% (w / w), about 0.060% (w / w), about 0.065% (w / w), about 0.070% (w / w), about 0.075% (w / w), or about 0.080% (w / w),about 0.085% (w / w), about 0.090% (w / w), about 0.095% (w / w), or about 0.10% (w / w), about 0.12% (w / w), about 0.125% (w / w), about 0.130% (w / w), about 0.135% (w / w), about 0.140% (w / w), about 0.145% (w / w), about 0.150% (w / w), about 0.155% (w / w), about 0.160% (w / w), about 0.165% (w / w), about 0.170% (w / w), about 0.175% (w / w), or about 0.180% (w / w), about 0.185% (w / w), about 0.190% (w / w), about 0.195% (w / w), about 0.20% (w / w), about 0.30% (w / w), or about 0.40% (w / w) adapalene.

[0130] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and tazarotene. In some aspects, the combination formulation suitable for use in the method can comprise about 0.010% (w / w) to about 0.20% (w / w) of tazarotene. In some aspects, the combination formulation can comprise about 0.02% (w / w), about 0.025% (w / w), about 0.030% (w / w), about 0.035% (w / w), about 0.040% (w / w), about 0.045% (w / w), about 0.050% (w / w), about 0.055% (w / w), about 0.060% (w / w), about 0.065% (w / w), about 0.070% (w / w), about 0.075% (w / w), or about 0.080% (w / w), about 0.085% (w / w), about 0.090% (w / w), about 0.095% (w / w), or about 0.10% (w / w), about 0.12% (w / w), about 0.125% (w / w), about 0.130% (w / w), about 0.135% (w / w), about 0.140% (w / w), about 0.145% (w / w), about 0.150% (w / w), about 0.155% (w / w), about 0.160% (w / w), about 0.165% (w / w), about 0.170% (w / w), about 0.175% (w / w), or about 0.180% (w / w), about 0.185% (w / w), about 0.190% (w / w), about 0.195% (w / w), or about 0.20% (w / w) tazarotene.

[0131] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and trifarotene. In some aspects, the combination formulation suitable for use in the method can comprise about 0.001% (w / w) to about 0.015% (w / w) of trifarotene. In some aspects, the combination formulation can comprise about 0.001% (w / w) trifarotene, or about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), about 0.006% (w / w), about 0.007% (w / w), about 0.008% (w / w), about 0.009% (w / w), about 0.010% (w / w), about 0.011% (w / w), about 0.012% (w / w), or about 0.013% (w / w), about 0.014% (w / w), or about 0.015% (w / w) trifarotene.

[0132] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and an antioxidant. In some aspects, the antioxidant suitable for use in the method can be sodium L-ascorbyl-2-phosphate. In some aspects, the combination formulation of the method can comprise about 0.1% (w / w) to about5.0% (w / w) CTX and from about 0.1% (w / w) to about 7.0% (w / w) sodium L-ascorbyl-2- phosphate, or from about 0.01% (w / w) to 5.0% (w / w) t, from about 0.01% (w / w) to 3.5% (w / w), from about 0.01% (w / w) to 2.0% (w / w), from about 0.01% (w / w) to 1.0% (w / w), or from about 0.01% (w / w) to 0.75% (w / w), from about 0.01% (w / w) to 0.5% (w / w), from about 0.01% (w / w) to 0.25% (w / w), from about 0.01% (w / w) to 0.1% (w / w), or from about 0.01% (w / w) to 0.05% (w / w) sodium L-ascorbyl-2-phosphate.

[0133] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and niacinamide. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 7.0% (w / w) niacinamide, or from about 0.01% (w / w) to 5.0% (w / w), from about 0.01% (w / w) to 3.5% (w / w), from about 0.01% (w / w) to 2.0% (w / w), from about 0.01% (w / w) to 1.0% (w / w), or from about 0.01% (w / w) to 0.75% (w / w), from about 0.01% (w / w) to 0.5% (w / w), from about 0.01% (w / w) to 0.25% (w / w), from about 0.01% (w / w) to 0.1% (w / w), or from about 0.01% (w / w) to 0.05% (w / w) niacinamide.

[0134] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and an organic acid. In some aspects, the organic acid can be selected from the group consisting of resorcinol, azelaic acid, salicylic acid, glycolic acid, and combinations thereof. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 20% (w / w) organic acid, or from about 0.1% (w / w) to 10.0% (w / w), from about 0.1% (w / w) to 7.5% (w / w), from about 0.1% (w / w) to 6.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 4.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), from about 0.1% (w / w) to 1.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) organic acid.

[0135] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and resorcinol. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 20% (w / w) resorcinol, or from about 0.1% (w / w) to 10.0% (w / w), from about 0.1% (w / w) to 7.5% (w / w), from about 0.1% (w / w) to6.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 4.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), from about 0.1% (w / w) to 1.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) resorcinol.

[0136] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and azelaic acid. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 25% (w / w) azelaic acid, or from about 0.1% (w / w) to 15.0% (w / w), from about 0.1% (w / w) to 10% (w / w), from about 0.1% (w / w) to 6.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 4.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), from about 0.1% (w / w) to 1.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) azelaic acid.

[0137] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and salicylic acid. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 20% (w / w) salicylic acid, or from about 0.1% (w / w) to 10.0% (w / w), from about 0.1% (w / w) to 7.5% (w / w), from about 0.1% (w / w) to 6.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 4.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), from about 0.1% (w / w) to 1.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) salicylic acid.

[0138] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and glycolic acid. In some aspects, the combination formulation suitable for use in the method can comprise about 0.1% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to about 70% (w / w) glycolic acid, or from about 0.1% (w / w) to 50.0% (w / w), from about 0.1% (w / w) to 30.0% (w / w), from about 0.1% (w / w) to 20.0% (w / w), from about 0.1% (w / w) to 15.0% (w / w), from about 0.1% (w / w) to 10.0% (w / w), from about 0.1% (w / w) to 5.0% (w / w), from about 0.1% (w / w) to 3.0% (w / w), from about 0.1% (w / w) to 2.0% (w / w), or from about 0.1% (w / w) to 0.5% (w / w) glycolic acid.

[0139] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and a corticosteroid. In someaspects, the corticosteroid can be selected from the group consisting of hydrocortisone, triamcinolone acetonide, and combinations thereof.

[0140] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and hydrocortisone. In some aspects, the combination formulation suitable for use in the method can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 10.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 5.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 3.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 2.5% (w / w) hydrocortisone, from about 0.01% (w / w) to 2.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 1.0% (w / w) hydrocortisone, from about 0.01% (w / w) to 0.5% (w / w) hydrocortisone, from about 0.01% (w / w) to 0.1% (w / w) hydrocortisone, or from about 0.01% (w / w) to 0.5% (w / w) hydrocortisone.

[0141] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and triamcinolone acetonide. In some aspects, the combination formulation suitable for use in the method can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 1.0% (w / w) triamcinolone acetonide, or from about 0.01% (w / w) to 0.20% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.30% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.40% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.50% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.6% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.7% (w / w) triamcinolone acetonide, from about 0.01% (w / w) to 0.8% (w / w) triamcinolone acetonide, or from about 0.01% (w / w) to 0.9% (w / w) triamcinolone acetonide.

[0142] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and an antiparasitic. In some aspects, the combination formulation suitable for use in the method can comprise ivermectin. In some aspects, the combination formulation of the method can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to about 5.0% (w / w) ivermectin, from about 0.01% (w / w) to about 3.0% (w / w) ivermectin, from about 0.01% (w / w) to 2.0% (w / w) ivermectin, from about 0.01% (w / w) to about 1.0% (w / w) ivermectin, from about 0.01% (w / w) to about 0.5% (w / w) ivermectin, from about 0.01% (w / w) to about 0.3% (w / w) ivermectin, from about 0.01%(w / w) to about 0.1% (w / w) ivermectin, or from about 0.01% (w / w) to about 0.5% (w / w) ivermectin.

[0143] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and elemental sulfur. In some aspects, the combination formulation suitable for use in the method can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.01% (w / w) to 15.0% (w / w) sulfur, from about 0.01% (w / w) to 10.0% (w / w) sulfur, from about 0.01% (w / w) to 5.0% (w / w) sulfur, from about 0.01% (w / w) to 2.0% (w / w) sulfur, from about 0.01% (w / w) to 1.0% (w / w) sulfur, from about 0.01% (w / w) to 0.5% (w / w) sulfur, or from about 0.01% (w / w) to 0.1% (w / w) sulfur. In some aspects, the sulfur can be formulated in combination with an effective amount of sodium sulfacetamide. In some aspects of the method, the sulfur can be formulated in combination with an effective amount of resorcinol.

[0144] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and urea. In some aspects, the combination formulation suitable for use in the method can comprise about 0.01% (w / w) to about 5.0% (w / w) CTX and from about 0.1% (w / w) to 50.0% (w / w) urea, from about 0.1% (w / w) to 20.0% (w / w) urea, from about 0.01% (w / w) to 10.0% (w / w) urea, from about 0.01% (w / w) to 5.0% (w / w) urea, from about 0.01% (w / w) to 2.0% (w / w) urea, from about 0.01% (w / w) to 1.0% (w / w) urea, or from about 0.01% (w / w) to 0.5% (w / w) urea.

[0145] In some aspects, the method of treating acne can comprise administering a combination formulation comprising an effective amount of CTX and more than one secondary anti-acne agent. In some aspects, more than two, more than three, more than four, more than five, more than six, more than seven, more than eight, more than nine, or more than ten secondary anti- acne agents can be administered in combination with CTX as a formulation.

[0146] In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, an antiseptic, and a third antiacne agent. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, an antiseptic, and an antibiotic. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising effective amount of CTX, benzoyl peroxide, and clindamycin.

[0147] In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, an antibiotic, and a third antiacne agent. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, an antibiotic, and an organic acid. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising effective amount of CTX, clindamycin, and salicylic acid.

[0148] In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, a retinoid, and a third anti-acne agent. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, a retinoid, and an antibiotic. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising effective amount of CTX, adapalene, and clindamycin.

[0149] In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, an antioxidant, and a third antiacne agent. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, an antioxidant, and an antibiotic. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising effective amount of CTX, sodium L-ascorbyl-2-phosphate, and clindamycin.

[0150] In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, an organic acid, and a third anti-acne agent. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, organic acid, and an retinoid. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising effective amount of CTX, azelaic acid, and adapalene.

[0151] In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, a corticosteroid, and a third anti-acne agent. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, a corticosteroid, and anantibiotic. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising effective amount of CTX, hydrocortisone, and clindamycin.

[0152] In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX and three anti-acne agents. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising an effective amount of CTX, a retinoid, an anti-bacterial, and an antibiotic. In some aspects, the method of treating acne can comprise topically administering a combination formulation comprising effective amount of CTX, adapalene, benzoyl peroxide, and clindamycin.

[0153] In some aspects, the method of treating acne can comprise the steps of administering a first combination formulation comprising an effective amount of CTX and one or more secondary anti-acne agents followed by administration of a second combination formulation comprising CTX and one or more secondary anti-acne agents after a delay of seconds, minutes, or hours. For example, and in some aspects, a first combination formulation can be administered in the morning and a second combination formulation can be administered in the evening.

[0154] In some aspects, the method of treating acne can comprise the steps of administering three anti-acne agents in two separate topical combination formulations after a delay of seconds, minutes, or hours. In some aspects, the method of treating acne can comprise administering a first topical formulation comprising more than one anti-acne agent, followed by administration of a second topical formulation comprising at least one anti-acne agent, wherein at least one formulation comprises an effective amount of CTX, after a delay of seconds, minutes, or hours.

[0155] In some aspects, the method of treating acne can comprise the steps of administering more than two anti-acne agents in three separate topical combination formulations. In some aspects, the method of treating acne can comprise administering a first topical formulation, followed by administration of second and third topical formulations, wherein at least one formulation comprises an effective amount of CTX, and each formulation is applied after a delay of seconds, minutes, or hours.

[0156] In some aspects, the method of treating acne can comprise administering a combination of more than one oral and more than one topical anti-acne agents. In some aspects, the method of treating acne can comprise administering a first anti-acne agent in an oralformulation within minutes or hours of the administration of a first topical formulation comprising at least one topical anti -acne agent, followed by the administration of a second topical formulation comprising at least one topical anti-acne agent, after a delay of seconds, minutes, or hours, wherein at least one topical formulation comprises CTX. For example, and in some aspects, a first anti-acne agent can be administered orally and a first topical formulation can be administered in the morning, and a second topical formulation, containing one or more anti-acne agents, can be administered in the evening, wherein at least one topical formulation comprises CTX. In some aspects, the method of treating acne can comprise mixing or combining the CTX-containing formulation and the secondary anti -acne agent just prior to use.Methods of Treating Acne Comprising Co-Administering a Formulation Comprising CTX and a Second Formulation Comprising One or More Secondary Anti-Acne Agents

[0157] In as much as CTX and one or more secondary anti -acne agents can be co-formulated, in some aspects, the CTX and secondary anti-acne agent or agents can be formulated separately, but can be co-administered. For example, in some aspects, the method of treating acne can comprise administering an effective amount of a first formulation comprising CTX, such as WINLEVI®, and co-administering an effective amount of a second formulation comprising one or more secondary anti-acne agents. Any known formulations of topical secondary anti-acne agents can be used in the methods of co-administration described herein.

[0158] Suitable second formulations comprising one or more secondary anti-acne agents include, but are not limited to ACUATIM Cream (1% w / w nadifloxacin), ACANYA (1.2% w / w clindamycin phosphate / 2.5% w / w benzoyl peroxide), ACZONE® (7.5% w / w diaminodiphenyl sulfone), ADULT ACNOMEL (2% w / w resorcinol / 8% w / w sulfur), AKLIEF (0.005% w / w trifarotene), AKNE-MYCIN (2% w / w erythromycin), AKTIPAK (3% w / w erythromycin / 5% w / w benzoyl peroxide), ALTRENO (0.05% w / w tretinoin), AMZEEQ (4% w / w minocycline), ARAZLO (0.045% w / w tazarotene), ATRALIN (0.05% w / w tretinoin), ATRIX (0.1% w / w salicylic acid), AV AGE (0.1% w / w tazarotene), AVAR (10% w / w sodium sulfacetamide / 5% w / w sulfur), AVITA (0.025% w / w tretinoin), AZELEX (20% w / w azelaic acid), BENOXYL (4% w / w benzoyl peroxide), BENZAC AC (2.5-10% w / w benzoyl peroxide), BENZACLIN (1% w / w clindamycin / 5% w / w benzoyl peroxide), BENZAMYCIN PAK (3% w / w erythromycin / 5%w / w benzoyl peroxide), BENZEFOAM( 5% w / w benzoyl peroxide), BENZEPRO ( 5.3% w / w benzoyl peroxide), BREVOXYL (4% w / w benzoyl peroxide), CLENIA (10% w / w sodium sulfacetamide / 5% w / w sulfur), CLINE) A DERM (1% w / w clindamycin phosphate), CLINDACIN (1% w / w clindamycin phosphate), CLINDAGEL (1% w / w clindamycin phosphate), CLINDAMAX (1% w / w clindamycin phosphate), DESQUAM-E (5% w / w benzoyl peroxide), DIFFERIN (0.1% w / w adapalene), DU AC CS (1.2% w / w clindamycin phosphate / 5% w / w benzoyl peroxide), EFF ACLAR DUO (5.5% w / w benzoyl peroxide), EMGEL (2% w / w erythromycin), ENZOCLEAR (9.8% w / w benzoyl peroxide), EPIDUO (0.1% w / w adapalene / 2.5% w / w benzoyl peroxide), EPSOLAY ( 5% w / w benzoyl peroxide), ERYGEL (2% w / w erythromycin), EVOCLIN (1% w / w clindamycin phosphate), FABIOR (0.1% w / w tazarotene), FINACEA ( 15% w / w azelaic acid), KENALOG (0.025-0.5% triamcinolone acetonide), KLARON (10% w / w sodium sulfacetamide), NADOXIN (1% w / w nadifloxacin), NEU AC (1.2% w / w clindamycin phosphate / 5% w / w benzoyl peroxide), NUCARARXPAK (1% w / w clindamycin phosphate), NUOX (6 % w / w benzoyl peroxide / 3% w / w sulfur), OVACE (10% w / w sodium sulfacetamide), PACNEX (7% w / w benzoyl peroxide), PANOXYL (Benzoyl peroxide 2.5%, 5%, 10% w / w benzoyl peroxide), PLEXION (9.8% w / w sodium sulfacetamide / 4.8% w / w sulfur), PRASCION (10% w / w sodium sulfacetamide / 5% w / w sulfur), REFISSA (0.05% w / w tretinoin), RENOVA (0.02% w / w tretinoin), RETIN-A MICRO (0.04% w / w tretinoin), RETIN- A (0.01-0.05% w / w tretinoin), RIAX (5.5-9.5% w / w benzoyl peroxide), ROSANIL (10% w / w sodium sulfacetamide / 5% w / w sulfur), SALEX (6% w / w salicylic acid), SALICYLIX SF12 (12% w / w salicylic acid), SALVAX (6% w / w salicylic acid), SEB-PREV (10% w / w sulfacetamide sodium), SOOLANTRA (1% w / w ivermectin), STRIDEX (0.1% w / w salicylic acid), SULFAMYLON (5% w / w mafenide acetate), SULFATOL C (10% w / w sulfacetamide sodium / 5% w / w sulfur), SULFO LO (3% w / w sulfur), SUMADAN (9% w / w sodium sulfacetamide / 4.5% w / w sulfur), SUMAXIN (10% w / w sodium sulfacetamide / 4% w / w sulfur), TAZORAC (0.05-0.1% w / w tazarotene), TRETIN-X (0.025% w / w tretinoin), TRIAZ (3-9% w / w benzoyl peroxide), TRIDERM (0.025-0.5% triamcinolone acetonide), TWYNEO (0.1% w / w tretinoin / 3% w / w benzoyl peroxide), VELTIN (1.2% w / w clindamycin phosphate / 0.025% w / w tretinoin), ZACLIR (8% w / w benzoyl peroxide), ZENCIA (9% w / w sodium sulfacetamide / 4% w / w sulfur), and ZIANA (1.2% w / w clindamycin phosphate / 0.025% w / w tretinoin).Methods of Treating Acne Comprising Topically Co-Administering CTX in Combination with One or More Oral Secondary Anti-Acne Agents

[0159] In some aspects, the present disclosure provides a method of treating or preventing acne comprising topically administering to a subject in need thereof an effective amount of a formulation comprising CTX, such as WINLEVI®, and orally co-administering an effective amount of one or more secondary oral anti-acne agents. In some aspects, the one or more oral secondary anti-acne agents can be selected from the group consisting of an antibiotic, a hormonal agent, a retinoid, a dietary supplement, and combinations thereof. Any known formulations of oral secondary anti-acne agents can be used in the methods of co-administration described herein.

[0160] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of an antibiotic selected from the group consisting of amoxicillin, azithromycin, cephalexin, doxycycline, erythromycin, minocycline, tetracycline, trimethoprim, sulfamethoxazole, diaminodiphenyl sulfone, and combinations thereof. The antibiotic can be delivered orally in any known suitable oral formulation, including in the form of a powder, solution, suspension, tablet, capsule, press, or soft gel.

[0161] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of amoxicillin. In some aspects, the amoxicillin can be orally administered in a total daily dose of about 50 mg to about 2000 mg, for example about 100 mg to about 1900 mg, about 250 mg to about 1750 mg, about 500 mg to about 1500 mg, or about 750 mg to about 1000 mg amoxicillin per day. In some aspects, the total daily dose of amoxicillin can be administered orally as 1, 2, 3, 4, 5, or more doses, with each dose comprising from about 100 mg to about 600 mg amoxicillin. In some aspects, each dose of amoxicillin can comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg amoxicillin.

[0162] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of azithromycin. In some aspects, the azithromycin can be orally administered in a dose of about 50 mg to about 2000 mg. In someaspects, the azithromycin can be administered in dosages of about 500 mg to about 2000 mg once a day. In some aspects, the azithromycin can be administered in dosages of about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg. In some aspects, following an initial dosage protocol, administration of azithromycin can be tapered to doses of about 50 to about 800 mg, about 250 mg to about 500 mg, once a day for several days.

[0163] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of cephalexin. In some aspects, the cephalexin can be orally administered in dose of about 50 mg to about 2000 mg. In some aspects, the cephalexin can be administered in dosages of about 500 mg to about 2000 mg. In some aspects, the cephalexin can be administered in dosages of about 200 mg to about 750 mg. In some aspects, the cephalexin can be administered in dosages of about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 950 mg, about 975 mg, about 1000 mg, about1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg.

[0164] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of doxycycline. In some aspects, the doxycycline can be orally administered in a dose of about 50 mg to about 500 mg. In some aspects, the doxycycline can be administered in dosages of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

[0165] In some aspects, the method of treating acne can comprise administering CTX and orally co-administering an effective amount of erythromycin. In some aspects, the erythromycin can be orally administered in a dose of about 50 mg to about 4000 mg. In some aspects, the erythromycin can be administered in dosages of about 500 mg to about 4000 mg. In some aspects, the erythromycin can be administered in dosages of about 200 mg to about 750 mg. In some aspects, the erythromycin can be administered in dosages of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, or about 4000 mg.

[0166] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of minocycline. In some aspects, the minocycline can be orally administered in a dose of about 50 mg to about 500 mg. In some aspects, the minocycline can be administered in dosages of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

[0167] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of tetracycline. In some aspects, the tetracycline can be orally administered in a dose of about 50 mg to about 2000 mg. In some aspects, the tetracycline can be administered in dosages of about 500 mg to about 2000 mg. In some aspects, the tetracycline can be administered in dosages of about 200 mg to about 750 mg. In some aspects, the tetracycline can be administered in dosages of about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg,about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg.

[0168] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of trimethoprim. In some aspects, the trimethoprim can be orally administered in a dose of about 50 mg to about 500 mg. In some aspects, the trimethoprim can be administered in dosages of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

[0169] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of sulfamethoxazole. In some aspects, the sulfamethoxazole can be orally administered in a dose of about 50 mg to about 1000 mg. In some aspects, the sulfamethoxazole can be administered in dosages of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

[0170] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a trimethoprim and sulfamethoxazole combination. In some aspects, the trimethoprim and sulfamethoxazole combination can be orally administered in a dosage of about 40 mg trimethoprim and about 200 mg sulfamethoxazole, about 160 mg trimethoprim and 800 mg sulfamethoxazole, or about 80 mg trimethoprim and 400 mg sulfamethoxazole.

[0171] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a hormonal agent selected from the group consisting of spironolactone, flutamide, cyproterone acetate, norethindrone, ethynodiol diacetate, levonorgestrel, desogestrel, gestodene, drospirenone, ethinyl estradiol, and combinations thereof. In some aspects, the hormonal agent can be orally administered in a cyclic protocol wherein the dosage regimen alternates between the administration of active and inactive dosages. In some aspects, an effective amount of more than one hormonal agent can be in a combined oral formulation. In some aspects, the effective amount of at least one hormonal agent can be in the form or a tablet.

[0172] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of spironolactone. In some aspects, the spironolactone can be orally administered in a dose of about 50 mg to about 500 mg. In some aspects, the spironolactone can be administered in dosages of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

[0173] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of flutamide. In some aspects, the flutamide can be orally administered in a dose of about 50 mg to about 600 mg. In some aspects, the flutamide can be administered in dosages of about 50 mg, about 55 mg, about 60 mg, about 70 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg.

[0174] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of cyproterone acetate. In some aspects, the cyproterone acetate can be orally administered in a dose of about 2 mg to about 200 mg. In some aspects, the cyproterone acetate can be administered in a dosage of about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg.

[0175] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of cyproterone acetate in combination with ethinyl estradiol. In some aspects, the cyproterone acetate can be orally administered in combination with about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, or about 0.07 mg of ethinyl estradiol.

[0176] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of norethindrone. In some aspects, the norethindrone can be orally administered in a dose of about 0.5 mg to about 20 mg. In some aspects, the norethindrone can be administered in a dosage of about 0.5 mg, about 0.75 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg.

[0177] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a combination of norethindrone and ethinyl estradiol. In some aspects, the norethindrone and ethinyl estradiol combination can be orally administered in a dosage of about 0.5 mg norethindrone acetate / 0.005 mg ethinyl estradiol or about 0.5 mg norethindrone acetate / 0.0025 mg ethinyl estradiol.

[0178] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of ethynodiol diacetate. In some aspects, the ethynodiol acetate can be administered in a dose of about 0.5 mg to about 5 mg. In some aspects, the ethynodiol diacetate can be orally administered in dosages of about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.5 mg, about 3 mg, or about 5 mg.

[0179] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a combination of ethynodiol diacetateand ethinyl estradiol. In some aspects, the ethynodiol diacetate and ethinyl estradiol combination can be orally administered in a dosage of about 1 mg ethynodiol diacetate / 35 mg ethinyl estradiol, about 1 mg ethynodiol diacetate / 50 mg ethinyl estradiol, or about 1 mg ethynodiol diacetate / 75 mg ethinyl estradiol.

[0180] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of levonorgestrel. In some aspects, the levonorgestrel can be orally administered in a dose of about 0.05 mg to about 5 mg. In some aspects, the levonorgestrel can be administered in dosages of about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, or about 5 mg.

[0181] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a combination of levonorgestrel and ethinyl estradiol. In some aspects, the levonorgestrel and ethinyl estradiol combination can be orally administered in a dosage of about 0.1 mg levonorgestrel / 0.02 mg ethinyl estradiol.

[0182] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of desogestrel in a dose of about 0.05 mg to about 5 mg. In some aspects, the desogestrel can be orally administered in dosages of about 0.05 mg, about 0.10 mg, about 0.15 mg, about 0.20 mg, about 0.25 mg, about 0.30 mg, about 0.40 mg, about 0.50 mg, about 0.60 mg, about 0.70 mg, about 0.75 mg, about 0.80 mg, about 0.90 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, or about 5.0 mg.

[0183] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a combination of desogestrel and ethinyl estradiol. In some aspects, the desogestrel and ethinyl estradiol combination can be orally administered in a dosage of about 0.15 mg desogestrel / 0.03 mg ethinyl estradiol, about 0.15 mg desogestrel / 0.02 mg ethinyl estradiol, about 0.10 mg desogestrel / 0.025 mg ethinyl estradiol, about0.125 mg desogestrel / 0.025 mg ethinyl estradiol, or about 0.15 mg desogestrel / 0.025 mg ethinyl estradiol.

[0184] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of gestodene. In some aspects, the gestodene can be orally administered in a dosage of about 0.020 mg to about 0.10 mg. In some aspects, the gestodene can be administered in a dosage of about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, about 0.060 mg, about 0.065 mg, about 0.070 mg, about 0.075 mg, or about 0.080 mg, about 0.085 mg, about 0.090 mg, about 0.095 mg, or about 0.10 mg.

[0185] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a combination of gestodene and ethinyl estradiol. In some aspects, the gestodene and ethinyl estradiol combination can be orally administered in a dosage of about 0.075 mg gestodene / about 0.020 mg ethinyl estradiol, about 0.075 mg gestodene / about 0.030 mg ethinyl estradiol, or about 0.060 mg gestodene / about 0.015 mg ethinyl estradiol.

[0186] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of drospirenone. In some aspects, the drospirenone can be orally administered in a dose of about 0.05 mg to about 10 mg. In some aspects, the drospirenone can be administered in dosages of about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.

[0187] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a combination of drospirenone and ethinyl estradiol. In some aspects, the drospirenone and ethinyl estradiol combination can be orally administered in a dosage of about 3.0 mg drospirenone / 0.020 mg ethinyl estradiol or about 3.0 mg drospirenone / 0.030 mg ethinyl estradiol.

[0188] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of ethinyl estradiol. In some aspects, the ethinyl estradiol can be orally administered in a dosage of about 0.020 mg to about 0.060 mg daily. In some aspects, the ethinyl estradiol can be administered in a dosage of about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, or about 0.060 mg. In some aspects, an effective amount of ethinyl estradiol can be combined with an effective amount of another hormonal agent.

[0189] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a retinoid. In some aspects, the retinoid can be isotretinoin. In some aspects, the isotretinoin can be orally administered in a dosage of about 0.25 mg / kg / day to about 2.5 mg / kg / day. In some aspects, the isotretinoin can be administered in a dosage of about 0.25 mg / kg / day, about 0.30 mg / kg / day, about 0.35 mg / kg / day, about 0.40 mg / kg / day, about 0.45 mg / kg / day, about 0.50 mg / kg / day, about 0.55 mg / kg / day, about 0.60 mg / kg / day, about 0.65 mg / kg / day, about 0.70 mg / kg / day, about 0.75 mg / kg / day, about 0.80 mg / kg / day, about 0.85 mg / kg / day, about 0.90 mg / kg / day, about 0.95 mg / kg / day, about 1.0 mg / kg / day, about 1.25 mg / kg / day, about 1.50 mg / kg / day, about 1.75 mg / kg / day, about 2.0 mg / kg / day, about 2.25 mg / kg / day, or about 2.50 mg / kg / day.

[0190] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of a dietary supplement. In some aspects, the dietary supplement can be selected from the group consisting of vitamin C, vitamin D, vitamin E, vitamin K, biotin, niacin, zinc, selenium, iron, copper, omega-3 fatty acids, and combinations thereof.

[0191] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of vitamin C. In some aspects, the vitamin C can be orally administered in a dose of about 50 mg to about 2000 mg. In some aspects, the vitamin C can be administered in dosages of about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg,about 925 mg, about 950 mg, about 975 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg.

[0192] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of vitamin D. In some aspects, the vitamin D can be orally administered in a dose of about 0.010 mg to about 0.060 mg. In some aspects, the vitamin D can be administered in dosages of about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, or about 0.060 mg.

[0193] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of vitamin E. In some aspects, the vitamin E can be administered in a dose of about 0.010 mg to about 0.060 mg. In some aspects, the vitamin E can be orally administered in dosages of about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, or about 0.060 mg.

[0194] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of vitamin K. In some aspects, the vitamin K can be orally administered in a dose of about 0.010 mg to about 0.150 mg. In some aspects, the vitamin E can be administered in dosages of about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, about 0.060 mg, about 0.065 mg, about 0.070 mg, about 0.075 mg, about 0.080 mg, about 0.085 mg, about 0.090 mg, about 0.100 mg, about 0.110 mg, about 0.120 mg, about 0.130 mg, about 0.140 mg, or about 0.150 mg.

[0195] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of biotin. In some aspects, the biotincan be orally administered in a dose of about 0.010 mg to about 0.150 mg. In some aspects, the biotin can be administered in dosages of about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, about 0.060 mg, about 0.065 mg, about 0.070 mg, about 0.075 mg, about 0.080 mg, about 0.085 mg, about 0.090 mg, about 0.100 mg, about 0.110 mg, about 0.120 mg, about 0.130 mg, about 0.140 mg, or about 0.150 mg.

[0196] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of niacin. In some aspects, the niacin can be orally administered in a dose of about 50 mg to about 2000 mg. In some aspects, the niacin can be administered in dosages of about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about1950 mg, about 1975 mg, or about 2000 mg.

[0197] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of zinc. In some aspects, the zinc can be orally administered in a dose of about 2 mg to about 20 mg. In some aspects, the zinc can be administered in dosages of about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.

[0198] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of selenium. In some aspects, the selenium can be orally administered in a dose of about 0.02 mg to about 0.40 mg. In some aspects, the selenium can be administered in dosages of about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.10 mg, about 0.11 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.20 mg, about 0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg, about 0.27 mg, about 0.28 mg, about 0.29 mg, about 0.30 mg, about 0.310 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about 0.35 mg, about 0.36 mg, about 0.37 mg, about 0.38 mg, about 0.39 mg, or about 0.40 mg.

[0199] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of iron. In some aspects, the iron can be orally administered in a dosage of about 5 mg to about 28 mg daily. In some aspects, the iron can be administered in a dosage of about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, or about 28 mg.

[0200] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of copper. In some aspects, the copper can be orally administered in a dose of about 1 mg to about 4 mg. In some aspects, the zinc can be administered in dosages of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg.

[0201] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering an effective amount of one or more omega-3 fatty acids. In some aspects, the omega-3 fatty acid can be contained within an oil selected from the group consisting of fish, krill, cod liver, and algal oils. In some aspects, the omega-3 fatty acid can be orally administered in a dose of about 200 mg to about 4000 mg. In some aspects, the omega-3 fatty acid can be administered in a dosage of about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, or about 4000 mg.

[0202] In some aspects, the method of treating acne can comprise administering CTX topically and orally co-administering a combination including an effective amount of more than one dietary supplement as discussed herein in the form of a multivitamin or combined dietary formulation.

[0203] Suitable oral secondary anti-acne agents include, but are not limited to ABSORICA (10, 20, 30, or 40 mg isotretinoin), ACCUTANE (10, 20, 30, or 40 mg isotretinoin), ADOXA (75 or 150 mg doxycycline hy elate), ALDACTONE (25, 50, or 100 mg spironolactone), BACTRIM(400 mg sulfamethoxazole / 80 mg trimethoprim or 800 mg sulfamethoxazole / 160 mg trimethoprim), BEY AZ (3 mg drospirenone / 20 mcg ethinyl estradiol / 0.451 mg levomefolate), CARSPIR (25 mg spironolactone / 5 mL suspension), CLARA VIS (10, 20, 30, or 40 mg isotretinoin), CLEOCIN (75, 150, or 300 mg clindamycin hydrochloride), DORYX (75 or 100 mg doxycycline hyclate), ERYTHROCIN (250 mg erythromycin), ESTROSTEP ( 1 mg norethindrone acetate / 20 mcg ethinyl estradiol), EULEXIN (125 mg flutamide), KEFLEX® (250 or 500 mg cephalexin), MINOCIN (50, 100 mg minocycline hydrochloride), MYORISAN (10, 20, 30, or 40 mg isotretinoin), ORTHO TRI-CYCLEN (0.180 mg norgestimate / 0.035 mg ethinyl estradiol), PRIMSOL (50 mg trimethoprim hydrochloride / 5 mL suspension), SEPTRA (400 mg sulfamethoxazole / 80 mg trimethoprim or 800 mg sulfamethoxazole / 160 mg trimethoprim), SOLOD YN (45, 65, 90, 115, or 135 mg minocycline hydrochloride), SOTRET (10, 20, 30, or 40 mg isotretinoin), SULFATRIM (200 mg sulfamethoxazole / 40 mg trimethoprim per 5 mL), YAZ (0.02 mg ethinylestradiol / 3 mg drospirenone), ZENATANE (10, 20, 30, or 40 mg isotretinoin), and ZITHROMAX (250 mg, 300 mg, 600 mg, 900 mg, or 1200 mg azithromycin).

[0204] Example 1: Binary Combination topical composition with cortexolone-17a- propionate.

[0205] A combination of cortexolone-17a-propionate (1 wt% (w / w)) and benzoyl peroxide is formulated as a topical treatment, as described in Table 1.Table 1q.s. - quantum satis

[0206] Example 2: Triple Combination topical composition with cortexolone-17a- propionate.

[0207] A combination of cortexolone-17a-propionate (1 wt% (w / w)), clindamycin phosphate (1.2%), and adapalene (0.15%), is formulated as a topical treatment, as described in Table 2. Table 2q.s. - quantum satis

[0208] Example 3: Quadruple Combination topical composition with cortexolone-17a- propionate.

[0209] A combination of cortexolone-17a-propionate (1 wt% (w / w)), clindamycin phosphate (1.2%), adapalene (0.15%), and benzoyl peroxide (3.1%) is formulated as a topical treatment, as described in Table 3.Table 3q.s. - quantum satis

[0210] 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.

[0211] 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.

[0212] All patents, patent applications, and other references noted or referenced in this application are hereby incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing acne comprising topically administering to a subject in need thereof an effective amount of cortexolone-17a-propionate in combination with an effective amount of one or more secondary anti-acne agents.2 The method of claim 1, wherein the one or more secondary anti -acne agents is an oral agent.3 The method of claim 2, wherein the oral agent is an antibiotic, a hormonal agent, a retinoid, a dietary supplement, or a combination thereof.4 The method of claim 3, wherein the antibiotic is amoxicillin, azithromycin, cephalexin, doxycycline, erythromycin, minocycline, tetracycline, trimethoprim, sulfamethoxazole, or a combination thereof.5 The method of claim 3 or 4, wherein the hormonal agent is flutamide, spironolactone, cyproterone acetate, norethindrone, ethynodiol diacetate, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, ethinyl estradiol, or a combination thereof.6 The method of any one of claims 3-5, wherein the retinoid is isotretinoin.7 The method of any one of claims 3-6, wherein the dietary supplement is vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, biotin, niacin, zinc, selenium, iron, copper, an omega-3 fatty acid, or a combination thereof.8 The method of claim 1, wherein the one or more secondary anti-acne agents is one or more secondary topical anti-acne agents.9 The method of claim 8, wherein the one or more secondary topical anti-acne agents and cortexolone-17a-propionate are provided in a topical composition comprising the cortexolone-17a-propionate, the one or more secondary anti-acne agents, and at least one pharmaceutically acceptable carrier.10 The method of claim 9, wherein the topical composition is a gel, cream, lotion, solution, suspension, foam, ointment, wash-off agent, hydrogel patch, microemulsion, or pledget.

11. The method of claim 9 or 10, wherein the topical composition is pre-prepared.

12. The method of claim 8, wherein the one or more secondary topical anti-acne agents and cortexolone-17a-propionate are provided in separate topical compositions, each comprising at least one active agent and at least one pharmaceutically acceptable carrier.

13. The method of claim 12, wherein the separate topical compositions are combined just prior to use.

14. The method of claim 12, wherein the separate topical compositions are administered sequentially.

15. The method of claim any one of claims 12-14, wherein each topical composition is independently selected from a gel, cream, lotion, solution, suspension, foam, ointment, wash- off agent, hydrogel patch, microemulsion, and pledget.

16. The method of any one of claims 8-15, wherein the at least one secondary topical anti -acne agent is an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, urea, or a combination thereof.

17. The method of claim 16, wherein the antiseptic is benzoyl peroxide; the antibiotic is clindamycin, erythromycin, nadifloxacin, metronidazole, mafenide, minocycline, sodium sulfacetamide, diaminodiphenyl sulfone, or a combination thereof; the retinoid is tretinoin, adapalene, tazarotene, trifarotene, or a combination thereof; the antioxidant is sodium L-ascorbyl-2 -phosphate; the organic acid is resorcinol, azelaic acid, salicylic acid, glycolic acid, or a combination thereof; the corticosteroid is hydrocortisone, triamcinolone acetonide, or a combination thereof; and the antiparasitic is ivermectin.

18. The method of any one of claims 1-17, wherein the acne is acne vulgaris of mild, moderate, or severe grade.

19. The method of claim 18, wherein the acne vulgaris is facial acne vulgaris.

20. A topical composition comprising cortexolone-17a-propionate, at least one topical anti-acne agent, and a pharmaceutically acceptable carrier.

21. The topical composition of claim 20, wherein the topical anti-acne agent is an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, urea, or a combination thereof.

22. The topical composition of claim 21, wherein the antiseptic is benzoyl peroxide.

23. The topical composition of claim 21 or 22, wherein the antibiotic is clindamycin, erythromycin, nadifloxacin, metronidazole, mafenide, minocycline, sodium sulfacetamide, diaminodiphenyl sulfone, or a combination thereof.

24. The topical composition of any one of claims 21-23, wherein the retinoid is tretinoin, adapalene, tazarotene, trifarotene, or a combination thereof.

25. The topical composition of any one of claims 21-24, wherein the antioxidant is sodium L- ascorbyl-2-phosphate or niacinamide.

26. The topical composition of any one of claims 21-25, wherein the organic acid is resorcinol, azelaic acid, salicylic acid, glycolic acid, or a combination thereof.

27. The topical composition of any one of claims 21-26, wherein the corticosteroid is hydrocortisone, triamcinolone acetonide, or a combination thereof.

28. The topical composition of any one of claims 21-27, wherein the antiparasitic is ivermectin.

29. The topical composition of any one of claims 20-28, wherein the composition is in the form of cream, lotion, gel, ointment, mousse, spray solution, suspension, emulsion, wash-off agent, patch, or pledget.

30. Cortexolone-17a-propionate in combination with one or more secondary anti-acne agents for use in the treatment or prevention of acne, characterized in that they are administered topically to a subject.

31. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claim 30, wherein the one or more secondary anti-acne agents is an oral agent.

32. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claim 31, wherein the oral agent is an antibiotic, a hormonal agent, a retinoid, a dietary supplement, or a combination thereof.

33. Cortexolone-17a-propionate in combination with one or more secondary anti-acne agents for use according to claim 32, wherein the antibiotic is amoxicillin, azithromycin, cephalexin, doxycycline, erythromycin, minocycline, tetracycline, trimethoprim, sulfamethoxazole, or a combination thereof.

34. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claim 32, wherein the hormonal agent is flutamide, spironolactone, cyproterone acetate, norethindrone, ethynodiol diacetate, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, ethinyl estradiol, or a combination thereof.

35. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claim 32, wherein the retinoid is isotretinoin.

36. Cortexolone-17a-propionate in combination with one or more secondary anti-acne agents for use according to claim 32, wherein the dietary supplement is vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, biotin, niacin, zinc, selenium, iron, copper, an omega-3 fatty acid, or a combination thereof.

37. Cortexolone-17a-propionate in combination with one or more secondary anti-acne agents for use according to claim 30, wherein the one or more secondary anti-acne agents is one or more secondary topical anti-acne agents.

38. Cortexolone-17a-propionate in combination with one or more secondary anti-acne agents for use according to claims 30-37, wherein the one or more secondary topical anti-acne agents and cortexolone-17a-propionate are provided in a topical composition comprising the cortexolone-17a-propionate, the one or more secondary anti-acne agents, and at least one pharmaceutically acceptable carrier.

39. Cortexolone-17a-propionate in combination with one or more secondary anti-acne agents for use according to claims 30-38, wherein the topical composition is a gel, cream, lotion, solution, suspension, foam, ointment, wash-off agent, hydrogel patch, microemulsion, or pledget.

40. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claim 39, wherein the topical composition is pre-prepared.

41. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claims 30-40, wherein the one or more secondary topical anti-acne agents and cortexolone-17a-propionate are provided in separate topical compositions, each comprising at least one active agent and at least one pharmaceutically acceptable carrier.

42. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claim 41, wherein the separate topical compositions are combined just prior to use.

43. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claims 41 or 42, wherein the separate topical compositions are administered sequentially.

44. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claims 41- 43, wherein each topical composition is independently selected from a gel, cream, lotion, solution, suspension, foam, ointment, wash-off agent, hydrogel patch, microemulsion, and pledget.

45. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claims 37-44, wherein the at least one secondary topical anti-acne agent is an antiseptic, an antibiotic, a retinoid, an antioxidant, an organic acid, a corticosteroid, an antiparasitic agent, sulfur, urea, or a combination thereof.

46. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to claim 45, wherein the antiseptic is benzoyl peroxide; the antibiotic is clindamycin, erythromycin, nadifloxacin, metronidazole, mafenide, minocycline, sodium sulfacetamide, diaminodiphenyl sulfone, or a combination thereof; the retinoid is tretinoin, adapalene, tazarotene, trifarotene, or a combination thereof; the antioxidant is sodium L-ascorbyl-2 -phosphate; the organic acid is resorcinol, azelaic acid, salicylic acid, glycolic acid, or a combination thereof; the corticosteroid is hydrocortisone, triamcinolone acetonide, or a combination thereof; and the antiparasitic is ivermectin.

47. Cortexolone-17a-propionate in combination with one or more secondary anti -acne agents for use according to any one of claims 30-46, wherein the acne is acne vulgaris of mild, moderate, or severe grade.

48. Cortexolone-17a-propionate in combination with one or more secondary anti-acne agents for use according to claim 47, wherein the acne vulgaris is facial acne vulgaris.