Compositions and formulations for topical use of AKT inhibitors for the prevention, treatment, and amelioration of skin disorders, diseases, and disorders - Patents.com

Abstract

The present specification provides a compound having the structure (1H tautomer) and / or (2H tautomer), or a pharma- ceutically acceptable salt thereof, and a) C 2-6 and one or more excipients selected from (a)-(g): alcohol, b) an organic solvent and / or a penetration enhancer, c) an antioxidant, d) a preservative, e) water, f) a pH adjuster, and g) a gelling agent; 2-6 The alcohol, organic solvent and / or penetration enhancer, antioxidant, preservative, water, pH adjuster, and gelling agent are defined and described herein. Methods of treating skin diseases, illnesses, or disorders, specifically seborrheic keratosis, with the above compositions are also provided herein.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 244,353, filed September 15, 2021, U.S. Provisional Application No. 63 / 344,440, filed May 20, 2022, and U.S. Provisional Application No. 63 / 400,014, filed August 22, 2022, all of which are incorporated by reference in their entireties herein. [Background technology]

[0002] Seborrheic keratosis (SK) is a benign skin tumor that generally develops as an individual ages, most commonly in individuals over the age of 50. The tumor affects over 80 million Americans and, while not cancerous, can be bothersome or cosmetically undesirable. Typically, SK is found on the head, neck, or trunk and can be found in several different forms, such as raised, flat, scaly, waxy, and light tan to black in color. SK can be anywhere from a few millimeters to several centimeters in size and can be seen as a single occurrence or multiple lesions in one individual. SK is the result of mutation and clonal expansion of keratinocytes that proliferate in the spinous layer of the epidermis. Although they are not malignant, SKs share many characteristics with malignant tumors, with over 80% of SKs harboring cancer gene mutations. Many of these mutations are in genes involved in tumor growth, keratinocyte differentiation, and apoptosis or cell death.

[0003] Despite resulting from clonal mutations, unlike skin cancer, SK has no malignant potential because it has normal activity of the p53 tumor suppressor gene. Akt kinase, also known as protein kinase B (PKB), is the central node of the tumorigenic / tumor suppressive pathways, tyrosine kinase / PI3K / Akt / mTOR and Ras / mitogen-activated protein kinase pathways. Akt is a family of serine / threonine kinases consisting of three isoforms named Akt1, Akt2, or Akt3. Akt1 can inhibit apoptotic machinery, participate in cell survival pathways, promote protein synthesis, and is important in cellular pathways that promote tissue growth. Increased Akt activity can block the p53 pathway, preventing apoptosis or normal cell death while promoting unregulated growth that leads to tumors. SK shows increased levels of Akt phosphorylation, indicating that Akt is more active in these cells, resulting in decreased cell death and increased growth and proliferation of benign tumorigenic cells. Summary of the Invention

[0004] Current methods for treating SK include superficial scraping, freezing, or shaving or tangential excision, or chemical ablation of SK using high-concentration hydrogen peroxide (40% w / w), which can cause skin irritation and damage to healthy keratinocytes. An alternative strategy for treating SK is to target and inhibit Akt, a pathway that subsequently regulates tumor development in SK.

[0005] The following formula:

[0006] [ka] The Akt inhibitor, represented by the formula: (herein referred to as Compound 1), and its pharma- ceutically acceptable salts, are particularly difficult to solubilize into compositions that are easily administered, therapeutically effective, and non-irritating to the skin.

[0007] Common solvents used to formulate other small molecule compounds, such as light mineral oil or water, do not solubilize Compound 1 for use in clinically acceptable compositions. Thus, there is an urgent need to develop topical compositions containing Compound 1 that can be delivered topically with reduced skin irritation to treat skin disorders such as seborrheic keratosis.

[0008] In a first aspect, the present disclosure provides a topical pharmaceutical composition. The topical pharmaceutical composition has the structure

[0009] [ka] or a pharma- ceutically acceptable salt or tautomer thereof; a)C 2-6 alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants; d) preservatives; e) water; f) pH adjusters, and g) gelling agents, and one or more excipients selected from (a) to (g). Here, C 2-6Alcohol, organic solvent and / or penetration enhancer, antioxidant, preservative, water, pH adjuster, and gelling agent are defined and described herein. In some embodiments, the composition may be formulated with about 0.01% to about 10%, about 0.01%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 5%, about 0.01%, or about 5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 10%, about 0.1%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0010] In a second aspect, the present invention provides a topical pharmaceutical composition, the composition comprising the structure

[0011] [ka] or a pharma- ceutically acceptable salt or tautomer thereof, and five or more excipients including ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, water, hydroxypropylcellulose, optionally an antioxidant, and optionally a preservative, where the antioxidant and preservative are as defined and described herein. In some embodiments, the composition may be formulated with about 0.01% to about 10%, about 0.01%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 5%, about 0.01%, or about 5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 10%, about 0.1%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0012] In a third aspect, the disclosure provides a method of treating a skin disease, condition, or disorder in a subject in need of such treatment, the method comprising administering to the subject a composition described herein. In some embodiments, the composition may be formulated with about 0.01% to about 10%, about 0.01%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 5%, about 0.01%, or about 5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 10%, about 0.1%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0013] In a fourth aspect, the present disclosure provides a kit comprising a topical pharmaceutical composition as described herein in a tube, a flexible aluminum tube, or a laminated plastic tube, together with instructions for use.

[0014] In a further aspect, the present disclosure provides a method of treating a cutaneous lesion, the method comprising: (i) Structure

[0015] [ka] or a salt thereof, and / or (ii) Structure

[0016] [ka] or a salt thereof, wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.1% to 1% by weight, or the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%, or 0.01% to 5%.

[0017] In some embodiments, the skin lesion is a keratosis. In some embodiments, the keratosis is a seborrheic keratosis. In some embodiments, the composition is administered once, twice, three times, or four times per day. In some embodiments, the composition is administered once, twice, three times, or four times per day for about 14 days to about 28 days. In some embodiments, the composition is administered once, twice, three times, four times, or five times per week. In some embodiments, the composition is administered in a cycle that includes administration 1-4 times daily for about 1-7 days, followed by about 1-7 days of no administration. In some embodiments, the cycle includes administration twice daily for about 4 days, followed by about 4 days of no administration. In some embodiments, the cycle is repeated about 2-10 times. In some embodiments, the cycle is repeated about 7 times. In some embodiments, the composition is administered at least once per day (e.g., about once or twice per day) for about 28 days. In some embodiments, the composition is administered once per day, three times per week. In some embodiments, the composition is administered for a total period of about 1, 2, 3, 4, 5, or 6 months.

[0018] In some embodiments, the method further comprises occlusion of the skin lesion.

[0019] In some embodiments, the skin lesion is present in a human subject. In some embodiments, the skin lesion is present on the face, trunk, or limbs of the human subject, or a combination thereof. In some embodiments, treating comprises an improvement of 1 or more grades in Physician's Lesion Assessment (PLA) score compared to before administering the composition. In some embodiments, the PLA score before administration is at least 2.

[0020] In some embodiments, treating comprises reducing the thickness of the skin lesion to less than 1 mm. In some embodiments, the thickness of the skin lesion before administration is 1 mm or more. In some embodiments, the length of the skin lesion before administration is 1 mm to 15 mm, and the width of the skin lesion before administration is 1 mm to 15 mm.

[0021] In some embodiments, the treating comprises inducing apoptosis of keratinocytes in the skin lesion.

[0022] In some embodiments, apoptosis is measured by a TUNEL assay.

[0023] In some embodiments, the composition is a gel formulation. In some embodiments, the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof.

[0024] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (i) Structure

[0025] [ka] or a salt thereof, and / or (ii) Structure

[0026] [ka] or a salt thereof, providing a composition comprising wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.1% to 1% by weight, or the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%, or 0.01% to 5%.

[0027] In some embodiments, the composition is a gel formulation.In some embodiments, the composition comprises alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof.In some embodiments, the composition further comprises a preservative.In some embodiments, the composition further comprises a gelling agent.

[0028] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (i) Structure

[0029] [ka] or a salt thereof, and / or (ii) Structure

[0030] [ka] or a salt thereof; And, a) alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants; d) preservatives, and e) gelling agents, and one or more excipients selected from (a) to (e).

[0031] In any of the aspects and embodiments described above and below, the composition may include an alcohol, an organic solvent and / or a penetration enhancer, an antioxidant, a preservative or a gelling agent, or a combination of two or more thereof. The composition may be administered in the manner described herein.

[0032] In some embodiments, the composition comprises an alcohol. In some embodiments, the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. In some embodiments, the alcohol comprises C 2-6 In some embodiments, C 2-6 The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, or a combination or two or more thereof. 2-6 The alcohol comprises ethanol. In some embodiments, 2-6 The alcohol is present in an amount of 1% to 30%, 5% to 30%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight of the composition, in some embodiments, the total amount of alcohol present in the composition is about 1% to about 80% by weight of the composition.

[0033] In some embodiments, the alcohol comprises an organic solvent and / or a penetration enhancer.

[0034] In some embodiments, the composition comprises an organic solvent and / or a penetration enhancer. In some embodiments, the organic solvent and / or the penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester, or fatty ether, or a combination of two or more thereof. 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol and the polyethylene glycol is PEG200, PEG400, or a combination thereof. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer is present in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0035] In some embodiments, the composition includes an antioxidant. In some embodiments, the antioxidant includes butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant includes butylated hydroxytoluene. In some embodiments, the antioxidant is present in an amount of 0.01% to 5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0036] In some embodiments, the composition comprises a preservative. In some embodiments, the preservative comprises phenoxyethanol. In some embodiments, the preservative is present in an amount of 0.5% to 5.0%, 0.5% to 2%, or about 1% by weight of the composition. In some embodiments, the composition further comprises water in an amount of 0% to 25%, 5% to 25%, 10% to 25%, 15% to 25%, or about 20% by weight of the composition.

[0037] In some embodiments, the composition comprises a gelling agent. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. In some embodiments, the gelling agent is present in an amount of 0.5% to 5% by weight, or about 2% by weight of the composition.

[0038] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose. In some embodiments, the ethanol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, the propylene glycol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, the 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% or about 2% by weight of the composition. In some embodiments, ethanol is present in an amount of about 15% by weight, propylene glycol is present in an amount of about 15% by weight, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight, and hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight of the composition.

[0039] In some embodiments, the composition further comprises an antioxidant and / or a preservative. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof, and the preservative comprises phenoxyethanol. In some embodiments, the antioxidant comprises butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight or about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the antioxidant comprises butylated hydroxytoluene in an amount of about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of about 1% by weight of the composition.

[0040] In some embodiments, the composition comprises a pH adjuster, optionally an acid, and further optionally citric acid.

[0041] In some embodiments, the propylene glycol is super refined propylene glycol.

[0042] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of >99.90%.

[0043] In some embodiments, the total amount of (i), (ii), or (i) and (ii) present in the composition is between 0.01% and 10%, between 0.1% and 10.0%, between 0.5% and 5%, between 0.5% and 2%, between 0.1% and 1%, or about 1% or about 0.1% by weight of the composition.

[0044] In some embodiments, the total amount of (i), (ii), or (i) and (ii) is about 1% by weight of the composition.

[0045] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (i) Structure

[0046] [ka] or a salt thereof, and / or (ii) Structure

[0047] [ka] or a salt thereof, and ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropylcellulose, and optionally an antioxidant, and optionally a preservative.

[0048] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0049] In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0050] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a topical composition. In some embodiments, the composition is in the form of a gel, ointment, lotion, foam, or emollient. In some embodiments, the composition is a component of a patch, tape, film, wafer, or bandage.

[0051] In one aspect, the disclosure provides a method of treating a skin disease, condition, or disorder in a subject in need of such treatment, comprising administering to the subject a composition described herein.

[0052] In some embodiments, the skin disease, condition, or disorder is seborrheic keratosis, a benign tumor, a malignant tumor, a parasite, a skin virus, an immune disease or disorder, or a bacterial, fungal, or microbial infection, hi some embodiments, the skin disease, condition, or disorder is seborrheic keratosis.In some embodiments, the skin disease, condition, or disorder is a benign tumor, the benign tumor being a benign vascular tumor, a benign fibrotic tumor, a benign adipocyte tumor, a benign sebaceous tumor, a benign epidermal tumor, a benign melanocytic lesion, or a benign neural tumor; and the skin disease, condition, or disorder is a malignant tumor, the malignant tumor being a malignant melanocytic tumor, a malignant epidermal tumor, a malignant vascular tumor, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous tumor, or a benign neural tumor. the skin disease, illness or disorder is a parasite, the parasite being Trypanasoma or Leishmania; the skin disease, illness or disorder is a virus, the virus being molluscum contagiosum virus or human papilloma virus; the skin disease, illness or disorder is a bacterial, fungal or microbial infection, the bacterial, fungal or microbial infection being otitis media, Staphylococcus aureus infection, Mycobacterium infection, Porphyromonas infection, Salmonella infection, Chlamydia infection, tuberculosis, gingivitis or periodontal disease.

[0053] In some embodiments, the composition is applied topically to the head, scalp, face, ear (or both ears), neck, chest, back, inframammary region, arm (or both arms), leg (or both legs), interdental area, hand (or both hands), foot or feet, or groin. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered for about 2 weeks to about 8 weeks. In some embodiments, the composition is administered for about 4 weeks.

[0054] In some embodiments, the composition is administered in a pulsed cycle, hi some embodiments, the composition is administered under occlusion.

[0055] In some embodiments, the skin disease, condition, or disorder is a skin pigmentation disorder, hi some embodiments, the skin pigmentation disorder is Acanthosis nigricans.

[0056] In another aspect, the disclosure provides a kit comprising a topical pharmaceutical composition in a tube, a flexible aluminum tube, or a laminated plastic tube, together with instructions for use. [Brief description of the drawings]

[0057] [Figure 1A] FIG. 1 shows the local skin tolerability of the four compositions of Example 2, including Compound 1 and their respective placebos, after dermal administration once daily or once every other day for 14 days to Gottingen Minipigs, as measured by erythema and edema scores. [Figure 1B] FIG. 1 shows the local skin tolerability of the four compositions of Example 2, including Compound 1 and the respective placebos, after dermal administration once daily or every other day to Göttingen minipigs for 14 days, as measured by erythema and edema scores. [Figure 1C] FIG. 1 shows the local skin tolerability of the four compositions of Example 2, including Compound 1 and the respective placebos, after dermal administration once daily or every other day to Göttingen minipigs for 14 days, as measured by erythema and edema scores. [Figure 1D] FIG. 1 shows the local skin tolerability of the four compositions of Example 2, including Compound 1 and the respective placebos, after dermal administration once daily or every other day to Göttingen minipigs for 14 days, as measured by erythema and edema scores. [Diagram 2] 1 shows explant TUNEL assay images. TUNEL (brown) shows increased apoptosis in human seborrheic keratinocytes treated with the composition of Example 5 containing 1% Compound 1 compared to untreated and vehicle-treated explants. Top row: 4X magnification, bottom row: 10X magnification. [Figure 3A] Time-to-event KM plots for a 1-point PLA score reduction for lesions during the first 8 weeks post-treatment, stratified by cohort. For cohort 1, the median duration of response to a 1-point PLA reduction is 42 days (28-42 days, 95% CI). For cohorts 2 and 3, the median duration of response to a 1-point PLA reduction is 21 days (cohort 2 95% CI 21-35 days, cohort 3 95% CI 21-56 days). Censoring time is set to the last visit. [Figure 3B] Time-to-event KM plots for lesions achieving a 1-point PLA score reduction across all cohorts during the first 8 weeks after treatment. For all cohorts combined, the median duration of response to a 1-point PLA reduction was 21 days (21-35 days, 95% CI). [Figure 3C]Time-to-event KM plot of time to PLA score reduction of 1 point for lesions during the first 8 weeks after treatment. For lesions with PLA baseline=2, median duration of response to PLA reduction of 1 point is 28 days (21-42 days, 95% CI). For lesions with PLA baseline=3, median duration of response to PLA reduction of 1 point is 21 days (7-42 days, 95% CI). [Figure 4A] Time-to-event KM plot for lesions achieving a 2-point PLA score reduction during the first 8 weeks post-treatment, stratified by cohort. For cohort 1, median duration of response to a 2-point PLA reduction is 84 days (84-84 days, 95% CI). For cohort 2, median duration of response to a 2-point PLA reduction is 63 days (42-98 days, 95% CI). For cohort 3, median duration of response to a 2-point PLA reduction is 98 days (56-98 days, 95% CI). Censoring time is set to the last visit. [Figure 4B] Time-to-event KM plot for lesions achieving a 2-point PLA score reduction in all cohorts during the first 8 weeks after treatment. For all cohorts combined, the median duration of response to a 2-point PLA reduction was 84 days (56-98 days, 95% CI). [Figure 4C] Time-to-event KM plot for lesions achieving a 2-point PLA score reduction during the first 8 weeks after treatment. For lesions with PLA baseline = 2, the median duration of response to a 2-point PLA reduction is 84 days (70-98 days, 95% CI). For lesions with PLA baseline = 3, the median duration of response to a 2-point PLA reduction is 56 days (28-56 days, 95% CI). [Figure 5A] Time-to-event KM plot for lesion PLA score reduction to 0 8 weeks after treatment, stratified by cohort. For cohort 1, median response duration is ≥84 days. For cohort 2, median response duration is 70 days (56-98 days, 95% CI). For cohort 3, median response time is ≥98 days. Censoring time is set to last visit. [Figure 5B] Time-to-event KM plot for lesion PLA score reduction to 0. For all cohorts, the overall median duration of response was ≥ 84 days. [Figure 5C] Time-to-event KM plot for lesions decreasing in PLA score to 0. For lesions with PLA baseline=2, median duration of response is 84 days (70-98 days, 95% CI) and for lesions with PLA baseline=3, median duration of response is 84 days (56-98 days, 95% CI). [Figure 6] Representative photographs show the response of Composition Ex.5-Compound 1 to SK (14 days BID) in cohort 1 and SK (28 days BID) in background lentigo in cohort 2, respectively. [Figure 7] Time-to-event KM plot for patients achieving a 1-point decrease in PLA score during the first 28 days of treatment, stratified by cohort (0.1% face, 1% face, and 1% torso three times per week). Detailed Description of the Invention

[0058] General In various aspects, provided herein are compositions comprising Compound 1 (as an Akt inhibitor), or a salt thereof, and methods of using these compositions to treat skin diseases, conditions, or disorders. The compositions can be administered topically, thereby treating skin diseases, conditions, or disorders. Skin diseases, conditions, or disorders include any one of seborrheic keratosis, benign tumors, malignant tumors, parasites, skin viruses, immune diseases or disorders, and bacterial, fungal, or microbial infections. In particular, the topical compositions are useful for treating seborrheic keratosis.

[0059] definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0060] An "alcohol" is an alkyl group, as defined herein, having a hydroxy group attached to a carbon in the chain (e.g., C 2-6 For example, alcohols useful in the present invention include, but are not limited to, ethanol, benzyl alcohol, propanol, isopropanol, butanol, isobutanol, tert-butanol, pentanol, and hexanol, among others. The alcohols useful in the present invention are fully saturated. In some embodiments, the alcohol is C 2-6 It's alcohol.

[0061] "Alkylene glycol" refers to a compound having the formula H-[O-alkylene]-OH, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, alkylene glycol is C 2-6 In some embodiments, C is an alkylene glycol. 2-6 The alkylene glycol is propylene glycol (1,2-propanediol). In some embodiments, the glycols are butylene glycol and hexylene glycol.

[0062] "Di-alkylene glycol" refers to a compound having the formula HO-(alkylene-O)2-H), where the alkylene group has 2-6, 2-4, or 2-3 carbon atoms. In some embodiments, the dialkylene glycol is di-(C 2-6 alkylene) glycol. In some embodiments, di-(C 2-6 The alkylene) glycol is dipropylene glycol. Dipropylene glycol can include one or more isomers, such as 4-oxa-2,6-heptanediol, 2-(2-hydroxy-propoxy)-propan-1-ol, 2-(2-hydroxy-1-methyl-ethoxy)-propan-1-ol, and 3,3'-oxybis(propan-1-ol).

[0063] "Polyethylene glycol" is a compound that varies with the subscript "n": HO-(CH2CH2O). n It refers to a polymer having the formula -OH. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., methyl group. Also suitable are derivatives of polyethylene glycol having esterifiable carboxy groups. Polyethylene glycols useful in the present invention may be polymers of any chain length or molecular weight and may include branching. In some embodiments, the PEG is a methoxy PEG (macrogol monomethyl ether or polyethylene glycol monomethyl ether). In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 9,000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 5,000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, PEG 200, PEG 300, PEG 400, PEG 600, and PEG 900. The number following the "PEG" in the name refers to the average molecular weight of the polymer.

[0064] "USP Grade" excipients refer to excipients that meet or exceed the requirements of the United States Pharmacopeia (USP) (e.g., alcohol, propylene glycol, polyethylene glycols such as PEG 200 and PEG 400).

[0065] "Super refined" excipients refer to excipients that have had their impurities removed. Super refining removes polar impurities (including primary and secondary oxidation products) from the excipient without changing its chemical composition. Removal of these impurities helps to reduce excipient-active pharmaceutical ingredient (API) interactions and subsequent API degradation, thereby maintaining the stability of both the drug and the final composition or formulation. In addition, removal of these impurities can minimize cell irritation, making it ideal for various drug administration routes. The highly refined excipients of the present invention include highly refined propylene glycol.

[0066] "Super refined propylene glycol" or "SR propylene glycol" refers to highly refined propylene glycol that can enhance drug activity and stability of a composition (or formulation). In some embodiments, the SR propylene glycol has a purity of about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or more. In some embodiments, the SR propylene glycol has a purity of about 99.8% or 99.9% or more.

[0067] "Transcutol" has the formula CH3CH2OCH2CH2OCH2CH2OH and has the preferred IUPAC name 2-(2-ethoxyethoxy)ethanol. Other names for 2-(2-ethoxyethoxy)ethanol include diethylene glycol monoethyl ether (abbreviated as DGME or DEGEE), diethylene glycol ethyl ether (abbreviated as DEGEE), ethyl diglycol, dioxytol, 3,6-dioxa-1-octanol, Carbitol, Carbitol Cellosolve, Polysolv DE, or Dowanal DE. Transcutol includes "Transcutol P", "Transcutol CG", and "Transcutol HP".

[0068] "Transcutol P" refers to a high purity grade of 2-(2-ethoxyethoxy)ethanol. "Transcutol CG" refers to a specific grade of 2-(2-ethoxyethoxy)ethanol, which is a potent solubilizer and efficacy booster used in the cosmetics and pharmaceutical industries. "Transcutol HP" refers to a highly purified grade of 2-(2-ethoxyethoxy)ethanol that can enhance drug activity and stability of a composition (or formulation). In some embodiments, Transcutol P, CG, or HP has a purity of about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or more. In some embodiments, Transcutol P or HP has a purity of 99.8% or 99.9% or more. In some embodiments, Transcutol HP has a purity of about 99.90%.

[0069] "Fatty alcohol" refers to a primary alcohol with a long aliphatic chain that is either saturated or unsaturated. Fatty alcohols can range from as few as 4-6 carbons to as many as 22-26 carbons. Fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol (unsaturated), heptadecyl alcohol, stearyl alcohol, oleyl alcohol (unsaturated), nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol (unsaturated), and lignoceryl alcohol.

[0070] "Fatty ester" or "fatty acid ester" refers to a type of ester resulting from the combination of a fatty acid with an alcohol. When the alcohol is polyethylene glycol, the fatty ester refers to a polyoxyethylene fatty ester or a polyoxyethylene fatty acid ester.

[0071] "Fatty ether" refers to a type of ether resulting from the combination of a fatty alcohol with a second alcohol. When the second alcohol is polyethylene glycol, the fatty ether refers to a polyoxyethylene fatty ether.

[0072] "Polysorbate" refers to a class of fatty esters derived from ethoxylated sorbitan (polyethylene glycol derivatives of sorbitol) with fatty acids. Examples of polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). Suitable polysorbates include, but are not limited to, the Tween™ series (available from Uniqema), including Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 60 (polyoxyethylene (20) sorbitan monostearate), and Tween 80 (polyoxyethylene (20) sorbitan monooleate). Other suitable polysorbates include those listed in R C Rowe and P J Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0073] "Glyceride" refers to a fatty ester where the alcohol component is glycerol. The glyceryl fatty ester (or glyceride) produced can be a monoglyceride, diglyceride, or triglyceride. A "monoglyceride" is a glyceride consisting of one fatty acid chain covalently attached to a glycerol molecule by an ester bond. A "diglyceride" is a glyceride consisting of two fatty acid chains covalently attached to a glycerol molecule by an ester bond. A "triglyceride" is a glyceride consisting of three fatty acid chains covalently attached to a glycerol molecule by ester bonds.

[0074] "Salt" refers to the acid or base salt of the compound of the present invention. Examples of pharmaceutically acceptable salts are inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (such as methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0075] "Tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another. Compound 1 is

[0076] [ka] Compound 1 can exist in the 1H and / or 2H tautomeric forms, as shown in Figure 1. As used herein, "Compound 1" includes the 1H tautomer, the 2H tautomer, and mixtures of the 1H and 2H tautomers. Compound 1 also includes salts of the 1H tautomer, salts of the 2H tautomer, and mixtures of salts of the 1H and 2H tautomers.

[0077] "Solvate" refers to a compound provided herein or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0078] "Hydrate" refers to a compound that is complexed with a water molecule. The compounds of the present invention can be complexed with 1 / 2 a water molecule or with 1-10 water molecules.

[0079] As used herein, a "composition" or "formulation" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the composition (or formulation) and not deleterious to the recipient thereof.

[0080] For any one of the topical compositions described herein, the water content refers to the total weight including the pH adjusting solution (if present) (e.g., a solution of 0.1 M, 0.5 M, or 1 M citric acid in water), ethanol (if the ethanol is not absolute ethanol), and the portion from the final QS100 (QS stands for quantum satis).

[0081] "A relative purity of the compound in the topical composition" refers to the purity of a compound (e.g., Compound 1) at a particular time point (e.g., 8 weeks) stored under stress conditions (e.g., 40° C.) or under normal storage conditions (e.g., room temperature or 25° C.) compared to the initial purity of the compound at time point zero (i.e., day 0). As usual, the relative purity of the compound at time point zero (i.e., day 0) is set as 100%.

[0082] "About" refers to a range of values ​​that includes the specified value, which one of ordinary skill in the art would consider to be reasonably similar to the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range that extends to + / - 10% of the specified value. In some embodiments, about refers to the specified value.

[0083] "Substantially free of ..." means 2-6 "Polyethylene glycol" refers to a composition containing 1% by weight or less of other excipients, such as polyethylene glycol (e.g., PEG 200 and / or PEG 400), glycerol, fatty alcohol, fatty ester (e.g., polysorbate), fatty ether, or combinations thereof, each of which is defined and described herein. 1-3 Alkyl-(OCH2CH2) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) contains impurities including ethylene glycol and / or diethylene glycol. Polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C 1-3 Alkyl-(OCH2CH2) 1-5When -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) is present in the composition, the composition contains 0.5% by weight or less of ethylene glycol and / or diethylene glycol as an impurity. In some embodiments, polyethylene glycol (e.g., PEG 200 and / or PEG 400) and / or C 1-3 Alkyl-(OCH2CH2) 1-5 When -OH (eg, 2-(2-ethoxyethoxy)ethanol or Transcutol HP) is present in the composition, the composition contains no more than 0.25% by weight ethylene glycol and / or diethylene glycol as impurities.

[0084] "Inhibition," "inhibits," and "inhibitor" refer to a compound or method that prevents a particular action or function.

[0085] "Administering" refers to providing a composition or formulation to a subject (e.g., a patient, such as a human patient) via a desired route, such as topical administration. Topical administration can include applying the composition to a surface of a subject, such as the subject's skin, for example, in the form of a gel, ointment, lotion, foam, emollient, or as a component of a patch, tape, film, wafer, or bandage. The area to which the composition is applied can vary based on, for example, the disease of the subject as well as the properties of the composition (e.g., form, drug load, etc.).

[0086] "Treat," "treating," and "treatment" refer to any indicia of success in treating or ameliorating an injury, pathology, or disease, including any objective or subjective parameter, such as abatement, remission, reduction of symptoms, or making the injury, pathology, or disease more tolerable to the patient, slowing the rate of degeneration or deterioration, making the final point of degeneration less debilitating, improving the physical or mental well-being of the patient, etc. The treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation.

[0087] "Patient" or "subject" refers to an organism suffering from or prone to a disease or disorder that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, cats, primates, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient or subject is a human.

[0088] "Therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition useful for treating or ameliorating an identified disease or disorder, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 13, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0089] "A," "an," or "a(n)," as used herein with respect to a substituted group or "substituent," means at least one. For example, a compound is substituted with "an" alkyl or aryl, where the compound is optionally substituted with at least one alkyl and / or at least one aryl, where each alkyl and / or aryl is optionally different. In another example, a compound is substituted with "a" substituent, where the compound is substituted with at least one substituent, where each substituent is optionally different.

[0090] Topical Compositions As will be understood, some excipients of the topical compositions described herein may have multiple functions.For example, a given substance may act as both a solvent and an enhancer, both an antioxidant and a stabilizer, both an emulsifier and a surfactant, both an emulsifier and a thickener, etc.In some such cases, the function of a given substance may be considered singular, even though its properties may allow for multiple functionalities.

[0091] In certain aspects, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (i) Structure

[0092] [ka] or a salt thereof, and / or (ii) Structure

[0093] [ka] or a salt thereof, providing a composition comprising wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.1% to 1% by weight, or the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%, or 0.01% to 5%.

[0094] In some embodiments, the composition is a gel formulation.In some embodiments, the composition comprises alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof.In some embodiments, the composition further comprises a preservative.In some embodiments, the composition further comprises a gelling agent.

[0095] In certain aspects, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (i) Structure

[0096] [ka] or a salt thereof, and / or (ii) Structure

[0097] [ka] or a salt thereof a) alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants; d) preservatives, and e) Gelling agent and one or more excipients selected from (a) to (e).

[0098] In some embodiments, the composition comprises an alcohol. In some embodiments, the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. In some embodiments, the alcohol comprises C 2-6 In some embodiments, C 2-6 The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, or a combination or two or more thereof. 2-6 The alcohol comprises ethanol. In some embodiments, 2-6 The alcohol is present in an amount of 1% to 30%, 5% to 30%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight of the composition.

[0099] In some embodiments, the total amount of alcohol present in the composition is from about 1% to about 80% by weight of the composition.

[0100] In some embodiments, the alcohol comprises an organic solvent and / or a penetration enhancer.

[0101] In some embodiments, the composition further comprises an organic solvent and / or a penetration enhancer. In some embodiments, the organic solvent and / or the penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester, or fatty ether, or a combination of two or more thereof. 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol and the polyethylene glycol is PEG200, PEG400, or a combination thereof.

[0102] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, hi some embodiments, the organic solvent and / or penetration enhancer is present in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0103] In some embodiments, the composition further comprises an antioxidant. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant comprises butylated hydroxytoluene. In some embodiments, the antioxidant is present in an amount of 0.01% to 5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0104] In some embodiments, a preservative is included. In some embodiments, the preservative includes phenoxyethanol. In some embodiments, the preservative is present in an amount of 0.5% to 5.0%, 0.5% to 2%, or about 1% by weight of the composition. In some embodiments, the composition further includes water in an amount of 0% to 25%, 5% to 25%, 10% to 25%, 15% to 25%, or about 20% by weight of the composition.

[0105] In some embodiments, the composition comprises a gelling agent. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. In some embodiments, the gelling agent is present in an amount of 0.5% to 5% by weight, or about 2% by weight of the composition.

[0106] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose.

[0107] In some embodiments, ethanol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, propylene glycol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight, and hydroxypropylcellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% or about 2% by weight.

[0108] In some embodiments, ethanol is present in an amount of about 15% by weight, propylene glycol is present in an amount of about 15% by weight, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight, and hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight.

[0109] In some embodiments, the composition further comprises an antioxidant and / or a preservative. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof, and the preservative comprises phenoxyethanol. In some embodiments, the antioxidant comprises butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the antioxidant comprises butylated hydroxytoluene in an amount of about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of about 1% by weight.

[0110] In some embodiments, the composition comprises a pH adjuster, optionally an acid, and further optionally citric acid.

[0111] In some embodiments, the propylene glycol is highly refined propylene glycol.

[0112] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of >99.90%.

[0113] In some embodiments, the total amount of (i), (ii), or (i) and (ii) present in the composition is between 0.01% and 10%, between 0.1% and 10.0%, between 0.5% and 5%, between 0.5% and 2%, between 0.1% and 1%, or about 1% or about 0.1% by weight of the composition.

[0114] In some embodiments, the combined amount of (i), (ii), or (i) and (ii) is about 1% by weight of the composition.

[0115] In certain aspects, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (i) Structure

[0116] [ka] or a salt thereof, and / or (ii) Structure

[0117] [ka] or a salt thereof, Ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropylcellulose, and optionally an antioxidant, and optionally a preservative. The present invention provides a composition comprising:

[0118] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0119] In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0120] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a topical composition. In some embodiments, the composition is in the form of a gel, ointment, lotion, foam, or emollient. In some embodiments, the composition is a component of a patch, tape, film, wafer, or bandage.

[0121] In certain aspects, the present disclosure provides a topical pharmaceutical composition. The topical pharmaceutical composition has the structure

[0122] [ka] or a pharma- ceutically acceptable salt or tautomer thereof; a)C 2-6 alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants; d) preservatives; e) water; f) pH adjusters, and g) Gelling Agent and one or more excipients selected from (a) to (g).

[0123] In some embodiments, the compositions may be formulated with about 0.01% to about 10%, about 0.01%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the compositions may be formulated with about 0.01% to about 5%, about 0.01%, or about 5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the compositions may be formulated with about 0.1% to about 10%, about 0.1%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0124] In some embodiments, the total amount of (i), (ii), or (i) and (ii) present in the composition is between 0.01% and 10%, between 0.1% and 10.0%, between 0.5% and 5%, between 0.5% and 2%, between 0.1% and 1%, or about 1% or about 0.1% by weight of the composition.

[0125] In some embodiments, the combined amount of (i), (ii), or (i) and (ii) is about 1% by weight of the composition.

[0126] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose.

[0127] In some embodiments, ethanol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, propylene glycol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight, and hydroxypropylcellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% or about 2% by weight.

[0128] In some embodiments, ethanol is present in an amount of about 15% by weight, propylene glycol is present in an amount of about 15% by weight, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight, and hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight.

[0129] Excipients A. Alcohol In some embodiments, the compositions herein include an alcohol. In some embodiments, the alcohol includes ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. In some embodiments, the alcohol is C 2-6 In some embodiments, C 2-6 The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, or a combination or two or more thereof. 2-6 The alcohol comprises ethanol. In some embodiments, 2-6The alcohol is present in an amount of 1% to 30%, 5% to 30%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight of the composition.

[0130] In some embodiments, the total amount of alcohol present in the composition is from about 1% to about 80% by weight of the composition.

[0131] In some embodiments, the alcohol comprises an organic solvent and / or a penetration enhancer.

[0132] In some embodiments, the alcohol comprises ethanol. In some embodiments, the alcohol comprises propylene glycol. In some embodiments, the alcohol comprises transcutol. In some embodiments, the alcohol comprises phenoxyethanol. In some embodiments, the total amount of alcohol present in the composition is about 1% to about 80% by weight of the composition, or about 30-80%, 40-80%, 50-80%, 60-80%, 70-80%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%.

[0133] C 2-6 alcohol In some embodiments, the composition is 2-6 In some embodiments, C 2-6 The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, benzyl alcohol, hexanol, pentanol, or tert-butanol, or a combination thereof. 2-6 The alcohol is ethanol or isopropanol. 2-6 The alcohol is ethanol, in some embodiments, the composition comprises ethanol.

[0134] In some embodiments, the composition is 2-6Alcohol-free In some embodiments, the composition is ethanol-free.

[0135] In some embodiments, the composition comprises C in an amount of 0.0% to 90%, 5% to 40%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight. 2-6 In some embodiments, C 2-6 The alcohol is present in the composition in an amount of 0.0% to 20% by weight, 5% to 20% by weight, 10% to 20% by weight, or about 15% by weight. 2-6 The alcohol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight. 2-6 The alcohol is present in an amount of 10% to 20% by weight. 2-6 The alcohol is present in an amount of about 15% by weight.

[0136] In some embodiments, the composition comprises ethanol in an amount of 0.0% to 90% by weight, 5% to 40% by weight, 10% to 30% by weight, 5% to 20% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, ethanol is present in the composition in an amount of 0.0% to 20% by weight, 5% to 20% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, ethanol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, ethanol is present in an amount of 10% to 20% by weight. In some embodiments, ethanol is present in an amount of about 15% by weight.

[0137] B. Organic Solvents and / or Penetration Enhancers In some embodiments, the composition comprises an organic solvent and / or a penetration enhancer. Suitable solvents and / or penetration enhancers include C 2-6 Alkylene glycols (e.g., propylene glycol), di-(C 2-6(alkylene) glycols (e.g., dipropylene glycol), C 1-3 Alkyl-(OCH2CH2) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol P), polyethylene glycol (e.g., PEG 200 and / or PEG 400), glycerol, fatty alcohols (e.g., octyldodecanol), diethers of anhydrosugar alcohols (e.g., dimethyl isosorbide), fatty esters (e.g., diisopropyl adipate, isopropyl myristate, medium chain triglycerides, sorbitan monooleate, etc.), or fatty ethers (e.g., laureth-4), or combinations thereof. In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester, or fatty ether, or a combination thereof.

[0138] In some embodiments, the organic solvent and / or penetration enhancer is an alcohol.

[0139] In some embodiments, the organic solvent and / or the penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester, or fatty ether, or a combination of two or more thereof. 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol and the polyethylene glycol is PEG200, PEG400, or a combination thereof.

[0140] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, hi some embodiments, the organic solvent and / or penetration enhancer is present in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0141] In some embodiments, the propylene glycol is highly refined propylene glycol.

[0142] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of >99.90%.

[0143] In some embodiments, the organic solvent and / or the penetration enhancer is C 2-6 Alkylene glycol and / or C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the organic solvent and / or the penetration enhancer is C 2-6 In some embodiments, the organic solvent and / or the penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the organic solvent and / or the penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the organic solvent and / or the penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition is a mixture of C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 Contains -OH.

[0144] In some embodiments, C 1-3Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol (i.e., Transcutol P). 2-6 The alkylene glycol is propylene glycol.

[0145] In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol. In some embodiments, the organic solvent and / or penetration enhancer comprises 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol.

[0146] In some embodiments, the organic solvent and / or penetration enhancer comprises polyethylene glycol. In some embodiments, the polyethylene glycol is PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, or PEG900, or a combination thereof. In some embodiments, the organic solvent and / or penetration enhancer is methoxy PEG (macrogol monomethyl ether or polyethylene glycol monomethyl ether). In some embodiments, the polyethylene glycol is PEG-200, or PEG-400, or a combination thereof. In some embodiments, the polyethylene glycol comprises PEG200. In some embodiments, the polyethylene glycol comprises PEG400. In some embodiments, the polyethylene glycol comprises a mixture of PEG200 and PEG400. In some embodiments, the polyethylene glycol is PEG-200 and / or PEG-400. In some embodiments, the organic solvent and / or penetration enhancer comprises PEG200. In some embodiments, the organic solvent and / or penetration enhancer comprises PEG400. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of PEG200 and PEG400. In some embodiments, the composition comprises PEG 200. In some embodiments, the composition comprises PEG 400. In some embodiments, the composition comprises a mixture of PEG 200 and PEG 400.

[0147] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty alcohol. As used herein, the term "fatty alcohol" refers to a saturated or unsaturated fatty alcohol. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12-20, 14-20, 12-18, 14-18, or 16-18 carbons. Suitable fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, henicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, octyldodecanol, or mixtures thereof. In some embodiments, the organic solvent and / or penetration enhancer comprises one or more fatty alcohols selected from capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleic alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, henicosyl alcohol, behenyl alcohol, erucyl alcohol, and lignoceryl alcohol. In some embodiments, the organic solvent and / or penetration enhancer comprises octyldodecanol. In some embodiments, the composition comprises octyldodecanol.

[0148] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty acid ester. In some embodiments, the fatty ester is a glyceryl fatty ester, an ethylene glycol monoester and diester of a fatty acid, a propylene glycol monoester and diester of a fatty acid, a sorbitan ester, a C ester of a fatty acid, a glyceryl fatty ester ... 1-6 Alkyl esters, di(C) of adipic acid 1-6 alkyl) esters, or combinations thereof.

[0149] In some embodiments, the fatty acid ester is a glyceride. In some embodiments, the glyceride is a monoglyceride, a diglyceride, or a triglyceride. The glyceride is optionally substituted with a sulfonic acid group, or a pharma- ceutically acceptable salt thereof. Suitable fatty acids from which to derive the fatty acid glyceride include, but are not limited to, those described herein. In some embodiments, the glyceride is a monoglyceride of a fatty acid having 12-18 carbon atoms. In some embodiments, the glyceride is a diglyceride of a fatty acid having 12-18 carbon atoms. In some embodiments, the glyceride is a triglyceride of a fatty acid having 12-18 carbon atoms (e.g., also referred to herein as a medium chain triglyceride). In some embodiments, the organic solvent and / or penetration enhancer comprises a triglyceride of a fatty acid having 12-18 carbon atoms (e.g., also referred to herein as a medium chain triglyceride). In some embodiments, the composition comprises triglycerides of fatty acids having 12 to 18 carbon atoms (eg, also referred to herein as medium chain triglycerides).

[0150] In some embodiments, the fatty ester is an ethylene glycol monoester of a fatty acid, a propylene glycol monoester of a fatty acid, or a C 1-6 In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C alkyl ester of a fatty acid. 1-4 Alkyl esters. Ethylene glycol monoesters, propylene glycol monoesters, and C fatty acids 1-4 Suitable fatty acids from which to derive any one of the alkyl esters include, but are not limited to, those described herein. In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C6 fatty acid having 12 to 18 carbon atoms. 1-4It is an alkyl ester. Non-limiting examples of esters of fatty acids include laurate, myristate, palmitate, stearate, or oleate. In some embodiments, the fatty acid ester is isopropyl myristate. In some embodiments, the organic solvent and / or the penetration enhancer comprises isopropyl myristate. In some embodiments, the composition comprises isopropyl myristate.

[0151] In some embodiments, the fatty acid ester is a sorbitan ester. Suitable fatty acids for deriving the sorbitan ester include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), including Span 20 (sorbitan monolaurate), Span 40 (sorbitan monopalmitate), Span 60 (sorbitan monostearate), Span 65 (sorbitan tristearate), Span 80 (sorbitan monooleate), and Span 85 (sorbitan trioleate). In some embodiments, the fatty acid ester is sorbitan monooleate. In some embodiments, the organic solvent and / or the penetration enhancer comprises sorbitan monooleate. In some embodiments, the composition comprises sorbitan monooleate. In some embodiments, the composition comprises a polyoxyethylene sorbitol ester (e.g., Tween).

[0152] In some embodiments, the fatty acid ester is a di-(C 1-4 di-(C alkyl) esters of sebacic acid (i.e., sebacates) 1-4 In some embodiments, the fatty acid ester is diisopropyl adipate. In some embodiments, the organic solvent and / or penetration enhancer comprises diisopropyl adipate. In some embodiments, the composition comprises diisopropyl adipate.

[0153] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty ether. In some embodiments, the organic solvent and / or penetration enhancer comprises a polyoxyethylene fatty ether. In some embodiments, the organic solvent and / or penetration enhancer comprises laureth-4. In some embodiments, the composition comprises laureth-4.

[0154] In some embodiments, the organic solvent and / or penetration enhancer is present in the composition in an amount of 30% to 99%, 40% to 99%, 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is present in the composition in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is present in the composition in an amount of 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is present in the composition in an amount of 50% to 70% or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is present in the composition in an amount of 50% to 70% by weight. In some embodiments, the organic solvent and / or penetration enhancer is present in the composition in an amount of about 60% by weight.

[0155] In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition is 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition is 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition is 50% to 70% or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition in an amount of 50% to 70% by weight. In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition in an amount of about 60% by weight.

[0156] In some embodiments, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition is between 50% and 80%, between 50% and 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition is between 50% and 80%, between 50% and 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition is between 50% and 70%, or about 60% by weight. In some embodiments, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition in an amount of 50% to 70% by weight. In some embodiments, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of which is present in the composition in an amount of about 60% by weight.

[0157] In some embodiments, propylene glycol is present in the composition in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, propylene glycol is present in the composition in an amount of 10% to 20% by weight or about 15% by weight. In some embodiments, propylene glycol is present in the composition in an amount of 10% to 20% by weight. In some embodiments, propylene glycol is present in the composition in an amount of about 15% by weight.

[0158] In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of 30% to 70% by weight, 40% to 60% by weight, or about 47% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of 40% to 60% by weight or about 47% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of 40% to 60% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 47% by weight.

[0159] In some embodiments, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol, wherein the propylene glycol is present in an amount of 10% to 20% by weight and the 2-(2-ethoxyethoxy)ethanol is present in an amount of 40% to 60% by weight. In some embodiments, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol, wherein the propylene glycol is present in an amount of about 15% by weight and the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight.

[0160] In some embodiments, the propylene glycol is highly refined propylene glycol.

[0161] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of >99.90%.

[0162] C. Antioxidants In some embodiments, the composition comprises an antioxidant. In some embodiments, the composition does not comprise an antioxidant.

[0163] In some embodiments, the composition comprises an antioxidant, and the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, alpha tocopherol, ascorbyl palmitate, ascorbic acid, citric acid or salts thereof, sodium meta / bisulfite, or a combination thereof. In some embodiments, the antioxidant is butylated hydroxytoluene. In some embodiments, the antioxidant is butylated hydroxyanisole. In some embodiments, the antioxidant is propyl gallate. In some embodiments, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole.

[0164] In some embodiments, the antioxidant is present in the composition in an amount of 0.001% to 5% by weight. In some embodiments, the antioxidant is present in an amount of 0.01% to 0.5% by weight, 0.01% to 0.2% by weight, 0.01% to 0.1% by weight, or about 0.05% by weight. In some embodiments, the antioxidant is present in an amount of 0.01% to 0.5% by weight. In some embodiments, the antioxidant is present in an amount of 0.01% to 0.2% by weight. In some embodiments, the antioxidant is present in an amount of 0.01% to 0.1% by weight. In some embodiments, the antioxidant is present in an amount of about 0.05% by weight. In some embodiments, the antioxidant is present in an amount of about 0.1% by weight. In some embodiments, the antioxidant is butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight or about 0.05% by weight. In some embodiments, the antioxidant is butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight. In some embodiments, the antioxidant is butylated hydroxytoluene in an amount of about 0.05% by weight. In some embodiments, the antioxidant is butylated hydroxyanisole in an amount of 0.01% to 0.1% by weight or about 0.05% by weight. In some embodiments, the antioxidant is butylated hydroxyanisole in an amount of 0.01% to 0.1% by weight. In some embodiments, the antioxidant is butylated hydroxyanisole in an amount of about 0.05% by weight. In some embodiments, the antioxidant is propyl gallate in an amount of 0.01% to 0.1% by weight or about 0.05% by weight. In some embodiments, the antioxidant is propyl gallate in an amount of 0.01% to 0.1% by weight or about 0.05% by weight. In some embodiments, the antioxidant is propyl gallate in an amount of 0.01% to 0.1% by weight. In some embodiments, the antioxidant is propyl gallate in an amount of about 0.05% by weight. In some embodiments, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each present in an amount of 0.01% to 0.1% or about 0.05% by weight. In some embodiments, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each present in an amount of 0.01% to 0.1% by weight.In some embodiments, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each present in an amount of about 0.05% by weight.

[0165] In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant comprises butylated hydroxytoluene. In some embodiments, the antioxidant is present in an amount of 0.01% to 5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0166] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0167] D. Preservatives In some embodiments, the composition comprises a preservative. In some embodiments, the composition does not comprise a preservative.

[0168] In some embodiments, the composition comprises a preservative, and the preservative is benzyl alcohol, phenoxyethanol, methylparaben, propylparaben, butylparaben, benzalkonium chloride, sodium benzoate, imidurea, chlorocresol, chloroxylenol, benzoic acid, sodium sulfite, sodium metabisulfite, boric acid, calcium acetate, or a combination thereof. In some embodiments, the preservative, when present, is benzyl alcohol. In some embodiments, the preservative, when present, is phenoxyethanol. In some embodiments, the preservative, when present, is a mixture of benzyl alcohol and phenoxyethanol.

[0169] In some embodiments, the preservative is present in the composition in an amount of 0.01% to 5% by weight. In some embodiments, the preservative is present in an amount of 0.5% to 5.0% by weight, 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the preservative is present in an amount of 0.5% to 2% by weight. In some embodiments, the preservative is present in an amount of about 1% by weight. In some embodiments, the preservative is phenoxyethanol in an amount of 0.5% to 5% by weight, 0.5% to 4% by weight, 0.5% to 3% by weight, or 0.5% to 2% by weight. In some embodiments, the preservative is phenoxyethanol in an amount of 0.5% to 2% by weight. In some embodiments, the preservative is phenoxyethanol in an amount of about 1% by weight.

[0170] In some embodiments, the preservative comprises phenoxyethanol, hi some embodiments, the preservative is present in an amount of 0.5% to 5.0%, 0.5% to 2%, or about 1% by weight of the composition.

[0171] In some embodiments, the composition further comprises an antioxidant and / or a preservative. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof, and the preservative comprises phenoxyethanol. In some embodiments, the antioxidant comprises butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight or about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the antioxidant comprises butylated hydroxytoluene in an amount of about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of about 1% by weight.

[0172] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0173] E.Water In some embodiments, the composition comprises water. In some embodiments, the composition does not comprise water.

[0174] In some embodiments, water is present in the composition in an amount of 0% to 80%, 5% to 25%, 10% to 25%, 15% to 25%, or about 20% by weight. In some embodiments, the composition includes water, and water is present in an amount of 5% to 25%, 10% to 25%, 15% to 25%, or about 20% by weight. In some embodiments, water is present in an amount of 10% to 25%, 15% to 25%, or about 20% by weight. In some embodiments, water is present in an amount of 10% to 25% by weight. In some embodiments, water is present in an amount of 15% to 25% by weight. In some embodiments, water is present in an amount of about 20% by weight.

[0175] In some embodiments, the composition further comprises water in an amount between 0% and 25%, between 5% and 25%, between 10% and 25%, between 15% and 25%, or about 20% by weight of the composition.

[0176] F. pH adjuster In some embodiments, the composition comprises a pH adjuster. In some embodiments, the composition does not comprise a pH adjuster.

[0177] In some embodiments, the composition comprises a pH adjuster, and the pH adjuster is an acid.

[0178] In some embodiments, the acid is an organic acid. Suitable organic acids include, but are not limited to, citric acid, formic acid, lactic acid, benzoic acid, oxalic acid, acetic acid, and propionic acid. In some embodiments, the acid is an organic acid such as citric acid, formic acid, lactic acid, benzoic acid, oxalic acid, acetic acid, or propionic acid. In some embodiments, the acid is an organic acid such as citric acid, formic acid, lactic acid, benzoic acid, acetic acid, or propionic acid. In some embodiments, the acid is an organic acid such as citric acid, formic acid, lactic acid, or acetic acid. In some embodiments, the acid is an organic acid such as citric acid or acetic acid. In some embodiments, the acid is an inorganic acid such as hydrochloric acid (HCl), boric acid (H3BO3), sulfuric acid (H2SO4), carbonic acid (H2CO3), or phosphoric acid (H3PO4). In some embodiments, the acid is an inorganic acid such as hydrochloric acid (HCl), boric acid (H3BO3), phosphoric acid (H3PO4). In some embodiments, the acid is an inorganic acid, such as hydrochloric acid (HCl) or phosphoric acid (H3PO4). In some embodiments, the acid is citric acid, acetic acid, or a combination thereof. In some embodiments, the acid is citric acid. In some embodiments, the acid is acetic acid.

[0179] The pH adjuster can be in the aqueous solution of the acid described herein.In some embodiments, the pH adjuster is an aqueous solution of citric acid.In some embodiments, the pH adjuster is an aqueous solution of citric acid with a concentration of 0.1M, 0.5M or 1M.

[0180] G. Gelling Agents In some embodiments, the composition includes a gelling agent (e.g., a polymeric thickener). Gelling agents include, for example, hydrophilic and hydroalcoholic gelling agents that are frequently used in the cosmetics and pharmaceutical industries. In some embodiments, the gelling agent is Carbopol (also called carbomer), carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate (Veegum), methylcellulose, poloxamer (Pluronics), polyvinyl alcohol, sodium alginate, dermacryl, acrylates, octylacrylamide copolymers, HPMC (hydroxypropylmethylcellulose), PVP (polyvinylpyrrolidone), bentonite clay, tragacanth, xanthan gum, Sepino P600, polyethylene glycol having an average molecular weight of at least about 2500 Da, or a combination thereof. In some embodiments, the gelling agent includes Sepino P600. In some embodiments, the gelling agent is Sepino P600. In some embodiments, the gelling agent comprises a polyethylene glycol (e.g., PEG 3350) having an average molecular weight of about 2500-3500 Da. In some embodiments, the gelling agent is a polyethylene glycol (e.g., PEG 3350) having an average molecular weight of about 2500-3500 Da. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the gelling agent is hydroxypropyl cellulose.

[0181] In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 40,000 Daltons (Da), about 80,000 Da, about 100,000 Da, about 140,000 Da, about 180,000 Da, about 280,000 Da, about 370,000 Da, about 700,000 Da, about 850,000 Da, about 1,000,000 Da, about 1,150,000 Da, or about 2,500,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 140,000 Da, about 180,000 Da, about 280,000 Da, about 370,000 Da, about 700,000 Da, about 850,000 Da, about 1,000,000 Da, or about 1,150,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 700,000 Da, about 850,000 Da, about 1,000,000 Da, or about 1,150,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 700,000 Da to about 1,150,000 Da.

[0182] Hydroxypropylcelluloses (HPCs) include, for example, Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, Nisso VH, Klucel ELF, Klucel EF, Klucel LF, Klucel JF, Klucel GF, Klucel MF, Klucel HF, and the like.

[0183] Nisso SSL has an average molecular weight of about 40,000 Da, Nisso SL has an average molecular weight of about 100,000 Da, Nisso L has an average molecular weight of about 140,000 Da, Nisso LM has an average molecular weight of about 180,000 Da, Nisso LMM has an average molecular weight of about 280,000 Da, Nisso M has an average molecular weight of about 700,000 Da, Nisso H has an average molecular weight of about 1,000,000 Da, and Nisso VH has an average molecular weight of about 2,500,000 Da. Suitable particle sizes of Nisso HPC (i.e., Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, and Nisso VH) in the composition include regular powder (40 mesh), fine powder (100 mesh), and super fine powder (300 mesh). See the technical data sheet for Nisso HPC, which is incorporated herein by reference in its entirety.

[0184] In some embodiments, the hydroxypropyl cellulose is Nisso L, Nisso LM, Nisso LMM, Nisso M, or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso LM, Nisso LMM, Nisso M, or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso LMM, Nisso M, or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso M or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso M. In some embodiments, the hydroxypropyl cellulose is Nisso H.

[0185] Klucel ELF has an average molecular weight of about 40,000 Da, Klucel EF has an average molecular weight of about 80,000 Da, Klucel LF has an average molecular weight of about 95,000 Da, Klucel JF has an average molecular weight of about 140,000 Da, Klucel GF has an average molecular weight of about 370,000 Da, Klucel MF has an average molecular weight of about 850,000 Da, and Klucel HF has an average molecular weight of about 1,150,000 Da. Suitable particle sizes of Klucel HPC in the composition include regular grade and fine grade. Please refer to the technical data sheet of Klucel HPC product, which is incorporated herein by reference in its entirety.

[0186] In some embodiments, the hydroxypropyl cellulose is Klucel JF, Klucel GF, Klucel MF, or Klucel HF. In some embodiments, the hydroxypropyl cellulose is Klucel GF, Klucel MF, or Klucel HF. In some embodiments, the hydroxypropyl cellulose is Klucel GF. In some embodiments, the hydroxypropyl cellulose is Klucel MF. In some embodiments, the hydroxypropyl cellulose is Klucel HF.

[0187] When a gelling agent is present in the composition, in some embodiments, the composition has a viscosity of 5,000 cP to 100,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 5,000 cP to 50,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 5,000 cP to 40,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 5,000 cP to 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 10,000 cP to 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 15,000 cP to 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0188] When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 100,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 50,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 40,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 10,000 cP to 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 15,000 cP to 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0189] In some embodiments, the gelling agent is present in the composition in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 5,000 cP to 100,000 cP. In some embodiments, the gelling agent is present in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 5,000 cP to 50,000 cP. In some embodiments, the gelling agent is present in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 5,000 cP to 40,000 cP. In some embodiments, the gelling agent is present in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 5,000 cP to 30,000 cP. In some embodiments, the gelling agent is present in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 10,000 cP to 30,000 cP. In some embodiments, the gelling agent is present in an amount of 0.5% to 30% by weight and the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the gelling agent is present in an amount of 0.5% to 30% by weight and the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0190] In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 5% to 10%, 10% to 20%, or 20% to 30% by weight, and the composition has a viscosity of 5,000 cP to 100,000 cP. When using hydroxypropyl cellulose having an average molecular weight of less than about 700,000 Da, in some embodiments, the hydroxypropyl cellulose is present in an amount of 5% to 30% by weight, and the composition has a viscosity of 5,000 cP to 100,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 0.5% to 4%, 0.5% to about 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight and the composition has a viscosity of 5,000 cP to 50,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 0.5% to 4%, 0.5% to about 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight and the composition has a viscosity of 5,000 cP to 40,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 0.5% to 4%, 0.5% to about 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight and the composition has a viscosity of 5,000 cP to 30,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight and the composition has a viscosity of 10,000 cP to 30,000 cP.In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, and the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, and the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0191] In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to about 2% by weight of the composition. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of about 5,000 cP to about 50,000 cP. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of about 5,000 cP to about 40,000 cP. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of about 5,000 cP to about 30,000 cP. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of 10,000 cP to 30,000 cP. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0192] In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 1% by weight of the composition. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 2% by weight of the composition.

[0193] In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. In some embodiments, the gelling agent is present in an amount of 0.5% to 5%, or about 2% by weight of the composition.

[0194] Apparent pH value If the composition is a non-aqueous formulation, the pH value of the composition is the apparent pH value. If the composition contains water, the composition may contain a significant amount of other excipients (e.g., C 2-6 The pH values ​​of partially aqueous solutions can therefore only be considered as apparent pH values. <791> According to USP Chapter 11, which is incorporated herein by reference in its entirety and for all purposes, the apparent pH value of a non-aqueous or partially aqueous solution is expected to vary by up to about 1 pH unit. <791> Please refer to.

[0195] In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 7.5 to about 9.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 7.5 to about 8.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 8.5 to about 9.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 8. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 9.

[0196] In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH value of about 7 or less. In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH value of about 5 to about 7 or about 6 to about 7. In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH value of about 6 to about 7.

[0197] compound In any one of the compositions described herein, the compound (i.e., Compound 1) has the formula

[0198] [ka] or a salt thereof,

[0199] [ka] or a salt thereof, or a mixture thereof.

[0200] In any one of the compositions described herein, the compound may be a pharmaceutically acceptable salt of 1H tautomer, 2H tautomer, or mixture thereof. Examples of pharmaceutically acceptable salts are inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid), and quaternary ammonium (such as methyl iodide, ethyl iodide).

[0201] In any one of the compositions described herein, the compound may be in the form of a solvate or hydrate of a 1H tautomer, a 2H tautomer, or a mixture thereof.

[0202] In some embodiments, the compound is a 1H tautomer or a pharma- ceutically acceptable salt thereof.

[0203] In some embodiments, the compound is a 2H tautomer or a pharma- ceutically acceptable salt thereof.

[0204] In some embodiments, the compound is a 1H tautomer, a 2H tautomer, or a mixture thereof.

[0205] In some embodiments, the compound is a mixture of 1H and 2H tautomers, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a mixture of 1H and 2H tautomers, or a pharma- ceutically acceptable salt thereof, and the 1H tautomer, or a pharma- ceutically acceptable salt thereof, is present in the mixture in an amount of 1%-99%. In some embodiments, the 1H tautomer, or a pharma- ceutically acceptable salt thereof, is present in the mixture in an amount of 50%-99%, 60%-99%, 70%-99%, 80%-99%, or 90%-99%. In some embodiments, the 1H tautomer, or a pharma- ceutically acceptable salt thereof, is present in the mixture in an amount of 80%-99%.

[0206] In some embodiments, the compound is a mixture of 1H and 2H tautomers. In some embodiments, the compound is a mixture of 1H and 2H tautomers, where the 1H tautomer is present in the mixture in an amount between 1% and 99%. In some embodiments, the 1H tautomer is present in the mixture in an amount between 50% and 99%, 60% and 99%, 70% and 99%, 80% and 99%, or 90% and 99%. In some embodiments, the 1H tautomer is present in the mixture in an amount between 80% and 99%.

[0207] In some embodiments, the compound is present in the composition in an amount of 0.01% to 10% by weight, 0.1% to 10.0% by weight, 0.5% to 5% by weight, 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the compound is present in an amount of 0.5% to 5% by weight, 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the compound is present in an amount of about 0.1% to about 1% by weight. In some embodiments, the compound is present in an amount of 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the compound is present in an amount of about 1% by weight. In some embodiments, the compound is present in an amount of about 0.1% by weight. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0208] Embodiment In some embodiments, the composition comprises: a) C 2-6 Alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises three or more excipients selected from (a)-(g): a) C-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjusting agent; and g) a gelling agent. 2-6 Alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises four or more excipients selected from (a)-(g): a) C-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjusting agent; and g) a gelling agent. 2-6 Alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises five or more excipients selected from (a)-(g): a) C-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjusting agent; and g) a gelling agent. 2-6 Alcohol, b) C 2-6 Alkylene glycol and C 1-3Alkyl-(OCH2CH2) 1-5 -OH), c) an antioxidant, d) a preservative, e) water, f) a pH adjusting agent, and g) a gelling agent. The composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0209] In some embodiments, the composition comprises: a) C 2-6 Alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises a) C 2-6 Alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises a) C-OH, c) an antioxidant, d) a preservative, e) water, and g) a gelling agent. 2-6 Alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, c) an antioxidant, d) a preservative, e) water, f) a pH adjusting agent, and g) a gelling agent. The composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0210] In some embodiments, the present invention provides a method for producing a compound comprising the steps of:

[0211] [ka] and / or a pharma- ceutically acceptable salt or tautomer thereof; a)C 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, c) optionally an antioxidant; d) optionally a preservative; e) water; f) optionally a pH adjuster, and g) gelling agents, and four or more excipients selected from (a) to (g), Here, compound C 2-6 Alcohol, C. 1-3 Alkyl-(OCH2CH2) 1-5 The -OH, antioxidants, preservatives, water, pH adjusters, and gelling agents are described herein. The composition may be formulated with about 0.01% to about 10%, about 0.01% to about 5%, about 0.1% to about 10%, about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0212] In some embodiments of composition (A), an antioxidant is not present in the composition. In some embodiments of composition (A), a preservative is not present in the composition. In some embodiments of composition (A), a pH adjuster is not present in the composition. In some embodiments of composition (A), all of an antioxidant, a preservative, and a pH adjuster are not present in the composition.

[0213] In some embodiments of composition (A), one or more of an antioxidant, a preservative, and a pH adjuster are present in the composition. In some embodiments of composition (A), both an antioxidant and a preservative are present in the composition, and a pH adjuster is not present in the composition.

[0214] In some embodiments, the present invention provides a method for producing a compound comprising the steps of:

[0215] [ka] or a pharma- ceutically acceptable salt or tautomer thereof; a)C 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) Water, and g) gelling agents, and excipients a), b), e), and g), Here, compound C 2-6 Alcohol, C. 1-3 Alkyl-(OCH2CH2) 1-5-OH), water, and gelling agent are as described herein. In some embodiments, the composition may be formulated with about 0.01% to about 10%, about 0.01%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 5%, about 0.01%, or about 5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 10%, about 0.1%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0216] In some embodiments, the present invention provides a method for producing a compound comprising the steps of:

[0217] [ka] or a pharma- ceutically acceptable salt or tautomer thereof; a)C 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, c) antioxidants; d) preservatives; e) Water, and g) gelling agents, and (C) the excipients a) to e) and g), Here, compound C 2-6 Alcohol, C. 1-3 Alkyl-(OCH2CH2) 1-5 The -OH, antioxidant, preservative, water, and gelling agent are as described herein. In some embodiments, the composition may be formulated with about 0.01% to about 10%, about 0.01%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 5%, about 0.01%, or about 5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 10%, about 0.1%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks.

[0218] In some embodiments of any one of composition (A), composition (B), and composition (C), C 2-6 The alcohol is present in the composition in an amount of 10% to 30%, 10% to 20%, or about 15% by weight. 2-6 The alcohol is present in an amount of 10% to 30%. 2-6 The alcohol is present in an amount of 10% to 20%. 2-6 The alcohol is present in an amount of about 15% by weight.

[0219] In some embodiments of any one of composition (A), composition (B), and composition (C), C 2-6 The alkylene glycol is present in the composition in an amount of 10% to 30%, 10% to 20%, or about 15% by weight. 2-6 The alkylene glycol is present in an amount of 10% to 30%. 2-6 The alkylene glycol is present in an amount of 10% to 20%. 2-6 The alkylene glycol is present in an amount of about 15% by weight.

[0220] In some embodiments of any one of composition (A), composition (B), and composition (C), C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is present in an amount of 30% to 70% by weight, 40% to 60% by weight, or about 47% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, C is present in an amount of 30% to 70% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, C is present in an amount of 40% to 60% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 The -OH is present in an amount of about 47% by weight.

[0221] In some embodiments of any one of Composition (A), Composition (B), and Composition (C), water is present in an amount of 10% to 30% by weight, 15% to 25% by weight, or about 20% by weight. In some embodiments, water is present in an amount of 10% to 30% by weight. In some embodiments, water is present in an amount of 15% to 25% by weight. In some embodiments, water is present in an amount of about 20% by weight.

[0222] In some embodiments of any one of composition (A), composition (B), and composition (C), the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, and the composition has a viscosity of 5,000 cP to 30,000 cP. In some embodiments, the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, and the composition has a viscosity of 10,000 cP to 30,000 cP. In some embodiments, the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, and the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, and the composition has a viscosity of 20,000 cP to 30,000 cP.

[0223] In some embodiments of any one of composition (A), composition (B), and composition (C), C 2-6 The alcohol is ethanol, C 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol and the gelling agent is hydroxypropyl cellulose.

[0224] In some embodiments, composition (A1) comprises a compound comprising: a) ethanol, b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) optionally an antioxidant; d) optionally a preservative; e) water; f) optionally a pH adjuster, and g) Hydroxypropyl cellulose and four or more excipients selected from (a) to (g); wherein the compounds, antioxidants, preservatives, and pH adjusters are as described herein.

[0225] In some embodiments, composition (B1) comprises a compound comprising: a) ethanol, b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; e) Water, and g) hydroxypropyl cellulose, and excipients a), b), e), and g), wherein the compound is as described herein.

[0226] In some embodiments, the composition (C1) comprises a compound, a) ethanol, b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) antioxidants; d) preservatives; e) Water, and g) hydroxypropyl cellulose, and excipients a) to e) and g), wherein the compounds, antioxidants, and preservatives are as described herein.

[0227] In some embodiments of Composition (A) or Composition (A1), the pH adjuster, when present, is an acid. In some embodiments, the pH adjuster, when present, is citric acid.

[0228] In some embodiments of any one of Composition (A), Composition (C), Composition (A1), and Composition (C1), the antioxidant, when present, is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination thereof. In some embodiments, the antioxidant, when present, is butylated hydroxytoluene.

[0229] In some embodiments of any one of Composition (A), Composition (C), Composition (A1), and Composition (C1), the preservative, if present, is phenoxyethanol.

[0230] In some embodiments of any one of Composition (A), Composition (C), Composition (A1), and Composition (C1), the antioxidant, if present, is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination thereof, and the preservative, if present, is phenoxyethanol. In some embodiments, the antioxidant, if present, is butylated hydroxytoluene, and the preservative, if present, is phenoxyethanol.

[0231] In some embodiments of any one of Composition (A), Composition (C), Composition (A1), and Composition (C1), the antioxidant, if present, is present in an amount of 0.01% to 0.1% by weight or about 0.05% by weight. In some embodiments, the antioxidant, if present, is present in an amount of 0.01% to 0.1% by weight. In some embodiments, the antioxidant, if present, is present in an amount of about 0.05% by weight.

[0232] In some embodiments of any one of Composition (A), Composition (C), Composition (A1), and Composition (C1), the preservative, if present, is present in an amount of 0.5% to 2% by weight or about 1% by weight. In some embodiments, the preservative, if present, is present in an amount of 0.5% to 2% by weight. In some embodiments, the preservative, if present, is present in an amount of about 1% by weight.

[0233] In some embodiments, composition (C1a) comprises a compound: a) ethanol, b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) butylated hydroxytoluene, d) phenoxyethanol, e) Water, and g) hydroxypropyl cellulose, and excipients a) to e) and g), wherein the compound is as described herein.

[0234] In some embodiments of any one of Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), ethanol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, ethanol is present in an amount of 10% to 30% by weight. In some embodiments, ethanol is present in an amount of 10% to 20% by weight. In some embodiments, ethanol is present in an amount of about 15% by weight.

[0235] In some embodiments of any one of Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), propylene glycol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, propylene glycol is present in an amount of 10% to 30% by weight. In some embodiments, propylene glycol is present in an amount of 10% to 20% by weight. In some embodiments, propylene glycol is present in an amount of about 15% by weight.

[0236] In some embodiments of any one of Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70% by weight, 40% to 60% by weight, or about 47% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of 40% to 60% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight.

[0237] In some embodiments of any one of Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), water is present in an amount of 10% to 30% by weight, 15% to 25% by weight, or about 20% by weight. In some embodiments, water is present in an amount of 10% to 30% by weight. In some embodiments, water is present in an amount of 15% to 25% by weight. In some embodiments, water is present in an amount of about 20% by weight.

[0238] In some embodiments of any one of Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% by weight or about 2% by weight. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% by weight. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 1% by weight. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 2% by weight. In some embodiments, the hydroxypropyl cellulose is Klucel MF in an amount of about 2% by weight.

[0239] In some embodiments of composition (C1a), the butylated hydroxytoluene is present in the composition in an amount of 0.01% to 0.1% by weight or about 0.05% by weight. In some embodiments, the butylated hydroxytoluene is present in an amount of 0.01% to 0.1% by weight. In some embodiments, the butylated hydroxytoluene is present in an amount of about 0.5% by weight.

[0240] In some embodiments of composition (C1a), phenoxyethanol is present in the composition in an amount of 0.5% to 2% by weight or about 1% by weight. In some embodiments, phenoxyethanol is present in an amount of 0.5% to 2% by weight. In some embodiments, phenoxyethanol is present in an amount of about 1% by weight.

[0241] In some embodiments of composition (C1a), the butylated hydroxytoluene is present in an amount of about 0.5% by weight and the phenoxyethanol is present in an amount of about 1% by weight.

[0242] In some embodiments of Composition (A), Composition (B), Composition (C), Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), the propylene glycol is highly purified propylene glycol.

[0243] In some embodiments of Composition (A), Composition (B), Composition (C), Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of >99.90%.

[0244] In some embodiments of Composition (A), Composition (B), Composition (C), Composition (A1), Composition (B1), Composition (C1), and Composition (C1a), the compound is present in the composition in an amount of 0.5% to 2% by weight or about 1% by weight. In some embodiments, the compound is present in an amount of 0.5% to 2% by weight, or about 0.1% to about 1% by weight. In some embodiments, the compound is present in an amount of about 1% by weight. In some embodiments, the compound is present in an amount of about 0.1% by weight.

[0245] Form of the composition Useful topical compositions for delivering compounds to a subject (e.g., the skin of a subject) include, but are not limited to, foams, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, and suspensions.See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, (Alfonso R.Gennaro ed.19th ed.1995), and Introduction to Pharmaceutical Dosage Forms,4th ed.,Lea & Febiger,Philadelphia(1985).In some embodiments, the topical composition used for delivering compounds is a gel, an ointment, a lotion, a foam, or an emollient.

[0246] In some embodiments, the topical composition used to deliver the compound is a lotion or cream.The cream and lotion that can be used as topical composition and their preparation are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R.Gennaro ed.19th ed.1995), the relevant parts of which are incorporated herein by reference.

[0247] In some embodiments, the topical composition used to deliver the compound is a gel, for example, a two-phase gel or a single-phase gel. Gels are semisolid systems that consist of a suspension of small inorganic particles or large organic molecules interpenetrated by liquid. If the gel mass contains a network of small, separate inorganic particles, it is classified as a two-phase gel. Single-phase gels consist of organic macromolecules that are uniformly dispersed throughout the liquid, such that there is no clear boundary between the dispersed macromolecules and the liquid. Gels suitable for use in the present disclosure are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso R.Gennaro ed.19th ed.1995), which is incorporated herein by reference. Other suitable gels for use with the present disclosure are disclosed in U.S. Patent Nos. 6,387,383 (issued May 14, 2002), 6,517,847 (issued February 11, 2003), and 6,468,989 (issued January 22, 2002).

[0248] In some embodiments, the topical composition used to deliver the compound is an ointment. Ointments are oleaginous semisolids that contain little, if any, water. In some examples, the ointment is hydrocarbon-based, such as wax, petrolatum, or gelled mineral oil. Ointments suitable for use according to the present disclosure include those disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1585-1591 (Alfonso R. Gennaro ed. 19th ed. 1995). In some embodiments, the topical composition used to deliver the compound is an emulsified gel. In some embodiments, the topical composition used to deliver the compound is an emulsified spray.

[0249] In some embodiments, topical composition can be achieved in the form of a patch, tape, film, wafer, or bandage that comprises the topical composition described herein.In some embodiments, the patch, tape, film, wafer, or bandage is in contact with the affected area on the skin.In some embodiments, the patch, tape, film, wafer, or bandage is in contact with the area of ​​the subject's skin adjacent to the affected area or target area when applied to a subject.

[0250] In some embodiments, topical administration can be achieved in the form of a patch, tape, film, wafer, or bandage that comprises the topical composition described herein.In some embodiments, the patch, tape, film, wafer, or bandage is in contact with the affected area on the skin.In some embodiments, the patch, tape, film, wafer, or bandage is in contact with the area of ​​the subject's skin adjacent to the affected area or target area when applied to a subject.

[0251] In some embodiments, the patch, tape, film, wafer, or bandage comprises an adhesive.

[0252] In some embodiments, the topical composition can be applied to the seborrheic keratosis using a tape or film that provides an occluding environment for the seborrheic keratosis. The tape or film can be an adhesive tape, a waterproof adhesive tape, or a plastic film (with or without an adhesive layer). In some embodiments, the clear film used to form the occlusion is Tegaderm.

[0253] In some embodiments, the composition is impregnated into a tape or film. In some embodiments, the tape or film is a foam-containing tape or film. Pores or interstitial spaces in the foam may be filled with the composition described herein. The foam may have an adhesive layer to adhere the foam to the skin. If the foam is porous, an outer non-porous layer may be provided on the back side of the foam to enhance tape closure.

[0254] In some embodiments, the composition may be in the form of a sustained release wafer or dot, may be made by using a porous foam, may have a quantity of the composition disposed behind the porous foam, and may have a non-porous backing layer disposed behind the composition. The non-porous backing layer may have a portion that extends beyond the composition containing Compound 1 and the porous layer. This portion may include an amount of adhesive to facilitate the attachment of the wafer or dot to the user's skin around the seborrheic keratosis to be treated.

[0255] In some embodiments, the composition for application can be covered by a film or thermosensitive gel material, which includes, but is not limited to, poly(ethylene glycol) / poly(propylene glycol) block copolymers (poloxamers), poly(ethylene glycol) / poly(butylene glycol) block copolymers, poloxamer-g-poly(acrylic acid), and N-isopropylacrylamide copolymers that exhibit a sol-gel transition in aqueous solution. In some embodiments, the film or thermosensitive gel material can be impregnated with the composition. In some embodiments, the film or thermosensitive gel material impregnated with the composition can include, but is not limited to, poly(ethylene glycol) / poly(propylene glycol) block copolymers (poloxamers), poly(ethylene glycol) / poly(butylene glycol) block copolymers, poloxamer-g-poly(acrylic acid), and N-isopropylacrylamide copolymers that exhibit a sol-gel transition in aqueous solution.

[0256] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a topical composition. In some embodiments, the composition is in the form of a gel, ointment, lotion, foam, or emollient. In some embodiments, the composition is a component of a patch, tape, film, wafer, or bandage.

[0257] method In certain aspects, the present disclosure provides a method of treating a skin disease, condition, or disorder in a subject in need of such treatment, comprising administering to the subject a composition described herein.

[0258] In one aspect, the disclosure provides a method of treating a skin lesion, the method comprising topically administering to the skin lesion a composition having the structure: (i)

[0259] [ka] or a salt thereof; and / or (ii) a compound having the structure

[0260] [ka] or a salt thereof, Including, wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.1% to 1% by weight, or the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%, or 0.01% to 5%.

[0261] In some embodiments, the skin lesion is a keratosis. In some embodiments, the keratosis is a seborrheic keratosis. In some embodiments, the composition is administered once, twice, three times, or four times per day. In some embodiments, the composition is administered once, twice, three times, or four times per day for about 14 days to about 28 days. In some embodiments, the composition is administered once, twice, three times, four times, or five times per week. In some embodiments, the composition is administered in a cycle that includes administration 1-4 times daily for about 1-7 days, followed by about 1-7 days of no administration. In some embodiments, the cycle includes administration twice daily for about 4 days, followed by about 4 days of no administration. In some embodiments, the cycle is repeated about 2-10 times. In some embodiments, the cycle is repeated about 7 times. In some embodiments, the composition is administered at least once daily (e.g., about once or twice per day) for about 28 days. In some embodiments, the composition is administered once daily for three times per week. In some embodiments, the composition is administered for a total period of about 1, 2, 3, 4, 5, or 6 months.

[0262] In some embodiments, the method further comprises occlusion of the skin lesion.

[0263] In some embodiments, the skin lesion is present in a human subject. In some embodiments, the skin lesion is present on the face, torso, or extremities, or a combination thereof, of the human subject.

[0264] Physician's Lesion Assessment (PLA) is an assessment of the severity of target and non-target seborrheic keratoses at a particular time point. Assessments can refer to other assessments (e.g., previous photographs) to assist in these assessments. The PLA assessment is a point scoring system used to assess disease severity. PLA is a 4-point scoring system with scores ranging from 0 to 3. A score of 3 indicates seborrheic keratoses at least 1 mm thick, a score of 2 indicates seborrheic keratoses less than 1 mm thick, a score of 1 indicates nearly clear but containing residual surface changes, suggesting seborrheic keratoses, and a score of 0 indicates no visible surface changes remain. In some embodiments, treating includes an improvement of 1 grade or more in the Physician's Lesion Assessment (PLA) score compared to before administering the composition. In some embodiments, the PLA score before administration is at least 2.

[0265] In some embodiments, treating comprises reducing the thickness of the skin lesion to less than 1 mm. In some embodiments, the thickness of the skin lesion before administration is 1 mm or more. In some embodiments, the length of the skin lesion before administration is 1 mm to 15 mm, and the width of the skin lesion before administration is 1 mm to 15 mm.

[0266] In some embodiments, the treating comprises inducing apoptosis of keratinocytes in the skin lesion.

[0267] Terminal deoxynucleotidyl transferase dUTP nick end labeling assay or TUNEL assay is a method for detecting or quantifying cell apoptosis by labeling the 3'-hydroxyl end of double-stranded DNA breaks of DNA fragmentation that occurs during apoptosis. TUNEL assay utilizes terminal deoxynucleotidyl transferase (TdT), an enzyme that catalyzes the attachment of deoxynucleotides tagged with a fluorescent dye or another marker to the 3'-hydroxyl end of DNA double-stranded breaks. In some embodiments, apoptosis is measured by TUNEL assay.

[0268] In some embodiments, the composition is a gel formulation. In some embodiments, the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof.

[0269] In one aspect, the disclosure provides a method of treating a skin disease, condition, or disorder in a subject in need of such treatment, comprising administering to the subject a composition described herein.

[0270] In some embodiments, the skin disease, condition, or disorder is a seborrheic keratosis, a benign tumor, a malignant tumor, a parasite, a cutaneous virus, an immune disease or disorder, or a bacterial, fungal, or microbial infection. In some embodiments, the skin disease, condition, or disorder is a seborrheic keratosis. In some embodiments, the skin disease, condition, or disorder is a benign tumor, the benign tumor is a benign vascular tumor, a benign fibrous tumor, a benign adipocyte tumor, a benign sebaceous tumor, a benign epidermal tumor, a benign melanocytic lesion, or a benign neural tumor; the skin disease, condition, or disorder is a malignant tumor, the malignant tumor is a malignant melanocytic tumor, a malignant epidermal tumor, a malignant vascular tumor, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous tumor, or a malignant fibrous tumor; the skin disease, condition, or disorder is a parasite, the parasitic The insect is a Trypanasoma or Leishmania genus; the skin disease, illness, or disorder is a virus, and the virus is Molluscum contagiosum virus or Human Papillomavirus; or the skin disease, illness, or disorder is a bacterial, fungal, or microbial infection, and the bacterial, fungal, or microbial infection is Otitis media, Staphylococcus aureus infection, Mycobacterium infection, Porphyromonas infection, Salmonella infection, Chlamydia infection, tuberculosis, gingivitis, or periodontal disease.

[0271] In some embodiments, the composition is applied topically to the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, interdental areas, hands, one or both feet, or groin area. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered for about 2 weeks to about 8 weeks. In some embodiments, the composition is administered for about 4 weeks.

[0272] In some embodiments, the composition is administered in a pulsatile cycle, hi some embodiments, the composition is administered under occlusion.

[0273] In some embodiments, the skin disease, condition, or disorder is a skin pigmentation disorder, hi some embodiments, the skin pigmentation disorder is acanthosis nigricans.

[0274] In some embodiments, the skin disease, condition, or disorder is seborrheic keratosis, a benign tumor or skin disease, a malignant tumor, a parasite, a skin virus, an immune disease or disorder, and a bacterial, fungal, or microbial infection.

[0275] In some embodiments, the skin disease, condition, or disorder is seborrheic keratosis.

[0276] In some embodiments, the compositions described herein are useful for treating a benign tumor or skin disease, hi some embodiments, the benign tumor is a benign vascular tumor, a benign fibrous tumor, a benign adipocyte tumor, a benign sebaceous tumor, a benign epidermal tumor, a benign melanocytic lesion, or a benign neural tumor. Benign tumors or skin diseases include nodules, benign skin tumors, angiomas, hemangiomas, pyogenic granulomas, angiofibromas, tuberous sclerosis complex, angiomyofibromas, angiolipomas, dermatofibromas, fibromas, neurofibromas, scars, scar tissue, keloids, lipomas, acrochordons, melanoacanthomas, acanthomas, clear cell acanthomas, acanthosis nigricans, epidermoid cysts, pilar cysts, dermoid cysts, melanocytic nevi, melanocytic nevus ... In some embodiments, benign tumors include, but are not limited to, nodules, benign skin tumors, hemangiomas, hemangiomas, pyogenic granulomas, angiofibromas, tuberous sclerosis, angiomyofibromas, angiolipomas, dermatofibromas, fibromas, neurofibromas, scars, scar tissue, keloids, lipomas, acrochordons, melanoacanthomas, acanthomas, clear cell acanthomas, acanthosis nigricans, epidermoid cysts, hairy cysts, dermoid cysts, melanocytic nevi, epidermal nevi, verrucous epidermal nevi, lentigos, cafe au lait spots, neuromas, schwannomas, and neurolemmomas.

[0277] In some embodiments, the compositions described herein are useful for treating malignant tumors, hi some embodiments, the malignant tumor is a malignant melanocytic tumor, a malignant epidermal tumor, a malignant vascular tumor, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous tumor, or a malignant fibrous tumor. Malignant tumors include, but are not limited to, melanoma, squamous cell carcinoma, keratoacanthoma, actinic keratoses, basal cell carcinomas, angiosarcoma, Kaposi sarcoma, cutaneous breast cancer, Merkel cell cancer, liposarcoma, sebaceoma, sebaceous carcinom, dermatofibroma sarcoma protuberens, and fibrosarcoma. In some embodiments, the malignant tumor is melanoma, squamous cell carcinoma, keratinocyte carcinoma, actinic keratosis, basal cell carcinoma, angiosarcoma, Kaposi's sarcoma, cutaneous carcinoma of the breast, Merkel cell carcinoma, liposarcoma, sebaceous adenoma, sebaceous gland carcinoma, dermatofibroma protuberans, or fibrosarcoma.

[0278] In some embodiments, the compositions described herein are useful for treating a skin disease, illness, or disorder caused by a parasite. In some embodiments, the parasite is a parasite of the genus Trypanasoma or Leishmania. In some embodiments, the parasite is a parasite of the genus Leishmania, Endotrypanum, Novymonas, Porcisia, or Zelonia. In some embodiments, the parasite is L. major, L. tropica, L. aethiopica, L. Mexicana, or L. braziliensis. In some embodiments, the disease or illness caused by or associated with a parasite is in the skin or mucosa or mucocutaneous. In some embodiments, the parasite is Leishmania aethiopica, Leishmania amazonensis, Leishmania arabica, Leishmania aristidesi, Leishmania donovani, Leishmania forattinii, Leishmania gerbilli, Leishmania infantum, Leishmania killicki, Leishmania major, Leishmania Mexicana, Leishmania pifanoi, Leishmania tropica, Leishmania turanica, Leishmania venezeulensis, Leishmania waltoni, Leishmania enriettii, Leishmania macropodum, Leishmania martiniquensis, Leishmania orientalis, Leishmania adleri, Leishmania agamae, Leishmania ceramodactyli, Leishmania gulikae, Leishmania gymnodactyli, Leishmania helioscopi, Leishmania hemidactyli, Leishmania hoogstraali, Leishmania nicollei, Leishmaniaplatycephala, Leishmania phrynocephali, Leishmania senegalensis, Leishmania sofieffi, Leishmania tarentolae, Leishmania zmeevi, Leishmania zuckermani, Leishmania braziliensis, Leishmania guyanensis, Leishmania lainsoni, Leishmania lindenbergi, Leishmania naiffi, Leishmania panamensis, Leishmania peruviana, Leishmania shawi, Leishmania utingensis, Endotrypanum colombiensis, Endotrypanum equatorensis, Endotrypanum herreri, Endotrypanum monterogeii, Endotrypanum schaudinni, Novymonas esmeraldas, Porcisia deanei, Porcisia hertigi, Zelonia australiensis, or Zelonia costaricensis.

[0279] In some embodiments, the compositions described herein are useful for treating skin diseases, illnesses, or disorders caused by viruses. Viral pathogens include, but are not limited to, adenovirus, influenza, human herpesvirus, avian virus, HIV, and coronavirus. In some embodiments, the virus is a poxvirus that causes molluscum contagiosum, or a human papillomavirus that causes warts.

[0280] In some embodiments, the compositions described herein are useful for treating a skin disease, illness, or disorder associated with a bacterial, fungal, or microbial infection, hi some embodiments, the bacterial, fungal, or microbial infection is otitis media, Staphylococcus aureus infection, Mycobacterium infection, Salmonellosis, Chlamydia infection, tuberculosis, Porphyromonas infection, gingivitis, or periodontal disease.

[0281] In some embodiments, the compositions described herein are administered to the face of a subject. In some embodiments, the compositions described herein are administered to the body of a subject. In some embodiments, the compositions described herein are administered topically to the head, scalp, face, ears, neck, chest, back, under the breasts, arms, legs, interdental areas of the groin, hands, and / or feet. In some embodiments, the composition covers (e.g., occludes) skin associated with a disease, illness, or disorder. As a non-limiting example, the composition covers seborrheic keratosis.

[0282] In some embodiments, the compositions described herein are administered to the face of a subject, thereby treating seborrheic keratosis on the face.In some embodiments, the compositions described herein are administered to the body of a subject, thereby treating seborrheic keratosis.In some embodiments, the compositions described herein are administered topically to one or more areas selected from the head, scalp, face, ears, neck, chest, back, subbreast, arms, legs, groin, interdental area, hands, and / or feet, thereby treating seborrheic keratosis in any one of these areas.

[0283] In some embodiments, the skin disease, condition, or disorder to be alleviated, ameliorated, treated, or prevented is seborrheic keratosis. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve partial or complete resolution, involution, or elimination of at least one seborrheic keratosis in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve partial resolution of at least one seborrheic keratosis in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve complete resolution of at least one seborrheic keratosis in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve regression of at least one seborrheic keratosis in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve elimination of at least one seborrheic keratosis in a subject.

[0284] The compositions disclosed herein may be administered at least once, multiple times daily, daily, multiple times weekly, weekly, multiple times monthly, or monthly. In some embodiments, the compositions are administered twice daily. In some embodiments, the compositions are administered at least twice weekly. In some embodiments, the compositions are administered at least twice monthly. In some embodiments, the compositions are administered for 2, 3, 4, or 5 months. In some embodiments, the compositions are administered in pulsed dosing. In some embodiments, the compositions are applied twice daily for 2, 3, 4, 5, or 6 consecutive days, followed by a break in treatment (e.g., 1, 2, 3, 4, 5, 6, or 7 days), and then applied twice daily for 2, 3, 4, 5, or 6 consecutive days. In some embodiments, this pulsed cycle of application is repeated 2, 3, 4, 5, or 6 times. In some embodiments, this pulsed cycle of application is repeated up to 15 times. In some embodiments, the composition is administered in a pulsed administration or pulsed application. In some embodiments, the composition is applied once daily for 2, 3, 4, 5, or 6 consecutive days, followed by a break in treatment (e.g., 1, 2, 3, 4, 5, 6, or 7 days), followed by application once daily for 2, 3, 4, 5, or 6 consecutive days. In some embodiments, this pulsed application cycle is repeated 2, 3, 4, 5, or 6 times. In some embodiments, this pulsed application cycle is repeated up to 10, 11, 12, 13, 14, or 15 times. In some embodiments, a composition comprising an amount of a compound (i.e., Compound 1) of 0.01% to 10% by weight is administered as a single dose, multiple times daily, daily, multiple times weekly, weekly, twice weekly, multiple times monthly, monthly, twice monthly, or in a pulsed application. In some embodiments, a composition comprising an amount of a compound (i.e., Compound 1) of 0.01% to 5% by weight is administered as a single dose, multiple times per day, daily, multiple times per week, weekly, twice per week, multiple times per month, monthly, twice per month, or in a pulsed application.In some embodiments, a composition comprising an amount of a compound (i.e., Compound 1) of 0.1% to 10% by weight is administered as a single dose, multiple times per day, daily, multiple times per week, weekly, twice per week, multiple times per month, monthly, twice per month, or in a pulsed application, in some embodiments, the composition is administered for a total period of about 1, 2, 3, 4, 5, or 6 months.

[0285] In some embodiments, the compositions may be formulated with about 0.01% to about 10%, about 0.01%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the compositions may be formulated with about 0.01% to about 5%, about 0.01%, or about 5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the compositions may be formulated with about 0.1% to about 10%, about 0.1%, or about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1%, about 0.1%, or about 1% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), or a salt thereof. In some cases, the composition is administered once or twice daily. For example, the composition is administered twice daily. In some cases, the composition is administered for about 2 weeks to about 8 weeks. In some cases, the composition is administered for about 2 weeks. In some cases, the composition is administered for about 4 weeks. In some cases, the composition is administered in a pulsatile application cycle as described herein. In some cases, the composition is administered under occlusion.

[0286] In some embodiments, the composition administered is in the form of a gel, ointment, lotion, foam, or emollient.

[0287] In some embodiments, the composition to be administered is a component of a patch, tape, film, wafer, or bandage.

[0288] In some embodiments, the subject in need is a human.

[0289] kit Also provided is a kit for use in a method of treating a skin disease, illness, or disorder, in which a subject requires treatment of a skin disease, illness, or disorder with a composition described herein in a tube, flexible aluminum tube, or laminated plastic tube. The kit may include a topical composition containing a compound (i.e., Compound 1), a second agent or composition, and instructions that provide a healthcare provider with information regarding use to treat a skin disease, illness, or disorder. The instructions may be provided in printed form, or in the form of an electronic or digital medium such as a floppy disk, CD, or DVD, a data storage device, a flash drive, or in the form of a website address where such instructions can be obtained. A unit dose of the compound or topical composition provided herein, or a second agent or composition, may include a dose that, when administered to a subject, can maintain a therapeutically or prophylactically effective level of the compound or topical composition at the treatment site in the subject for at least one day.

[0290] In another aspect, the disclosure provides a kit comprising a topical pharmaceutical composition in a tube, a flexible aluminum tube, or a laminated plastic tube, together with instructions for use.

[0291] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes solid matrices or solid materials that are conventionally used in systems and that can hold within fixed limits the compounds provided herein and / or second agents suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes, and the like. If e-beam sterilization techniques are used, the packaging must have a sufficiently low density to allow sterilization of the contents. EXAMPLES

[0292] Example 1. Preparation of the composition The topical compositions of the present disclosure can be prepared according to the procedures provided below. Reaction conditions, steps, and reactants not provided in the procedures below will be apparent and known to those skilled in the art.

[0293] Excipients (i.e., C 2-6 The mixture was formed by dispensing or weighing the components (alcohol, organic solvent, and / or penetration enhancer, antioxidant, preservative, and / or water) into individual containers. The compound (i.e., Compound 1) was added to the mixture to achieve the desired concentration. The gelling agent (e.g., HPC) was then added, if appropriate. In some of the compositions that used a pH adjuster (e.g., citric acid), the pH of the formed mixture was adjusted to the desired apparent pH (e.g., about 5.5-6.5) using an aqueous citric acid solution (e.g., a 0.1 M, 0.5 M, or 1 M solution). In some of the compositions, a second addition of water (if present) was finally used to titrate the composition to 100% by weight. The final mixture was then mixed well to form the composition.

[0294] Example 2. Various compositions with / without Compound 1 The following compositions were prepared according to the general procedure using the excipients in Tables 1-7.

[0295] [Table 1]

[0296] [Table 2]

[0297] [Table 3]

[0298] [Table 4]

[0299] [Table 5]

[0300] [Table 6]

[0301] [Table 7]

[0302] Example 3. 14-Day Dermal Tolerability Study in Gottingen Minipigs overview The objective of this study was to determine the local dermal tolerability of four compositions of Compound 1 and the respective placebo (Sepineo Gel from Table 2, Anhydrous Sepino Gel from Table 3, High Transcutol Gel from Table 4, or Low Transcutol Gel from Table 5) following dermal administration once daily or once every other day for 14 days to Göttingen minipigs.

[0303] material and method Test articles and placebo (Sepineo gel from Table 2, Sepineo anhydrous gel from Table 3, Transcutol high gel from Table 4, or Transcutol low gel from Table 5) were administered via dermal application to the left side of each animal once daily for 14 days during the study. Test articles and placebo were administered via dermal application to the right side of each animal once every other day, starting on day 2 (days 2, 4, 6, 8, 10, 12, and 14). Compound 1 dose concentrations were 0.01% and 0.1% (first animal / sex), or 0.1% and 1% (second animal / sex) and were administered in a dose volume of 0.5 mL / site. The day before the first dose administration, the hair was clipped from the back of the animals. Repeated clipping was performed as necessary. Care was taken not to abrade the skin. The corners of each exposure site were marked with an indelible marker. Test articles and placebos were distributed onto individual sites (6 / side), each 1.4 x 1.4 inches, on the dorsal surface by gentle inunction with a glass stir rod or appropriate implement (e.g., stainless steel spatula). Test articles and placebos were applied evenly to the test sites with a thin, uniform film of the appropriate dosing material. Areas were not occluded.

[0304] Sites were observed for gross signs of irritation (i.e., erythema, and edema, lesions) and any other signs of local or systemic effects and were ranked on a scale of 0 to 5, with 0 corresponding to "no effect." Clinical observations unrelated to application site observations were recorded as unscheduled observations, as appropriate.

[0305] After dosing on day 14 (2-4 hours post-dose), all animals were euthanized for skin biopsy sample collection. Prior to collection, dosing sites were gently washed with a 10% soap solution (e.g., Dawn dish soap) followed by rinsing with warm water using Wypall® or equivalent. A hose was utilized to facilitate rinsing using a low pressure stream of warm tap water, followed by tape stripping to remove residual composition before punch biopsy was performed. Full thickness samples were collected from each dosing site (including placebo sites) and a single naïve site per animal via a 5 mm circular or oval punch biopsy instrument or by incision with a surgical blade.

[0306] Results, interpretation, and conclusions All compositions and placebo were generally well tolerated after 14 days of dermal administration once daily or once every other day. All test articles and placebo were generally well tolerated. The only observation of irritation occurred in a male (1002). Following daily administration, very slight erythema was present at site 3 on days 12-14 (approximately 2D-1% in Table 4) and at site 6 on days 4 and 7-14 (approximately 2E-1% in Table 5). Edema was not present in any animal at any time point.

[0307] Figures 1A-1D show the local skin tolerability, as measured by erythema and edema scores, of four compositions containing Compound 1 and the respective placebo after cutaneous administration once daily or once every other day for 14 days to Gottingen minipigs. The four compositions correspond to the compositions in Tables 2-5 as follows:

[0308] [Table 8]

[0309] Example 4. Further optimization of compositions containing high Transcutol The compositions of Table 4 containing about 47-48% Transcutol P ((2-(2-ethoxyethoxy)ethanol)) were further tested with the addition of antioxidants (e.g., butylated hydroxytoluene (BHT) and / or butylated hydroxyanisole (BHA), or propyl gallate), preservatives (e.g., phenoxyethanol), and / or pH adjusters (e.g., aqueous citric acid). The compositions are thus shown in Tables 8 and 9.

[0310] [Table 9-1]

[0311] [Table 9-2]

[0312] [Table 10-1]

[0313] [Table 10-2]

[0314] Example 5. Induction of apoptosis in seborrheic keratosis overview A non-clinical ex-vivo human SK explant model was used to test compositions containing 1% Compound 1 to induce apoptosis in SK samples. The purpose of this study was to investigate the ability of topically applied compounds to suppress cell viability in SK. The use of human explants allowed for the evaluation of the composition's assay and the effect of the formulation on local penetration in an environment that closely mimics the clinical setting. Shaved biopsies of SK were taken from patients undergoing SK resection for clinical purposes. 3-4 mm 2Biopsy pieces of the size of 100 μl were embedded in medium and agar for the experiment. The protruding sample surface was treated with 2.5 microliters (μl) of a composition containing 1% Compound 1 (e.g., Ex.4-6a or Ex.5-1%) with vehicle only, or left untreated. The explants were then incubated for 72 hours (hr) and fixed for staining and histological assessment. The 72-hr time frame was used as the efficacy endpoint, and relative apoptosis was assessed by TUNEL staining at the end of the experiment. The resulting images were qualitatively evaluated by visual inspection and showed more apoptosis observable in explants treated with Compound 1 compared to those treated with vehicle or left untreated. This non-clinical explant study was designed to build confidence in the use of 1% Compound 1 for the treatment of SK, and indeed, when applied to SK explants, induced an observable increase in apoptosis.

[0315] material and method Materials required for tissue culture include RPMI 1640 (Thermo Fisher, 11875093), human serum (GeminiBio #100-110), amphotericin B (Thermo Fisher, Cat# 15290018), and penicillin streptomycin (5,000U / mL, Thermo Fisher, Cat# 15140-122), agarose (Sigma, CAS 9012-36-6) DMSO Sigma Aldrich (#D8418), Transwell Permeable Supports, 12-well plates (Corning 12mm Transwell®, 3.0μm PorePolycarbonate Membrane Insert, Sterile Cat#3402).

[0316] Compositions containing Compound 1 and the corresponding vehicle, as shown in Table 10, were used in the study.

[0317] [Table 11]

[0318] To determine whether compound 1 in a composition containing high levels of Transcutol (e.g., Ex.4-6a or Ex.5-1% in Example 4) can penetrate human skin lesions and cause increased apoptosis as measured by TUNEL assay, an ex vivo study was performed. Human seborrheic keratosis biopsies were collected and immediately prepared for drug treatment as described in the experimental model section.

[0319] A total of five seborrheic keratoses were collected from patients under an IRB approved protocol with informed consent. Each collected SK was divided into pieces for use in different treatment groups. Two separate experiments were performed at different time points. In the first experiment, two keratoses were collected and each was divided into two pieces. A section of each sample was treated with 1% Compound 1 and a section of each sample was treated with vehicle. The treatment groups were: 1) 1% Compound 1 (N=2), and 2) Vehicle (N=2).

[0320] In the second study, three seborrheic keratoses were collected and divided into three pieces, each of which was treated with 1% Compound 1, vehicle only, or left untreated. The treatment groups were: 1) 1% Compound 1 (N=3), 2) vehicle (N=3), and 3) untreated (N=3). In both experiments, either 1% Compound 1 in composition (Ex. 5-1%) or vehicle was applied topically to approximately 3.5 mm2 partially submerged tissue samples. Specifically, 2.5 microliters (μl) of Ex. 5-1% composition (containing 1% Compound 1) was added to the samples, as described above, or, as a control, 2.5 μl of vehicle was added to the samples. In the second experiment, an additional three pieces of SK were left untreated for comparison. The formulation or vehicle was added topically to each sample by pipetting onto the exposed surface area immediately after seeding. After 72 h of incubation at 37° C. and 5% CO 2 , specimens were fixed in 10% formalin for 24 h and then transferred to 70% ethanol for TUNEL staining.

[0321] Results, interpretation, and conclusions All seborrheic keratoses (n=5) treated with Ex.5-1% composition (containing 1% Compound 1) showed a relative increase in apoptosis as measured by TUNEL staining compared to vehicle (n=5) and untreated samples (n=3). One vehicle-treated sample also showed increased apoptosis compared to untreated, while the remaining four vehicle-treated samples had similar apoptosis levels compared to untreated controls. Figure 2 shows the explant TUNEL assay images.

[0322] It can be concluded that a single ex vivo topical application of the composition (eg, Ex. 5-1%) can result in increased keratinocyte apoptosis in seborrheic keratosis 72 hours after application.

[0323] Example 6. Short-term stability of the composition of Example 4 The compositions in Tables 8 and 9 were subjected to a short-term physicochemical stability study after storage for up to 8 weeks at 25° C. and 40° C. The parameters evaluated were compound (i.e., Compound 1) content and purity, apparent pH, macroscopic observation, and microscopic observation.

[0324] Compound content and purity The content and purity of Compound 1 in the compositions after storage for up to 8 weeks are detailed in Tables 11 and 12, respectively (Note: only Ex.4-1a and Ex.4-6a were further extended to t=8 weeks).

[0325] Recovery (%) compares the response of the drug peak to a standard of known concentration, whereas peak purity (% area) compares the area of ​​the drug peak to the sum of the areas of all peaks in the chromatogram. The change in purity (%) of Compound 1 in the compositions after stability study from t=0 to 8 weeks is detailed in Table 13.

[0326] [Table 12-1]

[0327]

Table 12-2

[0328]

Table 13-1

[0329]

Table 13-2

[0330]

Table 14-1

[0331]

Table 14-2

[0332] The content of compound 1 in all seven aqueous gels was within the range of values ​​of 95-105% from t=0 to 2 weeks. However, after 4 weeks of storage, the drug recovery decreased by up to 5% in Ex.4-4a (t=4 weeks, 94.25% at 2-8°C) and Ex.4-6a (t=4 weeks, 95.91% at 40°C). At t=0, the purity of compound 1 in all seven aqueous gels was >97 area%. After 4 weeks of storage, the drug purity of the compositions decreased by approximately 0.36-2.64 area% at 25°C and 0.88-4.13 area% at 40°C. The decrease in drug purity was lower in the compositions stored at 2-8°C (0.18-0.38 area%). The relative purity of compound 1 in all seven aqueous gels was maintained at >95% up to 4 weeks at both 25°C and 40°C. Ex. 4-4a (without preservatives, antioxidants, and pH adjusters) and Ex. 4-6a (based on Ex. 4-4a with BHT) were stable for up to 8 weeks at both 25° C. (<1 area % loss in purity) and 40° C. (<1.5 area % loss in purity). The addition of antioxidants and preservatives (without adjusting the pH) appeared to further stabilize the compositions (see Ex. 4-6a).

[0333] Apparent pH The apparent pH of compositions with or without Compound 1 at t=0 and 4 weeks (2-8° C., 25° C., and 40° C.) is shown in Table 14.

[0334] [Table 15]

[0335] At t=0, the apparent pH of the compositions containing the pH adjuster ranged from 5.94 to 7.67, with no significant (±1 pH unit) differences in pH between the placebo and the corresponding active compositions. After 4 weeks of storage, pH values ​​ranged from 5.52 to 6.86 (2-8°C), 5.54 to 8.06 (25°C), and 5.48 to 7.67 (40°C), consistent with the pH values ​​at t=0. The pH of the gel compositions that were not pH adjusted remained at about pH 9, Ex. 4-1a (activity) (9.13 at t=0, 9.21 at t=4 weeks, 2-8°C, 9.15 at t=4 weeks, 25°C, and 9.11 at t=4 weeks, 40°C), and Ex. 4-6a (activity) (9.42 at t=0, 8.94 at t=4 weeks, 2-8°C, 8.82 at t=4 weeks, 25°C, and 8.79 at t=4 weeks, 40°C).

[0336] Macroscopic Observation The macroscopic appearance and macroscopic images against light and dark backgrounds were evaluated for all seven compositions, including Compound 1 and the corresponding vehicle.

[0337] At t=0, all compositions (both active and vehicle) were clear with medium viscosity and smooth application. The placebo compositions appeared colorless, while the active compositions had a light beige coloration. When stored at 2-8°C, 25°C, and 40°C for t=4 weeks, no obvious changes were observed in the compositions, except for a slight discoloration observed at t=4 weeks (40°C) for Ex. 4-4b (vehicle) where propyl gallate was present in the composition.

[0338] Microscopic observation Microscopic appearance and microscopic images (unpolarized and polarized) were accessed for all seven compositions, including Compound 1 and the corresponding vehicle.

[0339] There was no evidence of drug particulates in all compositions (both active and vehicle) over the experimental period (t=0-4 weeks, 2-8°C, 25°C, and 40°C). Most of the compositions tested were free of excipient particulates, but excipient particulates were observed in three placebo compositions (Ex. 4-4b, Ex. 4-7b, Ex. 4-8b) and Ex. 4-8a (active). At t=4 weeks, excipient particulates were observed in 4-1a (active) (40°C), Ex. 4-1b (vehicle) (25°C), Ex. 4-2a (active) and Ex. 4-2b (vehicle) (2-8°C), Ex. 4-4a (active) (40°C), and Ex. 4-7a (active) (t=2 and 4 weeks, 25 and 40°C). It should be noted that the morphology of the microparticles was not consistent across time points and may be unhydrated gelling agent (HPC), indicating that the gelling agent requires a longer hydration time, which will be further optimized during process development.

[0340] Compositions Ex.4-6a (active) and Ex.4-6b (vehicle) were observed to be free of particulates of both drug and excipients over the experimental period (t=0-4 weeks, 2-8°C, 25°C, and 40°C).

[0341] viscosity As shown in Table 15, Ex. 4-4a (1.00 wt / wt% Compound 1) (as Ex. 6-4a-1%), the same composition (0.10 wt / wt% Compound 1) (as Ex. 6-4a-0.1%), and Ex. 4-4b (vehicle) (as Ex. 6-4b) were monitored for three months.

[0342] [Table 16]

[0343] Example 7. Human demonstration of topical application for the treatment of seborrheic keratosis overview Promising in vitro and explant studies prompted further investigation of the benefits of Composition Ex.5-Compound 1 in human clinical trials for the treatment of SK. This is a first-in-human open label adaptive design trial investigating the safety and efficacy of Composition Ex.5-Compound 1 in excipient topical gel at concentrations of 1.0% or 0.1% in patients with seborrheic keratosis (SK).

[0344] method The study will enroll up to 35 subjects with four SK target lesions (SKTS) each across six cohorts with different treatment regimens. Subjects will participate for approximately 12-16 weeks.

[0345] All three completed cohorts had torso SKs treated with Composition Ex.5-Compound 1, cohort 1 was treated at 1.0% twice daily (BID) for 14 days, cohort 2 was treated at 1.0% BID for 28 days, and cohort 3 was treated at 1.0% pulsed-BID 4 days on / 4 days off for 28 days. All subjects were followed for a minimum of 4 weeks after the last dose, at which time all 4 SKTL lesions were scored using the PLA scale. Forty-three lesions were included for primary and secondary analyses. Seventeen lesions were excluded, three lesions were biopsied as non-responsive SK without 4-week follow-up after treatment, and 14 lesions were histologically confirmed as not SK (6 nevi, 4 verrucous keratoses, and 4 lentigines) as defined by the protocol.

[0346] The primary and secondary efficacy endpoints were based on PLA scoring, which was rated on a 4-point scale, with SK >1mm thick being rated as 3, SK <1mm thick being rated as 2, nearly clear but with residual surface changes suggestive of SK being rated as 1, and no visible residual surface changes being rated as 0.

[0347] Results, interpretation, and conclusions Across all three cohorts combined, 81% of lesions improved by at least 1 point on the Physician's Lesion Assessment (PLA) score, 74% of SK lesions were clear (PLA 0) or almost clear (PLA 1), and 44% of lesions were completely clear (PLA 0). The study showed early dose response efficacy, with cohorts 2 and 3, the 28-day treatment regimen, showing the highest improvement rates of SKTL, with 100% of SKTL in both cohorts showing at least one PLA improvement, 79% and 100% were clear or almost clear, and 57% and 46% were completely clear, respectively. Treatment was well tolerated with no serious adverse events or adverse events and only mild (16.7%) or moderate (3.3%) inflammation in a small percentage of lesions.

[0348] [Table 17]

[0349] [Table 18]

[0350] [Table 19]

[0351] [Table 20]

[0352] [Table 21]

[0353] [Table 22]

[0354]

Table 23

[0355]

Table 24

[0356]

Table 25

[0357]

Table 26

[0358]

Table 27

[0359]

Table 28

[0360]

Table 29

[0361]

Table 30

[0362]

Table 31

[0363]

Table 32

[0364] [Table 33]

[0365] [Table 34]

[0366] [Table 35] Figures 3A-5C provide time-to-event KM plots as described in the brief description of the figures. Representative photographs showing the response of composition Ex.5-Compound 1 to SK in cohort 1 (14 days BID) and the response of SK to background lentigo in cohort 2 (28 days BID) are shown in Figure 6, Table 22, respectively. There were no SAEs or AEs in the first three cohorts of the study. Pain, pruritus, erythema, edema, and excoriation were rated as none (0), mild (1), moderate (2), or severe (3).

[0367] [Table 36]

[0368] These data demonstrate that composition Ex.5-compound 1 is an effective, selective and safe treatment for SK and represents an improvement over current treatment modalities.

[0369] Example 8. Human Demonstration of Topical Application for the Treatment of Facial and Occluded Seborrheic Keratosis

[0370] overview Promising in vitro and explant studies prompted further investigation into the benefits of composition Ex.5-Compound 1 in human clinical trials for the treatment of SK. The study is a first-in-human, open-label, adaptive design study investigating the safety and efficacy of composition Ex.5-Compound 1 vehicle topical gel at concentrations of 1.0% or 0.1% in patients with seborrheic keratosis (SK). Cohorts will have a two-week treatment period of twice-daily applications, followed by a four-week follow-up period. Based on the results at any given time from the first cohort and subsequent cohorts, additional cohorts will explore different dosing regimens.

[0371] method The study will enroll up to 35 subjects with four SK target lesions (SKTLs) each across seven cohorts with different treatment regimens. Subject participation period was approximately 12-16 weeks. Cohorts 4, 5, 6, and 7 were enrolled or planned to be enrolled in the second part of this adaptive design study (results from cohorts 1, 2, and 3 are described in Example 7). All cohorts had SKs treated with Composition Ex.5-Compound 1.

[0372] Cohort 4 (n=5 subjects) had each subject apply Composition Ex.5-1.0% Compound 1 BID (twice daily) to four facial seborrheic keratosis target lesions (SKTL). Composition Ex.5-1.0% Compound 1 was applied twice daily to facial SKTL for 28 days.

[0373] Cohort 5 (n=5 subjects) will have each subject apply Composition Ex.5-1.0% Compound 1 QD (once a day) / TIW (three times a week) under Tegaderm occlusion to four seborrheic keratosis target lesions (SKTLs) on the trunk and extremities. Composition Ex.5-1.0% Compound 1 will be applied once a day, three times a week and maintained under occlusion.

[0374] In cohort 6 (n=5 subjects), each subject will have Composition Ex.5-1.0% Compound 1 applied BID to 4 seborrheic keratosis target lesions (SKTLs) on the trunk (including the intertibial space) or extremities. Composition Ex.5-1.0% Compound 1 will be applied twice daily for 28 days.

[0375] Cohort 7 (n=5 subjects) Each subject will have Composition Ex.5-0.1% Compound 1 applied BID to 4 seborrheic keratosis target lesions (SKTLs) on the face. Composition Ex.5-0.1% Compound 1 will be applied twice daily for 28 days.

[0376] All subjects were followed for a minimum of 4 weeks after the last dose. All four SKTL lesions were scored using the PLA scale at each visit.

[0377] The primary and secondary efficacy endpoints were based on PLA scoring, which was rated on a 4-point scale, with SK >1mm thick being rated as 3, SK <1mm thick being rated as 2, nearly clear but with residual surface changes suggestive of SK being rated as 1, and no visible residual surface changes being rated as 0.

[0378] Specifically, the primary outcome measures are as follows: 1. Proportion of treated SKs with at least 1 grade improvement in PLA score, change from treatment-period status through 4-week safety follow-up [time frame: 4 weeks after last dose].

[0379] Secondary primary outcome measures included: 2. Proportion of treated SKs with Physician Lesion Assessment (PLA) of 0 or 1, change from start of treatment period through 4-week safety follow-up [time frame: 4 weeks after last dose] 3. Proportion of treated SKs with 0 PLA, change from start of treatment period through 4-week safety follow-up [time frame: 4 weeks after last dose] 4. Proportion of treated SKs with PLA 0 or 1, change from start of treatment period to week 12 [Time frame: week 12] 5. Percentage of treated SKs with 0 PLA, change from start of treatment period to week 12 [Time frame: week 12] 6. Proportion of treated SKs with a Subject Self-Assessment (SSA) of 0 or 1, change from start of treatment period through 4-week safety follow-up [Time frame: 4 weeks after last dose] 7. Proportion of treated SKs with 0 SSA, change from start of treatment period through 4-week safety follow-up [Time frame: 4 weeks after last dose] 8. Proportion of treated SKs with SSA 0 or 1, change from start of treatment period to week 12 [Time frame: week 12] 9. Proportion of treated SK with 0 SSA, change from start of treatment period to week 12 [Time frame: week 12] 10. Time to treated SKs achieving a PLA of 0 or 1, time from baseline / day 1 (PLA of 3 or 2) to achieving a PLA of 0 or 1 [Time Frame]: End of study. In this adaptive design study, end of study is 4-10 weeks after completion of the treatment period] 11. Time to treated SK achieve PLA of 0, duration from baseline / day 1 (PLA3 or 2) to PLA of 0 [Time frame: end of study. In this adaptive design study, end of study is 4-10 weeks after completion of the treatment period.]

[0380] Inclusion criteria included: 1. At least 18 years of age. 2. Have four eligible SKs on the face, torso, or limbs. Eligible SKs are: a. Have a clinically typical appearance, b. Have a Physician Lesion Assessment (PLA) of ≥ 2, c. Have a length of ≥ 1mm and ≤ 15mm, d. Have a width of ≥ 1mm and ≤ 15mm, e. Have a thickness of ≤ 2mm, f. Be separate lesions, g. Not covered with hair that, in the Investigator's opinion, would interfere with treatment with the study drug or with the study evaluations, h. Not pedunculated. 3. Be of good general health and free of any known disease or physical condition that, in the opinion of the investigator, may interfere with the assessment of any target SK lesions or that would place the subject at unacceptable risk from study participation. 4. Willing and able to follow all study instructions and attend all study visits. 5. Have the technical capability and willingness to apply Investigational Medicinal Products (IP), where applicable. 6. Be sure you understand the informed consent form (ICF) and are willing to sign it.

[0381] Exclusion criteria included: 1. Women of childbearing potential who have a positive urine pregnancy test, are pregnant, lactating, or do not consent to using active birth control methods during the study period. 2. Having SK lesions that are clinically atypical and / or rapidly increasing in size. 3. Presence of multiple eruptive SK lesions (Leser-Trelat sign) 4.Currently, systemic malignant tumor. 5. Use of any of the following systemic therapies within the specified period prior to the Screening Visit: a. Retinoids 180 days, b. Glucocorticosteroids 28 days, c. Antimetabolites (e.g. methotrexate) 28 days 6. Use of the following local therapies on or in close proximity to SK target lesions within the specified period prior to the screening visit that the investigator believes may interfere with investigational drug treatment or study evaluations: a. Laser, light, or other energy-based treatments [e.g., intense pulsed light (IPL), photodynamic therapy (PDT)] for 180 days, b. Liquid nitrogen, electrodesiccation, curettes, imiquimod, 5-fluorouracil, or ingenol mebutate for 60 days, c. Microdermabrasion or superficial chemical peels for 14 days, d. Glucocorticosteroids or antibiotics for 14 days 7. The occurrence or presence of any of the following on or near the target SK lesion within a specific period prior to screening, which the investigator determines may interfere with investigational drug treatment or study evaluation: a. Skin malignancy 180 days, b. Sunburn present, c. Excessive suntan present, d. Premalignant (e.g. actinic keratosis) present, e. Body art (e.g. tattoos, piercings, etc.) present 8. History of sensitivity to any of the components of the investigational drug 9. Any current skin disease (e.g., psoriasis, atopic dermatitis, eczema, sun damage, etc.) or skin disorder (e.g., sunburn, excess hair, open wounds) that the investigator determines may place the subject at undue risk through study participation or interfere with the conduct or evaluation of the study. 10. Participation in an investigational drug trial involving administration of an investigational drug within 30 days prior to the screening visit.

[0382] [Table 37]

[0383] result The clinical trial is ongoing and the results reported here are interim: Cohort 7 is fully enrolled, with participants completing the day 28 visit; Cohort 4 is fully enrolled, with visits completed through day 14 and some participants completing through day 21; Cohort 5 has enrolled 4 of 5 potential participants, with participants completing the screening visit and some participants completing through day 7; and Cohort 6 has not yet enrolled.

[0384] The columns in Tables 24-29 entitled "Missing" indicate whether there are any lesions for any participant or enrolled participants who have not yet completed the visit and been evaluated on the specified date. The percentage of all predicted lesions or individuals that have not yet been scored is also shown.

[0385] Treatment was well tolerated, and analysis of all SK lesions across all treatments showed only mild local tolerability reactions, if any, and no moderate or severe reactions. The highest number of mild tolerability reactions by lesion was 8 or 15.4% of lesions on day 7 (Table 24), with all other lesions unresponsive. Local tolerance was also assessed at the patient level with each patient having multiple lesions treated. The majority of patients across all treatment groups did not have a local tolerance reaction, with the highest number of mild tolerability reactions seen on day 7, when 3 patients or 27.3% of patients had a mild tolerability reaction. There were no moderate or severe reactions (Table 25).

[0386] In Cohort 4 (1% face) and Cohort 7 (0.1% face), the majority of patients (approximately 70%) showed at least a 1 point decrease in PLA score 28 or 21 days after treatment, respectively (Figure 7, Table 27 and Table 29). In Cohort 5 (1% TIW), at least 1 of 3 patients who completed the day 7 screening showed a 1 point decrease in PLA score (Table 28).

[0387] [Table 38]

[0388] [Table 39]

[0389] [Table 40]

[0390] [Table 41]

[0391] [Table 42]

[0392] [Table 43]

[0393] Example 9. Composition Ex.5-Stability of 0.1% and 1.0% Compound 1. The content and purity of Compound 1 in compositions Ex.5-0.1% and Ex.5-1.0% after storage for up to 6 months are shown in Table 30.

[0394] Percent recovery was determined by comparing the response of the drug peak to standards of known concentration in the chromatogram using standard HPLC methods. Percent change in Compound 1 content in the compositions after stability testing up to 6 months was measured starting at t=0, with three technical replicates performed at each stability time point for each storage condition and each Compound 1 content. Compound 1 content in the compositions Ex.5-0.1% and 1.0% did not deviate from the expected range over time. The acceptable range for Compound 1 content was 90.0%-110.0%.

[0395] Apparent pH The apparent pH of Compound 1 in Ex.5-0.1% composition and Compound 1 in Ex.5-1.0% composition after 6 months storage at 25° C. and 40° C. is shown in Table 24. The apparent pH was measured using standard equipment and methods in the art.

[0396] The apparent pH remained constant from 0 to 6 months for Compound 1 in Ex.5-0.1% and Compound 1 in Ex.5-1.0% at 25°C and 40°C. The pH for Compound 1 in Ex.5-1.0% at both temperatures ranged from 8.49 to 8.62. The pH for Compound 1 in Ex.5-0.1% at both temperatures ranged from 7.78 to 8.18.

[0397] Macroscopic Observation The compositions Ex.5-0.1% Compound 1 and Ex.5-1.0% Compound 1 were evaluated for macroscopic appearance and macroscopic images against a light and dark background after storage at 25° C. and 40° C. for 6 months (Table 30).

[0398] At t=0, all compositions were yellow or slightly yellow, slightly hazy, with medium viscosity and smooth application. Color, viscosity, and feel remained consistent over time and temperature. The color development of composition Ex.5-1.0% Compound 1 was scored as more intense than composition Ex.5-0.1% Compound 1.

[0399] Microscopic observation Micrographs and micrographs (unpolarized and polarized) were evaluated using standard microscopy techniques for all compositions at the specified time points and storage temperatures.

[0400] There was no evidence of drug particles or crystals in any of the compositions (Table 30).

[0401] viscosity The viscosity of compositions Ex.5-0.1% Compound 1 and Ex.5-1.0% Compound 1 was evaluated after storage for 6 months at 25°C and 40°C (Table 24). Viscosity was measured using a standard method. The viscosity of Ex.5-1.0% Compound 1 ranged from 22440cp to 29600cp. The viscosity of compositions Ex.5-0.1% Compound 1 ranged from 12800cp to 28400cp.

[0402] [Table 44-1]

[0403] [Table 44-2]

[0404] [Table 44-3]

[0405] [Table 44-4]

[0406] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims. Further, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. In the event of a conflict between this application and a reference provided herein, the present application shall control.

Claims

1. 1. A composition for use in the topical treatment of skin lesions, said composition comprising: (i) Structure 【Chemical 1】 or a salt thereof, and / or (ii) Structure 【Chemistry 2】 or a salt thereof topically administering a composition comprising wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10% by weight, 0.01% to 5% by weight, or 0.1% to 1% by weight.

2. The composition of claim 1 , wherein the skin lesion is a tumor, and the tumor is optionally cancerous.

3. The composition of claim 1 or 2, wherein the topical treatment comprises administering the composition once, twice, three or four times daily, and / or once, twice, three, four or five times weekly, optionally wherein the composition is administered in a cycle comprising administering the composition 1 to 4 times daily for about 1 to 7 days, followed by about 1 to 7 days without administration, and further optionally wherein the cycle comprises administering the composition twice daily for about 4 days, followed by about 4 days without administration.

4. The composition described in claim 1, wherein the topical treatment includes occlusion of the skin lesion.

5. The composition described in claim 1, wherein the topical treatment includes reducing the length and / or thickness of the skin lesion.

6. The composition described in claim 5, wherein the topical treatment includes reducing the thickness of the skin lesion to less than 1 mm.

7. The composition described in claim 1, wherein the topical treatment includes inducing apoptosis in the skin lesion.

8. (i) Structure 【Chemistry 3】 or a salt thereof, and / or (ii) Structure 【Chemistry 4】 or a salt thereof A composition comprising: wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10% by weight, 0.01% to 5% by weight, or 0.1% to 1% by weight.

9. A composition described in claim 1 or 8, comprising an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof.

10. (i) Structure 【Chemistry 5】 or a salt thereof, and / or (ii) Structure 【Chemistry 6】 or a salt thereof; a) alcohol, b) an antioxidant, and c) Gelling Agent and one or more excipients selected from (a) to (c).

11. The composition of claim 10, comprising an alcohol, wherein the alcohol optionally comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, a C2-6 alcohol, or a combination or two or more thereof, wherein optionally the C2-6 alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, or a combination or two or more thereof.

12. The composition of claim 11, wherein the C2-6 alcohol is present in an amount of 1% to 30%, 5% to 30%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight of the composition.

13. The composition of claim 11 or 12, wherein the alcohol comprises an organic solvent and / or a penetration enhancer, the composition comprises the organic solvent and / or penetration enhancer, and optionally the organic solvent and / or penetration enhancer comprises a C 2-6 alkylene glycol, a C 1-3 alkyl-(OCH 2 CH 2 ) 1-5 -OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

14. The composition of claim 13, wherein the C 2-6 alkylene glycol is propylene glycol, the C 1-3 alkyl-(OCH 2 CH 2 ) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol, and the polyethylene glycol is PEG 200 or PEG 400, or a combination thereof.

15. The composition of claim 13, wherein the organic solvent and / or penetration enhancer is present in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

16. The composition of claim 9, comprising an antioxidant, optionally comprising butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof, and optionally present in an amount of 0.01% to 5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.05% by weight of the composition.

17. The composition of claim 8, comprising a preservative, optionally comprising phenoxyethanol, and further optionally present in an amount of 0.5% to 5.0%, 0.5% to 2%, or about 1% by weight of the composition.

18. The composition of claim 8, comprising a gelling agent, optionally comprising hydroxypropyl cellulose, and further optionally present in an amount of 0.5% to 5% by weight, or about 2% by weight, of the composition.

19. The composition of claim 8 or 10, comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose.

20. The composition of claim 19, wherein ethanol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight, propylene glycol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight, 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70% by weight, 40% to 60% by weight, or about 47% by weight, and hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% by weight or about 2% by weight.

21. The composition of claim 19, further comprising an antioxidant and / or a preservative, optionally wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof, and the preservative comprises phenoxyethanol, and further optionally wherein the antioxidant comprises butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight or about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of 0.5% to 2% by weight, or about 1% by weight.

22. The composition of claim 10, wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%, 0.1% to 10.0%, 0.5% to 5%, 0.5% to 2%, 0.1% to 1%, or about 1% or about 0.1% by weight of the composition.

23. (i) Structure 【Chemistry 7】 or a salt thereof, and / or (ii) Structure 【Chemistry 8】 or a salt thereof, and A composition comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropyl cellulose, optionally an antioxidant, and optionally a preservative.

24. The composition of claim 23, wherein the antioxidant, if present, comprises butylated hydroxytoluene, and the preservative, if present, comprises phenoxyethanol.

25. The composition described in claim 8 or 24, having a viscosity of about 10,000 cp to about 30,000 cp.

26. The composition of claim 1, wherein the composition is a topical composition, optionally in the form of a gel, ointment, lotion, foam, or emollient.

27. The composition of claim 1, which is a component of a patch, tape, film, wafer, or bandage.

28. The composition of claim 8 for use in treating a skin disease, illness, or disorder.

29. The composition described in claim 28, wherein the skin disease, illness, or disorder is a benign or malignant tumor, and optionally the skin disease, illness, or disorder is basal cell carcinoma, squamous cell carcinoma, or actinic keratosis.

30. The composition described in claim 28 or 29, wherein the composition is administered twice daily, optionally in a pulsatile cycle and / or under occlusion.

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